Review
Elucidation of the mTOR Pathway and Therapeutic Applications in Dermatology
Bases moleculares y aplicaciones farmacológicas de la vía de mTOR en dermatología
R. Salido-Vallejo
, G. Garnacho-Saucedo, A. Vélez
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Servicio de Dermatología, Hospital Universitario Reina Sofía, Córdoba, Spain
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Esta erupción se asemeja clínicamente a la desarrollada con inhibidores del factor de crecimiento epidérmico. Se caracteriza por la aparición, 2-4 semanas tras el inicio del tratamiento, de pápulas y pústulas centrofoliculares, monomorfas, de prurito variable, sin comedones ni quistes, que asientan preferentemente en el tronco.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "R. Salido-Vallejo, G. Garnacho-Saucedo, A. Vélez" "autores" => array:3 [ 0 => array:2 [ "nombre" => "R." "apellidos" => "Salido-Vallejo" ] 1 => array:2 [ "nombre" => "G." "apellidos" => "Garnacho-Saucedo" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Vélez" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S1578219016300154" "doi" => "10.1016/j.adengl.2016.03.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219016300154?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731015005748?idApp=UINPBA000044" "url" => "/00017310/0000010700000005/v1_201605260143/S0001731015005748/v1_201605260143/es/main.assets" ] ] "itemSiguiente" => array:18 [ "pii" => "S1578219016300166" "issn" => "15782190" "doi" => "10.1016/j.adengl.2016.03.002" "estado" => "S300" "fechaPublicacion" => "2016-06-01" "aid" => "1303" "documento" => "article" "crossmark" => 1 "subdocumento" => "pgl" "cita" => "Actas Dermosifiliogr. 2016;107:391-9" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 754 "formatos" => array:3 [ "EPUB" => 71 "HTML" => 492 "PDF" => 191 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Consensus Document</span>" "titulo" => "Process of Care for Patients With Benign Cysts and Tumors: Consensus Document of the Andalusian Regional Section of the Spanish Academy of Dermatology and Venereology (AEDV)" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "391" "paginaFinal" => "399" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Proceso de atención a las personas con lesiones quísticas y tumorales benignas. Documento de consenso de la sección territorial andaluza de la Academia Española de Dermatología Médico-Quirúrgica y Venereología" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2778 "Ancho" => 3450 "Tamanyo" => 795099 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Clinical pathway showing how the patient with a benign cyst or tumor moves through the various care settings. Numerical references refer to <a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 or 2</a>, which list quality-of-care characteristics to apply in primary care centers and dermatology CMUs, respectively. Patients treated in a minor outpatient surgery unit or in the dermatology CMU will be referred back to the family practitioner or dermatologist at the primary care center who first attended the patient so that the referring physician can see the results of pathologic examination. CMU refers to clinical management unit.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "D. Moreno-Ramírez, R. Ruiz-Villaverde, M. de Troya, V. Reyes-Alcázar, M. Alcalde, M. Galán, E. García-Lora, E.I. García, M. Linares, L. Martínez-Pilar, Á. Pulpillo, C. Suárez, A. Vélez, A. Torres" "autores" => array:14 [ 0 => array:2 [ "nombre" => "D." "apellidos" => "Moreno-Ramírez" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Ruiz-Villaverde" ] 2 => array:2 [ "nombre" => "M." 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"apellidos" => "Torres" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0001731015004998" "doi" => "10.1016/j.ad.2015.10.009" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731015004998?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219016300166?idApp=UINPBA000044" "url" => "/15782190/0000010700000005/v2_201703310310/S1578219016300166/v2_201703310310/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1578219016300919" "issn" => "15782190" "doi" => "10.1016/j.adengl.2016.05.021" "estado" => "S300" "fechaPublicacion" => "2016-06-01" "aid" => "1319" "copyright" => "Elsevier España, S.L.U. and AEDV" "documento" => "article" "crossmark" => 1 "subdocumento" => "ssu" "cita" => "Actas Dermosifiliogr. 2016;107:369-78" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 1358 "formatos" => array:3 [ "EPUB" => 51 "HTML" => 714 "PDF" => 593 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Sweet Syndrome: A Review and Update" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "369" "paginaFinal" => "378" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Síndrome de Sweet: Revisión y puesta al día" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 4004 "Ancho" => 2837 "Tamanyo" => 484406 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Recommendations algorithm for the initial workup in newly diagnosed Sweet's syndrome patients.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "C.D. Villarreal-Villarreal, J. Ocampo-Candiani, A. Villarreal-Martínez" "autores" => array:3 [ 0 => array:2 [ "nombre" => "C.D." "apellidos" => "Villarreal-Villarreal" ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Ocampo-Candiani" ] 2 => array:2 [ "nombre" => "A." 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Salido-Vallejo, G. Garnacho-Saucedo, A. Vélez" "autores" => array:3 [ 0 => array:4 [ "nombre" => "R." "apellidos" => "Salido-Vallejo" "email" => array:1 [ 0 => "rsalidovallejo@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "G." "apellidos" => "Garnacho-Saucedo" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Vélez" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología, Hospital Universitario Reina Sofía, Córdoba, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Bases moleculares y aplicaciones farmacológicas de la vía de mTOR en dermatología" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2503 "Ancho" => 3337 "Tamanyo" => 406154 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Schematic of the mTOR molecular pathway.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The mammalian target of rapamycin (mTOR) is a serine/treonin kinase that regulates the phosphatidylinosital-3-kinase (PI3<span class="elsevierStyleHsp" style=""></span>K)/Akt molecular signaling pathway. In 1965, a Canadian expedition to Easter Island (Rapa Nui) isolated a bacterium named <span class="elsevierStyleItalic">Streptomyces hygroscopicus</span> from soil samples. One of the fermentation products of this bacterium had antifungal properties. This product formed the basis for the development of rapamycin (also known as sirolimus). Subsequently, this molecule has shown potent immunosuppressive, antiproliferative, and antiangiogenic activity through inhibition of the mTOR pathway. Investigation into the pathways implicated in mTOR regulation has made considerable progress in recent decades. The pathophysiology associated with this pathway is, as a result, much better understood and new inhibitors of the mTOR pathway have been developed with different therapeutic indications.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The objective of this article is to review the impact of the mTOR pathway on the pathophysiology of different dermatoses with which it has been associated, and also to assess the safety and efficacy of inhibitors of this pathway that are currently available or in development.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Molecular Basis of the mTOR Pathway</span><p id="par0015" class="elsevierStylePara elsevierViewall">The mTOR pathway is a basic molecular signaling pathway in the regulation of cell metabolism, proliferation, and differentiation and it also plays an important role in immune system modulation and autophagy mechanisms.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">1</span></a> mTOR is a protein included in the PI3K-kinase family. It comprises 5 protein domains with different functions, with binding to other proteins to form complexes with particularly noteworthy kinase activity. In 2002, Kim et al.