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Clinical Science
NDRG1 protein overexpression in malignant thyroid neoplasms
Renê Gerhard1,
Corresponding author
regerhard@terra.com.br

Tel.: 55 11 3069-7292
, Suely Nonogaki2, José Humberto Tavares Guerreiro Fregnani3, Fernando Augusto Soares4, Maria Aparecida Nagai1
1 Disciplina de Oncologia, Departamento de Radiologia da Faculdade de Medicina da Universidade de São Paulo - São Paulo/SP, Brazil
2 Instituto Adolfo Lutz, Divisão de Patologia - São Paulo/SP, Brazil
3 Departamento de Ginecologia Oncológica e Núcleo de Apoio ao Pesquisador, Hospital de Câncer de Barretos - Barretos/SP, Brazil
4 Fundação Antonio Prudente - São Paulo/SP, Brazil
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Immunohistochemical expression of NDRG1 in thyroid lesions&#46; <span class="elsevierStyleBold">A&#46;</span> Nodular goiter&#59; original magnification&#44; 400&#215;&#46; <span class="elsevierStyleBold">B&#46;</span> Follicular adenoma&#59; original magnification&#44; 400&#215;&#46; <span class="elsevierStyleBold">C&#46;</span> Classical papillary thyroid carcinoma&#59; original magnification&#44; 400&#215;&#46; <span class="elsevierStyleBold">D&#46;</span> Follicular variant of papillary thyroid carcinoma&#59; original magnification&#44; 400&#215;&#46; <span class="elsevierStyleBold">E&#46;</span> Follicular carcinoma&#59; original magnification&#44; 400&#215;&#46; <span class="elsevierStyleBold">F&#46;</span> Metastatic classical papillary thyroid carcinoma&#59; original magnification&#44; 200&#215;&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Thyroid cancer is the most common malignant tumor of the endocrine system&#59; approximately 37&#44;200 new cases were expected to occur in the United States in 2009&#46;<a class="elsevierStyleCrossRef" href="#bib1">1</a> In the city of S&#227;o Paulo&#44; Brazil&#44; 1207 and 6004 cases of thyroid cancer in males and females&#44; respectively&#44; were identified from 1997 to 2003&#46;<a class="elsevierStyleCrossRef" href="#bib2">2</a> According to some studies&#44; the increase in the incidence of thyroid cancer can be explained by a higher frequency of early tumor detection due to the use of more sophisticated diagnostic techniques&#46;<a class="elsevierStyleCrossRefs" href="#bib3">3&#44;4</a> Thyroid carcinomas that are derived from follicular epithelium can be classified into well-differentiated carcinomas &#40;including papillary and follicular carcinomas&#41;&#44; poorly differentiated carcinomas and undifferentiated &#40;or anaplastic&#41; carcinomas&#44; based on well-established clinical findings and histological criteria&#46;<a class="elsevierStyleCrossRef" href="#bib5">5</a> However&#44; despite standardized criteria and nomenclature&#44; variations exist in the histological classification of thyroid tumors among different observers&#46; This disagreement is greater for encapsulated follicular thyroid tumors &#40;adenoma&#44; follicular carcinoma and some cases of the follicular variant of papillary carcinoma&#41;&#44; in which the histological diagnosis is prone to subjective and discordant interpretations among pathologists&#46;<a class="elsevierStyleCrossRefs" href="#bib6">6-8</a> Histological findings may not be sufficient to establish a precise diagnosis and&#44; consequently&#44; to predict the clinical courses of these cases&#46; Objective criteria and the identification of markers that permit better characterization of thyroid tumors are therefore required&#46;<a class="elsevierStyleCrossRef" href="#bib9">9</a></p><p id="para20" class="elsevierStylePara elsevierViewall">N-myc downstream-regulated gene 1 &#40;NDRG1&#41; is a member of the NDRG gene family and encodes a 43-kD protein &#40;NDRG1&#41; with 394 amino acids&#46;<a class="elsevierStyleCrossRef" href="#bib10">10</a> NDRG1 is located on human chromosome 8q24 and has been recognized as a gene whose mutation is associated with a demyelinating neuropathy called Charcot-Marie-Tooth disease&#44; type 4D&#46;<a class="elsevierStyleCrossRef" href="#bib11">11</a> NDRG1 is ubiquitously expressed in human tissues&#44; and its messenger RNA has been detected in a variety of tissues&#44; such as the digestive and respiratory tracts&#44; liver&#44; pancreas&#44; kidneys&#44; reproductive organs&#44; placenta&#44; skeletal muscle&#44; heart&#44; and brain&#46;<a class="elsevierStyleCrossRefs" href="#bib10">10&#44;12</a> Immunohistochemical studies have shown that the NDRG1 protein is mainly expressed in the epithelial cells of different tissues&#44; whereas no expression could be demonstrated in mesenchymal or endothelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib12">12</a> Other members of the NDRG family &#40;NDRG2&#44; NDRG3 and NDRG4&#41; are homologous to the NDRG1 gene&#46; However&#44; in contrast to NDRG1&#44; these genes most likely exert tissue-specific functions&#44; as they are only expressed in certain types of tissues&#46;<a class="elsevierStyleCrossRef" href="#bib13">13</a></p><p id="para30" class="elsevierStylePara elsevierViewall">NDRG1 protein expression is known to be induced by a variety of physiological and pathological stimuli&#46; Expression of this protein is associated with cell growth arrest and terminal cell differentiation&#44; as observed in squamous epithelial cells of the more superficial layers