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Effectiveness was evaluated at 2 months<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> and was classified as follows&#58; complete response if no abnormalities were detected in the treated area &#40;normal skin&#41;&#59; partial response if the abnormalities had diminished but were still present to some degree&#44; making a cycle of any other treatment necessary&#59; and no response if the lesions were unchanged&#46; The regimen prescribed was 3 doses for facial lesions and 2 doses if the site affected was on the body&#46; Correct adherence to treatment was defined as the application by the patient of all the doses prescribed&#59; if any dose was skipped&#44; adherence was defined as partial&#46; To assess tolerance&#44; the patients were asked about localized irritation at the site of application using the terminology specified in the Summary of Product Characteristics &#40;minimum&#44; type I&#59; mild&#44; type II&#59; moderate&#44; type III&#59; and severe&#44; type IV&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">The mean age of the group of patients treated was 76 years&#46; Only 1 patient had a history of melanoma skin cancer&#44; and 3 patients a history of non-melanoma skin cancer&#46; None of the prior skin cancer lesions were located in the area treated with ingenol mebutate&#46; Fourteen of the 17 patients &#40;82&#37;&#41; had previously received treatment for AKs&#44; mainly cryotherapy &#40;76&#37;&#41;&#44; imiquimod &#40;29&#37;&#41;&#44; or diclofenac &#40;29&#37;&#41;&#46; The mean interval between the last prior treatment and application of ingenol mebutate was 20 months &#40;median&#44; 6 months&#41;&#46; All the patients in the present study received treatment with ingenol mebutate for AK lesions on the face &#40;76&#37;&#59; 13&#47;17&#41; or scalp &#40;24&#37;&#59; 4&#47;17&#41;&#46; The response to treatment was complete in 35&#37; &#40;6&#47;17&#41; and partial in 53&#37; &#40;9&#47;17&#41;&#46; In 2 cases &#40;12&#37;&#41;&#44; there was no response&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a> shows a case of complete response to ingenol mebutate&#46; Long-term follow-up was variable after the assessment of response at 2 months post-treatment&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the maximum follow-up period and the clinical outcome at the end of follow-up for the patients who presented a complete response &#40;mean&#58; 10 mo&#44; median&#58; 11 mo&#59; complete remission in 67&#37; of cases&#41;&#46; Adherence was correct in 94&#37; &#40;16&#47;17&#41; of the patients&#46; The only case in which there was partial compliance was due to a type IV local reaction after application of the first dose&#59; the following 2 applications were not administered because of the severe symptoms associated with that reaction &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; In addition to that case&#44; 2 other patients had local type IV reactions &#40;3&#47;17 in total&#44; 18&#37;&#41;&#46; The rates for type III and type I&#47;II reactions were similar&#58; 41&#37; in both groups&#46; No relationship was observed between the severity of the reaction and a better or worse response &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;4&#59; Fisher test&#41;&#46; None of the patients reported cosmetic alterations or scarring in the treated area&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0025" class="elsevierStylePara elsevierViewall">In this case series of patients treated with ingenol mebutate in routine clinical practice&#44; we observed a response rate of 88&#37; &#40;complete response&#44; 35&#37;&#59; partial response&#44; 53&#37;&#41;&#44; high adherence &#40;94&#37;&#41;&#44; and frequent local skin reactions &#40;minimal to mild&#44; 41&#37;&#59; moderate to severe&#44; 59&#37;&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The response rates in this study were slightly lower than those reported in the literature &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> It has been observed that the success rate may be higher when ingenol mebutate is combined with other therapies &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">It is difficult to perform a direct comparison of the different treatment options for AK due to the heterogeneity of the available studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">4&#44;5</span></a><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarizes the results of studies which&#44; based on the best scientific evidence&#44; analyze the effectiveness of various interventions&#44; including ingenol mebutate&#46; In terms of effectiveness&#44; ingenol mebutate is ranked midway between the most effective treatment &#40;5-fluorouracil&#41; and the least effective options &#40;cryotherapy and diclofenac&#41;&#44; achieving results comparable to treatments of intermediate effectiveness &#40;photodynamic therapy and IMQ&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">6&#44;7</span></a> In the case of ingenol mebutate&#44; relative effectiveness is influenced by the site of treatment&#44; with higher rates of clearance for the head region&#44; for which it has proved more effective than 5&#37; IMQ&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">With respect to adherence to treatment&#44; 94&#37; of our patients completed treatment&#44; a percentage similar to that reported by other authors&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> Adherence to treatment with ingenol mebutate is much higher than with other patient-applied topical therapies &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a> a phenomenon that can be explained by the short treatment cycle required&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">9</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Although localized skin reactions at the site of application of ingenol mebutate are common &#40;&#62;96&#37;&#41;&#44; these usually occur after the treatment cycle has been completed and do not&#44; therefore&#44; lead the patients to abandon treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a> Local inflammatory reactions in the treated area are also common during the administration of the other topical treatments used to treat AK&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The retrospective design of the present study has allowed us to describe the characteristics of treatment with ingenol mebutate in clinical practice&#46; However&#44; it also has several limitations&#46; Since no histological analysis is available of the lesions in the treated area&#44; the selection of non-hyperkeratotic or &#8220;superficial&#8221; AKs was necessarily subjective&#46; This subjectivity may have given rise to minor differences in the severity of the treated area and could therefore have affected our results&#46; In the absence of any exact count of the number of lesions at baseline&#44; there was also a degree of subjectivity in the assessment of whether response was complete or partial&#46; The early assessment of response to treatment &#40;at 2 months&#41; may also have positively influenced our results&#46; Nonetheless&#44; we considered 2 months to be the best moment for this evaluation because it allowed us to assess all the patients in the study at the same time point since the prescribing physicians followed the indications of the Summary of Product Characteristics with respect to the timing of follow-up&#46; Finally&#44; the small number of patients treated makes it difficult to compare our results with other studies&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Our conclusion is that ingenol mebutate is useful in the treatment of AKs and field cancerization&#44; and that the dosage used favors adherence to treatment&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Ethical Disclosures</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Protection of human and animal subjects</span><p id="par0060" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed adhered to the ethical guidelines of the responsible committee on human experimentation and comply with the Declaration of Helsinki of the World Medical Association&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Data confidentiality</span><p id="par0065" class="elsevierStylePara elsevierViewall">The authors declare that they followed the protocols of their institution with respect to the publication of private patient data&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Right to privacy and informed consent</span><p id="par0070" class="elsevierStylePara elsevierViewall">The authors obtained the informed consent of the patients and&#47;or subjects referred to in this article&#46; These documents are in the possession of the corresponding author&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflicts of Interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">Ana Batalla and &#193;ngeles Fl&#243;rez have received lecture fees from Leo-Pharma Spain for interventions on the topic of actinic keratosis&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">The other authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xres586320"
