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Chromogranin A (CgA) as a biomarker in carcinoid heart disease and NETG1/G2 neuroendocrine neoplasms of the small intestine (SI-NENs) related carcinoid syndrome
Valor de la cromogranina A como biomarcador de enfermedad cardiaca en el síndrome carcinoide asociado a tumores neuroendocrinos del intestino delgado
Sonia J. Konsek-Komorowskaa,
Corresponding author
sonia.konsek@interia.pl

Corresponding author.
, Mariola Pęczkowskab, Agnieszka D. Kolasińska-Ćwikłac, Marek Konkab, Eryk Chrapowickic, Jarosław B. Ćwikład
a Department of Cardiology and Internal Medicine, School of Medicine, University of Warmia and Mazury, 10-082 Olsztyn, Poland
b The Cardinal Stefan Wyszyński National Institute of Cardiology, 04-628 Warsaw, Poland
c MSC Memorial Cancer Centre and Institute – Maria Sklodowska-Curie, 02-034 Warsaw, Poland
d Diagnostic and Therapeutic Center – Gammed, 02-351 Warsaw, Poland
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Neuroendocrine neoplasms of the small intestine &#40;SI-NEN&#41; are the most commonly identified types of gastro-entro-pancreatic NEN &#40;GEP&#41;&#44; and often leading to overproduction of specific hormones or biogenic amines&#46; Actively secreting SI-NEN are the most likely to result in clinical symptoms of disease&#44; and primarily manifest as the most common paraneoplastic syndrome&#44; carcinoid syndrome &#40;CS&#41;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">1</span></a> and causing symptoms such as flushing&#44; diarrhea&#44; abdominal pain&#44; bronchospasm&#44; in addition to other less common clinical symptoms&#46; Although liver metastases are the primary cause of CS&#44; about 5&#37; of patients develop CS from primary ovarian or midgut carcinoids with retroperitoneal metastases&#46; The frequent cause of death in patients with CS is carcinoid heart disease &#40;CHD&#41;&#46; Symptoms of CHD differ depending upon the cardiac components affected&#59; with right-sided heart failure being most common&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Elevated blood chromogranin A &#40;CgA&#41; concentration&#44; is a widely used biomarker for diagnosing NEN&#44;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">3&#8211;6</span></a> however other malignancies&#44; or unrelated conditions such as severe liver failure&#44; chronic atrophic gastritis&#44; proton pump inhibitor &#40;PPI&#41; therapy&#44; renal insufficiency or systemic hypertension can cause elevated CgA&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">CgA is an effective biomarker in the diagnosis of NEN&#44; being inexpensive and simple to measure using a blood sample to perform an immunological assay&#46; Other biomarkers used for diagnosing NEN include 5-hydroxyindoleacetic acid &#40;5-HIAA&#41; and neuron-specific enolase &#40;NSE&#41;&#44; however 5-HIAA levels can be affected by diet&#44; and NSE&#44; as a cytosolic protein&#44; is found in low levels in the blood and the levels of which also relate to the death rate of neuroendocrine cells&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a> Whilst biomarkers are currently used to diagnose NEN&#44; there are currently no widely established biomarkers in use for determination of disease severity&#44; or prognosis in patients with NEN&#44; and specifically those who have developed CS and CHD&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of this study was to retrospectively evaluate the value of CgA as a prognostic biomarker of OS in patients with SI-NEN presenting CS using initial and follow-up measurements of CgA&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">The protocol for this retrospective study was authorized by the institution&#39;s ethics committee&#44; with signed informed consent from all patients&#46; The subjects group was selected from data sets of 351 patients with confirmed in pathology SI-NEN&#46; The study group includes a total of 108 patients &#40;58 females and 50 males&#41; with confirmed SI-NENs and diagnosis of CS&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Patients were diagnosed and treated between 2004 and 2019&#46; In all cases&#44; a pathologist specialising in NEN&#44; verified and reported the histology results&#44; detailing the histological grade and the stage of the neuroendocrine neoplasm &#40;TNM&#41; according to AJCC&#47;UICC 2017 classification&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">8</span></a> If tumor size was not specified in the histopathology report&#44; tumor size evaluation was based on structural imaging using CT or MRI after i&#46;v&#46; contrast enhancement&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">This study group comprised 40&#37; of patients with well differentiated &#40;G1&#41; and 60&#37; with moderately differentiated &#40;G2&#41; SI-NEN&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">8</span></a> Carcinoid heart disease &#40;CHD&#41; was detected in 28 of the 108 patients&#46; Serum concentration of CgA was determined in 57 patients with CS&#44; and in 27 patients who subsequently developed CHD&#44; at the point of diagnosis and&#47;or during clinical follow-up&#46; None of the patients had severe liver failure&#44; chronic atrophic gastritis&#44; PPI therapy&#44; renal insufficiency or systemic hypertension&#46; CgA concentrations were determined using the Kryptor system&#44; B&#46;R&#46;A&#46;H&#46;M&#46;S GmbH kits&#44; Thermo Fisher &#40;Henningsdorf&#44; Germany&#41;&#46; This immunometric assay used a time resolved