of the epidermis&#46;<a class="elsevierStyleCrossRef" href="#bib12">12</a> During embryogenesis&#44; NDRG1 expression is repressed by N-Myc and c-Myc during cell proliferation phases&#46;<a class="elsevierStyleCrossRef" href="#bib14">14</a> Conversely&#44; ligands such as vitamin D and retinoic acid&#44; which bind to transcription factors involved in cell differentiation&#44; inhibit growth and induce cell differentiation and NDRG1 expression&#46;<a class="elsevierStyleCrossRef" href="#bib15">15</a> Other factors&#44; such as an increase in intracellular calcium concentration&#44; a reduction in glucose concentration&#44; hypoxia&#44; DNA damage and neoplasms&#44; are also associated with NDRG1 expression&#46;<a class="elsevierStyleCrossRef" href="#bib16">16</a> Heavy metals &#40;such as nickel&#41; induce cellular hypoxia and the expression of various genes that are responsive to hypoxia&#44; including NDRG1&#46;<a class="elsevierStyleCrossRefs" href="#bib17">17&#44;18</a></p><p id="para40" class="elsevierStylePara elsevierViewall">NDRG1 has also been characterized as a mediator of p53-dependent&#44; anti-oncogenic functions&#46; Stein et al&#46; demonstrated that the p53-induced NDRG1 expression reduces cell proliferation in metastatic pulmonary cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib19">19</a> However&#44; the role of NDRG1 in tumor progression and the formation of metastases is controversial&#46; Some studies have suggested that NDRG1 overexpression reduces the metastatic potential of tumor cells&#44;<a class="elsevierStyleCrossRefs" href="#bib20">20&#44;21</a> whereas others have associated its increased expression with less differentiated or more metastatic aggressive tumors and a poor prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib22">22&#44;23</a></p><p id="para50" class="elsevierStylePara elsevierViewall">In the present study&#44; we analyzed the quantitative immunohistochemical expression of the NDRG1 protein in normal thyroid glands and benign and malignant thyroid lesions&#46; We also investigated the correlation between NDRG1 protein expression and clinical-pathological variables in cases of primary thyroid carcinoma&#46; To our knowledge&#44; this is the first study to analyze NDRG1 protein expression in benign and malignant thyroid lesions&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">MATERIALS AND METHODS</span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">Samples</span><p id="para60" class="elsevierStylePara elsevierViewall">Paraffin blocks from 225 patients&#44; including 62 cases of nodular goiter &#40;NG&#41;&#44; 53 cases of follicular adenoma &#40;FA&#41;&#44; 41 cases of classical papillary thyroid carcinoma &#40;PTC&#41;&#44; 31 cases of the follicular variant of papillary thyroid carcinoma &#40;FV-PTC&#41;&#44; and 36 cases of follicular carcinoma &#40;FC&#41; were selected from the archives of the Department of Pathology&#44; University of S&#227;o Paulo Medical School &#40;comprising the period from 2000 to 2006&#41; and the Department of Pathology&#44; A&#46; C&#46; Camargo Hospital &#40;comprising the period from 1984 to 2001&#41;&#46; Histological diagnoses were made according to the classification of thyroid tumors proposed by the WHO&#46;<a class="elsevierStyleCrossRef" href="#bib5">5</a> When available&#44; paraffin blocks of lymph node metastases from thyroid carcinomas &#40;M-TC&#41; were also selected and included 17 cases of metastatic PTC&#44; 5 cases of metastatic FV-PTC&#44; and 1 case of metastatic FC&#46; One case of bone metastasis from FC was also included in the study&#46; The patient age ranged from 15 to 88 years &#40;mean&#58; 48&#46;4 years old&#41;&#44; and 184 &#40;81&#46;8&#37;&#41; patients were female&#46;</p><p id="para70" class="elsevierStylePara elsevierViewall">Data regarding the TNM stage<a class="elsevierStyleCrossRef" href="#bib24">24</a> and age&#44; metastasis&#44; and extent and size &#40;AMES&#41; death risk criteria<a class="elsevierStyleCrossRef" href="#bib25">25</a> were obtained from the clinical records of patients with thyroid carcinoma &#40;PTC&#44; FV-PTC and FC&#41;&#46; The median time of clinical follow-up and the interval for recurrence for patients with thyroid carcinoma was 53&#46;5 months &#40;range&#58; 1 to 175 months&#41; and 18&#46;0 months &#40;range&#58; 2 to 48 months&#41;&#44; respectively&#46; No clinical follow-up data were available for eight patients &#40;six with FC&#44; one with PTC and one with FV-PTC&#41;&#46; During this period&#44; 16 cases of recurrence &#40;4 followed by death&#41; and 4 cases of death due to disseminated metastatic disease were observed&#46; All deaths occurred in the group of patients with FC&#44; and four patients were alive but still had diseases &#40;two with PTC and two with FC&#41;&#46;</p><p id="para80" class="elsevierStylePara elsevierViewall">This study was approved by the Ethics Committee for the Analysis of Research Projects of the University of S&#227;o Paulo Medical School and the Research Ethics Committee of A&#46; C&#46; Camargo Hospital&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Construction of the tissue microarray</span><p id="para90" class="elsevierStylePara elsevierViewall">Slides were prepared for the tissue microarray &#40;TMA&#41; from the selected blocks&#44; stained with hematoxylin-eosin and