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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">Telomerase is an enzyme made up of a catalytic subunit &#40;telomerase reverse transcriptase or TERT&#41; and a ribonucleic acid &#40;TERC&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> It is known to play a major role in telomere maintenance and cell senescence&#46; Under normal conditions&#44; it is only expressed in germline cells&#44; fetal tissue&#44; and stem cells&#46; The somatic cells of other tissues lack telomerase activity&#44; resulting in the progressive shortening of their telomeres after repeated cell division&#46; Many studies have shown that telomerase activity is detected in more than 90&#37; of malignant tumors&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a> including different types of skin cancer&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> In melanocyte tumors in particular&#44; several studies have identified increased telomerase activity in the neoplastic cells&#44; from nevi to melanomas&#44; with the highest telomerase activity detected in metastatic melanomas&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">4</span></a> Furthermore&#44; the role of <span class="elsevierStyleItalic">TERT</span> promoter mutations in the pathogenesis of melanoma has recently been demonstrated&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">5&#44;6</span></a> Several studies have identified recurring mutations in the <span class="elsevierStyleItalic">TERT</span> promoter region &#40;c&#46;1-146C&#62;T&#44; c&#46;1-124C&#62;T&#44; c&#46;1-124&#47;-125CC&#62;TT&#44; c&#46;1-138&#47;-139CC&#62;TT&#41; in between 22&#37; and 71&#37; of sporadic melanomas associated with older patients&#44; with melanomas in areas exposed to sunlight&#44; of the nodular histologic subtype&#44; a higher Breslow thickness&#44; presence of ulceration&#44; and high mitotic index&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">7&#8211;9</span></a> Studies in tissue and cell lines have shown that these mutations produce increased expression of telomerase by creating new binding sites for transcription factors of the ETS family&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">9&#8211;12</span></a> The presence of these mutations has been shown to be an independent prognostic factor linked to reduced disease-free and overall survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">8&#44;13</span></a> Furthermore&#44; this link to survival has been found to vary depending on the type of mutation identified&#44; and is modified by the presence of rs2853669 polymorphism&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">14&#44;15</span></a> Recent studies have also shown the prognostic value of telomere length by identifying lower survival rates in patients with shorter telomeres&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">16&#44;17</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">It therefore appears that telomerase expression plays a major role in melanoma carcinogenesis&#59; however&#44; few studies have analyzed telomerase expression at the protein level&#44; and those studies include small series with few melanomas&#46; Moreover&#44; the study of telomerase expression may be of utility for stratifying patients based on prognosis&#46; The objectives of this study are to analyze telomerase expression by means of immune staining in a series of melanomas &#40;primary and metastatic&#41; and melanocytic nevi&#44; and to correlate expression levels with the clinical and pathologic characteristics and the course of the patients&#44; and with mutations in the <span class="elsevierStyleItalic">TERT</span> promoter&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Selected Patients and Samples</span><p id="par0015" class="elsevierStylePara elsevierViewall">We performed a retrospective observational study in the Dermatology and Anatomical Pathology Department of Hospital Universitario y Polit&#233;cnico La Fe&#44; Valencia&#44; Spain&#44; in a sample of 85 patients diagnosed with melanoma and 22 patients diagnosed with melanocytic nevus &#40;5 with intradermal nevus&#44; 7 with compound nevus&#44; and 10 with dysplastic nevus&#41;&#44; who were seen at our department between January 1&#44; 2014 and December 1&#44; 2016&#46; Samples with sufficient quantity of sample in the paraffin block were selected for immune staining&#46; In the case of primary melanomas&#44; the only samples included were those with an invasive component&#44; classified in 4 main histologic subtypes &#40;lentigo maligna melanoma&#44; surface spreading melanoma&#44; nodular melanoma&#44; and acral lentiginous melanoma&#41;&#44; and those for which a study of the <span class="elsevierStyleItalic">TERT</span> promoter was available&#46; The primary tumor was studied in the 85 patients with melanoma and melanoma metastasis was also studied in 12 of these patients&#46; The clinical and pathologic data of each of the patients with melanoma was collected&#46; Breslow thickness was characterized using the classification of the American Joint Committee on Cancer &#40;AJCC&#41; &#40;&#8804;1&#46;00&#44; 1&#46;01-2&#44; 2&#46;01-4&#44; and &#62; 4<span class="elsevierStyleHsp" style=""></span>mm&#41;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">18</span></a>&#59; the mitotic index was expressed as the number of cells undergoing mitosis per square millimeter and was characterized by the presence or absence of mitosis&#59; histologic regression was defined as described in previous studies&#44;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">19</span></a> and was characterized as absent or present&#44; and growth rate was defined as described in previous studies&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> All patients provided written consent to take part in the study&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Telomerase Expression With Immune