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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Despite recent advances&#44; non-small cell lung cancer &#40;NSCLC&#41; still leads to a great mortality in most of the continents<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#44;2</span></a>&#44; reaching up to one third of deaths in certain countries<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#44;3</span></a>&#46; Clinical factors such as chronic obstructive pulmonary disease &#40;COPD&#41; or airway obstruction underlie the pathophysiology of LC in many patients<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">1&#44;4&#8211;6</span></a>&#46; Several relevant investigations have clearly demonstrated that airway obstruction and emphysema render the patients more susceptible to the development of LC<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">7&#8211;9</span></a>&#46; Despite this consolidated knowledge&#44; full elucidation of the underlying biological features is still underway&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In the airways&#44; lungs&#44; and blood compartment of patients with LC and underlying COPD&#44; mechanisms such as redox imbalance&#44; inflammatory events&#44; epigenetics&#44; and immune alterations were shown to be disrupted compared to LC patients with no COPD<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">10</span></a>&#46; As a result of the interaction of those biological events with key cellular processes&#44; namely angiogenesis&#44; cell death and repair&#44; and the cell survival machinery&#44; COPD patients are more prone to lung tumorigenesis<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">11</span></a>&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Stroma is defined as the part of a tissue or organ that confers mainly structure with no specific function&#44; and is mainly composed by blood vessels&#44; nerves&#44; and connective tissue&#46; In LC&#44; several components such as extracellular matrix &#40;ECM&#41;&#44; endothelial cells&#44; and cancer-associated fibroblasts &#40;CAFs&#41; play a significant role in tumorigenesis and cancer progression<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">12</span></a>&#46; CAFs are a major component of the stroma in tumors&#46; Growth factors&#44; hormones&#44; and cytokines mediate the tumor cell proliferation favored by CAFs&#46; The most specific and widely used marker of CAFs is alpha-smooth muscle actin &#40;SMA&#41;&#44; which is indeed a specific marker of myofibroblasts<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">12</span></a>&#46; The differentiation process of epithelial cells into mesenchymal cells is known as epithelial-mesenchymal transition &#40;EMT&#41;&#44; characterized by the appearance of mesenchymal properties<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">13&#44;14</span></a>&#46; Interestingly&#44; CAFs may also regulate EMT <a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">13</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Extracellular macromolecules such as collagen&#44; enzymes&#44; and glycoproteins conform a specific network of the ECM&#44; which is also involved in tumor development and progression<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">15</span></a>&#46; In cancer stroma&#44; collagen was demonstrated to be the most abundant protein<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">16</span></a>&#46; Importantly&#44; type I collagen promotes growth of cancer cells&#44; invasion&#44; and distant metastasis&#44; thus favoring tumor progression<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">17</span></a>&#44; as well as resistance to therapy<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">18</span></a>&#46; Whether a distinct expression of extracellular matrix markers or CAFs may take place in the stroma of lung tumor samples of patients with COPD remains to be answered&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The formation of new vessels in tumors can be identified using specific markers such as platelet endothelial cell adhesion molecule also known as cluster of differentiation &#40;CD&#41; 31&#46; CD31 is involved in several physiological processes&#44; namely maintenance of vascular endothelial and inflammatory cell functions and is also expressed in tumor cells<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">19</span></a>&#46; In fact&#44; the immunohistochemical measurement of CD31 expression can be reliably used as a marker of neoangiogenesis in tumors<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">20</span></a>&#46; In mice with experimental airway inflammation mimicking COPD&#44; an immunosuppressive microenvironment of the lung tumors was characterized by increased angiogenesis<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">21</span></a>&#46; Whether differences in CD31 expression may exist in tumors of patients with COPD compared to non-COPD remain to be identified&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">On this basis&#44; we hypothesized that in LC patients with airway obstruction&#44; cancer stroma as analyzed using specific markers may differ from tumors of patients with no underlying COPD&#46; Accordingly&#44; our objectives were to determine in lung tumors and non-tumor specimens &#40;control samples&#41; of LC patients with and without COPD the following parameters&#58; 1&#41; CAFs and non-tumor fibroblasts &#40;cultured fibroblasts&#41;&#44; 2&#41; type I collagen as a marker of extracellular matrix&#44; and 3&#41; CD31 expression levels as a marker of endothelial cells and blood vessels&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Study design and ethics</span><p id="par0035" class="elsevierStylePara elsevierViewall">This is a cross-sectional&#44; prospective study designed following the World Medical Association guidelines &#40;Seventh revision of the Declaration of Helsinki&#44; Fortaleza&#44; Brazil&#44; 2013&#41;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">22</span></a> for research on human beings and was approved by the institutional Ethics Committee on Human Investigation &#40;protocol &#35; 2008&#47;3390&#47;I&#44; Hospital del Mar&#8211;IMIM&#44; Barcelona&#44; Spain&#41;&#46; All patients invited to participate in the study signed the informed written consent&#46; The current investigation followed the international STROBE guidelines<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">23</span></a>&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Patients