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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cutaneous melanoma is a clinically heterogeneous disease&#44; with both mild and life-threatening cases&#46; A range of clinical&#44; histologic&#44; and molecular factors that help predict survival have been identified&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a> Many patients&#44; however&#44; have tumors of uncertain behavior&#44; hence the importance of investigating other factors that could help determine prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The 2 main forms of vitamin D that are important to humans are vitamin D<span class="elsevierStyleInf">2</span> &#40;ergocalciferol&#41; and vitamin D<span class="elsevierStyleInf">3</span> &#40;cholecalciferol&#41;&#46; While they can both be obtained from diet&#44; 90&#37; of vitamin D<span class="elsevierStyleInf">3</span> is obtained via skin exposure to UV radiation from the sun&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">3</span></a> Excessive exposure&#44; however&#44; contributes to skin aging and favors the development of skin cancer&#46; It is not surprising thus that patients with melanoma are often found to have low vitamin D levels during follow-up&#44; as they tend to take extreme measures to protect themselves from the sun&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> Vitamin D may be involved in the natural history of cancer because it supports the proper function of the immune system and also has a role in cell division&#44; where it induces differentiation and apoptosis and inhibits cell proliferation and angiogenesis in both normal and cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Vitamin D levels and germline vitamin D receptor polymorphisms could have a pathogenic role in cutaneous melanoma&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">5&#8211;9</span></a> Previous studies have suggested that vitamin D might be of prognostic value in melanoma&#44; with low levels indicating potentially shorter survival&#44; independently of well-known poor prognosis factors&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">10&#8211;16</span></a> The studies to date&#44; however&#44; have used highly heterogeneous methods&#44; especially in terms of how vitamin D serum levels are measured&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of this study was to evaluate the prognostic value of vitamin D serum levels in a retrospective cohort of patients with cutaneous melanoma&#44; with adjustment for key prognostic markers and use of a specific statistical methodology to select an optimal vitamin D serum cutoff associated with survival&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Study design</span><p id="par0025" class="elsevierStylePara elsevierViewall">We conducted a retrospective&#44; observational&#44; longitudinal&#44; analytical cohort study of patients with a histologic diagnosis of localized &#40;stage I and II&#41; melanoma and data on vitamin D serum level at the time of diagnosis&#46; The patients were seen at Instituto Valenciano de Oncolog&#237;a in Valencia&#44; Spain&#44; between February 1&#44; 2011 and November 30&#44; 2020&#46; All the patients provided informed consent for inclusion in this study&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">In order to evaluate the prognostic value of vitamin D serum level&#44; the patients were divided into 2 groups&#58; those with a level &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL and those with a higher level&#46; This cutoff of 9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL was identified using an iterative loop&#44; described in the statistical analysis section&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Independent variables were sex&#44; age &#40;&#60;65 years vs&#46; &#8805;65 years&#41;&#44; tumor location &#40;head&#47;neck vs&#46; upper extremity vs&#46; trunk vs&#46; lower extremity vs&#46; acral site&#41;&#44; histologic subtype &#40;lentigo maligna melanoma &#91;LMM&#93; vs&#46; superficial spreading melanoma &#91;SSM&#93; vs&#46; nodular melanoma &#91;NM&#93; vs&#46; acral lentiginous melanoma &#91;ALM&#93; vs&#46; other&#47;unspecified&#41;&#44; Breslow thickness &#40;&#8804;2<span class="elsevierStyleHsp" style=""></span>mm vs&#46; &#62;2<span class="elsevierStyleHsp" style=""></span>mm&#41;&#44; mitotic rate &#40;&#8804;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span> vs&#46; &#62;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span>&#41;&#44; and a histologic finding of ulceration&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The cutoff for age was identified in the final multivariate Cox regression model&#59; the cutoffs used for Breslow thickness and mitotic rate were pre-established by the researchers&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Overall survival&#44; defined as time from primary tumor excision to death&#44; was used as the dependent variable to assess the prognostic value of vitamin D serum level&#46; Patient status was updated at the end of the study &#40;April 30&#44; 2021&#41; by consulting the national death registry&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">Continuous variables are expressed as mean &#40;SD&#41; for normally distributed variables and median &#40;interquartile range &#91;IQR&#93;&#41; otherwise&#46; Normality of distribution was checked using the Kolmogorov&#8211;Smirnov test Qualitative variables are expressed as absolute and relative frequencies&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Differences in the distributions of each variable according to vitamin D level &#40;&#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL vs&#46; &#8805;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; were evaluated using contingency tables&#46; The groups were compared using the Pearson <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span> test or&#44; when the expected count was less than 5 in at least 1 cell in the 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 tables&#44; the Fisher exact test&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Potential vitamin D cutoff points &#40;each quarter of a unit for measured levels at time of diagnosis&#41; were tested using an iterative loop in which patients were split into 2 groups to test for significant differences in survival&#46; These differences were tested using the log-rank test&#46; The cutoff showing the most significant difference between groups &#40;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; was chosen and used to build the corresponding Kaplan&#8211;Meier survival curves&#46; Univariate and multivariate Cox proportional hazards models were built using stepwise backward selection to evaluate the association between vitamin D serum level and overall survival&#46; Finally&#44; Schoenfeld residuals were used to check the proportional hazards assumption&#46; The results determined that age&#44; which was considered a continuous variable in the initial model&#44; should be entered as a categorical variable &#40;&#60;65 years vs&#46; &#8805;65 years&#41; in the final version&#46; Statistical analyses were conducted in IBM SPSS version 20&#46;0 and R Studio version 4&#46;1&#46;0&#46; All <span class="elsevierStyleItalic">P</span> values were 2-tailed and values less than &#46;05 were considered statistically significant&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><p id="par0065" class="elsevierStylePara elsevierViewall">The patients&#8217; characteristics according to vitamin D level are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; We studied 286 patients&#44; mostly men &#40;57&#37;&#41;&#44; with a median age of 57&#46;5 years &#40;IQR&#44; 45&#46;75&#8211;70 years&#41;&#46; The most common tumor was an SMM &#40;186&#44; 65&#37;&#41; located on the trunk &#40;129&#44; 45&#46;1&#37;&#41; with a Breslow thickness &#8804;2<span class="elsevierStyleHsp" style=""></span>mm &#40;234&#44; 81&#46;8&#37;&#41;&#44; a mitotic rate &#8804;5&#47;mm<span class="elsevierStyleSup">2</span> &#40;243&#44; 86&#46;2&#37;&#41;&#44; and no ulceration &#40;85&#46;6&#37;&#41;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Thirteen patients &#40;4&#46;5&#37;&#41; had a vitamin D serum level &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL while 273 &#40;95&#46;5&#37;&#41; had a level above this cutoff&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Tumor location varied significantly according to vitamin D level&#46; Patients in the lower cutoff group were significantly more likely than those with a level &#8805;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL to have LMM or ALM and significantly less likely to have SSM or NM &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;005&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Ulceration was also more common in these patients &#40;38&#46;5&#37; vs&#46; 13&#46;2&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;026&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">No significant between-group differences were found for sex&#44; age&#44; location&#44; Breslow thickness&#44; or mitotic rate&#46;</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Overall survival</span><p id="par0085" class="elsevierStylePara elsevierViewall">Twenty-four patients &#40;8&#46;4&#37;&#41; died over a median follow-up of 39&#46;4 months&#46; Of these&#44; 5 had a vitamin D level &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;5&#47;13&#44; 38&#46;5&#37;&#41; and 19 had a level &#8805;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;19&#47;273&#44; 7&#46;0&#37;&#41;&#46; Overall survival was significantly different between the 2 groups &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0024&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">The univariate Cox regression model confirmed that patients with a vitamin D level &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL were more likely to have worse overall survival than those with a level above the cutoff &#40;hazard ratio &#91;HR&#93;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;2&#59; 95&#37; CI&#44; 0&#46;1&#8211;0&#46;7&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;005&#41;&#46; Worse survival was also observed in patients aged 65 years or older &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;6&#59; 95&#37; CI&#44; 2&#46;0&#8211;10&#46;9&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; and patients with a Breslow thickness &#62;2<span class="elsevierStyleHsp" style=""></span>mm &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#46;1&#59; 95&#37; CI&#44; 2&#46;7&#8211;13&#46;6&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; a mitotic rate &#62;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span> &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#46;3&#59; 95&#37; CI&#44; 2&#46;8&#8211;4&#46;4&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; and ulceration &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;6&#59; 95&#37; CI&#44; 2&#46;0&#8211;10&#46;7&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; Location on the upper extremities or trunk was associated with better overall survival &#40;&#91;upper extremity vs&#46; head&#47;neck&#58; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;2&#59; 95&#37; CI&#44; 0&#46;0&#8211;0&#46;9&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;032&#93;&#59; &#91;trunk vs&#46; head&#47;neck&#58; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;3&#59; 95&#37; CI&#44; 0&#46;1&#8211;0&#46;8&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;013&#93;&#41;&#46; Better survival was also observed in patients with SSM versus LMM &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;3&#59; 95&#37; CI&#44; 0&#46;1&#8211;0&#46;8&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;020&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">The variables included in the final multivariate model were age &#40;&#8805;65 years vs&#46; &#60;65 years&#59; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;4&#59; 95&#37; CI&#44; 1&#46;8&#8211;10&#46;4&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; mitotic rate &#40;&#62;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span> vs&#46; &#8804;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span>&#59; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#46;3 95&#37; CI&#44; 2&#46;6&#8211;15&#46;1&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; ulceration &#40;yes vs&#46; no&#59; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;7&#59; 95&#37; CI&#44; 1&#46;5&#8211;9&#46;1&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;005&#41;&#44; and vitamin D level &#40;&#8805;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL vs&#46; &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#59; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;3&#59; 95&#37; CI&#44; 0&#46;1&#8211;1&#46;0&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;050&#41;&#46; Age&#44; mitotic rate&#44; ulceration&#44; and vitamin D level were independent predictors of overall melanoma survival in the multivariate analysis &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0100" class="elsevierStylePara elsevierViewall">In this study of 286 patients with melanoma&#44; a vitamin D serum level &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL was associated with worse overall survival&#44; independently of Breslow thickness and ulceration&#40;2 key prognostic factors&#41; and other known factors such as mitotic rate and age&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Our findings are consistent with previous reports&#44; summarized in a recent meta-analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">13</span></a> Studies to date&#44; however&#44; have used highly heterogeneous methods&#44; particularly to measure serum vitamin D levels&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In their first study of the association between vitamin D and melanoma&#44; Newton-Bishop et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a> found an association between low levels and worse recurrence-free and overall survival&#44; even after adjustment for Breslow thickness&#46; They analyzed vitamin D levels as a continuous variable and a categorical variable based on tertiles calculated using values reported for the study population&#46; In addition&#44; blood sampling was performed 3&#8211;6 months after diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">In a second study&#44; the same group observed worse melanoma-specific survival in patients with a low vitamin D level at diagnosis &#40;&#60;20<span class="elsevierStyleHsp" style=""></span>nmol&#47;L&#44; which is equivalent to &#60;8&#46;01<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#91;conversion factor&#44; 2&#46;496&#93;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">15</span></a> They also observed an improvement in survival for each 10-nmol&#47;L increase&#44; as apart from considering vitamin D as a continuous variable&#44; they also analyzed it by categories &#40;&#60;20&#44; 20&#8211;60&#44; 60&#8211;85&#44; 85&#8211;100&#44; and 100&#43; nmol&#47;L&#41;&#46; Similarly to in the first study&#44; they adjusted for Breslow thickness but not ulceration&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Timerman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a> reported worse melanoma-specific mortality in patients with a low vitamin D serum level&#44; particularly in those with metastatic melanoma&#46; They used the standard cutoff of 20<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; which is the established level for adequate bone metabolism&#46; Blood sampling was performed at different times during follow-up&#46; No adjustments were made for Breslow thickness or tumor ulceration&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">In the study by Weinsten et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">16</span></a> season-specific vitamin D levels categorized by quantiles were associated with worse prognosis in melanoma following adjustment for age&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Bade et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">14</span></a> observed shorter overall survival in patients with vitamin D serum levels in the lowest quartile compared with those in the top quartile&#46; Only univariate Kaplan&#8211;Meier curves&#44; however&#44; were used&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Unlike the above authors&#44; Saiag et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">17</span></a> found no differences in overall