Staining</span><p id="par0020" class="elsevierStylePara elsevierViewall">Immune staining was performed in 5-&#181;m slices&#44; using the hTERT monoclonal antibody &#40;Rockland&#41;&#44; as described previously&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">21</span></a> The same technique&#44; with omission of the antibody&#44; was used as a negative control&#46; In the case of melanomas for which several blocks were available&#44; those with the highest percentage of tumor cells were selected&#46; Telomerase expression in all the samples included was performed by 2 independent observers &#40;BU and RB&#41;&#46; In the event of discrepancies in the observations of the 2 researchers&#44; the observations of the researcher with most experience &#40;RB&#41; were used for the analysis&#46; The extent of expression was quantified by establishing a score based on the percentage of positive cells &#40;0&#44; 0&#37;&#59; 1&#44; &#60; 10&#37;&#59; 2&#44; 10&#37;-50&#37;&#59; and 3&#44; &#62; 50&#37;&#41;&#46; The intensity of expression was scored from 0 to 3 &#40;0&#44; absent&#59; 1&#44; mild&#59; 2&#44; moderate&#59; 3&#44; intense&#41;&#46; The expression pattern was classified as homogeneous or heterogeneous depending on the uniformity of expression in tumor cells&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical Analysis</span><p id="par0025" class="elsevierStylePara elsevierViewall">Descriptive analysis of the variables was performed using absolute and relative frequencies&#46; Inferential analysis of the qualitative variables was performed using tests based on the &#967;<span class="elsevierStyleSup">2</span> distribution&#46; Analysis of disease-free survival and overall survival was performed using the Kaplan-Meyer method&#46; The degree of agreement between the independent observers was evaluated using the &#954; coefficient&#46; Statistical analysis was performed using the SPSS statistical software package and statistical significance was established for values of p &#60;0&#46;05&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Telomerase Expression in Healthy Skin</span><p id="par0030" class="elsevierStylePara elsevierViewall">In the healthy skin surrounding the melanocytic lesions&#44; telomerase expression was observed in the epidermis&#44; hair follicles&#44; sweat glands&#44; and sebaceous glands&#44; and in the endothelium of the dermal blood vessels&#46; Expression was mild in the epidermis and follicles&#44; moderate in the sweat glands&#44; and intense in the sebaceous glands &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; <a class="elsevierStyleCrossRef" href="#sec0070">&#40;Figs&#46; S1- S3 of the additional material available in the online version&#41;</a>&#46; Expression in these appendages was used as a positive control in all the analyzed cases&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Telomerase Expression in Melanocytic Tumors</span><p id="par0035" class="elsevierStylePara elsevierViewall">The degree of agreement observed in the 3 parameters analyzed by the 2 researchers was good&#44; with a &#954; index of 0&#46;65 in intensity and 0&#46;83 in extent&#44; and 0&#46;73 in telomerase expression pattern&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Telomerase was found to be expressed in all the melanocytic tumors analyzed&#46; In the case of the primary melanomas&#44; the expression pattern was homogeneous in all cell tumors in 59&#37; &#40;50&#47;85&#41; of cases &#40;<a class="elsevierStyleCrossRef" href="#sec0070">Fig&#46; S4 of the additional material</a>&#41;&#44; whereas it was heterogeneous in 41&#37; &#40;35&#47;85&#41; of cases&#44; with different expression intensity between tumor cells &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41; &#40;<a class="elsevierStyleCrossRef" href="#sec0070">Fig&#46; S5 of the additional material</a>&#41;&#46; In most of the cases analyzed &#40;95&#37;&#59; 81&#47;85&#41;&#44; expression was observed in over 50&#37; of tumor cells &#40;Fig&#46; S6 of the additional material&#41;&#44; and expression in less than 10&#37; of the tumorous infiltrate was only observed in 1 case &#40;<a class="elsevierStyleCrossRef" href="#sec0070">Fig&#46; S7 of the additional material</a>&#41;&#46; In terms of intensity&#44; expression was intense in 41&#37; &#40;35&#47;85&#41; of the samples &#40;Fig&#46; S8 of the additional material&#41;&#44; moderate in 51&#37; &#40;43&#47;85&#41; &#40;Fig&#46; S9 of the additional material&#41;&#44; and mild in only 8&#37; &#40;7&#47;85&#41; of the samples &#40;<a class="elsevierStyleCrossRef" href="#sec0070">Fig&#46; S10 of the additional material</a>&#41;&#46; Melanomas with a precursor nevus lesion &#40;5&#37;&#59; 4&#47;85&#41; revealed intense telomerase expression in the tumor cells of the melanoma but mild expression in the accompanying nevus cells &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>A-3D&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">In the metastatic melanomas&#44; the expression pattern was homogeneous in 67&#37; &#40;8&#47;12&#41; and heterogeneous in 33&#37; &#40;4&#47;12&#41;&#46; Expression of hTERT was observed in over 50&#37; of tumor cells in 100&#37; of the samples&#44; and was intense in 41&#37; &#40;5&#47;12&#41;&#44; moderate in 50&#37; &#40;6&#47;12&#41;&#44; and mild in 8&#46;3&#37; &#40;1&#47;12&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Telomerase expression revealed a homogeneous pattern in 100&#37; of the melanocytic nevi&#44; with an extent of over 50&#37; in the tumor cells in 91&#37; &#40;20&#47;22&#41; of the samples&#46; Expression intensity was mild in 64&#37; &#40;14&#47;22&#41;&#44; moderate in 32&#37; &#40;7&#47;22&#41;&#44; and intense in 4&#37; &#40;1&#47;22&#41; of the samples&#46; &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">In terms of differences in expression based on the clinical and pathologic characteristics of the primary melanomas&#44; the heterogeneous