examined under a binocular light microscope &#40;Nikon&#44; Eclipse E100&#41; for the selection of representative areas of the lesion&#46; The areas of interest in the slides were stained with Indian ink and compared to the corresponding areas in the paraffin blocks&#44; which were also stained with Indian ink&#46;</p><p id="para100" class="elsevierStylePara elsevierViewall">Using a tissue microarrayer &#40;Beecher Instruments&#44; Silver Springs&#44; MD&#44; USA&#41;&#44; the areas of interest in each block were punctured with a 1-mm diameter needle&#44; and cylindrical fragments were transferred in an ordered fashion to a recipient paraffin block &#40;TMA block&#41;&#44; as described previously&#46;<a class="elsevierStyleCrossRef" href="#bib26">26</a> For the detailed identification of each cylindrical fragment&#44; a map was constructed in an Excel spreadsheet to permit the exact localization of each case&#46; The TMA block contained 265 thyroid cases &#40;one core per case&#41;&#44; corresponding to fragments of normal thyroid tissue &#40;NT&#44; n &#61; 18&#41;&#44; NG &#40;n &#61; 62&#41;&#44; FA &#40;n &#61; 53&#41;&#44; PTC &#40;n &#61; 41&#41;&#44; FV-PTC &#40;n &#61; 31&#41;&#44; FC &#40;n &#61; 36&#41;&#44; and M-TC &#40;n &#61; 24&#44; including 17 fragments of PTC metastases&#44; 5 FV-PTC metastases&#44; and 2 FC metastases&#41;&#46;</p><p id="para110" class="elsevierStylePara elsevierViewall">A total of 120 histological 5-&#181;m-thick sections were cut from each TMA block&#46; The slides were covered with a layer of paraffin to prevent oxidation and stored in a freezer at &#8722;20&#176;C&#46; Two slides from different levels of the TMA block were used in this study&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">Immunohistochemistry</span><p id="para120" class="elsevierStylePara elsevierViewall">Slides were left overnight in an oven at 56&#176;C&#44; followed by deparaffinization in xylene&#44; graded alcohol&#44; tap water and distilled water&#46; Heat-induced antigen retrieval was performed using a domestic pressure cooker &#40;Nigro&#44; model Eterna 41&#47;2 L&#44; Brazil&#41; with a boiled 0&#46;01 M sodium citrate buffered solution &#40;pH 6&#46;0&#41; for 4 min and cooled under running water&#44; as described previously&#46;<a class="elsevierStyleCrossRef" href="#bib27">27</a> Endogenous peroxidase activity was quenched with 3&#37; hydrogen peroxide for 20 min&#46; The antibody used was purchased from Santa Cruz Biotechnology &#40;NDRG1 N-19&#44; catalog sc-19464&#44; Santa Cruz&#44; CA&#44; USA&#41;&#46; The optimal dilution was defined using a well-known positive sample that was tested before it was used on TMA sections&#46; The antibody was diluted 1&#8758;1000 in 0&#46;01 M phosphate-buffered saline &#40;PBS&#41;&#44; pH 7&#46;4&#44; with 0&#46;1&#37; sodium azide &#40;Sigma&#44; catalog S8032&#44; St&#46; Louis&#44; MO&#44; USA&#41; and 1&#37; bovine serum albumin &#40;Sigma&#44; catalog A9647&#44; USA&#41; to reduce background staining and incubated overnight at 4&#176;C in a moist chamber&#46; The staining procedure was performed using the labeled streptavidin-biotin method &#40;LSAB&#43; System-HRP&#44; DakoCytomation&#44; catalog K0690&#44; Carpinteria&#44; CA&#44; USA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib28">28</a> Slides were incubated for 30 min at 37&#176;C with the Link&#44; washed with PBS and incubated for another 30 min at 37&#176;C with streptavidin&#46; The slides were developed with 60 mg 3&#44;3&#8242;-diaminobenzidine tetrahydrochloride &#40;Sigma&#44; catalog D5637&#44; St Louis&#44; MO&#44; USA&#41;&#44; 1&#37; dimethyl sulfoxide &#40;Sigma&#44; catalog D5879&#44; St&#46; Louis&#44; MO&#44; USA&#41; and 0&#46;06&#37; hydrogen peroxide in PBS for 5 min and counterstained with Harris&#39;s hematoxylin&#44; dehydrated and mounted with Entellan neu &#40;Merck&#44; catalog 1&#46;07961&#44; Damstadt&#44; Germany&#41;&#46; A sample of FC was used as a positive control&#46; A negative control was performed by omitting the primary antibody&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">Quantitative immunohistochemical evaluation</span><p id="para130" class="elsevierStylePara elsevierViewall">Cytoplasmic NDRG1 protein expression was analyzed quantitatively using a computer image capture system &#40;Automated Cellular Imaging System - ACIS&#174; III&#44; K0690&#59; Dako&#41;&#46; The two slides were first scanned to capture and digitalization the image&#46; Next&#44; parameters were established regarding the staining intensity of NDRG1-immunostained thyroid follicular cells and unstained stromal &#40;fibroblasts and endothelial cells&#41; cells &#40;&#8220;blue area&#8221;&#41;&#46; Between two and five circular areas per core were analyzed for each of the 265 cases in both slides&#46; First&#44; we calculated the integrated optical density &#40;IOD&#41;&#44; which is related to the amount &#40;density&#41; of the antigen&#46;<a class="elsevierStyleCrossRef" href="#bib29">29</a> A numerical value corresponding to the IOD for each circular area was obtained by multiplying the staining intensity by the area of positive staining &#40;&#8220;brown area&#8221;&#41;&#46; Then&#44; the IOD was normalized to the tissue area&#58; the numerical IOD value was divided by the total circular area &#40;sum of the positively stained &#8220;brown area&#8221; and unstained &#8220;blue area&#8221;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib30">30</a> For each core&#44; the final numerical value corresponded to the mean value of the corrected IODs of the two to five circular areas analyzed&#46; Cores presenting more than 50&#37; tissue loss were excluded from the analysis&#46; Finally&#44; the mean of the final numerical values obtained for the cores present in each of the two slides was calculated for each case&#46;</p></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">Statistical analysis</span><p id="para140" class="elsevierStylePara elsevierViewall">Box plots were constructed for the different thyroid lesions using the results of the quantitative analysis of NDRG1 immunohistochemical expression&#46; These groups were compared using the Kruskal-Wallis and Mann-Whitney tests&#46; For cases with a thyroid carcinoma diagnosis &#40;PTC&#44; FV-PTC or FC&#41;&#44; the association between the quantitative immunohistochemical expression of NDRG1 and the clinical-pathological variables &#40;age&#44; tumor size&#44; TNM stage and AMES risk classification&#41; was determined using a Student&#39;s t-test&#46; A <span class="elsevierStyleItalic">P</span>-value of less than 0&#46;05 was considered to be statistically significant&#46; All statistical analyses were performed using SPSS software&#44; version 15&#46;0 &#40;SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41;&#46;</p></span></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">RESULTS</span><p id="para150" class="elsevierStylePara elsevierViewall">NDRG1 protein expression was observed in epithelial &#40;follicular&#41; cells&#44; with no staining in stromal or endothelial cells&#46; The positive cases showed moderate-to-strong cytoplasmic NDRG1 immunoreactivity &#40;<a class="elsevierStyleCrossRef" href="#fig1-cln_65p757">Figure 1</a>&#41;&#46; For each case with a thyroid lesion and NT&#44; the numerical values obtained by the quantitative analysis of the immunohistochemical expression of NDRG1 are reported as means and standard deviations &#40;<a class="elsevierStyleCrossRef" href="#t1-cln_65p757">Table 1</a>&#41;&#46; The quantitative expression of NDRG1 was higher in carcinomas compared to NTs and NGs&#44; with higher expression levels in PTC and M-TC &#40;<span class="elsevierStyleItalic">P</span> &#60; 0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig2-cln_65p757">Figure 2</a>&#41;&#46; When analyzed together&#44; the quantitative expression of NDRG1 was higher in the group of malignant lesions &#40;PTC&#44; FV-PTC&#44; FC&#44; and M-TC&#41; compared to the group of benign thyroid lesions &#40;NG and AF&#41; &#40;<span class="elsevierStyleItalic">P</span> &#61; 0&#46;043&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig3-cln_65p757">Figure 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig1-cln_65p757"></elsevierMultimedia><elsevierMultimedia ident="t1-cln_65p757"></elsevierMultimedia><elsevierMultimedia ident="fig2-cln_65p757"></elsevierMultimedia><elsevierMultimedia ident="fig3-cln_65p757"></elsevierMultimedia><p id="para160" class="elsevierStylePara elsevierViewall">The association between the quantitative immunohistochemical expression of NDRG1 and the clinical-pathological variables was analyzed in cases of primary thyroid carcinoma &#40;PTC&#44; FV-PTC and FC&#41;&#46; In this group of tumors&#44; the quantitative expression of NDRG1 was significantly higher in patients who were aged 45 years or older &#40;<span class="elsevierStyleItalic">P</span> &#61; 0&#46;019&#41;&#44; at an advanced TNM stage &#40;stages III and IV&#41; &#40;<span class="elsevierStyleItalic">P</span> &#61; 0&#46;007&#41;&#44; and in an AMES high-risk group &#40;<span class="elsevierStyleItalic">P</span> &#61; 0&#46;012&#41; &#40;<a class="elsevierStyleCrossRef" href="#t2-cln_65p757">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="t2-cln_65p757"></elsevierMultimedia></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle150">DISCUSSION</span><p id="para170" class="elsevierStylePara elsevierViewall">To our knowledge&#44; this is the first study to analyze the immunohistochemical expression of the NDRG1 protein in a large number of benign &#40;NG and FA&#41; and malignant &#40;PTC&#44; FV-PTC&#44; FC&#44; and M-TC&#41; thyroid lesions&#46; We demonstrated increased expression of NDRG1 in thyroid tumors compared to NGs and NTs&#46; Cangul also studied the immunohistochemical expression of NDRG1 in a variety of human tumors &#40;including breast&#44; kidney&#44; lung and prostate carcinomas&#44; and melanoma and glioblastoma multiforme&#41; and reported higher NDRG1 protein expression in tumors compared to normal tissue&#46;<a class="elsevierStyleCrossRef" href="#bib18">18</a> In the colon&#44; Wang et al&#46; observed increased NDRG1 expression in carcinomas compared to adenomas and normal colon mucosa&#46;<a class="elsevierStyleCrossRef" href="#bib31">31</a> Reis et al&#46; analyzed 213&#44;636 transcripts that were derived from normal and tumor tissues of the oral cavity&#44; larynx&#44; pharynx and thyroid using the open reading frame expressed sequence tags &#40;ORESTES&#41; technique&#46; Three &#40;ZRF1&#44; RAP140 and NDRG1&#41; of the 250 potential markers selected in that study were analyzed by quantitative RT-PCR in oral cavity and