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">2</span></a> found that mTOR formed 2 multiprotein complexes well-differentiated from each other both in their composition and molecular signaling functions. These complexes are known as molecular target of rapamycin complex 1 (mTORC1) and mTORC2. mTOR responds to different types of signal, such as growth factors, cytokines, mitogens, insulin, amino acids, and cell stress. These mediators activate the PI3<span class="elsevierStyleHsp" style=""></span>K/Akt pathway, leading to phosphorylation of the protein tuberin (TSC2), which is bound to hamartin (TSC1) forming the TSC1/TSC2 complex. Phosphorylation leads to rupture of the hamartin-tuberin complex, which no longer inhibits conversion of Rheb-GDP to Rheb-GTP and mTORC1 is activated. The MAPK/ERK pathway also activates mTORC1 through dissociation of the TSC1/TSC2 complex. Other factors that downregulate this pathway are AMPK, PRAS40, HIF-1, and the Wnt pathway through GSK3 (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Activation of mTORC1 has different consequences in cell homeostasis. The main one is its implication in regulation of cell growth and regulation. mTORC1 promotes protein synthesis, ribosomal biogenesis, mRNA transcription, and synthesis of lipids and nucleotides through different ribosomal mediators such as S6<span class="elsevierStyleHsp" style=""></span>K and 4E-BP1.<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">3</span></a> mTORC1 also intervenes in the regulation of autophagy, the process of self-degradation of cell components with the objective of maintaining homeostasis in normal or stress conditions. mTORC1 inhibits Ulk1, leading to activation of autophagy mechanisms to obtain energy and eliminate damaged organules.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">4</span></a> Prolonged inhibition of these autophagy mechanisms has been associated with the development of neurodegenerative diseases, epilepsy, and autism due to intracellular accumulation of protein aggregates. The mTOR pathway plays a fundamental role in the regulation of both innate and acquired immunity. mTORC1 and mTORC2 control the differentiation, maturation, and function of antigen-presenting cells and of B and T cells through NF-kB transcription factor and GATA3, respectively, although the specific mechanism of action by which the 2 complexes modulate the immune system is not known.<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">5</span></a> The angiogenic activity of mTOR is essentially exercised through translation and activation of HIF-1, a molecule that is associated with VEGF expression in situations of cell hypoxia and that maintains mTORC1 innactive.<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">6</span></a> Although less is known of the molecular functions of mTORC2, this complex has been associated with regulation of cell survival and organization of the actin cytoskeleton through the Rho/rac pathway.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Hyperactivation of this mTOR pathway has been associated with different genetic disorders and neurodegenerative, metabolic, and immune-mediated diseases. In addition, this pathway has been implicated in uncontrolled proliferation processes, malignant transformation, and chemoresistance in different types of cancer.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">mTOR Inhibitors</span><p id="par0030" class="elsevierStylePara elsevierViewall">The knowledge and investigation of the mTOR pathway has led to the design of pharmacological agents that target this molecular signaling cascade. Sirolimus was the first in the class of mTOR inhibitors. It was initially marketed as an immunosuppressive agent in transplant patients. Subsequently, other derivative drugs have been developed, such as everolimus and temsirolimus, and new indications have been added in different types of advanced cancer due to their antiproliferative action (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">The mechanism of action of mTOR inhibitors is based on inhibition of the mTOR kinase activity through binding to the immunophilin FKBP12. This inhibition exerted by the sirolimus/FKBP12 complex blocks activation of protein synthesis and detains the process in the G1 phase of the cell cycle. The result is antitumoral action (thanks to activation of cellular apoptosis, reduction in VEGF expression, and inhibition of migration and cell invasion) and an immunodulatory action (as a result of suppression of activation and proliferation of T cells and decreased antibody production).</p><p id="par0040" class="elsevierStylePara elsevierViewall">Metabolism of sirolimus and other mTOR inhibitors is mediated by the 3A4 cytochrome. This pharmacokinetic conditioning factor should be taken into account given that many drugs used in everyday dermatology practice may interact with mTOR inhibitors either inhibiting their activity (antifungals, macrolides, cyclosporin, imatinib) or enhancing it (rifamycin, dexamethasone).</p><p id="par0045" class="elsevierStylePara elsevierViewall">A wide range of adverse effects have been reported and these vary with mTOR inhibitor used, the dose, and the underlying diseases. In general, there is a greater predisposition to infections and gastrointestinal, hematological, and metabolic disorders (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Skin toxicity is often observed.<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">7</span></a> The most common dermatological disorders are stomatitis, exanthemas (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>), and nail disorders (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Dermatological Applications of mTOR Inhibitors</span><p id="par0050" class="elsevierStylePara elsevierViewall">The antiproliferative, immunomodulatory, and antiangiogenic properties of mTOR inhibitors have led to their off-label use in a range of dermatological diseases of genetic, inflammatory, or tumoral origin (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Genodermatoses</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Tuberous Sclerosis Complex</span><p id="par0055" class="elsevierStylePara elsevierViewall">Tuberous sclerosis complex (TSC) is a genodermatosis of autosomal dominant inheritance characterized by the multisystemic formation of hamartomatous tumors. The disease is caused by mutations in the <span class="elsevierStyleItalic">TSC1</span> and <span class="elsevierStyleItalic">TSC2</span> genes, leading to constitutive activation of mTORC1. This stimulation translates into uncontrolled cell proliferation and differentiation, resulting in the appearance of hamartomas in different tissues (such as skin, brain, and kidneys) and that are responsible for the clinical characteristics of these patients. The direct implication of the mTOR pathway in the pathogenesis of this disease has prompted the use of different mTOR inhibitors to palliate the skin and systemic manifestations. The good outcomes with oral everolimus in the treatment of subependymal giant cell astrocytomas<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">8</span></a> and renal angiomyolipomas<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">9</span></a> have led to these indications being added the labeling of this drug. Recent studies have also shown these drugs to be effective, with a good safety profile, in the treatment of lymphangioleiomyomatosis,<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">10</span></a> leading to approval by the Food and Drug Administration of this indication in the case of sirolimus.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">11</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Among the multiple skin manifestations of TSC, hypomelanotic macules and facial angiofibromas (FAs) are the most frequent. Traditionally, treatment of FA was based on local destructive techniques such as CO<span class="elsevierStyleInf">2</span> laser or electrocoagulation, but these are associated with a high risk of sequelae.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">12</span></a> The substantial improvement observed in FA in a patient in treatment with oral sirolimus<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">13</span></a> led to the use of different topical formulations for treatment with concentrations ranging from 0.015% to 1%.<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">14–17</span></a> Good outcomes were attained with this regimen (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>), while minimizing potential side effects associated with systemic sirolimus administration. Local irritation was only observed in patients in whom a solution was applied (4.8% of cases),<a class="elsevierStyleCrossRef" href="#bib0440"><span class="elsevierStyleSup">18</span></a> with the other formulations being well tolerated. Sirolimus has also been used topically with good response in hypomelanotic macules<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">19</span></a> and in a patient with subungual fibromas.