expression pattern was associated with fast-growing melanomas &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;028&#41; with a Breslow thickness of more than 4<span class="elsevierStyleHsp" style=""></span>mm &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;004&#41;&#44; with mitosis &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;032&#41;&#44; and with mutations in the <span class="elsevierStyleItalic">TERT</span> promoter &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;002&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The expression pattern showed no significant differences between the type of mutation in the <span class="elsevierStyleItalic">TERT</span> promoter &#40;c&#46;1-146C&#62;T&#44; c&#46;1-124C&#62;T&#44; and c&#46;1-124&#47;-125CC&#62;TT&#41;&#46; No statistically significant differences were observed in intensity or extent of expression &#40;Table S1 of the additional material&#41;&#46; Expression intensity was higher in melanomas of the lentigo maligna melanoma subtype and lower in acral lentiginous melanomas&#44; although this difference was not statistically significant &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;523&#41;&#46; Analysis of survival revealed no statistically significant differences based on telomerase expression&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">The comparative analysis of nevus with primary and metastatic melanoma revealed that telomerase expression in the nevi was less intense than in the primary and metastatic melanomas &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and that&#44; unlike the melanomas&#44; the nevi revealed a characteristic pattern of homogeneous expression in all the tumor cells &#40;p &#60; 0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>&#41;&#46; No statistically significant differences were observed between primary and metastatic melanomas&#46; Moreover&#44; in the case of the nevi&#44; intensity was lowest in the intradermal nevi&#44; followed by the compound and dysplastic nevi&#44; although the differences were not statistically significant &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;054&#41;&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discussion</span><p id="par0065" class="elsevierStylePara elsevierViewall">The results of this study show that telomerase expression occurs in all the melanocytic tumors analyzed&#44; and that a gradually increasing trend from nevus to melanoma exists&#44; which may be implicated in the tumor progression in this type of cancer&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In the primary melanomas in our series&#44; we showed that the heterogeneous expression pattern is associated with more aggressive melanomas &#40;faster-growing melanomas with a tumor thickness of more than 4<span class="elsevierStyleHsp" style=""></span>mm&#44; with mitosis&#44; and with mutations in the <span class="elsevierStyleItalic">TERT</span> promoter&#41;&#59; this has not been previously reported&#46; These results contrast with those recently reported by Hugdahl et al&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a> who describe homogeneous expression in most of their cases&#46; Our findings&#44; however&#44; may support those reported by Kohli et al&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">23</span></a> who report heterogeneous expression of non-nuclear telomerase in melanomas but not in benign lesions&#46; This heterogeneous expression pattern may be the result of intratumoral heterogeneity in melanoma&#44; which has been linked to different tumor subpopulations&#44; and is linked to resistance to systemic treatments&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">24&#44;25</span></a> Furthermore&#44; we cannot rule out the possibility that the heterogeneity observed in our study may be due to a defect in the staining procedure&#44; although this is unlikely&#44; as this pattern was not observed in any of the benign melanocytic lesions&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Unlike other studies&#44; in our series&#44; the intensity and extent of telomerase expression were independent of the clinical and pathologic characteristics&#46; Hugdahl et al<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">22</span></a> reported a statistically significant link between telomerase expression &#40;44&#37; of primary melanomas in that series&#41; and tumor thickness&#44; and Zygouris et al<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a> described a link with Breslow thickness and ulceration&#46; Our findings contrast with several studies that have analyzed telomerase activity&#44; such as the study by Ram&#237;rez et al&#44; which found greater telomerase activity in melanomas with greater tumor thickness&#44; a higher Clark score&#44; and mitosis<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a>&#59; the results of Miracco et al&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a> in which telomerase activity was also associated with Breslow thickness and the Clark score&#59; and the study by Carvalho et al&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">29</span></a> which found greater telomerase activity in ulcerated melanomas&#44; with a greater Breslow thickness&#44; mitosis&#44; vascular invasion&#44; and satellitosis&#46; In our series&#44; melanomas of lentigo maligna melanoma showed greater expression intensity&#44; although this did not reach statistical significance&#46; This last finding does not support the findings of the series by P&#243;pulo et al&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> in which telomerase expression was only associated with the surface spreading histologic subtype&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">With respect to the mutations in the <span class="elsevierStyleItalic">TERT</span> promoter&#44; in line with reporting by other authors&#44;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">8&#44;9</span></a> in