laryngeal samples&#46; The authors detected an increase in the levels of <span class="elsevierStyleItalic">NDRG1</span> mRNA in 50&#37; of oral cavity tumors&#46;<a class="elsevierStyleCrossRef" href="#bib32">32</a> In contrast&#44; Bandyopadhyay et al&#46; observed lower NDRG1 immunohistochemical expression in breast carcinoma but strong expression in normal mammary lobules&#46;<a class="elsevierStyleCrossRef" href="#bib33">33</a></p><p id="para180" class="elsevierStylePara elsevierViewall">The role of the NDRG1 protein in tumor progression and metastasis formation is still controversial and is likely to be tissue-specific&#46; Several studies have shown that a decrease in NDRG1 protein expression is associated with a more advanced tumor stage and lower survival rates&#46; In prostate carcinomas&#44; lower immunohistochemical expression of NDRG1 was associated with a Gleason grade &#62;7 and poorly differentiated tumors&#46; According to the authors&#44; 70&#37; of localized prostate tumors expressed NDRG1&#44; whereas only 25&#37; of metastatic tumors were positive for this marker&#46;<a class="elsevierStyleCrossRef" href="#bib21">21</a> In breast cancer&#44; 60&#37; of patients with bone metastases presented with reduced NDRG1 expression&#44; with survival being lower in patients whose tumors did not express NDRG1&#46;<a class="elsevierStyleCrossRef" href="#bib33">33</a> In esophageal squamous cell carcinoma&#44; reduced NDRG1 expression was associated with more invasive tumors and a more advanced TNM stage&#46; In addition&#44; a lower survival rate was observed in patients with low NDRG1 expression compared to those with high expression&#46;<a class="elsevierStyleCrossRef" href="#bib34">34</a> A less differentiated histological grade&#44; more advanced pathological stage and lower overall survival were correlated with reduced immunohistochemical expression of NDRG1 in pancreatic ductal adenocarcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib35">35</a></p><p id="para190" class="elsevierStylePara elsevierViewall">We found that increased immunohistochemical expression of NDRG1 was correlated with a more advanced TNM stage &#40;stages III and IV&#41; and an AMES high-risk category in patients with thyroid carcinoma &#40;PTC&#44; FV-PTC&#44; and FC&#41;&#46; An association between increased NDRG1 expression and more aggressive tumors and poor prognosis has been reported in other studies&#46; Chua et al&#46; observed that increased NDRG1 expression in hepatocellular carcinoma was associated with a more advanced tumor stage &#40;stages III and IV&#41;&#44; larger tumors and poorly differentiated tumors&#44; according to the Edmondson-Steiner histological classification&#46; In their study&#44; patients whose tumors presented increased NDRG1 protein expression showed lower overall survival compared to those with low NDRG1 levels&#46;<a class="elsevierStyleCrossRef" href="#bib22">22</a> In cervical adenocarcinoma&#44; increased immunohistochemical expression of NDRG1 was correlated with a larger tumor diameter&#44; greater depth of stromal invasion&#44; the presence of angiolymphatic invasion&#44; a larger number of lymph node metastases&#44; poorly or moderately differentiated tumors and poor prognosis&#44; as demonstrated by lower progression-free and overall survival rates&#46;<a class="elsevierStyleCrossRef" href="#bib23">23</a></p><p id="para200" class="elsevierStylePara elsevierViewall">Some studies have suggested that NDRG1 is a metastasis suppressor gene&#46; Guan et al&#46; observed lower NDRG1 expression in cell lines derived from colon cancer metastases compared to cell lines derived from primary colon cancer&#46; Inducing NDRG1 expression in metastatic cell lines&#44; the authors observed that neoplastic cells expressed markers related to cell differentiation of the colon epithelium&#44; such as CEA and E-cadherin&#46;<a class="elsevierStyleCrossRef" href="#bib20">20</a><span class="elsevierStyleItalic">In vivo</span> studies have shown that cell lines derived from colon and prostate cancers that were transfected with NDRG1 and injected into mice produced a smaller number of hepatic and pulmonary metastases&#44; respectively&#44; than control lines&#46;<a class="elsevierStyleCrossRefs" href="#bib20">20&#44;21</a> However&#44; in human colorectal carcinoma samples&#44; Wang et al&#46; demonstrated increased NDRG1 protein expression in primary tumors with metastases to the lymph nodes compared to those without metastases &#40;non-metastatic carcinoma&#41;&#46; The authors concluded that higher NDRG1 expression was associated with a higher probability of lymph node metastasis&#46; Within this context&#44; according to the authors&#44; NDRG1 could be a gene that is involved in tumor progression and the promotion of metastases of colorectal carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib31">31</a></p></span><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle160">CONCLUSIONS</span><p id="para210" class="elsevierStylePara elsevierViewall">The present study demonstrated an increase in the immunohistochemical expression of NDRG1 in primary and metastatic thyroid carcinomas compared to NT&#44; NG&#44; and FA&#46; We also observed an association between NDRG1 expression and a more advanced TNM stage and an AMES high-risk category in patients with thyroid carcinoma &#40;PTC&#44; FV-PTC&#44; and FC&#41;&#46; These findings suggest a role for NDRG1 in thyroid tumor progression&#46; More detailed studies are necessary to better define the role of NDRG1 in tumorigenesis and thyroid tumor progression&#44; including the investigation of this protein in poorly differentiated or anaplastic thyroid carcinomas&#46;</p></span></span>"