were prospectively recruited from the Lung Cancer Clinic of the Respiratory Medicine Department at <span class="elsevierStyleItalic">Hospital del Mar</span> &#40;Barcelona&#44; Spain&#41;&#46; All the patients were part of the <span class="elsevierStyleItalic">Lung Cancer Mar Cohort</span>&#46; For this observational study&#44; 30 patients with LC were recruited in 2019&#46; Candidates for tumor resection underwent pulmonary surgery prior to administration of any sort of adjuvant therapy&#46; LC diagnosis and staging were established by histological confirmation and classified according to currently available guidelines for the diagnosis and management of LC<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">24&#44;25</span></a>&#46; TNM &#40;tumor&#44; node&#44; and metastasis&#41; staging was defined as stated in the 8<span class="elsevierStyleSup">th</span> edition Lung Cancer Stage Classification<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">26</span></a>&#46; COPD diagnosis was established as a post-bronchodilator forced expiratory volume in one second &#40;FEV1&#41;&#47;forced vital capacity &#40;FVC&#41; &#8804; 0&#46;7 which is not fully reversible by spirometry according to currently available guidelines for diagnosis and management of COPD<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">27&#44;28</span></a>&#46; Exclusion criteria were&#58; small cell lung cancer &#40;SCLC&#41;&#44; chronic cardiovascular disease&#44; restrictive lung disease&#44; metabolic&#44; immune disease&#44; or clot system disorders&#44; signs of severe inflammation and&#47;or bronchial infection &#40;bronchoscopy&#41;&#44; current or recent invasive mechanical ventilation&#44; or long-term oxygen therapy&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Specimens from the tumor and non-tumor lungs were collected from all the study subjects&#46; Patients were further subdivided <span class="elsevierStyleItalic">post-hoc</span> into two groups on the basis of underlying COPD&#58; 1&#41; 15 patients with LC and COPD &#40;LC-COPD group&#41; and 2&#41; 15 patients with LC without COPD &#40;LC group&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Clinical assessment</span><p id="par0050" class="elsevierStylePara elsevierViewall">In all patients&#44; lung function parameters were assessed following standard procedures&#46; Diagnosis and severity of patients with COPD were determined according to currently available guidelines<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">6</span></a>&#46; Nutritional evaluation included the assessment of body mass index &#40;BMI&#41; and nutritional blood parameters from all patients&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Sample collection and preservation</span><p id="par0055" class="elsevierStylePara elsevierViewall">Lung samples were obtained from tumors and the surrounding non-tumor parenchyma following standard technical procedures during thoracotomy for the standard care in the treatment of lung tumors&#46; In all patients&#44; the expert pulmonary pathologist selected tumor and non-tumor lung specimens of approximately 10x10<span class="elsevierStyleHsp" style=""></span>mm<span class="elsevierStyleSup">2</span> area from the fresh samples as previously validated<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">4&#44;29</span></a>&#46; Non-tumor specimens were collected as far as possible from the lung to the tumor resection margins &#40;average<span class="elsevierStyleHsp" style=""></span>&#62;7<span class="elsevierStyleHsp" style=""></span>cm&#41;&#46; Fragments of both tumor and non-tumor specimens were fixed in formalin and embedded in paraffin blocks until further use&#46; Another fragment was harvested in Dulbecco&#39;s Modified Eagle Medium &#40;DMEM&#41; with 1&#37; of penicillin&#44; streptomycin&#44; and fungiozone for the cell culture process&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095"><span class="elsevierStyleBold">Cell culture</span></span><p id="par0060" class="elsevierStylePara elsevierViewall">Fresh human tumor and non-tumor lung samples were placed in Dulbecco&#39;s Modified Eagle Medium &#40;DMEM&#41; with 1&#37; of penicillin&#44; streptomycin&#44; and fungiozone immediately after obtaining lung specimens and transported on ice to the molecular laboratory&#46; Tumor and non-tumor specimens were minced finely and digested in 1&#37; collagenase type I &#40;Sigma-Aldrich&#44; St&#46; Louis&#44; MO&#41; at 37<span class="elsevierStyleHsp" style=""></span>&#176;C for two hours with occasional agitation&#46; Then the digested tissue was centrifuged at 1&#44;200<span class="elsevierStyleHsp" style=""></span>rpm for two minutes&#46; Cell suspensions were cultured on culture plates in proliferation medium consisting of the mixture of DMEM-medium&#44; 10&#37; fetal bovine serum&#44; and 1&#37; penicillin-streptomycin-fungizone solution at 37<span class="elsevierStyleHsp" style=""></span>&#176;C in a 5&#37; CO2 atmosphere&#46; The culture medium was changed after 48<span class="elsevierStyleHsp" style=""></span>hours to remove unattached cells and debris in suspension&#46; Cells were subcultured with 0&#46;025&#37; trypsin &#40;Life Technologies&#44; California&#44; USA&#41; and 0&#46;01&#37; EDTA when they reached 50-80&#37; confluence for ten minutes&#46; All the study experiments were performed on the cultured cells between passages 1 and 2 of the primary cultures to perform immunofluorescence as described below&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100"><span class="elsevierStyleBold">Immunoflorescence staining of CAFs and NFs</span></span><p id="par0065" class="elsevierStylePara elsevierViewall">CAFs and NFs were identified by analyzing the fibroblast-specific protein vimentin and alpha-SMA &#40;CAFs&#41;&#46; Briefly&#44; cells were fixed with acetone and methanol &#40;1&#58;1&#41; on the slides at -20<span class="elsevierStyleHsp" style=""></span>&#176;C for ten minutes&#44; and were then washed with PBS three times&#46; Subsequently&#44; slides were incubated with blocking solution &#40;50<span class="elsevierStyleHsp" style=""></span>mM Tris with PH<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#46;5&#44; 150 Mm NaCl&#44; 0&#46;01&#37; Triton&#44; 1&#37; bovine serum albumin and 1&#37; skimmed milk powder&#41; for one hour at room temperature in a humidifed chamber&#46; Subsequently&#44; primary antibodies incubation with anti-alpha SMA antibody &#40;anti-alpha-SMA