a previous publication&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a> we reported a prevalence of 33&#37; and an association with ulcerated melanomas with greater tumor thickness&#44; with mitosis&#44; and of the nodular histologic subtype&#46; As in other studies&#44; in this series&#44; we found no differences using immune staining in telomerase expression between mutated and nonmutated melanomas&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">8&#44;22&#44;23</span></a> This finding contrasts with several prior publications&#44; which found greater telomerase expression in melanomas with mutations in the promoter&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">9&#8211;12</span></a> This discrepancy may be due to the fact that those studies analyzed telomerase expression at the messenger RNA level and not at the protein level&#44; and other molecular mechanisms may therefore exist that regulate telomerase expression&#46; Indeed&#44; several studies have focused on epigenetic regulation of telomerase expression&#46; It has been reported that post-transcriptional regulation of the <span class="elsevierStyleItalic">TERT</span> through microRNA expression may suppress telomerase expression<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">31&#44;32</span></a> and that hypermethylation in the DNA of the <span class="elsevierStyleItalic">TERT</span> gene may increase telomerase expression&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">33</span></a> It may therefore be useful to measure the length of the telomeres and&#47;or telomerase activity and correlate it to the presence of the mutation in order to determine whether only mutated genes show increased activity or whether wild-type genes also show greater telomerase activity through these other molecular mechanisms&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Furthermore&#44; we have identified variable levels of telomerase expression in a series of 22 melanocytic nevi with mild expression in most of the samples&#44; and a tendency for expression to increase from intradermal nevi to dysplastic nevi&#46; It should also be noted that&#44; in all the melanomas with a nevus precursor&#44; telomerase expression in the accompanying nevus was much less intense than in the tumor cells of the melanoma&#46; These results suggest a potential role of telomerase in tumor progression in melanocytic cancers&#46; Several authors have analyzed telomerase activity in different types of melanocytic tumor and have found that telomerase expression increases progressively from common nevi to dysplastic nevi and melanomas&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">4&#44;34</span></a> These differences in telomerase expression between nevus and melanoma&#44; however&#44; have been found not to be of use in the differential diagnosis&#44; as expression may be variable in both types of tumor&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In this study&#44; telomerase expression was analyzed using immune staining&#44; unlike most previously published studies&#44; which analyzed telomerase activity using the telomere repeat amplification protocol &#40;TRAP&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">4&#44;23&#8211;25</span></a> Immune staining has the advantage of being a simple and cheap method that is performed using paraffinized samples and makes it possible to visualize the intensity and extent of expression&#44; not only in the cells of interest but also in adjacent healthy skin&#46; Indeed&#44; in line with what has already been described&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">30</span></a> we have identified variable levels of telomerase expression&#44; not only in the tumor cells but also in the epidermis&#44; hair follicles&#44; glands&#44; dermal blood vessels&#44; and even in the accompanying inflammatory infiltrate&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In conclusion&#44; the results of this study show that telomerase expression occurs in all the analyzed melanocytic tumors&#44; with greater expression in the melanomas than in the nevi&#46; In the case of the primary melanomas&#44; heterogeneous expression is linked to a more aggressive phenotype&#59; however&#44; expression intensity is independent of the clinical and pathologic characteristics of the tumors&#46; It has also been shown that no differences exist in telomerase expression based on the mutational state of the <span class="elsevierStyleItalic">TERT</span> gene and other molecular mechanisms must therefore exist that regulate expression of the <span class="elsevierStyleItalic">TERT</span> gene in the melanomas&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Funding</span><p id="par0100" class="elsevierStylePara elsevierViewall">This study was carried out with grants awarded by Fundaci&#243;n Piel Sana &#40;EUROMELANOMA 2016 grant from the AEDV Foundation&#41;&#44; Carlos III Institute of Health &#40;ISCII&#41; &#40;PI16&#47;01559&#41;&#44; IISLaFe &#40;2014&#47;0370&#41;&#44; and the Department of Education&#44; Research&#44; Culture and Sport of the autonomous government of Valencia &#40;GV&#47;2016&#47;064&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflicts of Interest</span><p id="par0105" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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              "titulo" => "Telomerase Expression in Melanocytic Tumors"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1097954"
          "palabras" => array:5 [
            0 => "Telomerase"
            1 => "Telomerase reverse transcriptase &#40;TERT&#41;"
            2 => "Melanoma"
            3 => "Nevus"
            4 => "Immunohistochemistry"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
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          "palabras" => array:5 [
            0 => "Telomerasa"