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          "titulo" => "INTRODUCTION"
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          "titulo" => "MATERIALS AND METHODS"
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              "titulo" => "Construction of the tissue microarray"
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              "titulo" => "Immunohistochemistry"
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              "titulo" => "Quantitative immunohistochemical evaluation"
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              "titulo" => "Statistical analysis"
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        3 => array:2 [
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          "titulo" => "RESULTS"
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          "titulo" => "DISCUSSION"
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          "identificador" => "cesec100"
          "titulo" => "CONCLUSIONS"
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          "titulo" => "REFERENCES"
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    "fechaRecibido" => "2010-03-23"
    "fechaAceptado" => "2010-05-03"
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          "palabras" => array:5 [
            0 => "NDRG1"
            1 => "Thyroid Gland"
            2 => "Thyroid Carcinoma"
            3 => "Immunohistochemistry"
            4 => "Tissue Microarray"
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVES&#58;</span><p id="spara70" class="elsevierStyleSimplePara elsevierViewall">The aim of this study was to examine the expression of the N-myc downstream-regulated gene 1 protein in benign and malignant lesions of the thyroid gland by immunohistochemistry&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">INTRODUCTION&#58;</span><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">N-myc downstream-regulated gene 1 encodes a protein whose expression is induced by various stimuli&#44; including cell differentiation&#44; exposure to heavy metals&#44; hypoxia&#44; and DNA damage&#46; Increased N-myc downstream-regulated gene 1 expression has been detected in various types of tumors&#44; but the role of N-myc downstream-regulated gene 1 expression in thyroid lesions remains to be determined&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">METHODS&#58;</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">A tissue microarray paraffin block containing 265 tissue fragments corresponding to normal thyroid&#44; nodular goiter&#44; follicular adenoma&#44; papillary thyroid carcinoma &#40;classical pattern and follicular variant&#41;&#44; follicular carcinoma&#44; and metastases of papillary and follicular thyroid carcinomas were analyzed by immunohistochemistry using a polyclonal anti- N-myc downstream-regulated gene 1 antibody&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">RESULTS&#58;</span><p id="spara100" class="elsevierStyleSimplePara elsevierViewall">The immunohistochemical expression of N-myc downstream-regulated gene 1 was higher in carcinomas compared to normal thyroid glands and nodular goiters&#44; with higher expression in classical papillary thyroid carcinomas and metastases of thyroid carcinomas &#40;<span class="elsevierStyleItalic">P</span> &#60; 0&#46;001&#41;&#46; A combined analysis showed higher immunohistochemical expression of NDRG1 in malignant lesions &#40;classical pattern and follicular variant of papillary thyroid carcinomas&#44; follicular carcinomas&#44; and metastases of thyroid carcinomas&#41; compared to benign thyroid lesions &#40;goiter and follicular adenomas&#41; &#40;<span class="elsevierStyleItalic">P</span> &#61; 0&#46;043&#41;&#46; In thyroid carcinomas&#44; N-myc downstream-regulated gene 1 expression was significantly correlated with a more advanced TNM stage &#40;<span class="elsevierStyleItalic">P</span> &#61; 0&#46;007&#41; and age&#44; metastasis&#44; tumor extent&#44; and size &#40;AMES&#41; high-risk group &#40;<span class="elsevierStyleItalic">P</span> &#61; 0&#46;012&#41;&#46;</p></span> <span id="ceabs50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle50">CONCLUSIONS&#58;</span><p id="spara110" class="elsevierStyleSimplePara elsevierViewall">Thyroid carcinomas showed increased immunohistochemical N-myc downstream-regulated gene 1 expression compared to normal and benign thyroid lesions and is correlated with more advanced tumor stages&#46;</p></span>"
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Immunohistochemical expression of NDRG1 in thyroid lesions&#46; <span class="elsevierStyleBold">A&#46;</span> Nodular goiter&#59; original magnification&#44; 400&#215;&#46; <span class="elsevierStyleBold">B&#46;</span> Follicular adenoma&#59; original magnification&#44; 400&#215;&#46; <span class="elsevierStyleBold">C&#46;</span> Classical papillary thyroid carcinoma&#59; original magnification&#44; 400&#215;&#46; <span class="elsevierStyleBold">D&#46;</span> Follicular variant of papillary thyroid carcinoma&#59; original magnification&#44; 400&#215;&#46; <span class="elsevierStyleBold">E&#46;</span> Follicular carcinoma&#59; original magnification&#44; 400&#215;&#46; <span class="elsevierStyleBold">F&#46;</span> Metastatic classical papillary thyroid carcinoma&#59; original magnification&#44; 200&#215;&#46;</p>"