survival between patients with a low vitamin D level at diagnosis&#44; although they did find that variations over time &#40;both increases and decreases from baseline&#41; had prognostic value&#46; Similarly to the other authors&#44; they used quartile values as cutoff points&#46; They adjusted for both Breslow thickness and ulceration&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">17</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Fang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a> used the most similar methodology to ours&#46; They used recursive partitioning to identify the split associated with the lowest <span class="elsevierStyleItalic">P</span> value in the log-rank test&#46; On applying the cutoff identified&#8212;16<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#8212;they found that patients with lower levels had significantly worse melanoma-specific&#44; disease-free&#44; and overall survival after adjustment for logarithmic C-reactive protein&#44; age&#44; sex&#44; clinical stage&#44; and blood draw season in the multivariate model&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">We identified a cutoff of 9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL in our study using an iterative loop and log-rank testing&#46; This methodology&#44; while different to that of Fang et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a> enabled us to identify the cutoff showing the most significant survival difference between groups&#46; Another methodological difference was that we adjusted for Breslow thickness and tumor ulceration rather than clinical stage &#40;III&#47;IV vs&#46; I&#47;II&#41; in the multivariate model&#46; We also adjusted for mitotic rate&#46; While this factor is no longer used to determine clinical stage in the latest melanoma staging system of the American Joint Committee on Cancer&#44;&#8217; it is still an important determinant of prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Methodologies such as that used in the present study are interesting because most studies to date have used reference values related to bone metabolism to analyze vitamin D levels&#46; These values&#44; however&#44; may not necessarily correlate with prognosis in cutaneous melanoma&#46; The prognostic value of vitamin D in melanoma needs to be studied by analyzing levels as a continuous variable across a wide range of measurements and in larger studies&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">While our findings show a direct association between vitamin D serum levels and prognosis in melanoma&#44; they also point to an indirect association&#46; They showed&#44; for example&#44; a link between low vitamin D levels &#40;&#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; and ulceration&#46; Previous studies have reported associations between low levels and greater Breslow thickness&#44;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">10&#44;11&#44;14&#44;17&#8211;19</span></a> a higher mitotic rate&#44;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">18&#44;20</span></a> a higher clinical stage&#44;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">11&#44;17</span></a> and ulceration&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">11&#44;15&#44;17&#44;18&#44;20</span></a> Bade et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">14</span></a> found that older melanoma patients had lower vitamin D levels&#44; although other studies have reported an inverse relationship&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">11&#44;12</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Neither our findings nor those of previous studies indicate a cause-effect relationship between vitamin D serum level and survival in cutaneous melanoma&#46; Rather&#44; they show a direct and indirect correlation between low levels and prognosis&#46; More prospective studies and clinical trials are needed to investigate the impact of vitamin D supplementation in this setting&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">The strengths of this study include the prospective recording of data&#44; adjustment for key prognostic factors in melanoma&#44; and the use of iterative looping to determine the vitamin D cutoff level most closely associated with survival&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Limitations include the small number of patients in certain categories and the considerable difference in the size of the 2 groups &#40;95&#46;5&#37; of patients had a vitamin D level<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41;&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">In conclusion&#44; vitamin D serum levels &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL are associated with worse prognosis in cutaneous melanoma&#46; More studies analyzing larger samples and vitamin D levels as a continuous variable are needed to identify a more accurate cutoff associated with survival in this setting and to examine the usefulness of vitamin D measurements in routine clinical practice&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflicts of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Abstract"
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            0 => array:2 [
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              "titulo" => "Introduction"
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          "titulo" => "Keywords"
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              "titulo" => "Materiales y m&#233;todos"
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              "identificador" => "abst0040"
              "titulo" => "Resultados"
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              "titulo" => "Conclusi&#243;n"
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          "identificador" => "xpalclavsec1518639"
          "titulo" => "Palabras clave"
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              "titulo" => "Statistical analysis"
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          "titulo" => "Results"
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              "titulo" => "Overall survival"
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          "titulo" => "Discussion"
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          "titulo" => "Conflicts of interest"
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          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2021-09-01"
    "fechaAceptado" => "2021-11-01"
    "PalabrasClave" => array:2 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1518640"
          "palabras" => array:4 [
            0 => "Vitamin D"
            1 => "Melanoma"
            2 => "Survival analysis"
            3 => "Prognosis"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
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          "palabras" => array:4 [
            0 => "Vitamina D"
            1 => "Melanoma"
            2 => "An&#225;lisis de supervivencia"
            3 => "Pron&#243;stico"
          ]
        ]
      ]
    ]
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    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Vitamin D plays a fundamental role in many metabolic pathways&#44; including those involved in cell proliferation and the immune response&#46; Serum levels of this vitamin have been linked to melanoma risk and prognosis&#46; This study aimed to assess the prognostic value of vitamin D serum level in melanoma&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Material and methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Retrospective&#44; observational&#44; longitudinal&#44; and analytical study of 286 patients with a histologic diagnosis of melanoma in whom serum levels of vitamin D were measured at the time of diagnosis&#46; We analyzed associations between serum level and epidemiologic and clinical variables and pathology findings&#59; we also analyzed the influence of vitamin D on overall survival&#46; An iterative loop was used to identify a vitamin D serum level to test for its an association with survival&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A vitamin D level less than 9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL was associated with a histologic finding of ulceration&#46; After a median follow-up period of 39&#46;4 months&#44; 24 patients &#40;8&#46;4&#37;&#41; had died&#46; The cutoff of 9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL was associated with lower overall survival according to both the Kaplan&#8211;Meier curves and multivariate Cox regression analysis&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusion</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Vitamin D levels less than 9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL are associated with ulceration in melanoma and serve as an independent prognostic factor for overall survival in this disease&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Introduction"