amplified cryptate emission and an anti-CgA mouse monoclonal antibody&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">4</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Overall survival &#40;OS&#41; was determined using the Kaplan-Meier method in all patients and calculated from the time of initial diagnosis of CS&#44; to either the date of death or last follow-up visit&#46; The difference in OS between groups was calculated using the Cox&#8211;Mantel test&#46; Univariate and multivariate analysis were used to identify variables associated with OS&#46; All statistical calculations were carried out using the Dell Inc&#46; &#40;2016&#41;&#44; Dell Statistica &#40;data analysis software system&#41;&#44; version 13&#44; software&#46;dell&#46;com&#44; with the level of statistical significance set at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46; Patients and tumor characteristics are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0045" class="elsevierStylePara elsevierViewall">The median overall survival &#40;OS&#41; was 72&#46;9 months for all patients &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>108&#41; &#40;confidence interval &#40;CI&#41; &#177;95&#37; 61&#46;5&#8211;89&#46;3&#41;&#44; 73&#46;0 months for patients with CS &#40;without CHD&#41; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>80&#41; &#40;CI &#177;95&#37; 61&#46;2&#8211;96&#46;7&#41; and 59&#46;4 months for patients with CHD &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>28&#41; &#40;CI &#177;95&#37; 49&#46;0&#8211;93&#46;3&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The median initial concentration of CgA for all subjects with CS &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>84&#41;&#44; reported as a proportion of the upper limit of normal &#40;ULN&#41; was 7&#46;5 &#40;CI &#177;95&#37; 6&#46;4&#8211;9&#46;5&#41; and the median maximum concentration of CgA during follow up was 21&#46;7 ULN &#40;CI &#177;95&#37; 15&#46;6&#8211;29&#46;8&#41;&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The analysis revealed a significant association between initial concentration of CgA in patients with confirmed CS and overall survival &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The OS of patients with an initial CgA concentration below the median ULN was 82&#46;6 months&#44; whereas patients with CgA levels above the median ULN OS was 51&#46;6 months &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Maximum concentration of CgA determined at follow-up &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; was strongly associated with overall survival&#46; OS in patients with a maximum concentration of CgA below the median&#44; was approximately 81&#46;8 months&#44; and 63&#46;8 months in patients above the median CgA concentration &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Univariate analysis revealed the initial &#40;at diagnosis&#41; and maximum &#40;during follow up&#41; concentrations of CgA were significantly associated with overall survival in patients with carcinoid syndrome&#44; with a Hazard Ratio &#40;HR&#41; as follows&#58; for initial concentration of CgA 2&#46;12 &#40;95&#37; CI 1&#46;28&#8211;3&#46;51&#41; and for a maximum concentration of CgA 1&#46;66 &#40;95&#37; CI 1&#46;00&#8211;2&#46;76&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Cox multivariate analysis included following elements&#58; CS vs&#46; CHD&#44; female vs&#46; male&#44; NETG1 vs&#46; NETG2&#44; age &#8804;60 vs&#46; &#62;60 years old&#44; primary tumor size &#8804;3<span class="elsevierStyleHsp" style=""></span>cm vs&#46; &#62;3<span class="elsevierStyleHsp" style=""></span>cm&#44; initial and maximum concentration of CgA below median value vs&#46; over median&#41; confirmed initial concentration of CgA as a significant independent prognostic factor for OS in patients with CS&#44; with a HR of 1&#46;89 &#40;95&#37; CI 1&#46;02&#8211;3&#46;53&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">Due to the increased incidence of GEP-NENs&#44; there is a need to identify useful biomarkers for predicting patient prognosis&#44; response to treatment &#40;predictors&#41;&#44; and recurrence or progression of disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">3&#8211;6</span></a> Serum CgA levels were determined &#40;as an Upper Limit of Normal&#41; in a cohort of patients with SI-NENs with confirmed CS&#44; at the point of diagnosis and during follow up to determine the use of CgA as a prognostic biomarker&#46; Our results agree with data previously reported&#44; with high levels of CgA &#40;relative to ULN&#41; found in patients with CS&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">1&#44;5&#8211;7</span></a> Patient serum CgA levels in our study were clearly and markedly increased above ULN in almost all patients &#40;96&#37;&#41; at the initial diagnosis of SI-NEN&#46; These findings were consistent with previous findings which revealed that CgA concentrations were elevated in patients with GEP-NEN which indicated valuable tumor marker in whole group of patients with GEP-NEN&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">3&#8211;6</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In our analysis&#44; patients with CS and initial and maximum levels of CgA below the median mentioned above&#44; had increased OS &#40;for initial level&#58; 82&#46;6 months vs&#46; 51&#46;6 months and for maximum level&#58; 81&#46;8 months vs&#46; 63&#46;8 months&#41;&#46; Tran et al&#46; also reported that increased CgA level