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        1 => array:2 [
          "identificador" => "xpalclavsec602166"
          "titulo" => "Keywords"
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          "identificador" => "xres586321"
          "titulo" => "Resumen"
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          "identificador" => "xpalclavsec602165"
          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
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          "identificador" => "sec0010"
          "titulo" => "Case Descriptions"
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        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Discussion"
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          "identificador" => "sec0020"
          "titulo" => "Ethical Disclosures"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Protection of human and animal subjects"
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            1 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Data confidentiality"
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            2 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Right to privacy and informed consent"
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        8 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Conflicts of Interest"
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        9 => array:1 [
          "titulo" => "References"
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    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec602166"
          "palabras" => array:4 [
            0 => "Actinic keratosis"
            1 => "Effectiveness"
            2 => "Ingenol mebutate"
            3 => "Treatment"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec602165"
          "palabras" => array:4 [
            0 => "Queratosis act&#237;nica"
            1 => "Efectividad"
            2 => "Ingenol mebutato"
            3 => "Tratamiento"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Cryotherapy is the most common treatment for actinic keratosis&#44; but its effect is limited to individual lesions&#46; Several topical drugs&#44; however&#44; are available that&#44; in addition to treating individual actinic keratoses&#44; target field cancerization and thereby act on subclinical lesions&#46; Examples are 5-fluorouracil&#44; imiquimod&#44; diclofenac&#44; and ingenol mebutate&#46; We report on 17 patients with actinic keratoses treated with ingenol mebutate and describe our findings on treatment effectiveness&#44; adherence&#44; and tolerance&#46; Complete and partial response rates were 35&#37; and 53&#37;&#44; respectively&#46; Ninety-four percent of patients fully adhered to treatment and 18&#37; developed severe local reactions&#46; Ingenol mebutate is an effective treatment for actinic keratosis&#46; Although it has a similar rate of local reactions to other treatments available for actinic keratosis&#44; its short treatment regimen favors better adherence&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La crioterapia es el tratamiento m&#225;s frecuentemente utilizado para las queratosis act&#237;nicas&#44; ejerciendo su efecto &#250;nicamente sobre lesiones individuales&#46; Existen f&#225;rmacos t&#243;picos que tratan adem&#225;s el campo de cancerizaci&#243;n&#44; actuando sobre queratosis act&#237;nicas no cl&#237;nicamente evidentes&#44; entre los que se encuentran el 5-fluorouracilo&#44; el imiquimod&#44; el diclofenaco o el ingenol mebutato&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Presentamos 17 pacientes con queratosis act&#237;nicas tratados con ingenol mebutato y describimos las observaciones en relaci&#243;n con la efectividad&#44; el cumplimiento terap&#233;utico y la tolerancia del f&#225;rmaco&#46; Las tasas de respuesta completa y parcial fueron del 35&#37; y del 53&#37;&#44; respectivamente&#46; El cumplimiento fue correcto en un 94&#37; de los casos&#46; En el 18&#37; de los pacientes existieron reacciones locales intensas&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">El ingenol mebutato es efectivo para el tratamiento de las queratosis act&#237;nicas&#46; Aunque presenta similar tasa de reacciones locales a los restantes tratamientos disponibles para esta indicaci&#243;n&#44; su pauta corta de administraci&#243;n favorece el cumplimiento&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as&#58; Batalla A&#44; Fl&#243;rez &#193;&#44; Feal C&#44; Pe&#243;n G&#44; Abalde MT&#44; Salgado-Boquete L&#44; et al&#46; Respuesta a ingenol mebutato en los pacientes con queratosis act&#237;nicas en la pr&#225;ctica cl&#237;nica&#46; Actas Dermosifiliogr&#46; 2015&#59;106&#58;e55&#8211;e61&#46;</p>"
      ]
    ]
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      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
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        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 975
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            "Tamanyo" => 223019
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        "descripcion" => array:1 [
          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Complete response to ingenol mebutate&#46; A&#44; Actinic keratosis on the nasal pyramid&#46; B&#44; Complete response at 2 months&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 514
            "Ancho" => 1600
            "Tamanyo" => 179442
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        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Partial Response to ingenol mebutate following treatment that was not completed due to a type <span class="elsevierStyleSmallCaps">iv</span> local reaction&#46; A&#44; Non-hyperkeratotic actinic keratosis on the left malar&#46; B&#44; Type <span class="elsevierStyleSmallCaps">iv</span> local reaction after administration of the first single dose of ingenol mebutate&#59; the following 2 applications were not administered&#46; C&#44; Residual actinic keratosis&#46; The patient required an additional session of cryotherapy&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; 5-FU&#44; 5-fluorouracil&#59; BCC&#44; basal cell carcinoma&#59; CT&#44; Cryotherapy&#59; DCF&#44; diclofenac&#59; ELC&#44; electrocoagulation&#59; IMQ&#44; imiquimod&#59; LM&#44; lentigo maligna&#59; M&#44; Man&#59; NMSC&#44; nonmelanoma skin cancer&#59; PDT&#44; photodynamic therapy&#59; SCC&#44; squamous cell carcinoma&#59; W&#44; woman&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col">Age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Past History of Skin Cancer</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Previous Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Time Since Last Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Site&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Adherence<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Tolerance<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> &#40;Severity