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          1 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Material and methods"
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          2 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Results"
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            "titulo" => "Conclusion"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducci&#243;n</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La vitamina D tiene un rol fundamental en m&#250;ltiples v&#237;as metab&#243;licas&#44; incluidas v&#237;as implicadas en la proliferaci&#243;n celular y la respuesta inmune&#46; Sus niveles han mostrado una asociaci&#243;n con el riesgo de desarrollar el melanoma cut&#225;neo y su pron&#243;stico&#46; El objetivo de este estudio fue evaluar si los niveles s&#233;ricos de vitamina D influyen en el pron&#243;stico del melanoma&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Materiales y m&#233;todos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Estudio de cohorte retrospectivo&#44; observacional&#44; longitudinal y anal&#237;tico en 286 pacientes con diagn&#243;stico histol&#243;gico de melanoma&#44; en los que se midieron los niveles s&#233;ricos de vitamina D en el momento del diagn&#243;stico&#46; Se analiz&#243; la relaci&#243;n entre los niveles de vitamina D y las caracter&#237;sticas epidemiol&#243;gicas&#44; cl&#237;nicas y patol&#243;gicas de los pacientes&#44; y el efecto de la vitamina D en la supervivencia global de los pacientes&#46; Mediante un bucle iterativo se encontr&#243; el punto de corte de los niveles s&#233;ricos de vitamina D de 9&#44;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL para su relaci&#243;n con la supervivencia&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Resultados</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Un nivel bajo de vitamina D &#40;&#60;9&#44;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; se relacion&#243; con la ulceraci&#243;n en el an&#225;lisis histol&#243;gico&#46; Tras una mediana de seguimiento de 39&#44;4 meses&#44; 24 pacientes &#40;8&#44;4&#37;&#41; fallecieron&#46; Unos niveles de vitamina D<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>9&#44;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL se asociaron con una menor supervivencia global&#44; tanto en el an&#225;lisis a trav&#233;s de curvas de Kaplan-Meier&#44; como tras la regresi&#243;n de Cox multivariada&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusi&#243;n</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Los niveles<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>9&#44;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL de vitamina D se asocian a la presencia de ulceraci&#243;n histol&#243;gica en el melanoma y son un factor pron&#243;stico independiente para la supervivencia global en estos pacientes&#46;</p></span>"
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            "titulo" => "Resultados"
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            "titulo" => "Conclusi&#243;n"
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    "NotaPie" => array:1 [
      0 => array:3 [
        "etiqueta" => "1"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">These authors contributed equally to this study&#46;</p>"
        "identificador" => "fn0005"
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    ]
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        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
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        "mostrarDisplay" => false
        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Overall survival was significantly worse in patients with a vitamin D serum level &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL versus &#8805;9&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#46;</p>"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Abbreviation&#58; MD&#44; missing data&#46;</p>"
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t" scope="col">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  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total <span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>286</th><th class="td" title="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">154&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">56&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">123&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">43&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">30&#46;8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&#46;563&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Histologic subtype</span></td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>SSM&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8804;2<span class="elsevierStyleHsp" style=""></span>mm&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;2<span class="elsevierStyleHsp" style=""></span>mm&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Mitotic rate &#40;MD</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#61;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">4&#41;</span></td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8804;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Ulceration &#40;MD</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#61;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">1&#41;</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">&#46;026&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">244&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  """
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                  \t\t\t\t">0&#46;1&#8211;0&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;4&#8211;4&#46;0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ALM&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;2&#8211;4&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Other&#47;not specified&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;1&#8211;3&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;451&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Breslow thickness</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8804;2<span class="elsevierStyleHsp" style=""></span>mm&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;2<span class="elsevierStyleHsp" style=""></span>mm&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;7&#8211;13&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " colspan="4" align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8804;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="4" align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ulceration &#40;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#41;</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Yes&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">4&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#62;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8805;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;005&nbsp;\t\t\t\t\t\t\n
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                  """
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;8&#8211;10&#46;4&nbsp;\t\t\t\t\t\t\n
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Original Article
Prognostic Value of Vitamin D Serum Levels in Cutaneous Melanoma
Efecto de los niveles séricos de vitamina D en el pronóstico del melanoma cutáneo
R. Moroa,b,1, A. Sánchez-Silvac,1, M. Aguerralde-Martind, R. González-Cuevase,f, L. Peruilh-Bagolinif,g, V. Travesh, E. Manrique-Silvaa,i, C. Requenai, E. Nagored,i,
Corresponding author
eduardo.nagore@ucv.es

Corresponding author.
