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Progress in the treatment of lymphangioleiomyomatosis: From bench to bedside
Progressos no tratamento da linfangioleiomiomatose: da investigação à clínica
Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
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Torrente, T. Martí, J. Escarrabill" "autores" => array:3 [ 0 => array:2 [ "nombre" => "E." "apellidos" => "Torrente" ] 1 => array:2 [ "nombre" => "T." "apellidos" => "Martí" ] 2 => array:2 [ "nombre" => "J." "apellidos" => "Escarrabill" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0873215912000244?idApp=UINPBA00004E" "url" => "/08732159/0000001800000003/v2_201509041307/S0873215912000244/v2_201509041307/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Comment</span>" "titulo" => "Progress in the treatment of lymphangioleiomyomatosis: From bench to bedside" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "142" "paginaFinal" => "144" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "A.M. Taveira-DaSilva, J. Moss" "autores" => array:2 [ 0 => array:4 [ "nombre" => "A.M." "apellidos" => "Taveira-DaSilva" "email" => array:1 [ 0 => "dasilvaa@nhlbi.nih.gov" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Moss" ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Progressos no tratamento da linfangioleiomiomatose: da investigação à clínica" ] ] "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" => 1064 "Tamanyo" => 118791 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Simplified schematic model of <span class="elsevierStyleItalic">TSC1</span> and <span class="elsevierStyleItalic">TSC2</span> pathways. The <span class="elsevierStyleItalic">TSC1/TSC2</span> complex has roles in cell cycle progression and in cell size and proliferation. This complex stimulates the conversion of active Rheb-GTP to inactive Rheb-GDP, resulting in inactive Rheb. Rheb controls mTOR, a kinase that controls translation through phosphorylation of S6K1. Sirolimus inhibits mTOR. <span class="elsevierStyleItalic">Abbreviations</span>: PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; mTOR: mammalian target of rapamycin; Rheb GAP: GTPase-activating protein for Ras homolog enriched in brain; S6K1: S6 kinase 1 (modified from Ref. <a class="elsevierStyleCrossRef" href="#bib0050">10</a>).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Lymphangioleiomyomatosis is a multisystem disease affecting women, which is characterized by cystic lung destruction, lymphatic abnormalities (e.g., lymphangioleiomyomas), and abdominal tumors which are found primarily in the kidneys, and consist of smooth muscle cells, vascular structures and adipocytes, termed angiomyolipomas.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Lymphangioleiomyomatosis occurs sporadically and in about one-third of women with tuberous sclerosis complex (TSC), an autosomal dominant disorder with variable penetrance.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> In either case, LAM is caused by mutations of <span class="elsevierStyleItalic">TSC1</span> or <span class="elsevierStyleItalic">TSC2</span>, two genes that encode, respectively, hamartin and tuberin, two proteins that regulate cell growth.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> Deficiency of these proteins causes activation of mammalian target of rapamycin (mTOR) downstream elements, leading to increased cell proliferation and size (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Sporadic lymphangioleiomyomatosis is a rare disease occurring in circa 2–5/1,000,000 persons.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Yet, for those afflicted, LAM is devastating. Progressive lung destruction leads to respiratory failure, lung transplantation or death.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Lymphatic involvement may cause chylous pleural effusions, ascites and lymphangioleiomyomas, abdominal tumors that may mimic lymphomas and sarcomas.