of Reaction&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Effectiveness<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Maximum Follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Melanoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">NMSC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;LM&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;BCC&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Facial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17 months &#40;No recurrence&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Facial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 months &#40;no recurrence&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;BCC&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;CT&#44; IMQ&#44; 5-FU&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 months &#40;CT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Facial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#47;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Partial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">82&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;CT&#44; DCF&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 months &#40;CT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Facial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Partial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">78&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;CT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 months &#40;CT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Facial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#47;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Partial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;CT&#44; ELC&#44; IMQ&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 y &#40;CT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Scalp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Partial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;CT&#44; DCF&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 months &#40;DCF&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Facial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#47;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Partial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">93&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;CT&#44; IMQ&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 months &#40;CT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Scalp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">86&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Scalp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;CT&#44; DIC&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 months &#40;DCF&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Facial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Partial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">77&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;CT&#44; DCF&#44; PDT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Facial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#47;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Partial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">64&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;CT&#44; IMQ&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7 months &#40;CT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Facial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10 months &#40;no recurrence&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">74&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;BCC&#44; SCC&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;CT&#44; IMQ&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 months &#40;CT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Scalp&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">I&#47;II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 months &#40;relapse&#58; 3 lesions&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">81&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;CT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 months &#40;CT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Facial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Partial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">51&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Facial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Partial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Partial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;CT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5 y &#40;CT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Facial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">89&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">W&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">None&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Yes &#40;CT&#44; DCF&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3 months &#40;DCF&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Facial&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Correct&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 months &#40;relapse&#58; 1 lesion&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab957420.png"
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            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The definitions used to classify adherence&#44; tolerability&#44; and effectiveness are described in the text&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Patients Treated With Ingenol Mebutate&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; 5-FU&#44; 5-fluorouracil&#59; ALA&#44; 5-aminolaevulinic acid&#59; AK&#44; actinic keratosis&#59; CT&#44; cryotherapy&#59; DCF&#44; diclofenac&#59; IM&#44; ingenol mebutate&#59; IMQ&#44; imiquimod&#59; MAL&#44; methyl aminolaevulinate&#59; PDT&#44; photodynamic therapy&#59; RCT&#44; randomized clinical trial&#46;</p>"
          "tablatextoimagen" => array:5 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Effectiveness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Lebwohl et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Phase 3 RCT- Effectiveness on face and scalp&#58; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>547 &#40;277 IM&#44; 270 placebo&#41;-Effectiveness on trunk and limbs<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>458 &#40;226 IM&#44; 232 placebo&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IM vs placeboObjective&#58; complete clearance rate &#40;assessment at 57 days&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete clearance&#58;AK on face and scalp&#58; 42&#37;AK on trunk and limbs&#58; 34&#37;Partial response &#40;clearance &#8805; 75&#37;&#41;&#58;AK on face and scalp&#58; 64&#37;AK on trunk and limbs&#58; 49&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Berman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Phase 3 RCTn<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>329&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IM<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>CT vs CTObjectives&#58;- Complete clearance rate at wk 11- Effectiveness at 12 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Complete clearance at wk 11CT and IM&#58; 61&#37;CT&#58; 49&#37;Complete clearance at 12 monthsCT and IM&#58; 55&#37;CT&#58; 40&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Vegter et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">7</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Meta-analysis25 RCTsn<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5562&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treatments for AK on face or scalp&#46;Objective&#58; to achieve complete clearance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">ALA-PDT gel&#58; 85&#46;3&#37;MAL-PDT&#58; 65&#46;9&#37;ALA-PDT patch&#58; 62&#37;5&#37; IMQ 4-wk&#58; 57&#46;2&#37;0&#46;5&#37; 5-FU&#58; 54&#46;6&#37;CT&#58; 49&#46;1&#37;5&#37; IMQ 16-wk&#58; 45&#46;1&#37;IM&#58; 43&#37;3&#37; DCF&#58; 35&#46;4&#37;3&#46;75&#37; IMQ 2- or 3-wk&#58; 34&#46;8&#37;Placebo&#58; 6&#46;9&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab957418.png"