a Escuela de Doctorado, Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain
b Clinica San Carlo, Paderno Dugnano, Italy
c Facultad de Medicina, Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain
d Máster de Ingeniería de Análisis de Datos, Toma de Decisiones y Mejora de Procesos, Universidad Politécnica de Valencia, Valencia, Spain
e Servicio de Dermatología, Hospital del Salvador, Santiago, Chile
f Facultad de Medicina, Universidad de Chile, Santiago, Chile
g Fundación Arturo López Pérez (FALP), Oncologic Institute, Santiago, Chile
h Servicio de Anatomía Patológica, Instituto Valenciano de Oncología, Valencia, Spain
i Servicio de Dermatología, Instituto Valenciano de Oncología, Valencia, Spain
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and vitamin D<span class="elsevierStyleInf">3</span> &#40;cholecalciferol&#41;&#46; While they can both be obtained from diet&#44; 90&#37; of vitamin D<span class="elsevierStyleInf">3</span> is obtained via skin exposure to UV radiation from the sun&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">3</span></a> Excessive exposure&#44; however&#44; contributes to skin aging and favors the development of skin cancer&#46; It is not surprising thus that patients with melanoma are often found to have low vitamin D levels during follow-up&#44; as they tend to take extreme measures to protect themselves from the sun&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> Vitamin D may be involved in the natural history of cancer because it supports the proper function of the immune system and also has a role in cell division&#44; where it induces differentiation and apoptosis and inhibits cell proliferation and angiogenesis in both normal and cancer cells&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Vitamin D levels and germline vitamin D receptor polymorphisms could have a pathogenic role in cutaneous melanoma&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">5&#8211;9</span></a> Previous studies have suggested that vitamin D might be of prognostic value in melanoma&#44; with low levels indicating potentially shorter survival&#44; independently of well-known poor prognosis factors&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">10&#8211;16</span></a> The studies to date&#44; however&#44; have used highly heterogeneous methods&#44; especially in terms of how vitamin D serum levels are measured&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of this study was to evaluate the prognostic value of vitamin D serum levels in a retrospective cohort of patients with cutaneous melanoma&#44; with adjustment for key prognostic markers and use of a specific statistical methodology to select an optimal vitamin D serum cutoff associated with survival&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Study design</span><p id="par0025" class="elsevierStylePara elsevierViewall">We conducted a retrospective&#44; observational&#44; longitudinal&#44; analytical cohort study of patients with a histologic diagnosis of localized &#40;stage I and II&#41; melanoma and data on vitamin D serum level at the time of diagnosis&#46; The patients were seen at Instituto Valenciano de Oncolog&#237;a in Valencia&#44; Spain&#44; between February 1&#44; 2011 and November 30&#44; 2020&#46; All the patients provided informed consent for inclusion in this study&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">In order to evaluate the prognostic value of vitamin D serum level&#44; the patients were divided into 2 groups&#58; those with a level &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL and those with a higher level&#46; This cutoff of 9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL was identified using an iterative loop&#44; described in the statistical analysis section&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Independent variables were sex&#44; age &#40;&#60;65 years vs&#46; &#8805;65 years&#41;&#44; tumor location &#40;head&#47;neck vs&#46; upper extremity vs&#46; trunk vs&#46; lower extremity vs&#46; acral site&#41;&#44; histologic subtype &#40;lentigo maligna melanoma &#91;LMM&#93; vs&#46; superficial spreading melanoma &#91;SSM&#93; vs&#46; nodular melanoma &#91;NM&#93; vs&#46; acral lentiginous melanoma &#91;ALM&#93; vs&#46; other&#47;unspecified&#41;&#44; Breslow thickness &#40;&#8804;2<span class="elsevierStyleHsp" style=""></span>mm vs&#46; &#62;2<span class="elsevierStyleHsp" style=""></span>mm&#41;&#44; mitotic rate &#40;&#8804;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span> vs&#46; &#62;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span>&#41;&#44; and a histologic finding of ulceration&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The cutoff for age was identified in the final multivariate Cox regression model&#59; the cutoffs used for Breslow thickness and mitotic rate were pre-established by the researchers&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Overall survival&#44; defined as time from primary tumor excision to death&#44; was used as the dependent variable to assess the prognostic value of vitamin D serum level&#46; Patient status was updated at the end of the study &#40;April 30&#44; 2021&#41; by consulting the national death registry&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">Continuous variables are expressed as mean &#40;SD&#41; for normally distributed variables and median &#40;interquartile range &#91;IQR&#93;&#41; otherwise&#46; Normality of distribution was checked using the Kolmogorov&#8211;Smirnov test Qualitative variables are expressed as absolute and relative frequencies&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Differences in the distributions of each variable according to vitamin D level &#40;&#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL vs&#46; &#8805;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; were evaluated using contingency tables&#46; The groups were compared using the Pearson <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span> test or&#44; when the expected count was less than 5 in at least 1 cell in the 2<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>2 tables&#44; the Fisher exact test&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Potential vitamin D cutoff points &#40;each quarter of a unit for measured levels at time of diagnosis&#41; were tested using an iterative loop in which patients were split into 2 groups to test for significant differences in survival&#46; These differences were tested using the log-rank test&#46; The cutoff showing the most significant difference between groups &#40;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; was chosen and used to build the corresponding Kaplan&#8211;Meier survival curves&#46; Univariate and multivariate Cox proportional hazards models were built using stepwise backward selection to evaluate the association between vitamin D serum level and overall survival&#46; Finally&#44; Schoenfeld residuals were used to check the proportional hazards assumption&#46; The results determined that age&#44; which was considered a continuous variable in the initial model&#44; should be entered as a categorical variable &#40;&#60;65 years vs&#46; &#8805;65 years&#41; in the final version&#46; Statistical analyses were conducted in IBM SPSS version 20&#46;0 and R Studio version 4&#46;1&#46;0&#46; All <span class="elsevierStyleItalic">P</span> values were 2-tailed and values less than &#46;05 were considered statistically significant&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><p id="par0065" class="elsevierStylePara elsevierViewall">The patients&#8217; characteristics according to vitamin D level are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; We studied 286 patients&#44; mostly men &#40;57&#37;&#41;&#44; with a median age of 57&#46;5 