before SI-NEN related surgery&#44; was related with lower OS &#40;median 87&#46;8 months vs not reached&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">3</span></a> These findings suggest that sequential evaluation of concentration of CgA is useful in both predicting and monitoring progression to CS&#44; and from CS to CHD&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Our univariate and multivariate analyses also confirmed that high initial concentration of CgA is a biomarker for poor prognosis in patients with CS &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; and therefore is effective in the clinical assessment of patients with SI-NEN&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">7</span></a> Other papers report CgA did not only reflect tumor burden&#44; but appears to be associated with tumor progression or response to treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">5</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In conclusion&#44; our analysis reinforces previous findings that elevated CgA concentration is associated with active SI-NEN&#46; Elevated CgA concentration is associated with poor OS in patients with SI-NENs and initial and sequential serum CgA measurements is a useful prognostic tool for predicting the progression from CS to CHD&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Ethical considerations</span><p id="par0095" class="elsevierStylePara elsevierViewall">The protocol for this retrospective study was authorized by the institution&#39;s ethics committee&#44; with signed informed consent from all patients&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflict of interest</span><p id="par0100" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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    "fechaAceptado" => "2021-06-30"
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            0 => "Neuroendocrine neoplasm of the small intestine"
            1 => "SI-NEN"
            2 => "Chromogranin A"
            3 => "Carcinoid syndrome"
            4 => "Carcinoid heart disease"
            5 => "Overall survival"
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            0 => "Tumores neuroendocrinos del intestino delgado"
            1 => "TNE-ID"
            2 => "Cromogranina A"
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Progression of carcinoid syndrome &#40;CS&#41; to carcinoid heart disease &#40;CHD&#41; is difficult to predict&#46; This retrospective analysis evaluates the use of chromogranin A &#40;CgA&#41;&#44; a biomarker widely used in the diagnosis of neuroendocrine tumours &#40;NET&#41;&#44; in monitoring CS and disease progression&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Patients and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">108 patients with confirmed CS&#44; selected from a group of 351 patients with neuroendocrine neoplasms of the small intestine &#40;SI-NENs&#41;&#44; including NETG1 well 40&#37; and NETG2 60&#37; moderately differentiated NET&#46; CgA concentration was measured during initial diagnosis and clinical follow up in 84 patients&#44; 27 of them subsequently developed CHD&#46; The patient&#39;s overall survival &#40;OS&#41; was evaluated using the Kaplan-Meier method&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Patients with CHD&#44; were found to have significantly shorter OS than patients with CS but without CHD &#40;67&#46;22 vs&#46; 73&#46;03 months&#41;&#46; Univariate and multivariate analyses revealed that initial high concentration of CgA and&#47;or increased concentration of CgA is significantly associated with decreased median OS in patients with CS &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">CgA has potential as a clinically useful biomarker in reporting disease status and predicting outcome in patients with CS and with CHD&#46;</p></span>"
        "secciones" => array:4 [
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          1 => array:2 [
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            "titulo" => "Patients and methods"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La progresi&#243;n hacia la afectaci&#243;n cardiaca en el s&#237;ndrome carcinoide &#40;SC&#41; es dif&#237;cil de predecir&#46; En el presente an&#225;lisis retrospectivo se evalu&#243; el uso de la cromogranina A &#40;CgA&#41;&#44; un biomarcador ampliamente utilizado en el diagn&#243;stico de los tumores neuroendocrinos &#40;TNE&#41;&#44; en el seguimiento del SC y en la progresi&#243;n de la enfermedad&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pacientes y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 108 pacientes con SC confirmado&#44; seleccionados de un grupo de 351 pacientes con tumores neuroendocrinos del intestino delgado &#40;TNE-ID&#41;&#46; El 40&#37; de pacientes ten&#237;an un TNE G1 bien diferenciado y un 60&#37; un TNE G2 moderadamente diferenciado&#46; Los niveles de CgA se determinaron en el momento del diagn&#243;stico y durante el seguimiento en 84 pacientes&#44; 27 de los cuales desarrollaron afectaci&#243;n cardiaca&#46; La supervivencia global de los pacientes se evalu&#243; mediante el m&#233;todo de Kaplan-Meier&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Los pacientes con afectaci&#243;n cardiaca tuvieron una supervivencia global significativamente m&#225;s corta que aquellos sin ella &#40;67&#44;22 frente a 73&#44;03 meses&#41;&#46; El an&#225;lisis univariado y multivariado mostr&#243; que los niveles inicialmente altos de CgA y&#47;o los niveles elevados de CgA durante la evoluci&#243;n se asocian de forma significativa con una menor supervivencia global en los pacientes con SC &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La CgA constituye un biomarcador cl&#237;nicamente &#250;til para evaluar la progresi&#243;n de la enfermedad y la afectaci&#243;n cardiaca en pacientes con SC&#46;</p></span>"