            1 => "<span class="elsevierStyleItalic">Telomerase reverse transcriptase</span> &#40;TERT&#41;"
            2 => "Melanoma"
            3 => "Nevus"
            4 => "Inmunohistoquimia"
          ]
        ]
      ]
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    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Telomerase is an enzyme involved in maintaining the length of telomeres and cell senescence&#46; Numerous studies have shown that in more than 90&#37; of malignant tumors telomerase activity is detected&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Retrospective observational study in a series of 85 cases of primary melanomas&#44; 12 metastatic melanomas&#44; and 22 melanocytic nevi&#46; We used the monoclonal antibody hTERT &#40;human telomerase reverse transcriptase&#44; Rockland&#41; to assess telomerase activity&#46; The SPSS software package was used to analyze data&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Telomerase expression was present in all the melanocytic neoplasms analyzed&#46; Expression was heterogenous and moderate or high in the melanomas&#46; In contrast&#44; expression was homogeneous and lower in the nevi&#46; Heterogeneous expression was associated with rapid melanoma growth &#40;<span class="elsevierStyleItalic">P<span class="elsevierStyleHsp" style=""></span></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;028&#41;&#44; a Breslow thickness of more than 4<span class="elsevierStyleHsp" style=""></span>mm &#40;<span class="elsevierStyleItalic">P<span class="elsevierStyleHsp" style=""></span></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;004&#41;&#44; mitosis &#40;<span class="elsevierStyleItalic">P<span class="elsevierStyleHsp" style=""></span></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;032&#41;&#44; and mutations in the <span class="elsevierStyleItalic">TERT</span> gene &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;002&#41;&#46; Activity was less intense in intradermal nevi&#44; and more intense in compound and dysplastic nevi &#40;<span class="elsevierStyleItalic">P<span class="elsevierStyleHsp" style=""></span></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;054&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Telomerase expression is found in all melanocytic neoplasms but is higher in melanomas than in nevi&#46; A heterogeneous pattern of expression in melanomas is associated with more aggressive tumors&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background and objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Material and methods"
          ]
          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
          ]
          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusions"
          ]
        ]
      ]
      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n y objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La telomerasa es una enzima implicada en el mantenimiento de los tel&#243;meros y la senescencia celular&#46; Numerosos estudios han demostrado que en m&#225;s del 90&#37; de las neoplasias malignas se detecta actividad telomer&#225;sica&#46; El objetivo del presente estudio es analizar la expresi&#243;n de telomerasa por inmunohistoqu&#237;mica en una serie de neoplasias melanoc&#237;ticas&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional retrospectivo realizado en una serie de 85 melanomas primarios&#44; 12 metast&#225;sicos y 22 nevus melanoc&#237;ticos&#46; La expresi&#243;n de telomerasa se analiz&#243; empleando el anticuerpo monoclonal hTERT &#40;Rockland&#41;&#46; El an&#225;lisis de los datos se realiz&#243; con el programa SPSS&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">En todas las neoplasias melanoc&#237;ticas analizadas se demostr&#243; expresi&#243;n de telomerasa&#46; En el caso de los melanomas predomin&#243; el patr&#243;n de expresi&#243;n heterog&#233;neo&#44; y la expresi&#243;n moderada o intensa&#46; En los nevus result&#243; m&#225;s frecuente una expresi&#243;n homog&#233;nea con intensidad leve&#46; El patr&#243;n de expresi&#243;n heterog&#233;neo se asoci&#243; a los melanomas de r&#225;pido crecimiento &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;028&#41;&#44; con Breslow &#62; 4<span class="elsevierStyleHsp" style=""></span>mm &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;004&#41;&#44; con mitosis &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;032&#41;&#44; y con mutaciones en el gen TERT &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;002&#41;&#46; En el caso de los nevus&#44; la intensidad fue menor en los nevus intrad&#233;rmicos&#44; seguidos de los compuestos y de los dipl&#225;sicos &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;054&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La expresi&#243;n de telomerasa est&#225; presente en la totalidad de las neoplasias melanoc&#237;ticas&#44; con mayor expresi&#243;n en los melanomas que en los nevus&#46; En el caso de los melanomas&#44; la expresi&#243;n de forma heterog&#233;nea se asocia a un fenotipo de mayor agresividad&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Introducci&#243;n y objetivos"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Material y m&#233;todos"
          ]
          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
          ]
        ]
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Bustos BdU&#44; Torralba AS&#44; Poveda PM&#44; Sim&#243; GP&#44; Farinos JS&#44; Ros ML&#44; et al&#46; Estudio de la expresi&#243;n de telomerasa en una serie de neoplasias melanoc&#237;ticas&#46; Actas Dermosifiliogr&#46; 2019&#59;110&#58;212&#8211;219&#46;</p>"
      ]
    ]
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      0 => array:1 [
        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="par0120" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="upi0005"></elsevierMultimedia><elsevierMultimedia ident="upi0010"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0070"
