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chest and upper extremities&#44; with small isolated pustules &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Mucous membrane involvement was confined to the lips&#46; Neither fever nor other systemic symptoms were evident&#46; Two months before&#44; she had initiated treatment with sorafenib due to an unresectable hepatocarcinoma&#46; Skin reaction developed gradually two days after initiating the treatment&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Laboratory examination revealed a hypereosinophilia of 1&#46;4<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&#46; A skin biopsy was performed&#44; rendering typical histological features of AGEP &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Attending to the validated EuroSCAR scoring system&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> our case was then classified as a <span class="elsevierStyleItalic">Probable</span> AGEP&#46; Sorafenib was discontinued immediately&#44; and treatment with intravenous methylprednisolone 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg was initiated&#46; Cutaneous lesions improved rapidly and were almost totally resolved after a week&#46; This clinical evolution strongly supports the diagnosis of sorafenib-induced AGEP&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">AGEP is characterized by numerous&#44; small&#44; non-follicular and sterile pustules arising within extensive areas of edematous erythema&#46; Fever and leukocytosis are common findings and severe cases of AGEP can associate visceral involvement&#46; Mucous membrane might also be affected&#46; Time interval between drug administration and the skin eruption onset is typically 48<span class="elsevierStyleHsp" style=""></span>h&#44; although it varies from 1 day to 4 weeks&#46; It typically resolves in two weeks after drug discontinuation&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#44;2</span></a> Main differential diagnoses of AGEP are other pustular diseases&#44; such as pustular psoriasis&#44; and other severe cutaneous adverse reactions&#44; such as Stevens Johnson syndrome &#40;SJS&#41; or Toxic Epidermal Necrolysis&#46; Compared to AGEP&#44; in SJS&#47;NET&#44; mucosal involvement and skin detachment &#40;Nikolsky sign&#41; are a constant&#46; However&#44; the possibility of overlap of different severe cutaneous reactions have been recently discussed in the literature&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Sorafenib is a multikinase inhibitor that mainly target tumor cell angiogenesis&#44; first used in advanced renal cell cancer and unresectable hepatocellular carcinoma with recent indications in other cancers&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">4</span></a> It inhibits multiple tyrosine-kinases&#44; such as RAF-1 and B-RAF&#44; and it blocks tyrosine-kinases receptors&#44; such as platelet-derived growth factor receptor &#40;PDGFR&#41;&#44; related with carcinogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Patients under treatment with multikinase inhibitors usually develop cutaneous reactions&#46; In a prospective study&#44; up to 72&#37; of the patients taking sorafenib presented dermatological symptoms&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">4&#44;7</span></a> Most of these reactions are maculopapular rashes and other grade 1&#8211;2 severity adverse reactions that can be easily managed&#46; Other non-severe skin reactions that can be found are hand&#8211;foot skin reaction&#44; stomatitis&#44; subungual splinter hemorrhages&#44; facial erythema or alopecia&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">4&#44;7</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">However&#44; some of these patients develop SCARs related to sorafenib&#44; such as Drug Reaction with Eosynophilia and Systemic Symptoms &#40;DRESS&#41;&#44; SJS or AGEP&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">5&#44;6&#44;8&#44;9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">To our knowledge&#44; only 2 more cases of sorafenib-induced acute exanthematous pustulosis have been published&#44; being one of them an acute localized exanthematous pustulosis &#40;ALEP&#41; and the other one a complete AGEP&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">5&#44;6</span></a> The main features of these cases are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Interestingly&#44; all the three cases occurred in women who were under treatment with sorafenib due to unresectable hepatocarcinoma&#46; Cases of AGEP have also been reported associated with other multikinase inhibitors such as imatinib&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> Therefore&#59; we believe that the association between kinase-inhibitors and AGEP might be an under-reported entity with an increasing incidence due to the appearance of new drugs of this nature&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">In conclusion&#44; we report a new case of sorafenib-induced AGEP&#46; We should be aware of this cutaneous side effect of sorafenib and other multikinase inhibitors&#44; given that drug discontinuation is the key point on AGEP treatment&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interests</span><p id="par0050" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clinical evolution&#46; &#40;a&#41; Exanthema affecting mainly face&#44; upper trunk&#44; superior limbs with isolated patches on abdomen and lower extremities&#46; &#40;b&#41; Closer image showing isolated pustules surrounded by erythema&#46; &#40;c&#41; Evolution of the exanthema 5 days after Sorafenib discontinuation&#46; Mild erythema and desquamation on upper trunk with pustules resolution&#46;</p>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Histopathology&#46; HE 10&#215;&#46; Neutrophilic spongiotic subcorneal pustules&#46; Perivascular infiltrate with lymphocytes and eosinophyles&#46;</p>"