antibody&#44; Santa Cruz&#41; and anti-vimentin antibody &#40;anti-vimentin antibody&#44; Santa Cruz&#41; was performed overnight at 4<span class="elsevierStyleHsp" style=""></span>&#176;C in the chamber&#46; After washing with PBS three times&#44; slides were incubated with corresponding secondary antibodies diluted in PBS for one hour&#58; anti-mouse IgG FITC &#40;Invitrogen&#44; Thermo Fisher Scientific&#41; and anti-rabbit IgG A647 &#40;Invitrogen&#44; Thermo Fisher Scientific&#41; at room temperature&#46; Finally&#44; the sections were mounted using the fluorescent mounting medium 4&#8217;&#44;6-diamidino-2-phenylindole &#40;DAPI&#41; G-Fluoromount medium &#40;Southern Biotech&#44; Birmingham&#44; AL&#44; USA&#41;&#44; which specifically stained DNA &#40;allowing identification of all nuclei&#41; in the cell sections&#46; A fluorescence microscope &#40;x 40 objectives&#44; Nikon Eclipse Ni&#44; Nikon&#44; Tokyo&#44; Japan&#41; coupled with a digitizing camera was used to identify and count the number of fibroblasts &#40;30 fields&#41; in each study sample&#46; Results were expressed as the percentage of either both alpha-SMA and vimentin positively stained fibroblasts for identification of CAFs or vimentin-only positively stained for detection of NFs to the total number of counted fibroblasts in the 30 fields&#46; Results are reported separately for both CAFs and NFs in each type of lung specimen and patient group&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105"><span class="elsevierStyleBold">Markers of ECM and endothelial cells using immunohistochemistry</span></span><p id="par0070" class="elsevierStylePara elsevierViewall">Type I collagen and endothelial cells were identified on three-micrometer lung tumor and non-tumor cross-sections using immunohistochemical procedures as previously described<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">10&#44;29</span></a>&#46; Following deparaffinization&#44; lung cross-sections were immersed in preheated antigen retrieval solution of ethylenediaminetetraacetic acid &#40;EDTA&#44; pH 9&#41;&#44; incubated at 95<span class="elsevierStyleHsp" style=""></span>&#176;C for 40<span class="elsevierStyleHsp" style=""></span>minutes to be then cooled down to room temperature&#46; Slides were washed over the following steps with phosphate buffer saline &#40;PBS&#41;&#46; Endogenous peroxidase activity was blocked with 6&#37; hydrogen peroxide for 15<span class="elsevierStyleHsp" style=""></span>minutes&#46; Primary antibody incubation with anti-collagen I antibody &#40;anti-collagen I antibody&#44; Abcam&#44; Cambridge&#44; UK&#41; and anti-CD31antibody &#40;anti-CD31 antibody&#44; Abcam&#44; Cambridge&#44; UK&#41; was performed for one hour&#46; Slides were incubated with biotinylated universal secondary antibody for 30<span class="elsevierStyleHsp" style=""></span>minutes followed by a 30-minute incubation with HRP-streptavidin and diaminobenzidine for five minutes &#40;kit LSAB<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HRP Dako Cytomation Inc&#46;&#44; Carpinteria&#44; CA&#44; USA&#41; as a substrate&#46; Hematoxylin counterstaining was performed for two minutes and slides were dehydrated and mounted for conventional microscopy&#46; Images of the stained lung sections &#40;tumor and non-tumor&#41; were captured with a light microscope &#40;Olympus&#44; Series BX50F3&#44; Olympus Optical Co&#46;&#44; Hamburg&#44; Germany&#41; coupled with an image-digitizing camera &#40;Pixera Studio&#44; version 1&#46;0&#46;4&#44; Pixera Corporation&#44; Los Gatos&#44; CA&#44; USA&#41;&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Expression of the markers collagen and CD31 was estimated as the percentage of type I collagen and CD31 using the semiquantitative immunohistochemical scoring system &#40;Hscore&#41; according to methodologies previously published<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">30</span></a>&#46; Type I collagen and CD31 staining in the tumor and non-tumor specimens was established according to the following categories&#58; Hscore 0 &#40;indicated the absence of staining&#41; and Hscore 1 &#40;indicated the presence of staining&#41;&#46; Data are shown as the percentage of both positively and negatively stained structures for all the histological sections in both tumor and non-tumor lung specimens&#46;</p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Statistical analyses</span><p id="par0080" class="elsevierStylePara elsevierViewall">The normality of the study variables was tested using the Shapiro-Wilk test&#46; The marker CD31 was used to estimate sample size&#46; For the one-way analysis of variance &#40;ANOVA&#41; of one factor&#44; considering the between-group variance to be 10486&#46;7 and the within-group error equal to 3160&#46;9&#44; a minimum of 12 patients &#40;24 patients in total&#41; per type of sample &#40;tumor and non-tumor&#41; sufficed to reach an 80&#37; power given an alpha error of 0&#46;05&#46; The software Stata&#47;MP release 15 &#40;StataCorp LLC&#44; College Station&#44; Texas&#44; USA&#41; was used for sample size calculation&#46; Clinical variables are shown in a Table&#46; Qualitative variables are represented as frequencies &#40;number and percentage&#41;&#44; while quantitative variables are shown as mean and standard deviations&#46; Differences in clinical variables between LC and LC-COPD groups of patients were assessed using Student&#39;s T-test&#46; Differences among the different biological variables were estimated using ANOVA and Tukey&#39;s post-hoc to adjust for multiple comparisons for the two sample types &#40;tumor and non-tumor&#41; and the two patient groups&#46; A subanalysis in which only ex-smokers and non-smokers was conducted&#46; Moreover&#44; one-way covariance &#40;ANCOVA&#41; was also used to adjust for cigarette smoking history in the analyses of all the biological&#46; Statistical significance was established at P &#8804; 0&#46;05&#46; All statistical analyses were conducted using the software Statistical Package for the Social Science &#40;SPSS&#44; version 23&#44; SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41;&#46;</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Results</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Clinical characteristics</span><p id="par0085" class="elsevierStylePara elsevierViewall">Clinical and functional characteristics of LC and LC-COPD patients are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Age&#44; sex&#44; or BMI did not