years &#40;IQR&#44; 45&#46;75&#8211;70 years&#41;&#46; The most common tumor was an SMM &#40;186&#44; 65&#37;&#41; located on the trunk &#40;129&#44; 45&#46;1&#37;&#41; with a Breslow thickness &#8804;2<span class="elsevierStyleHsp" style=""></span>mm &#40;234&#44; 81&#46;8&#37;&#41;&#44; a mitotic rate &#8804;5&#47;mm<span class="elsevierStyleSup">2</span> &#40;243&#44; 86&#46;2&#37;&#41;&#44; and no ulceration &#40;85&#46;6&#37;&#41;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Thirteen patients &#40;4&#46;5&#37;&#41; had a vitamin D serum level &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL while 273 &#40;95&#46;5&#37;&#41; had a level above this cutoff&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Tumor location varied significantly according to vitamin D level&#46; Patients in the lower cutoff group were significantly more likely than those with a level &#8805;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL to have LMM or ALM and significantly less likely to have SSM or NM &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;005&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Ulceration was also more common in these patients &#40;38&#46;5&#37; vs&#46; 13&#46;2&#37;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;026&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">No significant between-group differences were found for sex&#44; age&#44; location&#44; Breslow thickness&#44; or mitotic rate&#46;</p><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Overall survival</span><p id="par0085" class="elsevierStylePara elsevierViewall">Twenty-four patients &#40;8&#46;4&#37;&#41; died over a median follow-up of 39&#46;4 months&#46; Of these&#44; 5 had a vitamin D level &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;5&#47;13&#44; 38&#46;5&#37;&#41; and 19 had a level &#8805;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;19&#47;273&#44; 7&#46;0&#37;&#41;&#46; Overall survival was significantly different between the 2 groups &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0024&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">The univariate Cox regression model confirmed that patients with a vitamin D level &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL were more likely to have worse overall survival than those with a level above the cutoff &#40;hazard ratio &#91;HR&#93;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;2&#59; 95&#37; CI&#44; 0&#46;1&#8211;0&#46;7&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;005&#41;&#46; Worse survival was also observed in patients aged 65 years or older &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;6&#59; 95&#37; CI&#44; 2&#46;0&#8211;10&#46;9&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41; and patients with a Breslow thickness &#62;2<span class="elsevierStyleHsp" style=""></span>mm &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#46;1&#59; 95&#37; CI&#44; 2&#46;7&#8211;13&#46;6&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; a mitotic rate &#62;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span> &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#46;3&#59; 95&#37; CI&#44; 2&#46;8&#8211;4&#46;4&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; and ulceration &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;6&#59; 95&#37; CI&#44; 2&#46;0&#8211;10&#46;7&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46; Location on the upper extremities or trunk was associated with better overall survival &#40;&#91;upper extremity vs&#46; head&#47;neck&#58; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;2&#59; 95&#37; CI&#44; 0&#46;0&#8211;0&#46;9&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;032&#93;&#59; &#91;trunk vs&#46; head&#47;neck&#58; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;3&#59; 95&#37; CI&#44; 0&#46;1&#8211;0&#46;8&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;013&#93;&#41;&#46; Better survival was also observed in patients with SSM versus LMM &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;3&#59; 95&#37; CI&#44; 0&#46;1&#8211;0&#46;8&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;020&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">The variables included in the final multivariate model were age &#40;&#8805;65 years vs&#46; &#60;65 years&#59; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;4&#59; 95&#37; CI&#44; 1&#46;8&#8211;10&#46;4&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; mitotic rate &#40;&#62;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span> vs&#46; &#8804;5<span class="elsevierStyleHsp" style=""></span>mitoses&#47;mm<span class="elsevierStyleSup">2</span>&#59; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#46;3 95&#37; CI&#44; 2&#46;6&#8211;15&#46;1&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; ulceration &#40;yes vs&#46; no&#59; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;7&#59; 95&#37; CI&#44; 1&#46;5&#8211;9&#46;1&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;005&#41;&#44; and vitamin D level &#40;&#8805;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL vs&#46; &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#59; HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;3&#59; 95&#37; CI&#44; 0&#46;1&#8211;1&#46;0&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;050&#41;&#46; Age&#44; mitotic rate&#44; ulceration&#44; and vitamin D level were independent predictors of overall melanoma survival in the multivariate analysis &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0100" class="elsevierStylePara elsevierViewall">In this study of 286 patients with melanoma&#44; a vitamin D serum level &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL was associated with worse overall survival&#44; independently of Breslow thickness and ulceration&#40;2 key prognostic factors&#41; and other known factors such as mitotic rate and age&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Our findings are consistent with previous reports&#44; summarized in a recent meta-analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">13</span></a> Studies to date&#44; however&#44; have used highly heterogeneous methods&#44; particularly to measure serum vitamin D levels&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">In their first study of the association between vitamin D and melanoma&#44; Newton-Bishop et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a> found an association between low levels and worse recurrence-free and overall survival&#44; even after adjustment for Breslow thickness&#46; They analyzed vitamin D levels as a continuous variable and a categorical variable based on tertiles calculated using values reported for the study population&#46; In addition&#44; blood sampling was performed 3&#8211;6 months after diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">In a second study&#44; the same group observed worse melanoma-specific survival in patients with a low vitamin D level at diagnosis &#40;&#60;20<span class="elsevierStyleHsp" style=""></span>nmol&#47;L&#44; which is equivalent to &#60;8&#46;01<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#91;conversion factor&#44; 2&#46;496&#93;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">15</span></a> They also observed an improvement in survival for each 10-nmol&#47;L increase&#44; as apart from considering vitamin D as a continuous variable&#44; they also analyzed it by categories &#40;&#60;20&#44; 20&#8211;60&#44; 60&#8211;85&#44; 85&#8211;100&#44; and 100&#43; nmol&#47;L&#41;&#46; Similarly to in the first study&#44; they adjusted for Breslow thickness but not ulceration&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Timerman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a> reported worse melanoma-specific