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">NDRG1 expression in normal&#44; benign and malignant thyroid gland lesions&#46; Box plot shows the data of the quantitative immunohistochemical expression of NDRG1 for normal thyroid &#40;NT&#41;&#44; nodular goiter &#40;NG&#41;&#44; follicular adenoma &#40;FA&#41;&#44; classical papillary thyroid carcinoma &#40;PTC&#41;&#44; follicular variant of papillary thyroid carcinoma &#40;FV-PTC&#41;&#44; follicular carcinoma &#40;FC&#41;&#44; and metastases of thyroid carcinoma &#40;M-TC&#41; &#40;<span class="elsevierStyleItalic">P</span> &#60; 0&#46;001&#44; Kruskal-Wallis test&#41;&#46; The &#8220;o&#8221; and &#8220;&#8727;&#8221; symbols indicate outlier and extreme outlier values&#44; respectively&#46;</p>"
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          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">NDRG1 expression in benign and malignant thyroid lesions&#46; Box plot shows the data of the quantitative immunohistochemical expression of NDRG1 for benign &#40;nodular goiter and follicular adenoma&#41; and malignant &#40;classical papillary thyroid carcinoma&#44; follicular variant of papillary thyroid carcinoma&#44; follicular carcinoma&#44; and metastases of thyroid carcinoma&#41; thyroid lesions &#40;<span class="elsevierStyleItalic">P</span> &#61; 0&#46;043&#44; Mann-Whitney test&#41;&#46; The &#8220;o&#8221; and &#8220;&#8727;&#8221; symbols indicate outlier and extreme outlier values&#44; respectively&#46;</p>"
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          "leyenda" => "<p id="spara50" class="elsevierStyleSimplePara elsevierViewall">Eighteen cases were excluded from the analysis because of tissue loss &#40;normal thyroid&#44; three cases&#59; nodular goiter&#44; seven cases&#59; follicular adenoma&#44; two cases&#59; classical papillary thyroid carcinoma&#44; two cases&#59; follicular variant of papillary thyroid carcinoma&#44; one case&#59; follicular carcinoma&#44; two cases&#59; and papillary thyroid carcinoma metastases&#44; one case&#41;&#46;</p>"
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="bottom" scope="col" style="border-bottom: 2px solid black">Diagnosis&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="bottom" scope="col" style="border-bottom: 2px solid black">N&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="bottom" scope="col" style="border-bottom: 2px solid black">Mean&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="bottom" scope="col" style="border-bottom: 2px solid black">Standard deviation&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">Normal thyroid&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="top">15&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="top">3&#46;13&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="top">2&#46;67&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">Nodular goiter&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="top">55&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="top">8&#46;33&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="top">14&#46;89&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">Follicular adenoma&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="top">51&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="top">17&#46;30&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="top">27&#46;11&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">Classical papillary thyroid carcinoma&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="top">39&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="top">29&#46;22&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="top">25&#46;82&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">Follicular variant of papillary carcinoma&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="top">30&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="top">16&#46;86&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="top">25&#46;38&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">Follicular carcinoma&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="top">34&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="top">18&#46;79&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="top">31&#46;88&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">Thyroid carcinoma metastases<a class="elsevierStyleCrossRef" href="#tfn2-cln_65p757">1</a>&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="top">23&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="top">21&#46;34&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="top">25&#46;07&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
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          "notaPie" => array:1 [
            0 => array:3 [
              "identificador" => "tfn2-cln_65p757"
              "etiqueta" => "1"