significantly differ between the two groups of patients&#46; Ex-smokers and the number of pack-years were significantly greater in LC-COPD patients compared to LC patients&#44; while the number of never smokers was significantly greater in the latter group &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The lung functional parameters FEV<span class="elsevierStyleInf">1</span>&#44; FEV<span class="elsevierStyleInf">1</span>&#47;FVC&#44; DL<span class="elsevierStyleInf">CO</span> and K<span class="elsevierStyleInf">CO</span> were significantly lower in LC-COPD than in LC patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Most of the patients were in GOLD stages I and II &#40;93&#37;&#44; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; TNM staging or histological subtypes did not significantly differ between the two groups&#46; In LC-COPD compared to LC patients&#44; the levels of total leukocytes and neutrophils significantly increased&#44; while levels of albumin significantly decreased&#46; Total proteins&#44; fibrinogen&#44; C-reactive protein&#44; globular sedimentation velocity&#44; and body weight loss did not differ between LC-COPD and LC patients&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Levels of CAFs increased in tumor specimens</span><p id="par0090" class="elsevierStylePara elsevierViewall">Compared to non-tumor lungs&#44; levels of alpha-SMA significantly increased in tumor specimens both in LC and LC-COPD patients&#44; while levels of vimentin significantly decreased in tumor samples in both groups of patients &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Levels of the fibroblast markers alpha-SMA &#40;marker of CAFs&#41; and vimentin &#40;marker of NFs&#41; did not significantly differ in either tumor or non-tumor specimens between LC-COPD and LC patients &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#41;&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The subanalysis of the patients according to either GOLD stages or cigarette smoking history revealed identical results to those shown when the entire population was analyzed as a whole &#40;data not shown&#41;&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Markers of collagen and endothelial cells in lung specimens</span><p id="par0105" class="elsevierStylePara elsevierViewall">Levels of the ECM marker type I collagen and those of the endothelial marker CD31 did not significantly differ in either tumor or non-tumor lungs between the two patient groups &#40;<a class="elsevierStyleCrossRefs" href="#fig0015">Figures 3 and 4</a>&#44; respectively&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Levels of type I collagen did not differ between tumor and non-tumor samples in any study groups of patients &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>&#41;&#46; Importantly&#44; in LC patients&#44; levels of Hscore 1 &#40;presence of staining&#41; of CD31 significantly declined in tumor specimens compared to non-tumor samples&#44; whereas those of Hscore 0 &#40;absence of staning&#41; increased &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>&#41;&#46; In LC-COPD&#44; no significant differences were seen in CD31 marker leves between tumor and non-tumor samples &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>&#41;&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The subanalysis of the patients according to either GOLD stages or cigarette smoking history revealed identical results to those shown when the entire population was analyzed as a whole &#40;data not shown&#41;&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135"><span class="elsevierStyleBold">Discussion</span></span><p id="par0120" class="elsevierStylePara elsevierViewall">In the current investigation&#44; the main findings were that levels of the endothelial marker CD31 significantly decreased in tumors of LC patients&#44; but not in tumors of patients with airway obstruction&#46; In both groups of patients&#44; a rise in the expression of CAFs was seen in lung tumors&#46; Levels of type I collagen in tumor and non-tumor lungs did not differ between patient groups&#46; The most relevant findings collected in the study are discussed below&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">CAFs play a crucial role in cancer cell invasion through several mechanisms<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">31</span></a>&#46; Vimentin&#44; which is expressed in normal mesenchymal cells&#44; maintains cellular integrity and provides resistance against stress&#46; Its function has also been proposed in different cancer cell types including LC<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">32</span></a>&#46; In the present investigation&#44; the expression of CAFs was significantly greater in the tumor specimens in both groups of LC patients with and without COPD&#46; No significant differences in the levels of cultured CAFs in tumor lungs were seen between the study groups of patients&#46; These findings suggest that CAFs are similarly expressed in lung tumors regardless of underlying airway obstruction&#46; They also imply that fibroblasts are not likely to be involved in an accelerated process of cancer invasion and progression in patients with airway obstruction&#46; Conversely&#44; the percentage of fibroblasts-expressing vimentin-only was significantly reduced in the tumors of both groups of patients&#46; These results also reinforce the concept that CAFs are likely to be a predominant feature of the stroma in lung tumor progression in the patients regardless of the presence of airway obstruction&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Whether a similar profile of CAFs expression can be detected in lung tumors of patients with other underlying respiratory diseases remains to be elucidated&#46; In idiopathic pulmonary fibrosis&#44; myofibroblasts are persistently activated&#44; which secrete collagen type I&#44; and express alpha-SMA fibers&#44; thus they may favor lung tumorigenesis<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">35</span></a>&#46; Conversely&#44; in patients with non-cystic fibrosis bronchiectasis&#44; a lower or no risk of LC was demonstrated<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">33&#44;34</span></a>&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Activated myofibroblasts synthesize extracellular components that contribute to the remodeling of the ECM taking place during carcinogenesis&#46; As such CAFs secrete type I collagen&#44; which plays an important role