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">20</span></a> The topical formulation of everolimus has only been used in an isolated patient with FA.<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">21</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Neurofibromatosis Type 1 and Other RASopathies</span><p id="par0065" class="elsevierStylePara elsevierViewall">RASopathies are developmental abnormalities caused by germline mutations in the RAS/MAPK pathway. They are characterized by a broad spectrum of skin and systemic manifestations.<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">22</span></a> Neurofibromatosis and Legius, Noonan, Leopard, and cardiofaciocutaneous syndromes are all considered RASopathies. The link between the RAS/MAPK pathway and the PI3<span class="elsevierStyleHsp" style=""></span>K/Akt/TSC/mTOR pathway has aroused interest in mTOR inhibitors as possible therapeutic alternatives in these patients. In a recent phase <span class="elsevierStyleSmallCaps">ii</span> clinical trial, the use of oral sirolimus showed a modest decrease in plexiform neurofibroma growth with acceptable toxicity.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">23</span></a> Currently, a phase <span class="elsevierStyleSmallCaps">ii</span> clinical trial is ongoing to investigate administration of oral everolimus in patients with neurofibromatosis type 1, while another phase <span class="elsevierStyleSmallCaps">i</span> trial of the use of topical sirolimus for skin manifestations of this RASopathy has been completed although the results are not yet available.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Birt-Hogg-Dubé Syndrome</span><p id="par0070" class="elsevierStylePara elsevierViewall">Birt-Hogg-Dubé syndrome is characterized by mutations in the folliculin gene, which is implicated in the mTOR pathway. These patients have facial trichofolliculomas, lesions very similar to facial angiofibromas in TSC. However, topical application of sirolimus was of no benefit in these patients.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Familial Multiple Discoid Fibromas</span><p id="par0075" class="elsevierStylePara elsevierViewall">Familial multiple discoid fibroma, which was initially included in the spectrum of Birt-Hogg-Dubé syndrome, is a rare entity characterized by early onset in the facial region of fibrovascular tumors denoted discoid fibromas. An article has been published describing improvement in the lesions of 2 twins with this disorder after treatment with 1% topical sirolimus.<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Pachyonychia Congenita</span><p id="par0080" class="elsevierStylePara elsevierViewall">Pachyonychia congenita is a disorder of autosomal dominant inheritance characterized by the appearance of painful focal palmoplantar keratoderma, subungual hyperkeratosis, epidermoid cysts, and oral leukokeratosis. It can present in a range of clinical forms depending on the mutations present in the genes responsible for encoding keratins K6a, K6b, K6c, K16, and K17. Sirolimus has been demonstrated to inhibit keratinocyte proliferation by blocking keratin K6a expression. Clinically, sirolimus has been associated with an ostensible improvement in plantar keratoderma in 3 patients treated with oral sirolimus.<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">26</span></a> These findings have prompted a clinical trial with topical sirolimus for the treatment of this plantar keratoderma.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Hamartomatous Polyposis Syndromes</span><p id="par0085" class="elsevierStylePara elsevierViewall">Hamartomatous polyposis syndromes include a group of genetic disorders of autosomal dominant inheritance, characterized by the development of gastrointestinal hamartomatous polyps, as well as other extradigestive manifestations including different dermatological conditions.<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">27</span></a> These syndromes of hamartomatous polyposis include PTEN-associated hamartoma tumor syndrome, which covers a heterogenous group of clinical disorders sharing a PTEN germline mutation that suppresses the PI3K-Akt axis. A phase <span class="elsevierStyleSmallCaps">ii</span> clinical trial of the use of oral sirolimus in patients with PTEN-associated tumor hamartoma syndrome has been completed and we are awaiting the results.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Klumpen et al.<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">28</span></a> treated a patient with Peutz-Jeghers syndrome who developed a pancreatic carcinoma with oral everolimus. They observed a partial improvement in the tumor and the colonic polyps disappeared but the authors did not report on the effect on the patient's lentigines.</p><p id="par0095" class="elsevierStylePara elsevierViewall">In cases in which juvenile polyposis syndrome is associated with <span class="elsevierStyleItalic">SMAD4</span> mutations, the hereditary hemorrhagic telangiectasia or Rendu-Osler-Weber syndrome may also be present. There is a report of 1 case in which sirolimus led to remission of both the skin lesions and the intestinal lesions.<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">29</span></a></p></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Vascular Abnormalities</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Capillary Vascular Malformations</span><p id="par0100" class="elsevierStylePara elsevierViewall">Capillary vascular malformations are congenital malformations that may appear sporadically or associated with genetic syndromes such as Sturge-Weber syndrome. Related to <span class="elsevierStyleItalic">GNAQ</span> mutations, up to 70% of cases associated with Sturge-Weber syndrome present activation of the Akt pathway.<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">30</span></a> Recently, the results of a phase <span class="elsevierStyleSmallCaps">ii</span> clinical trial have been published in which patients with capillary vascular malformations associated with Sturge-Weber syndrome were treated with pulsed dye laser light and topical rapamycin. The areas to which the combined therapy was applied showed a greater response compared with those treated with laser light only or placebo.<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">PHACE Syndrome</span><p id="par0105" class="elsevierStylePara elsevierViewall">Posterior fossa malformations–hemangiomas–arterial anomalies–cardiac defects–eye abnormalities–sternal cleft and supraumbilical raphe syndrome (more commonly known as PHACE syndrome) is characterized by association of large facial hemangiomas and other underlying vascular disorders, such as posterior fossa brain malformations, cerebral artery abnormalities, and cardiac, aortic, and ocular disorders. The large deformation and functional problems arising from these hemangiomas, as well as safety issues observed with the use of oral propanol in some of these patients, have prompted a search for therapeutic alternatives. A case has been published of good cutaneous response with oral sirolimus; no complications were observed in the other vascular disorders.<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">32</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Kaposiform Hemangioendothelioma</span><p id="par0110" class="elsevierStylePara elsevierViewall">Kaposiform hemangioendothelioma is an uncommon childhood vascular tumor that can infiltrate deep structures such as muscle or bone. It is associated with the Kassabach-Merrit phenomenon, and is life-threatening. Sirolimus<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">33</span></a> and everolimus<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">34</span></a> have led to a decrease in or stabilization of the size of the lesions, as well as control of the associated symptoms (thrombocytopenia, coagulopathy) in isolated cases of kaposiform hemangioendothelioma refractory to other treatments.</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Other Vascular Abnormalities</span><p id="par0115" class="elsevierStylePara elsevierViewall">Case reports have been published of the use of sirolimus in other vascular abnormalities, such as lymphatic and venous malformations,<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">33</span></a> benign lymphangioendotheliomas,<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">35</span></a> hemangioendotheliomas associated with Mafucci syndrome,<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">36</span></a> blue rubber bleb nevus syndrome,<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">37</span></a> and complex vascular malformations.