mortality in patients with a low vitamin D serum level&#44; particularly in those with metastatic melanoma&#46; They used the standard cutoff of 20<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; which is the established level for adequate bone metabolism&#46; Blood sampling was performed at different times during follow-up&#46; No adjustments were made for Breslow thickness or tumor ulceration&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">In the study by Weinsten et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">16</span></a> season-specific vitamin D levels categorized by quantiles were associated with worse prognosis in melanoma following adjustment for age&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Bade et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">14</span></a> observed shorter overall survival in patients with vitamin D serum levels in the lowest quartile compared with those in the top quartile&#46; Only univariate Kaplan&#8211;Meier curves&#44; however&#44; were used&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Unlike the above authors&#44; Saiag et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">17</span></a> found no differences in overall survival between patients with a low vitamin D level at diagnosis&#44; although they did find that variations over time &#40;both increases and decreases from baseline&#41; had prognostic value&#46; Similarly to the other authors&#44; they used quartile values as cutoff points&#46; They adjusted for both Breslow thickness and ulceration&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">17</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Fang et al&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a> used the most similar methodology to ours&#46; They used recursive partitioning to identify the split associated with the lowest <span class="elsevierStyleItalic">P</span> value in the log-rank test&#46; On applying the cutoff identified&#8212;16<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#8212;they found that patients with lower levels had significantly worse melanoma-specific&#44; disease-free&#44; and overall survival after adjustment for logarithmic C-reactive protein&#44; age&#44; sex&#44; clinical stage&#44; and blood draw season in the multivariate model&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">We identified a cutoff of 9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL in our study using an iterative loop and log-rank testing&#46; This methodology&#44; while different to that of Fang et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a> enabled us to identify the cutoff showing the most significant survival difference between groups&#46; Another methodological difference was that we adjusted for Breslow thickness and tumor ulceration rather than clinical stage &#40;III&#47;IV vs&#46; I&#47;II&#41; in the multivariate model&#46; We also adjusted for mitotic rate&#46; While this factor is no longer used to determine clinical stage in the latest melanoma staging system of the American Joint Committee on Cancer&#44;&#8217; it is still an important determinant of prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Methodologies such as that used in the present study are interesting because most studies to date have used reference values related to bone metabolism to analyze vitamin D levels&#46; These values&#44; however&#44; may not necessarily correlate with prognosis in cutaneous melanoma&#46; The prognostic value of vitamin D in melanoma needs to be studied by analyzing levels as a continuous variable across a wide range of measurements and in larger studies&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">While our findings show a direct association between vitamin D serum levels and prognosis in melanoma&#44; they also point to an indirect association&#46; They showed&#44; for example&#44; a link between low vitamin D levels &#40;&#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; and ulceration&#46; Previous studies have reported associations between low levels and greater Breslow thickness&#44;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">10&#44;11&#44;14&#44;17&#8211;19</span></a> a higher mitotic rate&#44;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">18&#44;20</span></a> a higher clinical stage&#44;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">11&#44;17</span></a> and ulceration&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">11&#44;15&#44;17&#44;18&#44;20</span></a> Bade et al&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">14</span></a> found that older melanoma patients had lower vitamin D levels&#44; although other studies have reported an inverse relationship&#46;<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">11&#44;12</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Neither our findings nor those of previous studies indicate a cause-effect relationship between vitamin D serum level and survival in cutaneous melanoma&#46; Rather&#44; they show a direct and indirect correlation between low levels and prognosis&#46; More prospective studies and clinical trials are needed to investigate the impact of vitamin D supplementation in this setting&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">The strengths of this study include the prospective recording of data&#44; adjustment for key prognostic factors in melanoma&#44; and the use of iterative looping to determine the vitamin D cutoff level most closely associated with survival&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Limitations include the small number of patients in certain categories and the considerable difference in the size of the 2 groups &#40;95&#46;5&#37; of patients had a vitamin D level<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41;&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">In conclusion&#44; vitamin D serum levels &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL are associated with worse prognosis in cutaneous melanoma&#46; More studies analyzing larger samples and vitamin D levels as a continuous variable are needed to identify a more accurate cutoff associated with survival in this setting and to examine the usefulness of vitamin D measurements in routine clinical practice&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflicts of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Vitamin D plays a fundamental role in many metabolic pathways&#44; including those involved in cell proliferation and the immune response&#46; Serum levels of this vitamin have been linked to melanoma risk and prognosis&#46; This study aimed to assess the prognostic value of vitamin D serum level in melanoma&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Material and methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Retrospective&#44; observational&#44; longitudinal&#44; and analytical study of 286 patients with a histologic diagnosis of melanoma in whom serum levels of vitamin D were measured at the time of diagnosis&#46; We analyzed associations between serum level and epidemiologic and clinical variables and pathology findings&#59; we also analyzed the influence of vitamin D on overall survival&#46; An iterative loop was used to identify a vitamin D serum level to test for its an association with survival&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">A vitamin D level less than 9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL was associated with a histologic finding of ulceration&#46; After a median follow-up period of 39&#46;4 months&#44; 24 patients &#40;8&#46;4&#37;&#41; had died&#46; The cutoff of 9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL was associated with lower overall survival according to both the Kaplan&#8211;Meier curves and multivariate