          ]
        ]
      ]
    ]
    "multimedia" => array:9 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 637
            "Ancho" => 850
            "Tamanyo" => 237221
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Intense telomerase expression in sebaceous glands &#40;x100&#41;&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 638
            "Ancho" => 850
            "Tamanyo" => 267805
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Telomerase expression with a heterogeneous pattern in primary melanoma &#40;x100&#41;&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Figure 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 994
            "Ancho" => 1300
            "Tamanyo" => 736109
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">A&#44; Melanoma associated with intradermal nevus &#40;hematoxylin&#8211;eosin&#44; x40&#41;&#46; B&#44; Detail of intradermal nevus associated with the melanoma &#40;hematoxylin&#8211;eosin&#44; x100&#41;&#46; C&#44; Intense telomerase expression in melanoma tumor cells and mild expression in nevus cells &#40;x40&#41;&#46; D&#44; Detail of mild telomerase expression in the nevus cells &#40;x100&#41;&#46;</p>"
        ]
      ]
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        "identificador" => "fig0020"
        "etiqueta" => "Figure 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 638
            "Ancho" => 850
            "Tamanyo" => 296591
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Intense telomerase expression in metastatic melanoma &#40;x100&#41;&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "fig0025"
        "etiqueta" => "Figure 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 638
            "Ancho" => 850
            "Tamanyo" => 239142
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Mild telomerase expression in intradermal melanocytic nevus &#40;x100&#41;&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "fig0030"
        "etiqueta" => "Figure 6"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr6.jpeg"
            "Alto" => 891
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            "Tamanyo" => 135694
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        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">A&#44; Telomerase expression pattern in melanoma and nevus with predominantly homogeneous expression in melanocytic nevi&#46; B&#44; Progressive reduction in intensity of telomerase expression from metastatic melanomas to nevi&#46;</p>"
        ]
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        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Het indicates heterogeneous&#59; Hom&#44; homogeneous&#59; WT&#44; wild type&#46;</p>"
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              "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-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Variable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Total &#40;n &#61; 85&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Expression pattern</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Hom&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Het&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">p&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">N &#40;&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Age</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#60; 40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;5&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;40&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;60&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;678&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>40-65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">45 &#40;52&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27 &#40;60&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18 &#40;40&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#62; 65&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35 &#40;41&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21 &#40;60&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14 &#40;40&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Sex</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">46 &#40;54&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29 &#40;63&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17 &#40;37&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;526&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39 &#40;45&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21 &#40;53&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">18 &#40;46&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Location</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Head and neck&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;10&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;22&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7 &#40;77&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;025&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Torso&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">45 &#40;52&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">32 &#40;71&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 &#40;28&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Upper limbs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14 &#40;16&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;35&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;64&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lower limbs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">14 &#40;16&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;64&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;35&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Acral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;3&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;66&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;33&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Histologic