in tumor development&#44; growth&#44; and epithelial-mesenchymal transition<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">36</span></a>&#46; Moreover&#44; overall survival correlated with low levels of expression of type I collagen and cancer cell differentiation<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">36</span></a>&#46; In the present study&#44; expression levels of collagen did not significantly differ between tumor and non-tumor samples or between the study groups&#46; These findings suggest that collagen was not a major driver in lung tumor development in these patients&#44; probably because well-differentiated tumor types were analyzed in the study&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">CD31 is a glycoprotein expressed in endothelial cells&#44; leukocytes&#44; T cells&#44; and platelets<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">20</span></a>&#46; CD31 is also expressed in lung tumors<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">37</span></a>&#46; In the current investigation&#44; a significant decline in CD31 expression levels &#40;Hscore 1&#41; was detected in the tumor specimens of patients with LC&#44; while in patients with underlying airway obstruction no significant differences were seen between lung tumor and non-tumor samples&#46; These findings imply that the vascular endothelial component of stroma was probably involved in the prognosis of LC in patients with and without COPD&#46; In fact&#44; 47&#37; of LC-COPD and 80&#37; of LC patients are still alive in this series &#40;10-year follow-up&#44; data not shown&#41;&#46; In keeping with&#44; CD31 has proven to be a useful marker to evaluate angiogenesis in lung tumors<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">38</span></a> as well as to monitor the response to specific anti-angiogenic molecules such as vascular endothelial growth factor &#40;VEGF&#41; in clinical settings<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">38&#44;39</span></a>&#46; In this regard&#44; several investigations have demonstrated that VEGF inhibitors&#44; through reduced angiogenesis &#40;CD31 marker among others&#41;&#44; are currently prescribed as single agents in the third-line treatment of patients with NSCLC<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">38&#44;39</span></a>&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Study limitations</span><p id="par0145" class="elsevierStylePara elsevierViewall">A limitation in the study was the relatively reduced number of analyzed patients&#46; Nonetheless&#44; calculations of sample size estimated 12 patients in each group &#40;24 in total&#41;&#44; thus the number of patients included was sufficient to detect statistically significant differences in the study&#46; The degree of airway obstruction might have influenced the study results&#46; However&#44; as most of the patients were in GOLD stages I and particularly II&#44; COPD severity did not exert any significant impact on the results&#46; Almost half of the patients were non-smokers&#44; thus cigarette smoking might have influenced the study results&#46; Nevertheless&#44; a subanalysis in which non-smokers and ex-smokers were included revealed identical results to those obtained with the entire population&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">If non-tumor samples had been obtained from a closer distance from the tumors&#44; the profile of biological events might have differed as shown previously for other components of the extracellular matrix &#40;integrins&#41; that probably play a significant role in recurrence<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">40</span></a>&#46; Nonetheless&#44; this was not explored in the present study&#44; and warrants further attention&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conclusions</span><p id="par0155" class="elsevierStylePara elsevierViewall">Within the stroma&#44; the expression of the vascular endothelial marker CD31 was reduced in tumors of patients without airway obstruction&#44; while expression levels of the ECM component type I collagen did not differ between patient groups&#46; A rise in the levels of CAFs was detected in the lung tumors of patients irrespective of underlying airway obstruction&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Low levels of CD31 may have implications in the overall survival of LC patients&#44; especially in those without underlying airway obstruction&#46; Investigations aiming to decipher the specific role of CD31 as a predictor of survival and as a biomarker to monitor anti-angiogenic agents in lung tumors of patients with underlying respiratory diseases are warranted&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Authors&#8217; contributions</span><p id="par0165" class="elsevierStylePara elsevierViewall">Study conception and design&#58; EB&#44; VC&#59; Patient assessment and recruitment&#58; JT&#44; VC&#44; DRC&#44; MMJ&#44; ARF&#44; RA&#44; LP&#59; Molecular biology analyses&#58; JT&#44; DRC&#44; KA&#59; Statistical analyses and data interpretation&#58; XD&#44; JT&#44; DRC&#44; EB&#59; Manuscript drafting and intellectual input&#58; EB&#44; JT&#59; Manuscript writing final version&#58; EB&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Sources of funding</span><p id="par0170" class="elsevierStylePara elsevierViewall">This study has been supported by FIS 18&#47;00075 &#40;FEDER&#44; ISC-III&#41; &#38; CIBERES &#40;ISC-III&#41;&#44; SEPAR 2018 and SEPAR 2020&#44; and an unrestricted research grant from Menarini SA 2018 &#40;Spain&#41;&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Competing interests declared by all the authors</span><p id="par0175" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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              "titulo" => "Conclusiones"
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          "identificador" => "xpalclavsec1329613"
          "titulo" => "Palabras clave"
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        5 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        6 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Methods"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Study design and ethics"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Clinical assessment"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Sample collection and preservation"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Cell culture"
        ]
        8 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Immunoflorescence staining of CAFs and NFs"
        ]
        9 => array:3 [
          "identificador" => "sec0040"
          "titulo" => "Markers of ECM and endothelial cells using immunohistochemistry"
          "secciones" => array:1 [
            0 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Statistical analyses"
            ]
          ]
        ]
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          "identificador" => "sec0050"
          "titulo" => "Results"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Clinical characteristics"
            ]
            1 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Levels of CAFs increased in tumor specimens"
            ]
            2 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Markers of collagen and endothelial cells in lung specimens"
            ]
          ]
        ]
        11 => array:2 [
          "identificador" => "sec0070"
          "titulo" => "Discussion"
        ]
        12 => array:2 [
          "identificador" => "sec0075"
          "titulo" => "Study limitations"
        ]
        13 => array:2 [
          "identificador" => "sec0080"
          "titulo" => "Conclusions"
        ]
        14 => array:2 [
          "identificador" => "sec0085"
          "titulo" => "Authors&#8217; contributions"
        ]
        15 => array:2 [
          "identificador" => "sec0090"
          "titulo" => "Sources of funding"
        ]
        16 => array:2 [
          "identificador" => "sec0095"
          "titulo" => "Competing interests declared by all the authors"
        ]
        17 => array:2 [
          "identificador" => "xack510315"
          "titulo" => "Acknowledgments"
        ]
        18 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2020-05-18"
    "fechaAceptado" => "2020-09-04"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1329612"
          "palabras" => array:6 [
            0 => "Lung cancer"
            1 => "COPD"
            2 => "Stroma"
            3 => "Cancer-associated fibroblasts"
            4 => "Extracellular matrix"
            5 => "Endothelial cell marker CD31"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1329613"
          "palabras" => array:6 [
            0 => "C&#225;ncer de pulm&#243;n"
            1 => "EPOC"
            2 => "Estroma"
            3 => "Fibroblastos asociados al c&#225;ncer"
            4 => "Matriz extracelular"
            5 => "Marcador de c&#233;lulas endoteliales CD31"
          ]
        ]
      ]
    ]
    "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="spar0010" class="elsevierStyleSimplePara elsevierViewall">Stroma&#44; mainly composed by fibroblasts&#44; extracellular matrix &#40;ECM&#41; and vessels&#44; may play a role in tumorigenesis and cancer progression&#46; Chronic Obstructive Pulmonary Disease &#40;COPD&#41; is an independent risk factor for LC&#46; We hypothesized that markers of fibroblasts&#44; ECM and endothelial cells may differ in tumors of LC patients with&#47;without COPD&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Markers of cultured cancer-associated fibroblasts and normal fibroblasts &#91;CAFs and NFs&#44; respectively&#44; vimentin and alpha-smooth muscle actin &#40;SMA&#41; markers&#44; immunofluorescence in cultured lung fibroblasts&#93;&#44; ECM&#44; and endothelial cells &#40;type I collagen and CD31 markers&#44; respectively&#44; immunohistochemistry&#41; were identified in lung tumor and non-tumor specimens &#40;thoracotomy for lung tumor resection&#41; from 15 LC-COPD patients and 15 LC-only patients&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Numbers of CAFs significantly increased&#44; while those of NFs significantly decreased in tumor samples compared to non-tumor specimens of both LC and LC-COPD patients&#46; Endothelial cells &#40;CD31&#41; significantly decreased in tumor samples compared to non-tumor specimens only in LC patients&#46; No significant differences were seen in levels of type I collagen in any samples or study groups&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Vascular endothelial marker CD31 expression was reduced in tumors of non-COPD patients&#44; while type I collagen levels did not differ between groups&#46; A rise in CAFs levels was detected in lung tumors of patients irrespective of airway obstruction&#46; Low levels of CD31 may have implications in the overall survival of LC patients&#44; especially in those without underlying airway obstruction&#46; Identification of CD31 role as a prognostic and therapeutic biomarker in lung tumors of patients with underlying respiratory diseases warrants attention&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Background"
          ]
          1 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Methods"
          ]
          2 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Conclusions"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">El estroma&#44; compuesto principalmente por fibroblastos&#44; matriz extracelular &#40;MEC&#41; y vasos&#44; puede desempe&#241;ar un papel en la g&#233;nesis tumoral y la progresi&#243;n del c&#225;ncer&#46; La enfermedad pulmonar obstructiva cr&#243;nica &#40;EPOC&#41; es un factor de riesgo independiente para el carcinoma de pulm&#243;n &#40;CP&#41;&#46; Nuestra hip&#243;tesis fue que los marcadores de fibroblastos&#44; MEC y c&#233;lulas endoteliales pueden variar en los tumores de los pacientes con CP con o sin EPOC&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">M&#233;todos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se identificaron los marcadores de fibroblastos asociados al c&#225;ncer y los fibroblastos normales cultivados &#40;FAC y FN&#44; respectivamente&#59; marcadores&#58; vimentina y &#945;-actina del m&#250;sculo liso &#91;SMA por sus siglas en ingl&#233;s&#93;&#59; inmunofluorescencia en fibroblastos de pulm&#243;n cultivados&#41; y marcadores de la MEC y las c&#233;lulas endoteliales &#40;marcadores&#58; col&#225;geno tipo I y CD31&#44; respectivamente&#59; inmunohistoqu&#237;mica&#41; en muestras de pulm&#243;n tumoral y no tumoral &#40;toracotom&#237;a para resecci&#243;n de tumores pulmonares&#41; de 15 pacientes con EPOC-CP y 15 pacientes con solo CP&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Resultados</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El n&#250;mero de FAC aument&#243; de forma significativa&#44; mientras que el de FN disminuy&#243; significativamente en las muestras tumorales en comparaci&#243;n con las