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CS&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>80&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CHD&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>28&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-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">NETG1&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&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">NETG2&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&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">Female to male ratio&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;05&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;55&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">Mean age &#40;range&#41; in initial diagnosis&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">62&#46;25 &#40;34&#8211;84&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&#46;11 &#40;36&#8211;76&#41;&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">Size of the tumour &#40;pathology&#41; mean &#40;SD&#41;&#44; mm&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&#46;29<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;01&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&#46;21<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>17&#46;16&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">Ki-67 &#40;mean&#44; standard deviation&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;60<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;03&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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;25<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
            1 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">pT &#40;initial&#41;&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>108&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>80&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>28&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-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>pT1 &#40;&#37;&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;12&#46;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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#41;&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>pT2 &#40;&#37;&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;7&#46;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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#40;11&#41;&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>pT3 &#40;&#37;&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28 &#40;35&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 &#40;43&#41;&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>pT4 &#40;&#37;&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;39&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4 &#40;14&#41;&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>pTx or no data &#40;&#37;&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 &#40;17&#46;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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9 &#40;32&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
            2 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">N base on surgery&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>108&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>80&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>28&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-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>N0 &#40;&#37;&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 &#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#41;&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>N1 &#40;&#37;&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">76 &#40;80&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">28 &#40;100&#41;&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>Nx or no data &#40;&#37;&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;2&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
            3 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">M base on surgery&#47;follow-up&#47;imaging&#44; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>108&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>80&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>28&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-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>M0 &#40;&#37;&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 &#40;7&#46;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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;4&#41;&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>M1 &#40;&#37;&#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="char" valign="\n
                  \t\t\t\t\ttop\n
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                            3 => "A&#46; Ba&#322;dys-Walig&#243;rska"
                            4 => "T&#46; Bednarczuk"
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ISSN: 00257753
Original language: English
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