</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Inflammatory Diseases</span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Graft Versus Host Disease</span><p id="par0120" class="elsevierStylePara elsevierViewall">Graft versus host disease (GVHD) is a complication that can present in up to 80% of allogeneic stem cell transplant procedures. In a recent metaanalysis, treatment with sirolimus was shown to be useful in preventing the development of acute GVHD, with no signs of a decrease in relative risk in the chronic form.<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">38</span></a> Both sirolimus<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">39</span></a> and everolimus<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">40</span></a> have been shown to be effective in controlling the symptoms of chronic GVHD with low rates of graft dysfunction and thrombotic microangiopathy. In addition, sirolimus showed promising results in patients with acute corticosteroid-resistant GVHD.<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">41</span></a> However, mTOR inhibitors remain second-line therapies in the management of acute and chronic GVHD, behind corticosteroids whether used alone or in combination with calcineurin inhibitors.<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">42,43</span></a> In a study in 34 patients with chronic sclerodermatous GVHD,<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">44</span></a> mTOR inhibitors achieved an overall response rate of 76%, and so the authors considered sirolimus and everolimus as a good therapeutic option in these particularly refractory forms of the disease.</p><p id="par0125" class="elsevierStylePara elsevierViewall">These results in patients with chronic GVHD have prompted the use of mTOR inhibitors in sclerosing diseases. Su et al.<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">45</span></a> conducted a pilot clinical trial in 18 patients with diffuse systemic sclerosis in whom sirolimus showed a similar efficacy to methotrexate.</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Psoriasis</span><p id="par0130" class="elsevierStylePara elsevierViewall">Activation of the PI3<span class="elsevierStyleHsp" style=""></span>K/Akt/mTOR pathway in psoriatic plaques and perilesional skin<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">46</span></a> has led to speculation about the potential use of mTOR inhibitors in psoriasis. A clinical trial provided evidence that the combination of sirolimus at subtherapeutic doses of cyclosporin (1.25<span class="elsevierStyleHsp" style=""></span>mg/Kg) was as effective as high-dose cyclosporin, but with a better renal safety profile. However, when used in monotherapy, these agents did not produce any improvement in psoriasis.<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">47</span></a> Likewise, the use of topical sirolimus at much higher concentrations than those used in other indications (2.2%-8%) has not shown any clinically relevant effects.<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">48</span></a> There are only 2 clinical cases of oral everolimus use in patients with psoriasis.<a class="elsevierStyleCrossRefs" href="#bib0595"><span class="elsevierStyleSup">49,50</span></a> In both cases, the agent was combined with other immunosuppressants (cyclosporin and tacrolimus) that the patients had been taking previously to avoid graft rejection.</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Autoimmune Bullous Diseases</span><p id="par0135" class="elsevierStylePara elsevierViewall">The use of sirolimus for prevention of suprabasal acantholysis in an animal model<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">51</span></a> would explain the possible beneficial effect of mTOR inhibitor use in pemphigus vulgaris. However, current evidence in blistering diseases is limited to 3 cases of oral pemphigus treated with topical sirolimus without any improvement,<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">52</span></a> and a case of pemphigus vulgaris treated with sirolimus in combination with high doses of intravenous immunoglobulins during the maintenance phase.<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">53</span></a> Everolimus has recently been linked to the induction of 2 cases of bullous pemphigoid,<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">54</span></a> and so the possible beneficial role of mTOR inhibitors in autoimmune bullous diseases has been brought into question</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Oral Erosive Lichen Planus</span><p id="par0140" class="elsevierStylePara elsevierViewall">There is only 1 clinical study in patients with oral erosive lichen planus. In that study, Soria et al.<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">55</span></a> treated 7 women with topical sirolimus. They obtained a complete response in 4 patients and a partial response in 3, and the formulation was well tolerated.</p></span></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Skin Oncology</span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Nonmelanoma Skin Cancer</span><p id="par0145" class="elsevierStylePara elsevierViewall">Although there are isolated cases of patients with basal-cell carcinoma treated with everolimus,<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">56</span></a> prevention of nonmelanoma skin cancer is one the main uses of mTOR inhibitors. Several clinical trials have shown a decrease in the incidence of nonmelanoma skin cancer in transplant patients in treatment with sirolimus in comparison with calcineurin inhibitors. In a metaanalysis of 5876 transplant patients in 21 clinical trials, Knoll et al.<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">57</span></a> observed a risk reduction for developing nonmelanoma cancer of 56%, as well as an overall decrease in the risk of cancer at any site in patients in treatment with sirolimus. The study showed a greater risk reduction in patients treated with other immunosuppressive therapies who subsequently switched to sirolimus.</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Melanoma</span><p id="par0150" class="elsevierStylePara elsevierViewall">There are 3 phase <span class="elsevierStyleSmallCaps">ii</span> clinical trials with metastatic melanoma in which everolimus was administered in combination with other biologic agents such as bevacizumab,<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">58</span></a> or associated with monochemotherapy (temozolomide)<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">59</span></a> or polychemotherapy (paclitaxel<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>carboplatin).<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">60</span></a> Although the combination with bevacizumab showed a modest benefit, with a response rate of 12% and stable disease in 58% of the patients, the use of everolimus with cytostatic agents did not show any benefit at all.</p><p id="par0155" class="elsevierStylePara elsevierViewall">The association of temsirolimus with sorafenib in patients with metastatic melanoma was not efficaceous,<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">61</span></a> whereas in combination with bevacizumab better results were obtained in patients without the <span class="elsevierStyleItalic">BRAF</span> mutation.<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">62</span></a></p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Kaposi Sarcoma</span><p id="par0160" class="elsevierStylePara elsevierViewall">Sirolimus has been shown to be extremely effective in the treatment of skin and visceral involvement in Kaposi sarcoma in transplanted patients,<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">63</span></a> and this has led some authors to consider the agent as the first-choice immunosuppressant in this subgroup of patients and even to use it topically.