Cox regression analysis&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusion</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Vitamin D levels less than 9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL are associated with ulceration in melanoma and serve as an independent prognostic factor for overall survival in this disease&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducci&#243;n</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La vitamina D tiene un rol fundamental en m&#250;ltiples v&#237;as metab&#243;licas&#44; incluidas v&#237;as implicadas en la proliferaci&#243;n celular y la respuesta inmune&#46; Sus niveles han mostrado una asociaci&#243;n con el riesgo de desarrollar el melanoma cut&#225;neo y su pron&#243;stico&#46; El objetivo de este estudio fue evaluar si los niveles s&#233;ricos de vitamina D influyen en el pron&#243;stico del melanoma&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Materiales y m&#233;todos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Estudio de cohorte retrospectivo&#44; observacional&#44; longitudinal y anal&#237;tico en 286 pacientes con diagn&#243;stico histol&#243;gico de melanoma&#44; en los que se midieron los niveles s&#233;ricos de vitamina D en el momento del diagn&#243;stico&#46; Se analiz&#243; la relaci&#243;n entre los niveles de vitamina D y las caracter&#237;sticas epidemiol&#243;gicas&#44; cl&#237;nicas y patol&#243;gicas de los pacientes&#44; y el efecto de la vitamina D en la supervivencia global de los pacientes&#46; Mediante un bucle iterativo se encontr&#243; el punto de corte de los niveles s&#233;ricos de vitamina D de 9&#44;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL para su relaci&#243;n con la supervivencia&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Resultados</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Un nivel bajo de vitamina D &#40;&#60;9&#44;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41; se relacion&#243; con la ulceraci&#243;n en el an&#225;lisis histol&#243;gico&#46; Tras una mediana de seguimiento de 39&#44;4 meses&#44; 24 pacientes &#40;8&#44;4&#37;&#41; fallecieron&#46; Unos niveles de vitamina D<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>9&#44;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL se asociaron con una menor supervivencia global&#44; tanto en el an&#225;lisis a trav&#233;s de curvas de Kaplan-Meier&#44; como tras la regresi&#243;n de Cox multivariada&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusi&#243;n</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Los niveles<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>9&#44;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL de vitamina D se asocian a la presencia de ulceraci&#243;n histol&#243;gica en el melanoma y son un factor pron&#243;stico independiente para la supervivencia global en estos pacientes&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Introducci&#243;n"
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          1 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Materiales y m&#233;todos"
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          2 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0045"
            "titulo" => "Conclusi&#243;n"
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    "NotaPie" => array:1 [
      0 => array:3 [
        "etiqueta" => "1"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">These authors contributed equally to this study&#46;</p>"
        "identificador" => "fn0005"
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    ]
    "multimedia" => array:5 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Overall survival was significantly worse in patients with a vitamin D serum level &#60;9&#46;25<span class="elsevierStyleHsp" style=""></span>ng&#47;mL versus &#8805;9&#46;25<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#46;</p>"
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      1 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Abbreviation&#58; MD&#44; missing data&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total <span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>286</th><th class="td" title="\n
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                  \t\t\t\t">107&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Upper extremity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Trunk&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Lower extremity&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Acral site&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="7" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Histologic subtype</span></td><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>LMM&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>SSM&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NM&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ALM&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">95&#37; CI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">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  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Sex</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;3&#8211;1&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;320&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Age</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#60;65 y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8805;65 y&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;0&#8211;10&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Tumor location</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Head&#47;neck&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Upper extremity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;0&#8211;0&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#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="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Trunk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;1&#8211;0&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Lower extremity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;2&#8211;1&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;229&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Acral site&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;3&#8211;4&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;909&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Histologic subtype</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>LMM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>SSM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;1&#8211;0&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;020&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>NM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;4&#8211;4&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;765&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>ALM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;2&#8211;4&#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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;938&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Other&#47;not specified&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#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="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;1&#8211;3&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#46;451&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Breslow thickness</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8804;2<span class="elsevierStyleHsp" style=""></span>mm&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
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ISSN: 00017310
Original language: English
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