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            1 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Effectiveness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Gupta and Paquet<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">6</span></a> &#40;Cochrane review update&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Meta-analysis of36 RCTsn<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6473Data Collection&#58; up till April 2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Treatments for AKObjective&#58; to achieve complete clearance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No clearance percentage specified&#46; Treatments are shown in order of effectiveness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            2 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">All Sites&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Scalp Only&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Overall&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">5&#37; 5-FU &#62;<span class="elsevierStyleMonospace">0&#46;5&#37;</span>5-FU&#44; ALA-PDT &#62;<span class="elsevierStyleMonospace">5&#37;</span> IMQ<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>IM<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>MAL PDT<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>CT<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>DCF<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#37; 5-FU<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">0&#46;5&#37;</span>5-FU<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>IM<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">ALA</span>-PDT<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">5&#37;</span>IMQ<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleMonospace">MAL-P</span>DT<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>CT<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5-FU<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>ALA-PDT&#8776;<span class="elsevierStyleMonospace">5&#37;</span>IMQ &#8776; IM&#8776;MAL-PDT &#62;CT<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>DCF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab957416.png"
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            ]
            3 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics and Intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Local Adverse Effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Lebwohl et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">See above&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Local reactions&#58;-AK&#44; face and scalp&#58; 98&#37;Moderate-intense reactions in a &#8220;minority&#8221; of casesAK trunk and limbs&#58; 96&#37;70&#37; moderate to intense&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab957417.png"
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            4 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristics&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Adherence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Lebwohl et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">1</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">See above&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">See above&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#62;98&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="left" valign="top">Shergill et al&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">8</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cross-sectional studyn<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>305DCF&#44; 5&#37; 5-FU&#44; 5&#37; IMQ&#44; 0&#46;5&#37; 5-FU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Objective&#58; To identify adherence rate and factors conditioning adherence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Percentage of non-adherence or abandonment<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a>88&#37;Percentage of non-adherence by length of treatment52&#37; in treatments of 3-4 wks duration69&#37; in treatments of 6-8 wks duration71&#37; in treatments of 6-12 wks duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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            0 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Non-adherence indicates not using the correct dosage and abandoment indicates not completing the treatment cycle&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Main Studies That Have Assessed Effectiveness&#44; Adherence&#44; and Localized Reactions in Actinic Keratosis&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:10 [
            0 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ingenol mebutate gel for actinic keratosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46; Lebwohl"
                            1 => "N&#46; Swanson"
                            2 => "L&#46;L&#46; Anderson"
                            3 => "A&#46; Melgaard"
                            4 => "Z&#46; Xu"
                            5 => "B&#46; Berman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1111170"
                      "Revista" => array:6 [
                        "tituloSerie" => "N Engl J Med"
                        "fecha" => "2012"
                        "volumen" => "366"
                        "paginaInicial" => "1010"
                        "paginaFinal" => "1019"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22417254"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "New developments in the treatment of actinic keratosis&#58; Focus on ingenol mebutate gel"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "B&#46; Berman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2147/CCID.S28905"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Cosmet Investig Dermatol"
                        "fecha" => "2012"
                        "volumen" => "5"
                        "paginaInicial" => "111"
                        "paginaFinal" => "122"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/22956883"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Efficacy and safety of ingenol mebutate 0&#46;015&#37; gel 3 weeks after cryosurgery of actinic keratosis&#58; 11-week results"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46; Berman"
                            1 => "G&#46; Goldenberg"
                            2 => "C&#46;W&#46; Hanke"
                            3 => "S&#46;K&#46; Tyring"
                            4 => "W&#46;P&#46; Werschler"
                            5 => "K&#46;M&#46; Knudsen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Drugs Dermatol"
                        "fecha" => "2014"
                        "volumen" => "13"
                        "paginaInicial" => "154"
                        "paginaFinal" => "160"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/24509965"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Interventions for actinic keratoses"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46;K&#46; Gupta"
                            1 => "M&#46; Paquet"
                            2 => "E&#46; Villanueva"
                            3 => "W&#46; Brintnell"
                          ]
                        ]
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Journal Information
Vol. 106. Issue 10.
Pages e55-e61 (December 2015)
Visits
5807
Vol. 106. Issue 10.
Pages e55-e61 (December 2015)
E- Case Report
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Clinical Response to Ingenol Mebutate in Patients With Actinic Keratoses
Respuesta a ingenol mebutato en los pacientes con queratosis actínicas en la práctica clínica
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5807
A. Batalla
Corresponding author
anacebey@yahoo.es