<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">64</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">The limited experience with the use of everolimus in patients with Kaposi sarcoma is, on the other hand, more controversial. Although isolated clinical trials have been reported in which complete resolution of skin and systemic lesions has been attained,<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">65</span></a> a recent clinical trial in 11 patients with classic Kaposi sarcoma showed limited efficacy<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">66</span></a> with the onset of new lesions during treatment.</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Cutaneous T-Cell Lymphomas</span><p id="par0170" class="elsevierStylePara elsevierViewall">In vitro studies have shown excessive activation of the mTOR pathway in cells of patients with Sézary syndrome and cutaneous T cell lymphomas, suggesting that mTOR inhibitors may be a possible therapeutic alternative.</p><p id="par0175" class="elsevierStylePara elsevierViewall">Witzig et al.<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">67</span></a> recently published a phase <span class="elsevierStyleSmallCaps">ii</span> clinical trial in which patients with T-cell lymphomas were treated with oral everolimus. Seven of these had stage <span class="elsevierStyleSmallCaps">ii</span>B (6) and stage <span class="elsevierStyleSmallCaps">iii</span> (1) mycosis fungoides. Three of these (43%) attained partial response. Currently, there is a phase <span class="elsevierStyleSmallCaps">ii</span> clinical trial ongoing to investigate treatment of refractory cutaneous T-cell lymphomas with everolimus.</p></span></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Antiageing</span><p id="par0180" class="elsevierStylePara elsevierViewall">The report in 2009 in <span class="elsevierStyleItalic">Nature</span> of the increased life span observed in mice who received sirolimus<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">68</span></a> opened up a new avenue of investigation in the therapeutic applications of mTOR inhibitors, namely, cell ageing. The mTOR pathway has been implicated in the regulation of physiological mechanisms of geroconversion (irreversible passage of stem cells from quiescent to senescent cell stages). This cell cycle arrest leads to an irreversible weakening of the tissue regeneration processes and thus to ageing of the organism. Selective blockade of this step would keep the stem cells in quiescent state, thereby extending their regenerative function.</p></span></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">New mTOR Inhibitors and Future Lines of Investigation</span><p id="par0185" class="elsevierStylePara elsevierViewall">Currently, there are several studies in progress investigating the use of mTOR inhibitors in different types of dermatological diseases (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). In addition, new mTOR inhibitors are appearing, although most are in the initial phases of development. Ridaforolimus is the only one with phase <span class="elsevierStyleSmallCaps">iii</span> clinical data available in metastatic sarcomas.<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">69</span></a> A slight increase in progression-free survival was observed but there was no benefit in terms of overall survival.</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0190" class="elsevierStylePara elsevierViewall">The modest benefit observed with mTOR inhibitors in different oncology clinical trials performed to date may be due to the presence of multiple mTORC1 feedback mechanisms, such as activation of reflex signals of the PI3<span class="elsevierStyleHsp" style=""></span>K and RAS/MAPK pathways. To avoid these proposed escape mechanisms, combination therapies with PI3<span class="elsevierStyleHsp" style=""></span>K inhibitors and other cytostatic agents are being tested,<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">70</span></a> and dual PI3<span class="elsevierStyleHsp" style=""></span>K/mTOR or mTORC1/mTORC2 inhibitors are being developed.</p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Conclusions</span><p id="par0195" class="elsevierStylePara elsevierViewall">The PI3<span class="elsevierStyleHsp" style=""></span>K/Akt/TSC/mTOR pathway is key in multiple molecular processes and has been associated with numerous diseases of very different characteristics. Its impact in dermatology has increased markedly in recent years as the pathogenic relationships with different dermatoses become known. This has opened a new therapeutic pathway with mTOR inhibitors, especially in their topically administered forms. To realize the potential of these treatments that target the mTOR pathway, research will be required in different fields. Use of existing molecules should be optimized, while new pharmacological agents should be developed. These should be associated with inhibitors of other associated signaling pathways.</p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conflicts of Interest</span><p id="par0200" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres822686" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec819492" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres822685" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec819491" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Molecular Basis of the mTOR Pathway" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "mTOR Inhibitors" ] 7 => array:3 [ "identificador" => "sec0020" "titulo" => "Dermatological Applications of mTOR Inhibitors" "secciones" => array:5 [ 0 => array:3 [ "identificador" => "sec0025" "titulo" => "Genodermatoses" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Tuberous Sclerosis Complex" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Neurofibromatosis Type 1 and Other RASopathies" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Birt-Hogg-Dubé Syndrome" ] 3 => array:2 [ "identificador" => "sec0045" "titulo" => "Familial Multiple Discoid Fibromas" ] 4 => array:2 [ "identificador" => "sec0050" "titulo" => "Pachyonychia Congenita" ] 5 => array:2 [ "identificador" => "sec0055" "titulo" => "Hamartomatous Polyposis Syndromes" ] ] ] 1 => array:3 [ "identificador" => "sec0060" "titulo" => "Vascular Abnormalities" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0065" "titulo" => "Capillary Vascular Malformations" ] 1 => array:2 [ "identificador" => "sec0070" "titulo" => "PHACE Syndrome" ] 2 => array:2 [ "identificador" => "sec0075" "titulo" => "Kaposiform Hemangioendothelioma" ] 3 => array:2 [ "identificador" => "sec0080" "titulo" => "Other Vascular Abnormalities" ] ] ] 2 => array:3 [ "identificador" => "sec0085" "titulo" => "Inflammatory Diseases" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0090" "titulo" => "Graft Versus Host Disease" ] 1 => array:2 [ "identificador" => "sec0095" "titulo" => "Psoriasis" ] 2 => array:2 [ "identificador" => "sec0100" "titulo" => "Autoimmune Bullous Diseases" ] 3 => array:2 [ "identificador" => "sec0105" "titulo" => "Oral Erosive Lichen Planus" ] ] ] 3 => array:3 [ "identificador" => "sec0110" "titulo" => "Skin Oncology" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0115" "titulo" => "Nonmelanoma Skin Cancer" ] 1 => array:2 [ "identificador" => "sec0120" "titulo" => "Melanoma" ] 2 => array:2 [ "identificador" => "sec0125" "titulo" => "Kaposi Sarcoma" ] 3 => array:2 [ "identificador" => "sec0130" "titulo" => "Cutaneous T-Cell Lymphomas" ] ] ] 4 => array:2 [ "identificador" => "sec0135" "titulo" => "Antiageing" ] ] ] 8 => array:2 [ "identificador" => "sec0140" "titulo" => "New mTOR Inhibitors and Future Lines of Investigation" ] 9 => array:2 [ "identificador" => "sec0145" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0150" "titulo" => "Conflicts of Interest" ] 11 => array:2 [ "identificador" => "xack276052" "titulo" => "Acknowledgments" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-10-25" "fechaAceptado" => "2015-12-10" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec819492" "palabras" => array:4 [ 0 => "TOR Serine-Threonine Kinases" 1 => "Sirolimus" 2 => "Everolimus" 3 => "Dermatology" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec819491" "palabras" => array:4 [ 0 => "TOR Serina/treonina cinasa" 1 => "Sirolimus" 2 => "Everolimus" 3 => "Dermatología" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The member of the phosphatidylinositol 3-kinase family, mammalian target of rapamycin, is involved in modulating inflammatory response and regulating cellular processes associated with growth, differentiation, and angiogenesis. Recent years have seen major advances in our understanding of the mammalian target of rapamycin signaling pathway and the implication of this pathway in multiple genetic and inflammatory diseases and tumors. The development of the mammalian target of rapamycin inhibitors has given rise to new treatment approaches that have led to substantially improved outcomes in many diseases. In this article, we review the role of the mammalian target of rapamycin signaling pathway in the different skin diseases with which it has been associated, examine the therapeutic applications of drugs targeting this pathway, and provide an overview of current trends and future directions in research.