              "nota" => "<p class="elsevierStyleNotepara" id="cenpara10">Includes 16 cases of classical papillary thyroid carcinoma metastasis&#44; 5 of follicular variant of papillary thyroid carcinoma&#44; and 2 of follicular carcinoma&#46;</p> <p class="elsevierStyleNotepara" id="cenpara20">Kruskal-Wallis test&#44; <span class="elsevierStyleItalic">P</span> &#60; 0&#46;001&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">Quantitative analysis of NDRG1 immunohistochemical expression in thyroid lesions&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "t2-cln_65p757"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "tablatextoimagen" => array:1 [
            0 => 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="bottom" scope="col" style="border-bottom: 2px solid black">Variable&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="bottom" scope="col" style="border-bottom: 2px solid black">N&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="bottom" scope="col" style="border-bottom: 2px solid black">NDRG1 &#40;mean&#41;&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="bottom" scope="col" style="border-bottom: 2px solid black">Standard deviation&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="bottom" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span>&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">Age&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="top">&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="top">&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="top">&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="top">&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="elsevierStyleHsp" style=""></span>&#60;45 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="char" valign="top">38&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="top">13&#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="char" valign="top">23&#46;4&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="top">&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="elsevierStyleHsp" style=""></span>&#8805;45 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="char" valign="top">62&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="top">27&#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="char" valign="top">29&#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="char" valign="top">0&#46;019&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">Tumor size&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="top">&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="top">&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="top">&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="top">&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="elsevierStyleHsp" style=""></span>T1-T2<a class="elsevierStyleCrossRef" href="#tfn6-cln_65p757">2</a>&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="top">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="top">17&#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="char" valign="top">25&#46;4&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="top">&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="elsevierStyleHsp" style=""></span>T3-T4<a class="elsevierStyleCrossRef" href="#tfn7-cln_65p757">3</a>&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="top">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="char" valign="top">27&#46;5&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="top">30&#46;1&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="top">0&#46;076&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">TNM stage&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="top">&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="top">&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="top">&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="top">&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="elsevierStyleHsp" style=""></span>Stages I and II&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="top">51&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="top">17&#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="char" valign="top">26&#46;9&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="top">&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="elsevierStyleHsp" style=""></span>Stages III and 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
                  \t\t\t\t  " align="char" valign="top">36&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="top">34&#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="char" valign="top">29&#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="char" valign="top">0&#46;007&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">AMES classification&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="top">&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="top">&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="top">&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="top">&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="elsevierStyleHsp" style=""></span>Low risk&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="top">56&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="top">18&#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="char" valign="top">26&#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
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

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Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos