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CLINICAL SCIENCE
Interferon-gamma and interleukin-10 production by mononuclear cells from patients with advanced head and neck cancer
Luiz C Conti-Freitas
Corresponding author
lcconti@fmrp.usp.br

Tel.: 55-16-3602-2353
, Maria C Foss-Freitas, Rui C M Mamede, Norma T Foss
Universidade de São Paulo (USP), Medical School of Ribeirão Preto, Ribeirão Preto/SP, Brazil
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Although the mechanism of action of Bacille Calmette-Gu&#233;rin &#40;BCG&#41; has not been fully elucidated&#44; BCG is currently regarded as the most successful cancer immunotherapy &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#46; BCG seems to enhance the cellular immune response in a nonspecific manner by activating macrophages and lymphocytes&#46; Intravesical immunotherapy is clinically well established as a treatment for superficial bladder cancer&#44; but it remains an experimental treatment for other solid tumors&#44; such as laryngeal cancer &#40;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">Cytotoxic CD8<span class="elsevierStyleSup">&#43;</span> T cells play an important role in the control of tumor cells &#40;<a class="elsevierStyleCrossRef" href="#bib3">3</a>&#41;&#46; The immune process&#44; which culminates in the lysis of tumor cells&#44; often begins with dendritic cells&#44; which detect the tumor antigens presented by Major Histocompatibility Complex &#40;MHC&#41; molecules expressed on tumor cell surfaces and then phagocytose the presenting cells&#46; These dendritic cells activate lymphocytes&#44; starting the cytotoxic process and tumor cell lysis&#46; This entire cell interaction mechanism is coordinated by different cytokines &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#41;&#46; The proinflammatory activities of cytokines such as interferon-gamma &#40;IFN-&#947;&#41; are associated with Th1 T lymphocyte differentiation&#46; IFN-&#947; is thought to be associated with anti-tumoral cellular immunity&#46; However&#44; immune response activation involving cytokines such as interleukin-10 &#40;IL-10&#41; can promote Th2 T lymphocyte differentiation and lead to a predominantly humoral immune response &#40;<a class="elsevierStyleCrossRef" href="#bib5">5</a>&#41;&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">Although BCG has been used as a successful immunotherapy for cancer&#44; few studies have investigated cytokine release by BCG-activated immune cells&#46; In a previous study&#44; we evaluated the production of TNF-&#945; and IL-6 in the supernatant of adherent cells cultured from peripheral blood mononuclear cells &#40;PBMCs&#41; isolated from patients with supraglottic laryngeal cancer before and after surgical treatment&#46; We found that BCG is able to modulate the immune response of these patients &#40;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46; In this study&#44; we evaluated the production of IFN-&#947; and IL-10 by cultured PBMCs isolated from patients with advanced supraglottic laryngeal cancer&#46; PBMCs were isolated during the preoperative period &#40;PREOP&#41; and the late postoperative &#40;LP&#41; period&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">METHODS</span><p id="para40" class="elsevierStylePara elsevierViewall">Fourteen patients with stage III or IV supraglottic laryngeal carcinoma were selected at the outpatient clinic of the University Hospital of the Ribeir&#227;o Preto School of Medicine&#44; S&#227;o Paulo University&#46; Each tumor was staged according to the TNM classification&#46; Patients with infectious and&#47;or inflammatory diseases detected by blood and urine tests and chest X-rays and patients using immunosuppressive medications were excluded&#46; Surgical treatment consisted of total or partial laryngectomy according to lesion stage&#46; T3 stage patients underwent total or supraglottic laryngectomy&#44; and T4 stage patients were treated with total laryngectomy&#46; Blood samples were collected from all patients during the PREOP period and at 236&#177;18 days after surgery &#40;LP&#41;&#46;</p><p id="para50" class="elsevierStylePara elsevierViewall">Thirteen healthy age- and sex-matched individuals were recruited as the control group&#46; The presence of neoplasms in the control volunteers was ruled out by detailed physical investigation&#46; The study was approved by the Ethics Committee of the University Hospital of the Ribeir&#227;o Preto School of Medicine&#44; S&#227;o Paulo University&#44; and all patients gave written informed consent prior to participation in the study&#46;</p><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Measurement of the cytokine concentrations</span><p id="para60" class="elsevierStylePara elsevierViewall">Blood samples were collected from the peripheral vein under sterile conditions during both the PREOP and LP periods from patients with laryngeal cancer&#46; Blood staples were collected only once from the control subjects&#46; Peripheral blood mononuclear cells &#40;PBMCs&#41; were isolated with a Ficoll-Hypaque gradient&#44; and their viability was determined by 2&#37; Trypan Blue exclusion&#46; Cells were kept at a concentration of 2&#46;0x10<span class="elsevierStyleSup">5</span> cells&#47;mL in 12&#46;5&#37; bovine fetal serum&#46; Non-stimulated and stimulated cultures were evaluated&#59; stimulated cells were exposed to 10 &#181;g&#47;mL of concanavalin A &#40;ConA&#41; or 20 &#181;g&#47;mL of BCG&#46; After 72 h of culture at 37&#176;C in a humid environment containing nearly 5&#37; CO<span class="elsevierStyleInf">2</span>&#44; the supernatant was collected&#44; and the IL-10 and IFN-&#947; levels were measured &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#41;&#46;</p><p id="para70" class="elsevierStylePara elsevierViewall">Human monoclonal IL-10 and IFN-&#947; antibodies were used &#91;Pharmingen International &#40;Life Science Research&#41;&#44; San Diego&#44; CA&#44; USA&#93; as the capture antibodies&#44; and biotinylated antihuman antibodies against the analyzed cytokines &#40;Pharmingen&#41; were used as the detecting antibodies&#46; Binding was detected with peroxidase-labeled streptavidin &#40;DAKO&#44; Glostrup&#44; Denmark&#41; and <span class="elsevierStyleItalic">O</span>-phenylenediamine-2HCl&#47;substrate &#40;OPD&#44; Sigma&#44; St&#46; Louis&#44; MO&#44; USA&#41;&#46; The intra-assay and inter-assay variation levels were below 10&#37;&#46; The detection limits of the cytokine ELISAs were 78 pg&#47;mL and 39 pg&#47;mL for IFN-&#947; and IL-10&#44; respectively&#46;</p><p id="para80" class="elsevierStylePara elsevierViewall">The results are reported as the median &#40;<span class="elsevierStyleItalic">M</span>&#41;&#44; mean &#40;<span class="elsevierStyleItalic">x</span>&#41; and standard deviation &#40;SD&#41;&#46; GraphPad Prism &#40;San Diego&#44; CA&#44; USA&#41; was used for statistical analysis&#46; Between-group comparisons were performed using the Mann-Whitney and Wilcoxon tests&#44; and <span class="elsevierStyleItalic">p</span>&#60;0&#46;05 was considered statistically significant&#46;</p></span></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">RESULTS</span><p id="para90" class="elsevierStylePara elsevierViewall">Demographic data for the patients and controls are shown in <a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>&#46; All patients smoked an average of 20&#177;8&#46;5 &#40;x&#177;DP&#41; cigarettes&#47;day for 44&#46;5&#177;10 years&#46; Eight patients received adjuvant radiotherapy 27&#46;1&#177;8 days after surgery&#44; and the post-operative evaluation was conducted at least six months after the completion of the radiotherapy&#46; No patient exhibited evidence of tumor recurrence at the time of blood sample collection for LP evaluation&#44; as determined by endoscopy and radiography&#46; All patients had stopped smoking by the time of the postoperative evaluation&#46; Thirteen healthy control subjects were selected&#44; ten men and three women&#46; The control subjects ranged in age from 40 to 67 years &#40;52&#177;9&#46;3&#41;&#46; No significant differences were observed between the controls and the patients&#46;</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><p id="para100" class="elsevierStylePara elsevierViewall">The IFN-&#947; levels in the PREOP and LP BCG-stimulated cultures were similar to those in the control group cultures&#44; whereas&#44; the IFN-&#947; levels were lower in the non-stimulated PREOP and LP cultures than in the non-stimulated control cultures &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>&#41;&#46; For the control cultures&#44; the IFN-&#947; level was 154&#46;86 &#40;32&#46;32 &#8211; 192&#46;8&#41; pg&#47;ml in the non-stimulated cultures and 239&#46;9 &#40;139&#46;83 &#8211; 1&#44;718&#46;08&#41; pg&#47;ml in the BCG-stimulate cultures&#46; A higher elevation index was observed in patients at both the PREOP and LP timepoints&#44; with increases from 27&#46;63 &#40;1&#46;12 &#8211; 140&#46;25&#41; pg&#47;ml to 116&#46;19 &#40;5&#46;5 &#8211; 3&#44;030&#46;86&#41; pg&#47;ml and from 41&#46;47 &#40;30&#46;03 &#8211; 218&#46;09&#41; pg&#47;ml to 186&#46;47 &#40;27&#46;74 &#8211; 1&#44;459&#46;73&#41; pg&#47;ml&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia><elsevierMultimedia ident="tbl2"></elsevierMultimedia><p id="para110" class="elsevierStylePara elsevierViewall">The IFN-&#947; levels in the supernatants of non-stimulated PBMC cultures were lower for the PREOP and LP cultures than for the control cultures &#40;<span class="elsevierStyleItalic">p</span> &#61; 0&#46;001&#44; <span class="elsevierStyleItalic">p</span> &#61; 0&#46;04&#44; respectively&#41;&#46; However&#44; when the cultures were stimulated with ConA&#44; there were no significant differences between the control cultures and either the PREOP or LP cultures&#46; Higher levels of IFN-&#947; were observed in the supernatants of the ConA-stimulated LP cultures than in those of the ConA-stimulated PREOP cultures &#40;<span class="elsevierStyleItalic">p &#61;</span> 0&#46;005&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a>&#41;&#46;</p><p id="para120" class="elsevierStylePara elsevierViewall">The IL-10 levels in the supernatants of the ConA- and BCG-stimulated cultures of cells from patients in the PREOP and LP periods were also similar to in the levels for the control group cultures&#46; The IL-10 level was undetectable in non-stimulated cultures &#40;<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>&#41;&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">DISCUSSION</span><p id="para130" class="elsevierStylePara elsevierViewall">The impairment of immunological defense mechanisms may play an important role in cancer pathogenesis&#46; Decreased <span class="elsevierStyleItalic">in vitro</span> lymphocytic function&#44; lower numbers and percentages of lymphocytes and impaired lymphoproliferation have been reported in many cancer studies &#40;<a class="elsevierStyleCrossRefs" href="#bib8">8&#8211;12</a>&#41;&#46; Many researchers have examined different aspects of the immune behavior of head and neck cancer&#59; however&#44; few studies have examined supraglottic laryngeal cancer specifically&#46; This attention is justified by the local behavior&#44; regional dissemination capability and potential participation of the immune system in cancer prognosis in this type of cancer &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46;</p><p id="para140" class="elsevierStylePara elsevierViewall">IFN-&#947; is the first detectable cytokine at the immunization site after stimulation with protein antigen and plays a critical role in the activation and regulation of the immune response &#40;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#41;&#46; It is a Th1-specific cytokine and promotes the Th1 response and inhibits the Th2 response&#46; Moreover&#44; IFN-&#947; activates macrophages&#44; leading to the increased production of pro-inflammatory cytokines&#44; including TNF-&#945;&#44; in response to different stimuli&#46;</p><p id="para150" class="elsevierStylePara elsevierViewall">IFN-&#947; was expressed at lower levels in non-stimulated patient cultures &#40;PREOP and LP&#41; than in control group cultures&#44; confirming that the immune system is impaired in these patients&#46; When the cultures were stimulated with ConA&#44; the secretion of this cytokine was improved&#44; and the increase was greater in the LP group than in the PREOP group&#46; The higher levels of IFN-&#947; secretion by the LP cultures than by the PREOP cultures may be associated with improved nutritional status in the LP period or due to a reduction in smoking&#46; Although the effects of smoking and alcohol abuse on supraglottic laryngeal cancer are not fully clear&#44; some authors have demonstrated that smoking can affect some cytokines&#44; mainly IL-4 &#40;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#41;&#46;</p><p id="para160" class="elsevierStylePara elsevierViewall">Lymphocyte cultures from controls and patients with laryngeal cancer were stimulated with BCG &#40;<a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>&#41;&#46; BCG induced a more effective increase in IFN-&#947; production in patient cells &#40;4x increase&#41; than in control cells &#40;1&#46;5x increase&#41;&#46; As IFN-&#947; has a potent anti-tumor activity&#44; these data suggest that BCG should be tested further <span class="elsevierStyleItalic">in vivo</span>&#46;</p><p id="para170" class="elsevierStylePara elsevierViewall">Kim &#40;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#41; observed that <span class="elsevierStyleItalic">in vitro&#44;</span> IL-10 inhibited the destruction of squamous cell carcinoma tumor cells by peritumoral lymphocytes&#46; IL-10 inhibits macrophage differentiation and&#44; moreover&#44; inhibits antigen presentation to CD8 T lymphocytes&#44; preventing the effective destruction of tumor cells&#46; Thus&#44; IL-10 acts as a local immunosuppressive factor&#44; allowing the tumor to escape from the immune system &#40;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#44;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#41;&#46; In this study&#44; the level of IL-10 production by non-adherent cells was similar to that of the control cells&#46; This result indicates that the primary activity of IL-10 is not associated with the cellular response&#46; The true role of IL-10 in the immunoregulation of cancer remains controversial &#40;<a class="elsevierStyleCrossRefs" href="#bib19">19&#8211;21</a>&#41;&#46;</p><p id="para180" class="elsevierStylePara elsevierViewall">Although the influence of IFN-&#947; levels on patient prognosis has not been examined&#44; further studies that demonstrate the relationship between activity levels and angiogenic factors &#40;<a class="elsevierStyleCrossRef" href="#bib22">22</a>&#41; and that evaluate other variables that can alter the capacity of the immune system&#44; such as alcohol consumption&#44; poor nutrition and smoking&#44; may support the clinical application of BCG in selected patients&#46; Ultimately&#44; BCG may help modify disease progression in terms of survival and prognosis parameters&#46;</p><p id="para190" class="elsevierStylePara elsevierViewall">In conclusion&#44; patients with advanced supraglottic laryngeal cancer exhibited an <span class="elsevierStyleItalic">in vitro</span> deficiency in IFN-&#947; secretion by mononuclear cells&#46; Stimulated cells seem to recover this function in the postoperative period&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">AUTHOR CONTRIBUTIONS</span><p id="para200" class="elsevierStylePara elsevierViewall">Conti-Freitas LC made substantial contributions to the conception and design of the study&#59; participated in the acquisition and interpretation of the data and was involved in the drafting of the manuscript&#46; Foss-Freitas MC participated in the drafting of the manuscript and performed the statistical analysis&#46; Mamede RCM participated in the study conception and design and in the data interpretation&#46; Foss NT conceived the study&#44; participated in its design and coordination&#44; and helped to draft the manuscript&#46; All authors read and approved the final manuscript&#46;</p></span></span>"
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        0 => array:2 [
          "identificador" => "xpalclavsec1582601"
          "titulo" => "KEYWORDS"
        ]
        1 => array:2 [
          "identificador" => "cesec10"
          "titulo" => "INTRODUCTION"
        ]
        2 => array:3 [
          "identificador" => "cesec20"
          "titulo" => "METHODS"
          "secciones" => array:1 [
            0 => array:2 [
              "identificador" => "cesec30"
              "titulo" => "Measurement of the cytokine concentrations"
            ]
          ]
        ]
        3 => array:2 [
          "identificador" => "cesec40"
          "titulo" => "RESULTS"
        ]
        4 => array:2 [
          "identificador" => "cesec50"
          "titulo" => "DISCUSSION"
        ]
        5 => array:2 [
          "identificador" => "cesec60"
          "titulo" => "AUTHOR CONTRIBUTIONS"
        ]
        6 => array:2 [
          "identificador" => "xack639396"
          "titulo" => "ACKNOWLEDGMENTS"
        ]
        7 => array:1 [
          "titulo" => "REFERENCES"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2011-10-31"
    "fechaAceptado" => "2012-02-23"
    "PalabrasClave" => array:1 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "KEYWORDS"
          "identificador" => "xpalclavsec1582601"
          "palabras" => array:5 [
            0 => "BCG"
            1 => "Cytokines"
            2 => "Interferon-&#947;"
            3 => "Interleukin-10"