Corresponding author.
, Á. Flórez, C. Feal, G. Peón, M.T. Abalde, L. Salgado-Boquete, C. de la Torre
Servicio de Dermatología, Centro de Especialidades de Mollabao, Xestión Integrada Pontevedra-Salnés, Pontevedra, Spain
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Tables (2)
Table 1. Patients Treated With Ingenol Mebutate.
Table 2. Main Studies That Have Assessed Effectiveness, Adherence, and Localized Reactions in Actinic Keratosis.
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Abstract

Cryotherapy is the most common treatment for actinic keratosis, but its effect is limited to individual lesions. Several topical drugs, however, are available that, in addition to treating individual actinic keratoses, target field cancerization and thereby act on subclinical lesions. Examples are 5-fluorouracil, imiquimod, diclofenac, and ingenol mebutate. We report on 17 patients with actinic keratoses treated with ingenol mebutate and describe our findings on treatment effectiveness, adherence, and tolerance. Complete and partial response rates were 35% and 53%, respectively. Ninety-four percent of patients fully adhered to treatment and 18% developed severe local reactions. Ingenol mebutate is an effective treatment for actinic keratosis. Although it has a similar rate of local reactions to other treatments available for actinic keratosis, its short treatment regimen favors better adherence.

Keywords:
Actinic keratosis
Effectiveness
Ingenol mebutate
Treatment
Resumen

La crioterapia es el tratamiento más frecuentemente utilizado para las queratosis actínicas, ejerciendo su efecto únicamente sobre lesiones individuales. Existen fármacos tópicos que tratan además el campo de cancerización, actuando sobre queratosis actínicas no clínicamente evidentes, entre los que se encuentran el 5-fluorouracilo, el imiquimod, el diclofenaco o el ingenol mebutato.

Presentamos 17 pacientes con queratosis actínicas tratados con ingenol mebutato y describimos las observaciones en relación con la efectividad, el cumplimiento terapéutico y la tolerancia del fármaco. Las tasas de respuesta completa y parcial fueron del 35% y del 53%, respectivamente. El cumplimiento fue correcto en un 94% de los casos. En el 18% de los pacientes existieron reacciones locales intensas.

