RAPID COMMUNICATION
Anaplastic lymphoma kinase gene rearrangement in non-small-cell lung cancer in a Brazilian population
Consultoria em Patologia, Botucatu/SP, Brazil
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Non-small-cell lung carcinoma (NSCLC), which represents approximately 80% of all lung cancer cases, is frequently diagnosed at advanced stages of the disease and is associated with short survival time. Although the prognosis of this disease remains poor, significant advances in the genetics and treatment of NSCLC have been made in recent years.</p><p id="para20" class="elsevierStylePara elsevierViewall">In 2007, Soda et al. (<a class="elsevierStyleCrossRef" href="#bib2">2</a>) identified the transforming <span class="elsevierStyleItalic">EML4-ALK</span> fusion gene in 6.7% of NSCLC patients. This fusion transcript, which presents potent oncogenic activity both <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> (<a class="elsevierStyleCrossRef" href="#bib2">2</a>,<a class="elsevierStyleCrossRef" href="#bib3">3</a>), is formed by the translocation of the echinoderm microtubule-associated protein-like 4 (<span class="elsevierStyleItalic">EML4</span>) gene (2p21) and anaplastic lymphoma kinase (<span class="elsevierStyleItalic">ALK</span>) gene (2p23). Subsequent studies have shown that between two and eight percent of all NSCLC cases may harbor <span class="elsevierStyleItalic">ALK</span> rearrangements, which are almost always mutually exclusive with <span class="elsevierStyleItalic">EGFR</span> and <span class="elsevierStyleItalic">KRAS</span> mutations. Moreover, these patients are frequently younger, non- or light smokers and have adenocarcinomas (<a class="elsevierStyleCrossRef" href="#bib2">2</a>),. Recently, crizotinib, an orally available small-molecule inhibitor of the <span class="elsevierStyleItalic">ALK</span> tyrosine kinase, was approved for the treatment of <span class="elsevierStyleItalic">ALK</span>-rearranged NSCLC patients, with successful results (<a class="elsevierStyleCrossRefs" href="#bib24">24–29</a>). The two most widely used methods for the diagnosis of <span class="elsevierStyleItalic">ALK</span>-rearranged NSCLC are fluorescence <span class="elsevierStyleItalic">in situ</span> hybridization (FISH) and immunohistochemistry.</p><p id="para30" class="elsevierStylePara elsevierViewall">Because there is no information about the prevalence and clinical characteristics of <span class="elsevierStyleItalic">ALK</span>-rearranged NSCLC in Latin America in the literature, the aim of this study was to evaluate NSCLC with <span class="elsevierStyleItalic">ALK</span> rearrangement in Brazilian patients.</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">MATERIALS AND METHODS</span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">Case Selection</span><p id="para40" class="elsevierStylePara elsevierViewall">This study included 62 consecutive NSCLC cases received from August 2010 to September 2011 for <span class="elsevierStyleItalic">ALK</span> rearrangement testing using FISH (<a class="elsevierStyleCrossRef" href="#bib30">30</a>) by Consultoria em Patologia, a large Anatomic Pathology and Molecular Pathology reference laboratory located in Botucatu, São Paulo State, Brazil. Tissues from small biopsies and lung resection specimens were used. The ages and genders of the patients were registered.</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">Fluorescence <span class="elsevierStyleItalic">in situ</span> hybridization (FISH)</span><p id="para50" class="elsevierStylePara elsevierViewall">FISH was performed on formalin-fixed, paraffin-embedded tumor samples using a probe specific to the <span class="elsevierStyleItalic">ALK</span> locus (Vysis LSI <span class="elsevierStyleItalic">ALK</span> dual color, break apart rearrangement probe; Abbott Molecular, Des Plaines, IL, USA) according to the manufacturer's instructions. The FISH results were analyzed under a fluorescence microscope (Zeiss Axio Imager M1, Carl Zeiss AG, Oberkochen, Germany) with the appropriate filters (Chroma Technology GmbH, Fuerstenfeldbruck, Germany) and Metafer 4 software (MetaSystems, Altlussheim, Germany). FISH-positive cases were defined as those in which more than 15% of the cells (at least 40 neoplastic cells were counted) presented with split orange and green signals or an isolated orange signal, as previously described (<a class="elsevierStyleCrossRef" href="#bib31">31</a>,<a class="elsevierStyleCrossRef" href="#bib32">32</a>).