muestras no tumorales de pacientes con CP y EPOC-CP&#46; Las c&#233;lulas endoteliales &#40;CD31&#41; disminuyeron tambi&#233;n de forma significativa en las muestras tumorales en comparaci&#243;n con las muestras no tumorales solo en los pacientes con CP&#46; No se observaron diferencias significativas en los niveles de col&#225;geno tipo I en ninguna muestra o grupo de estudio&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusiones</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">La expresi&#243;n del marcador vascular endotelial CD31 se redujo en los tumores de los pacientes sin EPOC&#44; mientras que los niveles de col&#225;geno tipo I no difirieron entre los grupos&#46; Se detect&#243; un aumento en los niveles de FAC en los tumores de pulm&#243;n de los pacientes&#44; con independencia de la presencia de obstrucci&#243;n de las v&#237;as respiratorias&#46; Los niveles bajos de CD31 pueden tener implicaciones en la supervivencia general de los pacientes con CP&#44; en especial&#44; en aquellos sin obstrucci&#243;n subyacente de las v&#237;as respiratorias&#46; Convendr&#237;a estudiar e identificar el papel del CD31 como biomarcador terap&#233;utico y de pron&#243;stico en los tumores de pulm&#243;n de pacientes con enfermedades respiratorias subyacentes&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0030"
            "titulo" => "Antecedentes"
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            "identificador" => "abst0035"
            "titulo" => "M&#233;todos"
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          2 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Resultados"
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          3 => array:2 [
            "identificador" => "abst0045"
            "titulo" => "Conclusiones"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">A and B&#58;</span> Representative examples of immunofluorescence staining of the markers DAPI &#40;upper panel&#41;&#44; vimentin &#40;upper middle panel&#41;&#44; alpha-SMA &#40;lower middle panel&#41;&#44; and CAFs &#40;positively stained for both vimentin and alpha-SMA&#44; bottom panel&#41; in cultured fibroblasts obtained from non-tumor and tumor specimens of LC and LC-COPD patients&#46; Definition of abbreviations&#58; DAPI&#44; 4&#8217;&#44; 6-diamidino-2-phenylindole&#59; alpha-SMA&#44; alpha-smooth muscle actin&#59; CAFs&#44; cancer-associated fibroblasts&#59; LC&#44; lung cancer&#59; COPD&#44; chronic obstructive pulmonary disease&#46;</p>"
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        "mostrarFloat" => true
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        "figura" => array:1 [
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">A <span class="elsevierStyleBold">and B&#58;</span> Mean values and standard deviations &#40;SD&#41; of levels of the markers vimentin and vimentin and alpha-SMA as measured by percentage of the total fibroblasts&#46; Definition of abbreviations&#58; alpha-SMA&#44; alpha-smooth muscle actin&#59; LC&#44; lung cancer&#59; COPD&#44; chronic obstructive pulmonary disease&#46; Statistical analyses&#58; &#42;&#42;&#44; <span class="elsevierStyleItalic">p</span> &#8804; 0&#46;01 between tumor &#40;T&#41; and non-tumor &#40;NT&#41; lungs in both LC and LC-COPD patients&#46;</p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">A&#41;</span> Representative examples of immunohistochemical staining for type I collagen in tumor and non-tumor specimens &#40;collagen I<span class="elsevierStyleItalic">-</span>positively stained&#41; in LC and LC-COPD patients&#44; respectively&#46; Black arrows point towards areas stained in blue with hematoxylin &#40;negatively-stained for collagen&#41;&#44; while red arrows point towards positively-stained areas &#40;brown color&#41;&#46; <span class="elsevierStyleBold">B&#41;</span> Mean and standard deviations &#40;SD&#41; of levels of type I collagen in tumor and non-tumor of both groups as measured using histoscores &#40;see Methods&#41;&#46; Definition of abbreviations&#58; Hscore&#44; histochemical score&#59; LC&#44; lung cancer&#59; COPD&#44; chronic obstructive pulmonary disease&#46; Statistical analyses&#58; <span class="elsevierStyleItalic">n&#46;s&#46;</span>&#44; no significance between tumor &#40;T&#41; and non-tumor &#40;NT&#41; lungs in either LC or LC-COPD patients&#46;</p>"
        ]
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        "identificador" => "fig0020"
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        "mostrarFloat" => true
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">A&#41;</span> Representative examples of immunohistochemical staining for CD31 in tumor and non-tumor specimens &#40;CD31<span class="elsevierStyleItalic">-</span>positively stained&#41; in LC and LC-COPD patients&#44; respectively&#46; Black arrows point towards areas stained in blue with hematoxylin &#40;negatively-stained for CD31&#41;&#44; while red arrows point towards positively-stained areas &#40;brown color&#41;&#46; <span class="elsevierStyleBold">B&#41;</span> Mean and standard deviations &#40;SD&#41; of levels of CD31 in tumor and non-tumor of both groups as measured using specific histoscores &#40;see Methods&#41;&#46; Definition of abbreviations&#58; Hscore&#44; histochemical score&#59; LC&#44; lung cancer&#59; COPD&#44; chronic obstructive pulmonary disease&#46; Statistical analyses&#58; &#42;&#42;&#44; <span class="elsevierStyleItalic">p</span> &#8804; 0&#46;01 between tumor &#40;T&#41; and non-tumor &#40;NT&#41; lungs in LC patients&#59; <span class="elsevierStyleItalic">n&#46;s&#46;</span>&#44; no significance between tumor &#40;T&#41; and non-tumor &#40;NT&#41; lungs in LC-COPD patients&#46;</p>"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Continuous variables are presented as mean &#40;standard deviation&#41; while categorical variables are presented as the number of patients in each group and the percentage in the study group total population&#46; <span class="elsevierStyleItalic">Definition of abbreviations</span>&#58; N&#44; number&#59; kg&#44; kilograms&#59; m&#44; metres&#59; BMI&#44; body mass index&#59; FEV<span class="elsevierStyleInf">1</span>&#44; forced expiratory volume in one second&#59; FVC&#44; forced vital capacity&#59; DL<span class="elsevierStyleInf">CO</span>&#44; carbon monoxide transfer&#59; K<span class="elsevierStyleInf">CO</span>&#44; Krogh transfer factor&#59; GOLD&#58; Global initiative for Chronic Obstructive Lung Disease&#59; NA&#44; not