El ingenol mebutato es efectivo para el tratamiento de las queratosis actínicas. Aunque presenta similar tasa de reacciones locales a los restantes tratamientos disponibles para esta indicación, su pauta corta de administración favorece el cumplimiento.

Palabras clave:
Queratosis actínica
Efectividad
Ingenol mebutato
Tratamiento
Full Text
Introduction

Actinic keratoses (AK) are considered by most authors to be premalignant lesions that can progress to invasive squamous cell carcinoma.1 In addition to lesion-directed therapies such as cryotherapy, the available treatment options for AK also include topical treatments that act on both the isolated—clinically visible—lesions and on the surrounding area of skin with chronic actinic damage and subclinical AK. Treatments include 5-fluorouracil, imiquimod (IMQ), diclofenac (DCF), and photodynamic therapy.1,2

Ingenol mebutate is a treatment indicated for AK that has only recently become available. It has been shown to be effective in the treatment of both individual lesions and the cancerization field, with treatment cycles of 3 consecutive days for the face and scalp and 2-day cycles for the trunk or limbs, achieving a complete cure rate of around 40%.1 The main difference between ingenol mebutate and other field cancerization therapies is that the treatment cycle is shorter and adherence to the dosing schedule is easier.

Case Descriptions

We present a series of 17 patients treated with ingenol mebutate. Demographic and clinical characteristics were evaluated as well as treatment-related data (effectiveness, adherence to treatment, and tolerance) (Table 1). Effectiveness was evaluated at 2 months2 and was classified as follows: complete response if no abnormalities were detected in the treated area (normal skin); partial response if the abnormalities had diminished but were still present to some degree, making a cycle of any other treatment necessary; and no response if the lesions were unchanged. The regimen prescribed was 3 doses for facial lesions and 2 doses if the site affected was on the body. Correct adherence to treatment was defined as the application by the patient of all the doses prescribed; if any dose was skipped, adherence was defined as partial. To assess tolerance, the patients were asked about localized irritation at the site of application using the terminology specified in the Summary of Product Characteristics (minimum, type I; mild, type II; moderate, type III; and severe, type IV).

Table 1.

Patients Treated With Ingenol Mebutate.

Age  Sex  Past History of Skin CancerPrevious Treatment  Time Since Last Treatment  Site  Adherencea  Tolerancea (Severity of Reaction)  Effectivenessa  Maximum Follow-up 
    Melanoma  NMSC               
84  Yes (LM)  Yes (BCC)  None    Facial  Correct  III  Complete  17 months (No recurrence) 
88  None  None  None    Facial  Correct  IV  Complete  12 months (no recurrence) 
86  None  Yes (BCC)  Yes (CT, IMQ, 5-FU)  6 months (CT)  Facial  Correct  I/II  Partial   
82  None  None  Yes (CT, DCF)  6 months (CT)  Facial  Correct  III  Partial   
78  None  None  Yes (CT)  6 months (CT)  Facial  Correct  I/II  Partial   
64  None  None  Yes (CT, ELC, IMQ)  10 y (CT)  Scalp  Correct  III  Partial   
68  None  None  Yes (CT, DCF)  6 months (DCF)  Facial  Correct  I/II  Partial   
93  None  None  Yes (CT, IMQ)  6 months (CT)  Scalp  Correct  None   
86  None  None  None    Scalp  Correct  None   
80  None  None  Yes (CT, DIC)  8 months (DCF)  Facial  Correct  III  Partial   
77  None  None  Yes (CT, DCF, PDT)    Facial  Correct  I/II  Partial   
64  None  None  Yes (CT, IMQ)  7 months (CT)  Facial  Correct  III  Complete  10 months (no recurrence) 
74  None  Yes (BCC, SCC)  Yes (CT, IMQ)  3 months (CT)  Scalp  Correct  I/II  Complete  5 months (relapse: 3 lesions) 
81  None  None  Yes (CT)  8 months (CT)  Facial  Correct  III  Partial   
51  None  None  None    Facial  Partial  IV  Partial   
53  None  None  Yes (CT)  5 y (CT)  Facial  Correct  IV  Complete  11 months 
89  None  None  Yes (CT, DCF)  3 months (DCF)  Facial  Correct  III  Complete  4 months (relapse: 1 lesion) 

Abbreviations: 5-FU, 5-fluorouracil; BCC, basal cell carcinoma; CT, Cryotherapy; DCF, diclofenac; ELC, electrocoagulation; IMQ, imiquimod; LM, lentigo maligna; M, Man; NMSC, nonmelanoma skin cancer; PDT, photodynamic therapy; SCC, squamous cell carcinoma; W, woman.

a

The definitions used to classify adherence, tolerability, and effectiveness are described in the text.