</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle50">Immunohistochemistry</span><p id="para60" class="elsevierStylePara elsevierViewall">For comparison with FISH results, ALK protein expression was determined by immunohistochemistry using the mouse monoclonal antibody 5A4 (code ab17127, ABCAM, Cambridge, MA, USA), which was found to show high concordance with <span class="elsevierStyleItalic">ALK</span> gene status, as determined by molecular tests (<a class="elsevierStyleCrossRef" href="#bib13">13</a>,<a class="elsevierStyleCrossRef" href="#bib14">14</a>,<a class="elsevierStyleCrossRef" href="#bib23">23</a>),. Briefly, 3-µm-thick unstained histologic sections of lung carcinoma tissue were used in all cases. The sections were deparaffinized in xylene and rehydrated in a graded series of alcohol in phosphate-buffered saline. The sections then were submitted to antigen retrieval in a microwave. Subsequently, slides were incubated overnight with the 5A4 antibody at a pre-standardized concentration (1:200), washed with phosphate-buffered saline, and incubated with Novocastra Novolink Polymer Detection System (Leica Biosystems Newcastle Ltd., Newcastle upon Tyne, UK). Diaminobenzidine was used as the chromogen, and sections were counterstained with hematoxylin and coverslipped. A case was considered positive for ALK if ≥10% of the tumor cells showed intense cytoplasmic immunostaining.</p></span></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">RESULTS</span><p id="para70" class="elsevierStylePara elsevierViewall">Of the 62 NSCLC cases included in this study, two (3.2%) showed <span class="elsevierStyleItalic">ALK</span> rearrangement by FISH: one case presented an isolated orange signal along with one fusion signal in tumor cells, and the other showed split orange and green signals along with one fusion signal. These two FISH-positive cases were also positive for <span class="elsevierStyleItalic">ALK</span> by immunohistochemistry, with strong cytoplasmic immunostaining in virtually all tumor cells. All of the other sixty FISH-negative cases were also negative for <span class="elsevierStyleItalic">ALK</span> using immunohistochemistry.</p><p id="para80" class="elsevierStylePara elsevierViewall">Both of the patients with FISH- and <span class="elsevierStyleItalic">ALK</span> immunohistochemistry-positive NSCLC were men (36 years old and 45 years old; mean: 40 years). One of them had no history of tobacco smoking, and the other was a light smoker who had stopped smoking some months prior to the diagnosis. The group of patients (n = 60) presenting <span class="elsevierStyleItalic">ALK</span>-negative tumors by FISH varied in age from 32 to 87 years (mean: 58 years; median: 59 years), and most of these patients were male (33 patients).</p><p id="para90" class="elsevierStylePara elsevierViewall">According to the new international multidisciplinary classification of lung adenocarcinomas proposed by the International Association for the Study of Lung Cancer, the American Thoracic Society and the European Respiratory Society (<a class="elsevierStyleCrossRef" href="#bib37">37</a>), tumors from the two patients with <span class="elsevierStyleItalic">ALK</span>-positive FISH were classified as invasive adenocarcinoma, acinar predominant. One tumor had papillary areas, and the other was rich in mucinous areas. The 36-year-old patient with invasive adenocarcinoma, acinar predominant with papillary areas, was also tested for <span class="elsevierStyleItalic">EGFR</span> and <span class="elsevierStyleItalic">KRAS</span> mutations; the tumor was negative for both mutations. <a class="elsevierStyleCrossRef" href="#fig1">Figure 1</a> presents the morphologic characteristics of the two <span class="elsevierStyleItalic">ALK</span>-positive cases, including FISH and immunohistochemical findings.</p><elsevierMultimedia ident="fig1"></elsevierMultimedia></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">DISCUSSION</span><p id="para100" class="elsevierStylePara elsevierViewall">Clinical characteristics associated with <span class="elsevierStyleItalic">ALK</span> rearrangement in NSCLC include adenocarcinoma histology, younger age at diagnosis, and non- or light smoker status, similar to those described for <span class="elsevierStyleItalic">EGFR</span> mutations. The prevalence of NSCLCs with <span class="elsevierStyleItalic">ALK</span> fusion varies from 2% to 8% in the literature, and most studies have been conducted in Asian countries or in the United States of America. <a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a> presents the frequency of <span class="elsevierStyleItalic">ALK</span>-rearranged NSCLC in several countries. In Japan, the prevalence of lung cancer with <span class="elsevierStyleItalic">ALK</span> rearrangement varied widely, from 2.4% to 6.7% (<a class="elsevierStyleCrossRef" href="#bib2">2</a>,<a class="elsevierStyleCrossRef" href="#bib16">16</a>,<a