            4 => "Head and Neck cancer"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:1 [
      "en" => array:2 [
        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVE&#58;</span><p id="spara60" class="elsevierStyleSimplePara elsevierViewall">This study aims to evaluate the production of interferon-gamma and interleukin-10 by stimulated peripheral blood mononuclear cells isolated from patients with supraglottic laryngeal cancer before and after surgical treatment&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS&#58;</span><p id="spara70" class="elsevierStyleSimplePara elsevierViewall">Fourteen patients with advanced supraglottic laryngeal cancer were studied&#46; Cultures of peripheral blood mononuclear cells isolated during the preoperative and late postoperative periods were stimulated with concanavalin A and Bacille Calmette-Gu&#233;rin&#44; and the supernatant concentrations of interferon-gamma and interleukin-10 were measured&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS&#58;</span><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">For non-stimulated cultures&#44; the interferon-gamma levels produced by the preoperative period and the late postoperative period cultures were lower than the levels produced by the control group cultures&#46; The interferon-gamma levels after stimulation with concanavalin A were higher in the late postoperative period cultures than in the preoperative evaluation cultures&#46; Stimulation with Bacille Calmette-Gu&#233;rin led to the production of similar levels of interferon-gamma and interleukin-10 by all cultures&#59; thus&#44; stimulation increased the levels of interferon-gamma produced by both the preoperative and postoperative cultures relative to the levels produced by the corresponding unstimulated cultures&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSION&#58;</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">Patients with advanced supraglottic laryngeal cancer exhibit an <span class="elsevierStyleItalic">in vitro</span> deficiency in interferon-gamma secretion by mononuclear cells&#46; Stimulated cells seem to recover this function during the postoperative period&#46;</p></span>"
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            "identificador" => "ceabs10"
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            "titulo" => "RESULTS&#58;"
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          3 => array:2 [
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            "titulo" => "CONCLUSION&#58;"
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        ]
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    "NotaPie" => array:1 [
      0 => array:1 [
        "nota" => "<p class="elsevierStyleNotepara" id="cenpara10">No potential conflict of interest was reported&#46;</p>"
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        "identificador" => "fig1"
        "etiqueta" => "Figure 1"
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Control &#40;C&#41;&#44; Preoperative &#40;PREOP&#41; and Late Postoperative &#40;LP&#41; IFN-&#947; &#40;pg&#47;ml&#41; levels in the supernatant of non-stimulated lymphocytes cultures and in cultures stimulated with Con-A and BCG&#46;</p>"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">M&#58;</span> male&#44; <span class="elsevierStyleItalic">F&#58;</span> female&#44; <span class="elsevierStyleItalic">SD&#58;</span> Standard Deviation&#46;</p>"
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                  <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
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Patients&nbsp;\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="center" valign="top" scope="col" style="border-bottom: 2px solid black">Control Group&nbsp;\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  " align="left" valign="top"><span class="elsevierStyleBold">Sex</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="top">12<span class="elsevierStyleItalic">M</span>&#58;2<span class="elsevierStyleItalic">F</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="center" valign="top">10<span class="elsevierStyleItalic">M</span>&#58;3<span class="elsevierStyleItalic">F</span>&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  " align="left" valign="top"><span class="elsevierStyleBold">Age &#40;years&#41;</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="center" valign="top">58&#46;5 &#40;SD &#61; 9&#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="center" valign="top">52 &#40;SD &#61; 9&#46;3&#41;&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  " align="left" valign="top"><span class="elsevierStyleBold">Stage &#40;TNM&#41;</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="center" valign="top">7 stage III&#47; 7 stage IV&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