applicable&#59; TNM&#44; tumor&#44; nodes&#44; metastasis&#59; CRP&#44; C-reactive protein&#59; GSV&#44; globular sedimentation velocity&#59; L&#44; liter&#46; Statistical analyses and significance&#58; &#42; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; &#42;&#42;&#42; <span class="elsevierStyleItalic">p</span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 between LC-COPD patients and LC patients&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Anthropometric variables&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">LC &#40;N<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>15&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Age&#44; years</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">67 &#40;10&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">67 &#40;8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Male&#44; N &#47; Female&#44; N&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">8 &#47; 7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">12 &#47; 3&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>BMI&#44; kg&#47;m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">27 &#40;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">26 &#40;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Current&#58; N&#44; &#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">8&#44; 53&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#44; 53&nbsp;\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>Ex-smoker&#58; N&#44; &#37;&nbsp;\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">0&#44; 0&nbsp;\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">7&#44; 47&#42;&#42;&#42;&nbsp;\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>Never smoker&#58; N&#44; &#37;&nbsp;\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">7&#44; 47&nbsp;\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">0&#44; 0&#42;&#42;&#42;&nbsp;\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>Pack-years&nbsp;\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 &#40;18&#41;&nbsp;\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 &#40;25&#41;&#42;&#42;&nbsp;\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">Lung function parameters</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>FEV<span class="elsevierStyleInf">1</span>&#44; &#37;&nbsp;\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">89 &#40;11&#41;&nbsp;\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 &#40;14&#41;&#42;&#42;&#42;&nbsp;\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>FEV<span class="elsevierStyleInf">1</span>&#47;FVC&#44; &#37;&nbsp;\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">76 &#40;5&#41;&nbsp;\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 &#40;9&#41;&#42;&#42;&#42;&nbsp;\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>DLCO&#44; &#37;&nbsp;\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">84 &#40;11&#41;&nbsp;\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">60 &#40;15&#41;&#42;&#42;&#42;&nbsp;\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>KCO&#44; &#37;&nbsp;\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">85 &#40;11&#41;&nbsp;\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 &#40;15&#41;&#42;&#42;&#42;&nbsp;\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">GOLD stage</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>GOLD Stage I&#58; N&#44; &#37;&nbsp;\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">NA&nbsp;\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">2&#44; 13&nbsp;\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>GOLD Stage II&#58; N&#44; &#37;&nbsp;\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">NA&nbsp;\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">12&#44; 80&nbsp;\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>GOLD Stage III&#58; N&#44; &#37;&nbsp;\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">NA&nbsp;\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&#44; 7&nbsp;\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>GOLD Stage IV&#58; N&#44; &#37;&nbsp;\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">NA&nbsp;\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">0&#44; 0&nbsp;\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">TNM staging</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>Stage 0<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>I&#58; N&#44; &#37;&nbsp;\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&#44; 53&nbsp;\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&#44; 53&nbsp;\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 II<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>III&#58; N&#44; &#37;&nbsp;\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">7&#44; 47&nbsp;\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">7&#44; 47&nbsp;\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 IV&#58; N&#44; &#37;&nbsp;\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">0&#44; 0&nbsp;\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">0&#44; 0&nbsp;\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">Histological diagnosis</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>Squamous cell carcinoma&#58; N&#44; &#37;&nbsp;\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&#44; 20&#46;0&nbsp;\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&#44; 26&#46;6&nbsp;\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>Adenocarcinoma&#58; N&#44; &#37;&nbsp;\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">10&#44; 66&#46;7&nbsp;\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">10&#44; 66&#46;7&nbsp;\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>Others&#58; N&#44; &#37;&nbsp;\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">2&#44; 13&#46;3&nbsp;\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&#44; 6&#46;7&nbsp;\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">Blood parameters</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>Total leucocytes&#47;&#956;L&nbsp;\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">6&#46;46 &#40;1&#46;29&#41;<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">3</span>&nbsp;\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&#46;88 &#40;1&#46;84&#41;<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">3</span>&#42;&#42;&#42;&nbsp;\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>Total neutrophils&#47;&#956;L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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