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                  <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">Case&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">Sex&#44; age &#40;years old&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sorafenib indication&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">Latency&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">Distribution&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">Fever&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">Laboratory abnormalities&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">Mucosal involvement&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">Skin biopsy&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">Resolution&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-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Liang&#44; CP et al&#46; &#40;2011&#41;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">5</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">Woman&#44; 59 yo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Localized&#58; lower limbs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Subcorneal pustules with intraepidermal spongiform&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Spontaneous improvement after sorafenib discontinuation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pretel&#44; M et al&#46; &#40;2014&#41;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">6</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">Woman&#44; 50 yo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Generalized&#58; neck&#44; abdomen&#44; buttocks and lower limbs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neutrophilia 7&#46;1<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Subcorneal pustules with papillary edema&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Spontaneous improvement after sorafenib discontinuation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Our case &#40;2016&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Woman&#44; 78 yo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Generalized&#58; chest&#44; neck&#44; facial area and upper limbs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Eosinophilia 1&#46;4<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Labial mucosa desquamation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Subcorneal pustules with papillary edema&#46; Low necrosis keratinocyte and isolated eosinophils&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Improvement after sorafenib discontinuation and corticosteroids treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Demographical and clinical features of sorafenib-induced AGEP&#47;ALEP cases&#46;</p>"
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Case and Research Letter
Sorafenib-induced Acute Generalized Exanthematous Pustulosis: An Increasing Association?
Pustulosis exantemática generalizada aguda por sorafenib: ¿una relación en aumento?
A. Alegre-Sáncheza,
Autor para correspondencia
adrian.alegresanchez@gmail.com

Corresponding author.
, D. de Perosanz-Loboa, I. Pinilla-Pagnonb, E. Muñoz-Zatoa
a Dermatology Service, Ramon y Cajal Hospital, Madrid, Spain
b Pathology Sevice, Ramon y Cajal Hospital, Madrid, Spain
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chest and upper extremities&#44; with small isolated pustules &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Mucous membrane involvement was confined to the lips&#46; Neither fever nor other systemic symptoms were evident&#46; Two months before&#44; she had initiated treatment with sorafenib due to an unresectable hepatocarcinoma&#46; Skin reaction developed gradually two days after initiating the treatment&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">Laboratory examination revealed a hypereosinophilia of 1&#46;4<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&#46; A skin biopsy was performed&#44; rendering typical histological features of AGEP &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Attending to the validated EuroSCAR scoring system&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">2</span></a> our case was then classified as a <span class="elsevierStyleItalic">Probable</span> AGEP&#46; Sorafenib was discontinued immediately&#44; and treatment with intravenous methylprednisolone 1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg was initiated&#46; Cutaneous lesions improved rapidly and were almost totally resolved after a week&#46; This clinical evolution strongly supports the diagnosis of sorafenib-induced AGEP&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">AGEP is characterized by numerous&#44; small&#44; non-follicular and sterile pustules arising within extensive areas of edematous erythema&#46; Fever and leukocytosis are common findings and severe cases of AGEP can associate visceral involvement&#46; Mucous membrane might also be affected&#46; Time interval between drug administration and the skin eruption onset is typically 48<span class="elsevierStyleHsp" style=""></span>h&#44; although it varies from 1 day to 4 weeks&#46; It typically resolves in two weeks after drug discontinuation&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">1&#44;2</span></a> Main differential diagnoses of AGEP are other pustular diseases&#44; such as pustular psoriasis&#44; and other severe cutaneous adverse reactions&#44; such as Stevens Johnson syndrome &#40;SJS&#41; or Toxic Epidermal Necrolysis&#46; Compared to AGEP&#44; in SJS&#47;NET&#44; mucosal involvement and skin detachment &#40;Nikolsky sign&#41; are a constant&#46; However&#44; the possibility of overlap of different severe cutaneous reactions have been recently discussed in the literature&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Sorafenib is a multikinase inhibitor that mainly target tumor cell angiogenesis&#44; first used in advanced renal cell cancer and unresectable hepatocellular carcinoma with recent indications in other cancers&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">4</span></a> It inhibits multiple tyrosine-kinases&#44; such as RAF-1 and B-RAF&#44; and it blocks tyrosine-kinases receptors&#44; such as platelet-derived growth factor receptor &#40;PDGFR&#41;&#44; related with carcinogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Patients under treatment with multikinase inhibitors usually develop cutaneous reactions&#46; In a prospective study&#44; up to 72&#37; of the patients taking sorafenib presented dermatological symptoms&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">4&#44;7</span></a> Most of these reactions are maculopapular rashes and other grade 1&#8211;2 severity adverse reactions that can be easily managed&#46; Other non-severe skin reactions that can be found are hand&#8211;foot skin reaction&#44; stomatitis&#44; subungual splinter hemorrhages&#44; facial erythema or alopecia&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">4&#44;7</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">However&#44; some of these patients develop SCARs related to sorafenib&#44; such as Drug Reaction with Eosynophilia and Systemic Symptoms &#40;DRESS&#41;&#44; SJS or AGEP&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">5&#44;6&#44;8&#44;9</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">To our knowledge&#44; only 2 more cases of sorafenib-induced acute exanthematous pustulosis have been published&#44; being one of them an acute localized exanthematous pustulosis &#40;ALEP&#41; and the other one a complete AGEP&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">5&#44;6</span></a> The main features of these cases are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Interestingly&#44; all the three cases occurred in women who were under treatment with sorafenib due to unresectable hepatocarcinoma&#46; Cases of AGEP have also been reported associated with other multikinase inhibitors such as imatinib&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">10</span></a> Therefore&#59; we believe that the association between kinase-inhibitors and AGEP might be an under-reported entity with an increasing incidence due to the appearance of new drugs of this nature&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">In conclusion&#44; we report a new case of sorafenib-induced AGEP&#46; We should be aware of this cutaneous side effect of sorafenib and other multikinase inhibitors&#44; given that drug discontinuation is the key point on AGEP treatment&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interests</span><p id="par0050" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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          "titulo" => "References"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clinical evolution&#46; &#40;a&#41; Exanthema affecting mainly face&#44; upper trunk&#44; superior limbs with isolated patches on abdomen and lower extremities&#46; &#40;b&#41; Closer image showing isolated pustules surrounded by erythema&#46; &#40;c&#41; Evolution of the exanthema 5 days after Sorafenib discontinuation&#46; Mild erythema and desquamation on upper trunk with pustules resolution&#46;</p>"
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Histopathology&#46; HE 10&#215;&#46; Neutrophilic spongiotic subcorneal pustules&#46; Perivascular infiltrate with lymphocytes and eosinophyles&#46;</p>"
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                  <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">Case&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">Sex&#44; age &#40;years old&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sorafenib indication&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">Latency&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">Distribution&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">Fever&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">Laboratory abnormalities&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">Mucosal involvement&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">Skin biopsy&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">Resolution&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-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Liang&#44; CP et al&#46; &#40;2011&#41;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">5</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">Woman&#44; 59 yo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Localized&#58; lower limbs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Subcorneal pustules with intraepidermal spongiform&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Spontaneous improvement after sorafenib discontinuation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Pretel&#44; M et al&#46; &#40;2014&#41;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">6</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">Woman&#44; 50 yo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Generalized&#58; neck&#44; abdomen&#44; buttocks and lower limbs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Neutrophilia 7&#46;1<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Subcorneal pustules with papillary edema&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Spontaneous improvement after sorafenib discontinuation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Our case &#40;2016&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Woman&#44; 78 yo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Hepatocarcinoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Generalized&#58; chest&#44; neck&#44; facial area and upper limbs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Eosinophilia 1&#46;4<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>&#47;L&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Labial mucosa desquamation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Subcorneal pustules with papillary edema&#46; Low necrosis keratinocyte and isolated eosinophils&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Improvement after sorafenib discontinuation and corticosteroids treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Demographical and clinical features of sorafenib-induced AGEP&#47;ALEP cases&#46;</p>"
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    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
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