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Renal angiomyolipomas may be associated with abdominal hemorrhage, requiring partial or total nephrectomy or embolization of arterial feeding vessels.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In the past, patients with LAM were advised to undergo bilateral oophorectomy and hysterectomy and/or be treated with anti-estrogen agents such as progesterone or gonadotropin-releasing hormone analogues. No controlled studies showing that these therapies are beneficial to the patients have ever been carried out.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,8</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Several studies have demonstrated the important role of the TSC1/TSC2 complex in cell cycle progression and in cell size and proliferation.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a> Tuberin binds a cyclin-dependent kinase inhibitor, thus stabilizing it, resulting in inhibition of cell cycle progression. Tuberin also has a GTPase activating protein activity, which converts Ras homolog enriched in brain (Rheb)-GTP to Rheb-GDP, resulting in inactivation of Rheb (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>) and reduction in activity of mTOR, a kinase that controls translation through the phosphorylation of 4E-BP1 and S6K1 (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Protein kinase B (Akt), when activated by growth factors, phosphorylates and inhibits tuberin, resulting in increased cell size and proliferation.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Sirolimus (Rapamycin), in the presence of FKBP12 (FK506-binding protein), inhibits mTOR. Animal models with a functionally null germline mutation of <span class="elsevierStyleItalic">Tsc2</span> spontaneously develop renal cell carcinomas which decrease in size following administration of sirolimus.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,12</span></a> In patients with angiomyolipomas, tumor size decreased by half after 1 year of sirolimus therapy, while lung function improved in some patients but not in others.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Other studies have shown that sirolimus therapy leads to resolution of chylous effusions in post-transplant LAM patients,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> decreased the size of giant cell astrocytomas and reduced the frequency of seizures in TSC patients.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Results of a multicenter placebo-controlled randomized trial just completed (MILES trial), showed that sirolimus stabilized lung function, and improved symptoms and quality of life in patients with LAM.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> There was a highly significant difference in the change in lung function over 1 year of therapy between sirolimus-treated and placebo-treated patients.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> In another study, sirolimus therapy improved chylous effusions and/or lymphangioleiomyomas.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> By 3–6 months of therapy, effusions start to resolve and complete resolution may be observed, pre-empting the need for repeated thoracentesis, chest tube drainage or pleurodesis.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">These observations provide the rationale for the use of sirolimus in the treatment of selected LAM patients. Sirolimus therapy may be considered for patients that fulfill the inclusion/exclusion criteria for MILES, those with rapidly progressing lung disease, those with chylous effusions that compromise the lung function and require frequent drainage or pleurodesis, and patients with large symptomatic thoraco-abdominal lymphangioleiomyomas. The starting dose of sirolimus is 2<span class="elsevierStyleHsp" style=""></span>mg/day. Sirolimus levels must be monitored and dosage adjusted to attain serum trough levels between 5 and 15<span class="elsevierStyleHsp" style=""></span>ng/ml, a range thought to be therapeutic for patients with renal transplants. The occurrence of adverse events associated with sirolimus therapy, such as, oral mucosa ulcers, hypertension, hyperlipidemia, proteinuria, increased serum creatinine, infections, and sirolimus-related interstitial pneumonitis, mandate close patient monitoring, and may require withholding of the drug or reduction in dose. In addition, given the limited experience with sirolimus in the treatment of LAM, it is not known whether treatment may have to be continued for life, when it should be started, the optimal drug levels, or if sirolimus resistance will eventually develop.