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La molécula diana de la rapamicina en mamíferos es una cinasa perteneciente a la familia de fosfatidil-3-inositol que está involucrada en la regulación de diferentes procesos relacionados con el crecimiento y diferenciación celular, la angiogénesis y la modulación de la respuesta inflamatoria. En los últimos años hemos presenciado un profundo avance en el conocimiento de las bases moleculares de la vía de señalización de la molécula diana de la rapamicina en mamíferos y su implicación en multitud de enfermedades genéticas, inflamatorias o tumorales. El desarrollo de moléculas inhibidoras de esta vía ha propiciado una nueva posibilidad de abordaje terapéutico que ha permitido una mejora sustancial en muchas de estas enfermedades. En este artículo revisamos las implicaciones de la vía de la molécula diana de la rapamicina en mamíferos en las diferentes dermatosis con las que se ha relacionado, sus aplicaciones farmacológicas y las futuras direcciones que están tomando las diferentes líneas de investigación.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">Please cite this article as: Salido-Vallejo R, Garnacho-Saucedo G, Vélez A. Bases moleculares y aplicaciones farmacológicas de la vía de mTOR en dermatología. Actas Dermosifiliogr. 2016;107:379–390.</p>" ] ] "multimedia" => array:7 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2503 "Ancho" => 3337 "Tamanyo" => 406154 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Schematic of the mTOR molecular pathway.</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" => 766 "Ancho" => 1000 "Tamanyo" => 169016 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Papulopustular eruption in a patient in treatment with everolimus for subependymal giant cell astrocytoma associated with tuberous sclerosis. Clinically, this eruption resembles the eruption that develops with epidermal growth factor inhibitors. It is characterized by the appearance, 2 to 4 weeks after starting treatment, of monomorphic papules and follicular center pustules, with variable pruritus, without comedones or cysts, with a predilection for the trunk.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 752 "Ancho" => 1824 "Tamanyo" => 176044 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Patient with facial angiofibroma associated with tumorous sclerosis before (a) and 6 months after starting treatment with topical sirolimus (b).</p>" ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Abbreviations: EMA, European Medicines Agency; GI, gastrointestinal; MCL, mantel cell lymphoma; PPED, palmoplantar erythrodysesthesia; PPP, palmoplantar pustulosis; RCC, renal cell carcinoma; SEGA, subependymal giant cell astrocytoma; TSC, tuberous sclerosis complex; URT, upper respiratory tract; UTI, urinary tract infections.</p>" "tablatextoimagen" => array:1 [ 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">Drug \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">EMA Approval \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">Indications \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">Route of Administration \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">Very Common Adverse Effects (><span class="elsevierStyleHsp" style=""></span>10%) \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">Cutaneous Adverse Effects \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">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rapamune (2001) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Prophylaxis against renal transplant rejection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Edema, headache, fever, arterial hypertension, GI disorders, anemia, thrombocytopenia, hyperlipidemia, arthralgia, diabetes mellitus, infections \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(><span class="elsevierStyleHsp" style=""></span>10%): PPP;<br>(<<span class="elsevierStyleHsp" style=""></span>10%): delayed wound healing, stomatitis, exanthema, skin cancer<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>; (<<span class="elsevierStyleHsp" style=""></span>0.1%): lymphedema \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Everolimus</td><td class="td" title="table-entry " align="left" valign="top">Afinitor (2009) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Advanced breast cancer, advanced RCC, neuroendocrine tumors of pancreatic origin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Infections, anemia, anorexia, hyperglycemia, hyperlipidemia, headache, pneumonitis, epistaxis, GI disorders \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(><span class="elsevierStyleHsp" style=""></span>10%): exanthema, pruritus, stomatitis; (<<span class="elsevierStyleHsp" style=""></span>10%): PPP, xerosis, nail disorder, PPED; (<<span class="elsevierStyleHsp" style=""></span>0.1%): angioedema \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">Certican (2003) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Prophylaxis against kidney, heart, and liver transplant rejection \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Respiratory infections, UTI, leukopenia, thrombocytopenia, anemia, hyperlipidemia, diabetes, insomnia, headache, pericardial and pleural effusion, hypertension, dyspnea, GI disorder, edema \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(<<span class="elsevierStyleHsp" style=""></span>10%): PPP, exanthema, stomatitis, skin cancer, angioedema, delayed wound healing \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">Votubia (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Renal angiolipomas associated with TSC, SEGA associated with TSC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">URT infections, hyperlipidemia, amenorrhea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(><span class="elsevierStyleHsp" style=""></span>10%): PPP, stomatitis; (<<span class="elsevierStyleHsp" style=""></span>10%): exanthema, xerosis, pruritus, alopecia; (<<span class="elsevierStyleHsp" style=""></span>0.1%): angioedema \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">Temsirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Torisel (2007) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Advanced RCC, MCL (second line) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intravenous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anemia, thrombocytopenia, leukopenia, GI disorder, edema, astenia, epistaxis, hyperglycemia, hyperlipidemia, infections, pneumonia, dyspnea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(><span class="elsevierStyleHsp" style=""></span>10%): exanthema, pruritus, xerosis, stomatitis; (<<span class="elsevierStyleHsp" style=""></span>10%): dermatitis, nail disorders, PPP, purpura \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">Ridaforolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">In development \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Advanced endometrial carcinoma, metastatic sarcomas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral, intravenous \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Infections, fatigue, thrombocytopenia, GI disorder, anemia, hyperlipidemia, headache, anorexia, dyspnea, neutropenia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">(><span class="elsevierStyleHsp" style=""></span>10%): stomatitis, exanthema \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1383273.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The association of the use of sirolimus with the onset of skin cancer mentioned in the product labelling may be due to a bias in the pivotal trials to support approval. In these, the drug was combined with cyclosporin and corticosteroids in comparison with placebo to assess efficacy and safety in the prevention of graft rejection. This onset of carcinomas in certain subjects in the exposed group may be mainly due to the carcinogenic action of cyclosporin, as shown by subsequent studies in which the use of sirolimus monotherapy has not only been shown not to induce the development of skin cancers but also has a protective effect against their development.