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Sex&#44; age and tumor stage &#40;TNM classification&#59; American Joint Committee on Cancer&#41; of the patients and controls&#46;</p>"
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          "leyenda" => "<p id="spara50" class="elsevierStyleSimplePara elsevierViewall">Data are reported as the median and &#40;range&#41;&#46; ND &#8211; not detectable&#46;</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t  " align="left" valign="middle" scope="col">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle" scope="col" style="border-bottom: 2px solid black">IFN-&#947; &#40;pg&#47;ml&#41;</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="3" align="center" valign="middle" scope="col" style="border-bottom: 2px solid black">IL-10 &#40;pg&#47;ml&#41;</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="middle" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="middle" scope="col" style="border-bottom: 2px solid black">Nonstimulated cultures&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="middle" scope="col" style="border-bottom: 2px solid black">ConAStimulation&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="middle" scope="col" style="border-bottom: 2px solid black">BCGStimulation&nbsp;\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="center" valign="middle" scope="col" style="border-bottom: 2px solid black">Nonstimulated cultures&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="middle" scope="col" style="border-bottom: 2px solid black">ConAStimulation&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="middle" scope="col" style="border-bottom: 2px solid black">BCGStimulation&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="middle">1&#44;093&#46;48&#40;119&#46;42-2&#44;222&#46;62&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="middle">78&#46;63&#40;0&#46;9-314&#46;62&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="middle">27&#46;63&#40;1&#46;12-140&#46;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="middle">8&#44;976&#46;98&#40;887&#46;49-95&#44;346&#46;54&#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="center" valign="middle">116&#46;19&#40;5&#46;5-3&#44;030&#46;86&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="middle">1&#44;318&#46;25&#40;362&#46;85-6&#44;262&#46;97&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="middle">41&#46;47&#40;30&#46;03-218&#46;09&#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
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="middle">186&#46;47&#40;27&#46;74-1&#44;459&#46;73&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="middle">1&#44;374&#46;09&#40;739&#46;97-3&#44;714&#46;12&#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="center" valign="middle">151&#46;73&#40;17&#46;38-580&#46;91&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">Control&#44; preoperative &#40;PREOP&#41;&#44; and late postoperative &#40;LP&#41; IL-10 and IFN-&#947; levels in non-stimulated cell cultures and in cultures stimulated with ConA and BCG&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "REFERENCES"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "cebibsec10"
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              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Bacillus calmette-gu&#233;rin and bladder cancer"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              AH Razack \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S1015-9584(08)60045-7"
                      "Revista" => array:7 [
                        "tituloSerie" => "Asian J Surg"
                        "fecha" => "2007"
                        "volumen" => "30"
                        "numero" => "4"
                        "paginaInicial" => "302"
                        "paginaFinal" => "309"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17962138"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
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ISSN: 18075932
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