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Funding</span><p id="par0035" class="elsevierStylePara elsevierViewall">Research funded by the <span class="elsevierStyleGrantSponsor">Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute</span>.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interest</span><p id="par0040" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:2 [ "identificador" => "xpalclavsec565473" "titulo" => "Keywords" ] 1 => array:2 [ "identificador" => "xpalclavsec565472" "titulo" => "Palavras-chave" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 3 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflict of interest" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec565473" "palabras" => array:3 [ 0 => "Lymphangioleiomyomatosis" 1 => "Sirolimus therapy" 2 => "mTOR" ] ] ] ] "multimedia" => array:1 [ 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" => 1064 "Tamanyo" => 118791 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Simplified schematic model of <span class="elsevierStyleItalic">TSC1</span> and <span class="elsevierStyleItalic">TSC2</span> pathways. The <span class="elsevierStyleItalic">TSC1/TSC2</span> complex has roles in cell cycle progression and in cell size and proliferation. This complex stimulates the conversion of active Rheb-GTP to inactive Rheb-GDP, resulting in inactive Rheb. Rheb controls mTOR, a kinase that controls translation through phosphorylation of S6K1. Sirolimus inhibits mTOR. <span class="elsevierStyleItalic">Abbreviations</span>: PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; mTOR: mammalian target of rapamycin; Rheb GAP: GTPase-activating protein for Ras homolog enriched in brain; S6K1: S6 kinase 1 (modified from Ref. <a class="elsevierStyleCrossRef" href="#bib0050">10</a>).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:17 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The natural history of lymphangioleiomyomatosis: markers of severity, rate of progression and prognosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A.M. Taveira-DaSilva" 1 => "G. Gustavo Pacheco-Rodriguez" 2 => "J. Joel Moss" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Lymphatic Res Biol" "fecha" => "2010" "volumen" => "8" "paginaInicial" => "9" "paginaFinal" => "19" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.R. Johnson" 1 => "J.F. Cordier" 2 => "R. Lazor" 3 => "V. Cottin" 4 => "U. Costabel" 5 => "S. Harari" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1183/09031936.00076209" "Revista" => array:6 [ "tituloSerie" => "Eur Respir J" "fecha" => "2010" "volumen" => "35" "paginaInicial" => "14" "paginaFinal" => "26" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20044458" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evidence that lymphangiomyomatosis is caused by <span class="elsevierStyleItalic">TSC2</span> mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "T.A. Smolarek" 1 => "L.L. Wessner" 2 => "F.X. McCormack" 3 => "J.C. Mylet" 4 => "A.G. Menon" 5 => "E.P. Henske" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1086/301804" "Revista" => array:6 [ "tituloSerie" => "Am J Hum Genet" "fecha" => "1998" "volumen" => "62" "paginaInicial" => "810" "paginaFinal" => "815" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9529362" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Mutations in the tuberous sclerosis complex gene <span class="elsevierStyleItalic">TSC2</span> are a cause of sporadic pulmonary lymphangioleiomyomatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "T. Carsillo" 1 => "A. Astrinidis" 2 => "E.P. Henske" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Proc Natl Acad Sci USA" "fecha" => "2000" "volumen" => "97" "paginaInicial" => "6085" "paginaFinal" => "6090" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10823953" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Involvement of lymphatics in lymphangioleiomyomatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C.G. Glasgow" 1 => "A. Taveira-DaSilva" 2 => "G. Pacheco-Rodriguez" 3 => "W.K. Steagall" 4 => "K. Tsukada" 5 => "X. Cai" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1089/lrb.2009.0017" "Revista" => array:6 [ "tituloSerie" => "Lymphat Res Biol" "fecha" => "2009" "volumen" => "7" "paginaInicial" => "221" "paginaFinal" => "228" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20143921" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Renal angiomyolipomata" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J.J. Bissler" 1 => "J.C. Kingswood" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1111/j.1523-1755.2004.00838.x" "Revista" => array:6 [ "tituloSerie" => "Kidney Int" "fecha" => "2004" "volumen" => "66" "paginaInicial" => "924" "paginaFinal" => "934" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15327383" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "A.M. Taveira-Dasilva" 1 => "M.P. Stylianou" 2 => "C.J. Hedin" 3 => "O. Hathaway" 4 => "J. Moss" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1378/chest.126.6.1867" "Revista" => array:6 [ "tituloSerie" => "Chest" "fecha" => "2004" "volumen" => "126" "paginaInicial" => "1867" "paginaFinal" => "1874" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15596686" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of a gonadotrophin-releasing hormone analogue on lung function in lymphangioleiomyomatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Harari" 1 => "R. Cassandro" 2 => "J. Chiodini" 3 => "A.M. Taveira-DaSilva" 4 => "J. Moss" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1378/chest.07-2277" "Revista" => array:6 [ "tituloSerie" => "Chest" "fecha" => "2007" "volumen" => "133" "paginaInicial" => "448" "paginaFinal" => "454" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18071009" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pulmonary lymphangioleiomyomatosis (LAM): progress and current challenges" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "E.A. Goncharova" 1 => "V.P. Krymskaya" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/jcb.21419" "Revista" => array:6 [ "tituloSerie" => "J Cell Biochem" "fecha" => "2008" "volumen" => "103" "paginaInicial" => "369" "paginaFinal" => "382" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17541983" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Therapeutic options for lymphangioleiomyomatosis (LAM): where we are, where we are going" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A.M. Taveira-Dasilva" 1 => "W.K. Steagall" 2 => "J. Moss" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:3 [ "tituloSerie" => "Med Rep" "fecha" => "2009" "volumen" => "1" ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Perturbed IFN-gamma-Jak-signal transducers and activators of transcription signaling in tuberous sclerosis mouse models: synergistic effects of rapamycin-IFN-gamma treatment" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "N. El-Hashemite" 1 => "H. Zhang" 2 => "V. Walker" 3 => "K.M. Hoffmeister" 4 => "D.J. Kwiatkowski" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1158/0008-5472.CAN-03-3609" "Revista" => array:6 [ "tituloSerie" => "Cancer Res" "fecha" => "2004" "volumen" => "64" "paginaInicial" => "3436" "paginaFinal" => "3443" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15150095" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of rapamycin in the Eker rat model of tuberous sclerosis complex" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "H. Kenerson" 1 => "T.A. Dundon" 2 => "R.S. Yeung" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1203/01.PDR.0000147727.78571.07" "Revista" => array:6 [ "tituloSerie" => "Pediatr Res" "fecha" => "2005" "volumen" => "57" "paginaInicial" => "67" "paginaFinal" => "75" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15557109" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.J. Bissler" 1 => "F.X. McCormack" 2 => "L.R. Young" 3 => "J.M. Elwing" 4 => "G. Chuck" 5 => "J.M. Leonard" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa063564" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2008" "volumen" => "358" "paginaInicial" => "140" "paginaFinal" => "151" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18184959" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sirolimus ameliorated post-lung transplant chylothorax in lymphangioleiomyomatosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Ohara" 1 => "T. Oto" 2 => "K. Miyoshi" 3 => "H. Tao" 4 => "M. Yamane" 5 => "S. Toyooka" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.athoracsur.2008.07.062" "Revista" => array:6 [ "tituloSerie" => "Ann Thorac Surg" "fecha" => "2008" "volumen" => "86" "paginaInicial" => "e7" "paginaFinal" => "e8" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19021963" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.A. Krueger" 1 => "M.M. Care" 2 => "K. Holland" 3 => "K. Agricola" 4 => "C. Tudor" 5 => "P. Mangeshkar" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1001671" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2010" "volumen" => "363" "paginaInicial" => "1801" "paginaFinal" => "1811" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21047224" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "MILES Trial Group. Multicenter international lymphangioleiomyomatosis efficacy and safety of sirolimus (MILES) trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F.X. McCormack" 1 => "Y. Yoshikazu" 2 => "J. Moss" 3 => "L.G. Singer" 4 => "C. Strange" 5 => "K. Nakata" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa1100391" "Revista" => array:6 [ "tituloSerie" => "New Engl J Med" "fecha" => "2011" "volumen" => "364" "paginaInicial" => "1595" "paginaFinal" => "1606" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21410393" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Changes in lung function and chylous effusions in patients with lymphangioleiomyomatosis treated with sirolimus" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A.M. Taveira-DaSilva" 1 => "O. Hathaway" 2 => "M. Stylianou" 3 => "J. Moss" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.7326/0003-4819-154-12-201106210-00007" "Revista" => array:6 [ "tituloSerie" => "Ann Intern Med" "fecha" => "2011" "volumen" => "154" "paginaInicial" => "797" "paginaFinal" => "805" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21690594" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/08732159/0000001800000003/v2_201509041307/S0873215912000220/v2_201509041307/en/main.assets" "Apartado" => array:4 [ "identificador" => "9596" "tipo" => "SECCION" "pt" => array:2 [ "titulo" => "Comentário" "idiomaDefecto" => true ] "idiomaDefecto" => "pt" ] "PDF" => "https://static.elsevier.es/multimedia/08732159/0000001800000003/v2_201509041307/S0873215912000220/v2_201509041307/en/main.pdf?idApp=UINPBA00004E&text.app=https://journalpulmonology.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0873215912000220?idApp=UINPBA00004E" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 11 | 12 | 23 |
| 2024 October | 48 | 52 | 100 |
| 2024 September | 51 | 32 | 83 |
| 2024 August | 58 | 45 | 103 |
| 2024 July | 59 | 36 | 95 |
| 2024 June | 44 | 24 | 68 |
| 2024 May | 45 | 50 | 95 |
| 2024 April | 41 | 33 | 74 |
| 2024 March | 47 | 26 | 73 |
| 2024 February | 37 | 33 | 70 |
| 2024 January | 21 | 28 | 49 |
| 2023 December | 26 | 23 | 49 |
| 2023 November | 36 | 30 | 66 |
| 2023 October | 36 | 42 | 78 |
| 2023 September | 36 | 22 | 58 |
| 2023 August | 29 | 24 | 53 |
| 2023 July | 25 | 28 | 53 |
| 2023 June | 25 | 18 | 43 |
| 2023 May | 46 | 36 | 82 |
| 2023 April | 37 | 19 | 56 |