subtype</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lentigo maligna melanoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;3&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 &#40;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Surface spreading melanoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">64 &#40;75&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;67&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21 &#40;32&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Nodular melanoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;17&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;33&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;66&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Acral lentiginous melanoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 &#40;3&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;66&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;33&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Breslow thickness</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#60; 1 mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40 &#40;47&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29 &#40;72&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11 &#40;27&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> 1-2 mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29 &#40;34&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;55&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 &#40;44&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> 2-4 mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;7&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#40;66&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 &#40;33&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> &#62; 4 mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;11&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1 &#40;10&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;90&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Ulceration</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">69 &#40;81&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;62&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26 &#40;37&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;141&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16 &#40;18&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7 &#40;43&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">9 &#40;56&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Mitosis</span>&#47;mm<span class="elsevierStyleSup">2</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> &#60; 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;50&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 &#40;69&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">13 &#40;30&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;032&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> &#8805; 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">42 &#40;49&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19 &#40;47&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22 &#40;52&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Regression</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;50&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">23 &#40;53&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 &#40;46&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;215&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">42 &#40;49&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">27 &#40;64&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;35&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Tumor stage</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> Local&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">73 &#40;85&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 &#40;59&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">29 &#40;40&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;580&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> Local-regional&#47;distant disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 &#40;14&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7 &#40;58&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;41&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Growth rate</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> Slow growth&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">70 &#40;82&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25 &#40;64&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">45 &#40;35&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;028&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> Rapid growth&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">15 &#40;17&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 &#40;33&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 &#40;66&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Clinical course &#40;&#37;&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> Stable disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">69 &#40;81&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">41 &#40;57&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30 &#40;42&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;242&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> Local-regional&#47;distant relapse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11 &#40;13&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> Death&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">19 &#40;33&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span> Mutated&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 &#40;27&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 &#40;72&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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