The mean age of the group of patients treated was 76 years. Only 1 patient had a history of melanoma skin cancer, and 3 patients a history of non-melanoma skin cancer. None of the prior skin cancer lesions were located in the area treated with ingenol mebutate. Fourteen of the 17 patients (82%) had previously received treatment for AKs, mainly cryotherapy (76%), imiquimod (29%), or diclofenac (29%). The mean interval between the last prior treatment and application of ingenol mebutate was 20 months (median, 6 months). All the patients in the present study received treatment with ingenol mebutate for AK lesions on the face (76%; 13/17) or scalp (24%; 4/17). The response to treatment was complete in 35% (6/17) and partial in 53% (9/17). In 2 cases (12%), there was no response. Figure 1 shows a case of complete response to ingenol mebutate. Long-term follow-up was variable after the assessment of response at 2 months post-treatment. Table 1 shows the maximum follow-up period and the clinical outcome at the end of follow-up for the patients who presented a complete response (mean: 10 mo, median: 11 mo; complete remission in 67% of cases). Adherence was correct in 94% (16/17) of the patients. The only case in which there was partial compliance was due to a type IV local reaction after application of the first dose; the following 2 applications were not administered because of the severe symptoms associated with that reaction (Fig. 2). In addition to that case, 2 other patients had local type IV reactions (3/17 in total, 18%). The rates for type III and type I/II reactions were similar: 41% in both groups. No relationship was observed between the severity of the reaction and a better or worse response (P=0.4; Fisher test). None of the patients reported cosmetic alterations or scarring in the treated area.

Figure 1.

Complete response to ingenol mebutate. A, Actinic keratosis on the nasal pyramid. B, Complete response at 2 months.

(0.21MB).
Figure 2.

Partial Response to ingenol mebutate following treatment that was not completed due to a type iv local reaction. A, Non-hyperkeratotic actinic keratosis on the left malar. B, Type iv local reaction after administration of the first single dose of ingenol mebutate; the following 2 applications were not administered. C, Residual actinic keratosis. The patient required an additional session of cryotherapy.

(0.17MB).
Discussion

In this case series of patients treated with ingenol mebutate in routine clinical practice, we observed a response rate of 88% (complete response, 35%; partial response, 53%), high adherence (94%), and frequent local skin reactions (minimal to mild, 41%; moderate to severe, 59%).

The response rates in this study were slightly lower than those reported in the literature (Table 2).1 It has been observed that the success rate may be higher when ingenol mebutate is combined with other therapies (Table 2).3

Table 2.

Main Studies That Have Assessed Effectiveness, Adherence, and Localized Reactions in Actinic Keratosis.

Study  Characteristics  Intervention  Effectiveness 
Lebwohl et al.1  Phase 3 RCT- Effectiveness on face and scalp: n=547 (277 IM, 270 placebo)-Effectiveness on trunk and limbs=458 (226 IM, 232 placebo)  IM vs placeboObjective: complete clearance rate (assessment at 57 days)  Complete clearance:AK on face and scalp: 42%AK on trunk and limbs: 34%Partial response (clearance ≥ 75%):AK on face and scalp: 64%AK on trunk and limbs: 49% 
Berman et al.3  Phase 3 RCTn=329  IM+CT vs CTObjectives:- Complete clearance rate at wk 11- Effectiveness at 12 months  Complete clearance at wk 11CT and IM: 61%CT: 49%Complete clearance at 12 monthsCT and IM: 55%CT: 40% 
Vegter et al.7  Meta-analysis25 RCTsn=5562  Treatments for AK on face or scalp.Objective: to achieve complete clearance  ALA-PDT gel: 85.3%MAL-PDT: 65.9%ALA-PDT patch: 62%5% IMQ 4-wk: 57.2%0.5% 5-FU: 54.6%CT: 49.1%5% IMQ 16-wk: 45.1%IM: 43%3% DCF: 35.4%3.75% IMQ 2- or 3-wk: 34.8%Placebo: 6.9% 
Study  Characteristics  Intervention  Effectiveness 
Gupta and Paquet6 (Cochrane review update)  Meta-analysis of36 RCTsn=6473Data Collection: up till April 2012  Treatments for AKObjective: to achieve complete clearance  No clearance percentage specified. Treatments are shown in order of effectiveness 
All Sites  Scalp Only  Overall 
5% 5-FU >0.5%5-FU, ALA-PDT >5% IMQ>IM>MAL PDT>CT>DCF>placebo  5% 5-FU>0.5%5-FU>IM>ALA-PDT>5%IMQ>MAL-PDT>CT>placebo  5-FU>ALA-PDT≈5%IMQ ≈ IM≈MAL-PDT >CT>DCF 
Study  Characteristics and Intervention  Local Adverse Effects 
Lebwohl et al.1  See above  Local reactions:-AK, face and scalp: 98%Moderate-intense reactions in a “minority” of casesAK trunk and limbs: 96%70% moderate to intense 
Study  Characteristics  Intervention  Adherence 
Lebwohl et al.1  See above  See above  >98% 
Shergill et al.8  Cross-sectional studyn=305DCF, 5% 5-FU, 5% IMQ, 0.5% 5-FU  Objective: To identify adherence rate and factors conditioning adherence  Percentage of non-adherence or abandonmenta88%Percentage of non-adherence by length of treatment52% in treatments of 3-4 wks duration69% in treatments of 6-8 wks duration71% in treatments of 6-12 wks duration 