| 2023 March | 57 | 25 | 82 |
| 2023 February | 34 | 22 | 56 |
| 2023 January | 25 | 23 | 48 |
| 2022 December | 36 | 24 | 60 |
| 2022 November | 49 | 36 | 85 |
| 2022 October | 54 | 31 | 85 |
| 2022 September | 25 | 35 | 60 |
| 2022 August | 41 | 40 | 81 |
| 2022 July | 43 | 47 | 90 |
| 2022 June | 34 | 23 | 57 |
| 2022 May | 47 | 36 | 83 |
| 2022 April | 46 | 40 | 86 |
| 2022 March | 46 | 45 | 91 |
| 2022 February | 41 | 25 | 66 |
| 2022 January | 38 | 37 | 75 |
| 2021 December | 36 | 43 | 79 |
| 2021 November | 37 | 33 | 70 |
| 2021 October | 53 | 40 | 93 |
| 2021 September | 27 | 25 | 52 |
| 2021 August | 21 | 24 | 45 |
| 2021 July | 30 | 19 | 49 |
| 2021 June | 20 | 17 | 37 |
| 2021 May | 42 | 33 | 75 |
| 2021 April | 57 | 70 | 127 |
| 2021 March | 75 | 10 | 85 |
| 2021 February | 70 | 15 | 85 |
| 2021 January | 27 | 18 | 45 |
| 2020 December | 63 | 15 | 78 |
| 2020 November | 56 | 20 | 76 |
| 2020 October | 35 | 19 | 54 |
| 2020 September | 71 | 25 | 96 |
| 2020 August | 64 | 24 | 88 |
| 2020 July | 74 | 34 | 108 |
| 2020 June | 59 | 22 | 81 |
| 2020 May | 73 | 16 | 89 |
| 2020 April | 63 | 9 | 72 |
| 2020 March | 57 | 11 | 68 |
| 2020 February | 54 | 19 | 73 |
| 2020 January | 74 | 18 | 92 |
| 2019 December | 72 | 16 | 88 |
| 2019 November | 79 | 17 | 96 |
| 2019 October | 78 | 19 | 97 |
| 2019 September | 59 | 19 | 78 |
| 2019 August | 145 | 16 | 161 |
| 2019 July | 134 | 18 | 152 |
| 2019 June | 149 | 8 | 157 |
| 2019 May | 133 | 24 | 157 |
| 2019 April | 160 | 26 | 186 |
| 2019 March | 252 | 13 | 265 |
| 2019 February | 209 | 13 | 222 |
| 2019 January | 257 | 18 | 275 |
| 2018 December | 146 | 7 | 153 |
| 2018 November | 52 | 1 | 53 |
| 2018 October | 62 | 8 | 70 |
| 2018 September | 32 | 5 | 37 |
| 2018 August | 56 | 24 | 80 |
| 2018 July | 53 | 24 | 77 |
| 2018 June | 60 | 21 | 81 |
| 2018 May | 127 | 15 | 142 |
| 2018 April | 85 | 20 | 105 |
| 2018 March | 69 | 20 | 89 |
| 2018 February | 34 | 7 | 41 |
| 2018 January | 31 | 12 | 43 |
| 2017 December | 39 | 10 | 49 |
| 2017 November | 46 | 26 | 72 |
| 2017 October | 31 | 13 | 44 |
| 2017 September | 43 | 15 | 58 |
| 2017 August | 46 | 22 | 68 |
| 2017 July | 33 | 11 | 44 |
| 2017 June | 37 | 30 | 67 |
| 2017 May | 41 | 15 | 56 |
| 2017 April | 28 | 4 | 32 |
| 2017 March | 18 | 34 | 52 |
| 2017 February | 30 | 7 | 37 |
| 2017 January | 14 | 4 | 18 |
| 2016 December | 21 | 12 | 33 |
| 2016 November | 29 | 10 | 39 |
| 2016 October | 47 | 16 | 63 |
| 2016 September | 38 | 4 | 42 |
| 2016 August | 11 | 5 | 16 |
| 2016 July | 4 | 8 | 12 |
| 2016 June | 0 | 7 | 7 |
| 2016 May | 0 | 14 | 14 |
| 2016 April | 34 | 3 | 37 |
| 2016 March | 56 | 27 | 83 |
| 2016 February | 67 | 30 | 97 |
| 2016 January | 52 | 25 | 77 |
| 2015 December | 61 | 28 | 89 |
| 2015 November | 36 | 23 | 59 |
| 2015 October | 43 | 19 | 62 |
| 2015 September | 38 | 19 | 57 |
| 2015 August | 39 | 11 | 50 |
| 2015 July | 33 | 8 | 41 |
| 2015 June | 31 | 6 | 37 |
| 2015 May | 42 | 3 | 45 |
| 2015 April | 43 | 10 | 53 |
| 2015 March | 34 | 4 | 38 |
| 2015 February | 48 | 8 | 56 |
| 2015 January | 40 | 12 | 52 |
| 2014 December | 41 | 10 | 51 |
| 2014 November | 56 | 6 | 62 |
| 2014 October | 61 | 7 | 68 |
| 2014 September | 48 | 11 | 59 |
| 2014 August | 44 | 8 | 52 |
| 2014 July | 46 | 12 | 58 |
| 2014 June | 46 | 7 | 53 |
| 2014 May | 52 | 10 | 62 |
| 2014 April | 86 | 11 | 97 |
| 2014 March | 101 | 16 | 117 |
| 2014 February | 68 | 9 | 77 |
| 2014 January | 101 | 13 | 114 |
| 2013 December | 88 | 18 | 106 |
| 2013 November | 91 | 28 | 119 |
| 2013 October | 68 | 15 | 83 |
| 2013 September | 66 | 15 | 81 |
| 2013 August | 90 | 27 | 117 |
| 2013 July | 82 | 17 | 99 |
| 2013 June | 40 | 17 | 57 |
| 2013 May | 58 | 13 | 71 |
| 2013 April | 70 | 28 | 98 |
| 2013 March | 41 | 18 | 59 |
| 2013 February | 64 | 19 | 83 |
| 2013 January | 55 | 23 | 78 |
| 2012 December | 50 | 20 | 70 |
| 2012 November | 65 | 32 | 97 |
| 2012 October | 62 | 22 | 84 |
| 2012 September | 17 | 19 | 36 |
| 2012 January | 214 | 0 | 214 |
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