<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">58</span></a></p> <p class="elsevierStyleNotepara" id="npar0010">Source: Data obtained from the Summary of Product Characteristics available from http://www.ema.europa.eu</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">mTOR Inhibitors Currently Approved by the European Medicines Agency.</p>" ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 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="" valign="top" scope="col" style="border-bottom: 2px solid black"> \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 Toxicity (Frequency) \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">Clinical Characteristics \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 " rowspan="3" align="left" valign="top">Frequent (><span class="elsevierStyleHsp" style=""></span>10%)</td><td class="td" title="table-entry " align="left" valign="top">Stomatitis (25%-44%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Superficial sores<br>Differential diagnosis: chemotherapy-induced stomatitis (ulcers with pseudomembranes) \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">Exanthemas (27%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Morbilliform<br>Eczematous<br>Papulopustular \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">Nail disorders (5%-46%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Paronychia (+<span class="elsevierStyleHsp" style=""></span>frequent)<br>Onycholysis<br>Nail fragility<br>Yellow coloration<br>Pyogenic-like granuloma lesions<br>Dystrophy of all 20 nails \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">Uncommon (<<span class="elsevierStyleHsp" style=""></span>10%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Delayed wound healing<br>Edema<br>Pruritus<br>Xerosis<br>Alopecia<br>Hypertrichosis<br>Leukocytoclastic vasculitis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1383275.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Adverse Cutaneous Effects of mTOR Inhibitors.</p>" ] ] 5 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Abbreviations: BCC, basal cell carcinoma; CaLM, café-au-lait macules.</p>" "tablatextoimagen" => array:1 [ 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">Genodermatoses \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">Molecular Targets \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">Most Frequent Dermatological Manifestations \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">mTOR Inhitor Use \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">Studies (Year) \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"><span class="elsevierStyleBold">Tuberous Sclerosis Complex</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TSC1, TSC2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypomelanotic macules<br>Facial angiofibromas<br>Subungual fibromas<br>Connective tissue nevus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral and topical everolimus, oral and topical sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Wataya-Kaneda (2011, 2012, 2015<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">19</span></a>), Salido et al.<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">16</span></a> (2012), Foster et al.<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">14</span></a> (2012), Koenig et al.<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">15</span></a> (2012), etc. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleBold">RASopathies</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Neurofibromatosis 1</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NF1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CaLM, axillary and inguinal freckling, neurofibromas, xanthogranulomas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral and topical sirolimus, oral everolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Weiss et al.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">23</span></a> (2015), Koenig (in progress) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleBold">Hamartomatous Polyposis Syndromes</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Peutz-Jeghers syndrome</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">STK11, LKB1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mucocutaneous lentigines \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral everolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Klumpen et al.<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">28</span></a> (2011) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Juvenile polyposis syndrome</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">SMAD4, BMPR1A \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hereditary hemorrhagic telangiectasis (SMAD4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Skaro et al.<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">29</span></a> (2006) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">PHTS</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Cowden syndrome<br><span class="elsevierStyleHsp" style=""></span>Lhermitte-Duclos syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PTEN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Trichilemmomas, fibromas, acral keratosis, hemangiomas, CaLM, lipomas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rajan (in development) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Bannayan-Riley-Ruvalcaba syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Lipomatosis<br>Pigmented macules of the glans penis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Proteus syndrome<br><span class="elsevierStyleHsp" style=""></span>Proteus-like syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Connective tissue nevus, lipomatosis, vascular malformations, epidermal nevi \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Marsh (2008) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Muir-Torre Syndrome</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MSH2, MLH1 (not related) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sebaceous tumors, keratoacanthomas, BCC sebaceous differentiation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Levi (2007), Griffard (2011) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Congenital Pachyonichia</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">K6a, K6b, K6c, K16, K17 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Palmoplantar keratoderma, subungual hyperkeratosis, epidermal cysts, oral leukokeratosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Topical sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Teng (in progress) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Birt-Hogg-Dubé Syndrome</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FLCN \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Trichofolliculoma, trichodiscomas, fibromas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Topical sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Gijezen et al.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">24</span></a> (2014) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Familial Multiple Discoid Fibromas</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Not described \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Discoid fibromas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Topical sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Wee et al.<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">25</span></a> (2013) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1383274.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Studies of the Use of mTOR Inhibitors in Genetic Disorders Associated with Skin Manifestations.</p>" ] ] 6 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Abbreviations: HIV, human immunodeficiency virus; GVHD, graft-versus-host disease; PDL, pulsed dye laser; PTHS, PTEN-associated tumor hamartoma syndrome; TSC, tuberous sclerosis complex.</p>" "tablatextoimagen" => array:1 [ 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">NCT number \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">Drug \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">Administration \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">Indication \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">Clinical Phase \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">Year of Initiation \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">Status \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"><span class="elsevierStyleInterRef" id="intr0005" href="ctgov:NCT01031901">NCT01031901</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Topical \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cutaneous manifestations of neurofibromatosis type 1 and TSC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Completed \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0010" href="ctgov:NCT01853423">NCT01853423</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Topical \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Facial angiofibromas in TSC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2013 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recruiting \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0015" href="ctgov:NCT02057614">NCT02057614</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Topical \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Plantar keratoderma in congenital pachyonychia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recruiting \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0020" href="ctgov:NCT02123966">NCT02123966</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Topical \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Chronic oral GVHD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recruiting \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0025" href="ctgov:NCT02214706">NCT02214706</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Topical \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Capillary vascular malformations (sirolimus<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>erbium laser<span class="elsevierStyleHsp" style=""></span> +<span class="elsevierStyleHsp" style=""></span>PDL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recruiting \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0030" href="ctgov:NCT00450320">NCT00450320</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">HIV-associated Kaposi sarcoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Completed \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0035" href="ctgov:NCT00779194">NCT00779194</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Systemic lupus erythematosus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2008 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ongoing \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0040" href="ctgov:NCT00971789">NCT00971789</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cowen syndrome and other PTHS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Completed \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0045" href="ctgov:NCT01313923">NCT01313923</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pemphigus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase 0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2011 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recruiting \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0050" href="ctgov:NCT00975819">NCT00975819</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Complex vascular abnormalities \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ongoing \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0055" href="ctgov:NCT01811667">NCT01811667</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Complex vascular malformations \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recruiting \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0060" href="ctgov:NCT02042326">NCT02042326</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Arteriovenous malformations \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recruiting \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0065" href="ctgov:NCT02110069">NCT02110069</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Kaposiform hemangioendothelioma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recruiting \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0070" href="ctgov:NCT02509468">NCT02509468</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sirolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Slow-flow vascular malformations \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recruiting \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0075" href="ctgov:NCT01637090">NCT01637090</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Everolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cutaneous T cell lymphomas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recruiting \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0080" href="ctgov:NCT01960829">NCT01960829</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Everolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Metastatic melanoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2013 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recruiting \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0085" href="ctgov:NCT01997255">NCT01997255</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Everolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sturge-Weber syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2013 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recruiting \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleInterRef" id="intr0090" href="ctgov:NCT02332902">NCT02332902</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Everolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Skin manifestations of neurofibromatosis type 1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Phase II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2014 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Recruiting \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1383276.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Main Ongoing Clinical Trials With mTOR Inhibitors in Dermatological Diseases.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:70 [ 0 => array:3 [ "identificador" => "bib0355" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mammalian target of rapamycin and tuberous sclerosis complex" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 4 | 2 | 6 |
| 2024 Octubre | 89 | 56 | 145 |
| 2024 Septiembre | 85 | 41 | 126 |
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| 2023 Noviembre | 60 | 35 | 95 |
| 2023 Octubre | 61 | 44 | 105 |
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| 2023 Julio | 68 | 41 | 109 |
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| 2023 Marzo | 69 | 32 | 101 |
| 2023 Febrero | 55 | 31 | 86 |
| 2023 Enero | 44 | 59 | 103 |
| 2022 Diciembre | 44 | 42 | 86 |
| 2022 Noviembre | 35 | 29 | 64 |
| 2022 Octubre | 21 | 19 | 40 |
| 2022 Septiembre | 31 | 43 | 74 |
| 2022 Agosto | 25 | 40 | 65 |
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| 2022 Junio | 27 | 19 | 46 |
| 2022 Mayo | 53 | 46 | 99 |
| 2022 Abril | 47 | 18 | 65 |
| 2022 Marzo | 45 | 38 | 83 |
| 2022 Febrero | 27 | 29 | 56 |
| 2022 Enero | 51 | 38 | 89 |
| 2021 Diciembre | 50 | 34 | 84 |
| 2021 Noviembre | 40 | 41 | 81 |
| 2021 Octubre | 56 | 44 | 100 |
| 2021 Septiembre | 57 | 50 | 107 |
| 2021 Agosto | 41 | 33 | 74 |
| 2021 Julio | 22 | 26 | 48 |
| 2021 Junio | 34 | 23 | 57 |
| 2021 Mayo | 45 | 35 | 80 |
| 2021 Abril | 42 | 49 | 91 |
| 2021 Marzo | 57 | 23 | 80 |
| 2021 Febrero | 42 | 30 | 72 |
| 2021 Enero | 28 | 16 | 44 |
| 2020 Diciembre | 28 | 20 | 48 |
| 2020 Noviembre | 23 | 19 | 42 |
| 2020 Octubre | 23 | 22 | 45 |
| 2020 Septiembre | 46 | 13 | 59 |
| 2020 Agosto | 27 | 16 | 43 |
| 2020 Julio | 27 | 12 | 39 |
| 2020 Junio | 38 | 29 | 67 |
| 2020 Mayo | 25 | 23 | 48 |
| 2020 Abril | 27 | 22 | 49 |
| 2020 Marzo | 22 | 14 | 36 |
| 2020 Febrero | 3 | 2 | 5 |
| 2019 Diciembre | 4 | 0 | 4 |
| 2019 Septiembre | 4 | 0 | 4 |
| 2019 Mayo | 3 | 2 | 5 |
| 2019 Abril | 2 | 3 | 5 |
| 2019 Marzo | 3 | 3 | 6 |
| 2019 Febrero | 1 | 0 | 1 |
| 2019 Enero | 5 | 0 | 5 |
| 2018 Diciembre | 5 | 0 | 5 |
| 2018 Noviembre | 2 | 0 | 2 |
| 2018 Octubre | 2 | 0 | 2 |
| 2018 Septiembre | 5 | 0 | 5 |
| 2018 Febrero | 42 | 8 | 50 |
| 2018 Enero | 36 | 16 | 52 |
| 2017 Diciembre | 57 | 13 | 70 |
| 2017 Noviembre | 50 | 8 | 58 |
| 2017 Octubre | 42 | 8 | 50 |
| 2017 Septiembre | 47 | 18 | 65 |
| 2017 Agosto | 37 | 8 | 45 |
| 2017 Julio | 38 | 14 | 52 |
| 2017 Junio | 41 | 19 | 60 |
| 2017 Mayo | 24 | 9 | 33 |
| 2017 Abril | 32 | 12 | 44 |
| 2017 Marzo | 25 | 22 | 47 |
| 2017 Febrero | 27 | 14 | 41 |
| 2017 Enero | 24 | 4 | 28 |
| 2016 Diciembre | 29 | 15 | 44 |
| 2016 Noviembre | 30 | 22 | 52 |
| 2016 Octubre | 26 | 34 | 60 |
| 2016 Julio | 1 | 4 | 5 |
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