Abbreviations: 5-FU, 5-fluorouracil; ALA, 5-aminolaevulinic acid; AK, actinic keratosis; CT, cryotherapy; DCF, diclofenac; IM, ingenol mebutate; IMQ, imiquimod; MAL, methyl aminolaevulinate; PDT, photodynamic therapy; RCT, randomized clinical trial.

a

Non-adherence indicates not using the correct dosage and abandoment indicates not completing the treatment cycle.

It is difficult to perform a direct comparison of the different treatment options for AK due to the heterogeneity of the available studies.4,5Table 2 summarizes the results of studies which, based on the best scientific evidence, analyze the effectiveness of various interventions, including ingenol mebutate. In terms of effectiveness, ingenol mebutate is ranked midway between the most effective treatment (5-fluorouracil) and the least effective options (cryotherapy and diclofenac), achieving results comparable to treatments of intermediate effectiveness (photodynamic therapy and IMQ).6,7 In the case of ingenol mebutate, relative effectiveness is influenced by the site of treatment, with higher rates of clearance for the head region, for which it has proved more effective than 5% IMQ.6

With respect to adherence to treatment, 94% of our patients completed treatment, a percentage similar to that reported by other authors.1 Adherence to treatment with ingenol mebutate is much higher than with other patient-applied topical therapies (Table 2),8 a phenomenon that can be explained by the short treatment cycle required.9

Although localized skin reactions at the site of application of ingenol mebutate are common (>96%), these usually occur after the treatment cycle has been completed and do not, therefore, lead the patients to abandon treatment.1 Local inflammatory reactions in the treated area are also common during the administration of the other topical treatments used to treat AK.10

The retrospective design of the present study has allowed us to describe the characteristics of treatment with ingenol mebutate in clinical practice. However, it also has several limitations. Since no histological analysis is available of the lesions in the treated area, the selection of non-hyperkeratotic or “superficial” AKs was necessarily subjective. This subjectivity may have given rise to minor differences in the severity of the treated area and could therefore have affected our results. In the absence of any exact count of the number of lesions at baseline, there was also a degree of subjectivity in the assessment of whether response was complete or partial. The early assessment of response to treatment (at 2 months) may also have positively influenced our results. Nonetheless, we considered 2 months to be the best moment for this evaluation because it allowed us to assess all the patients in the study at the same time point since the prescribing physicians followed the indications of the Summary of Product Characteristics with respect to the timing of follow-up. Finally, the small number of patients treated makes it difficult to compare our results with other studies.

Our conclusion is that ingenol mebutate is useful in the treatment of AKs and field cancerization, and that the dosage used favors adherence to treatment.

Ethical DisclosuresProtection of human and animal subjects

The authors declare that the procedures followed adhered to the ethical guidelines of the responsible committee on human experimentation and comply with the Declaration of Helsinki of the World Medical Association.

Data confidentiality

The authors declare that they followed the protocols of their institution with respect to the publication of private patient data.

Right to privacy and informed consent

The authors obtained the informed consent of the patients and/or subjects referred to in this article. These documents are in the possession of the corresponding author.

Conflicts of Interest

Ana Batalla and Ángeles Flórez have received lecture fees from Leo-Pharma Spain for interventions on the topic of actinic keratosis.

The other authors declare that they have no conflicts of interest.

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Please cite this article as: Batalla A, Flórez Á, Feal C, Peón G, Abalde MT, Salgado-Boquete L, et al. Respuesta a ingenol mebutato en los pacientes con queratosis actínicas en la práctica clínica. Actas Dermosifiliogr. 2015;106:e55–e61.

Copyright © 2014. Elsevier España, S.L.U. and AEDV
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