class="elsevierStyleCrossRef" href="#bib19">19</a>). In Korea, the frequency of <span class="elsevierStyleItalic">ALK</span>-positive NSCLC ranged from 3.7% to 4.2% (<a class="elsevierStyleCrossRef" href="#bib11">11</a>,<a class="elsevierStyleCrossRef" href="#bib13">13</a>,<a class="elsevierStyleCrossRef" href="#bib14">14</a>). In China, it was approximately 5% (<a class="elsevierStyleCrossRef" href="#bib4">4</a>,<a class="elsevierStyleCrossRef" href="#bib12">12</a>,<a class="elsevierStyleCrossRef" href="#bib15">15</a>). In the USA, the prevalence varied from 5.6 to 8.2% (<a class="elsevierStyleCrossRef" href="#bib17">17</a>,<a class="elsevierStyleCrossRef" href="#bib23">23</a>). These findings show that ethnicity likely does not strongly influence the prevalence of <span class="elsevierStyleItalic">ALK</span>-rearranged lung carcinomas, which is in contrast to <span class="elsevierStyleItalic">EGFR</span>- and <span class="elsevierStyleItalic">KRAS</span>-mutated tumors (<a class="elsevierStyleCrossRefs" href="#bib38">38–41</a>).</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia><p id="para110" class="elsevierStylePara elsevierViewall">To the best of our knowledge, however, no information about the prevalence and clinical characteristics of these tumors in Latin America, including Brazil, is available in the literature.</p><p id="para120" class="elsevierStylePara elsevierViewall">In the present study, 3.2% (2 out of 62) of NSCLC cases in Brazilian patients were <span class="elsevierStyleItalic">ALK</span> fusion positive by FISH. These two male patients were younger than those with <span class="elsevierStyleItalic">ALK</span>-negative FISH, had a history of no or light smoking, and their tumors presented invasive adenocarcinoma histology similar to that described in the literature. Both tumors were histologically classified as acinar predominant: one tumor had papillary areas, and the other was rich in mucinous areas.</p><p id="para130" class="elsevierStylePara elsevierViewall">Consistent with the results of other studies (<a class="elsevierStyleCrossRef" href="#bib13">13</a>,<a class="elsevierStyleCrossRef" href="#bib14">14</a>,<a class="elsevierStyleCrossRef" href="#bib23">23</a>), a high concordance between FISH and immunohistochemistry results for the detection of <span class="elsevierStyleItalic">ALK</span>-positive NSCLCs was found in the present study. Although FISH remains the gold standard technique for the diagnosis of <span class="elsevierStyleItalic">ALK</span>-rearranged lung carcinoma, immunohistochemistry may play an important role in the determination of <span class="elsevierStyleItalic">ALK</span> status in NSCLC in the near future. Because data regarding the role of immunohistochemistry in the detection of <span class="elsevierStyleItalic">ALK</span>-positive lung cancer are limited in the literature, additional studies are necessary.</p><p id="para140" class="elsevierStylePara elsevierViewall">The use of crizotinib has changed the history of NSCLC treatment, with dramatic results in patients with <span class="elsevierStyleItalic">ALK</span>-rearranged tumors. A recent phase I/II clinical trial showed that 47 of 82 (57%) patients with <span class="elsevierStyleItalic">ALK</span> fusion-positive lung tumors confirmed by FISH had objective responses to crizotinib, and an additional 27 (33%) patients displayed stable disease (<a class="elsevierStyleCrossRef" href="#bib9">9</a>). These data highlight that the diagnosis of <span class="elsevierStyleItalic">ALK</span>-rearranged NSCLC is crucial.</p><p id="para150" class="elsevierStylePara elsevierViewall">As previously stated, the present study is the first in Latin America to present clinicopathologic information regarding <span class="elsevierStyleItalic">ALK</span>-rearranged NSCLC in patients from this geographic area. Further studies are encouraged to expand our knowledge on <span class="elsevierStyleItalic">ALK</span>-positive NSCLC in Latin America and Brazil.</p></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">AUTHOR CONTRIBUTIONS</span><p id="para160" class="elsevierStylePara elsevierViewall">Bacchi CE was responsible for designing and supervising the project, and writing and revising the manuscript. Lopes LF was responsible for data collection, data analysis, and writing the manuscript. All authors approved the final version of the manuscript.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:6 [ 0 => array:2 [ "identificador" => "cesec10" "titulo" => "INTRODUCTION" ] 1 => array:3 [ "identificador" => "cesec20" "titulo" => "MATERIALS AND METHODS" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "cesec30" "titulo" => "Case Selection" ] 1 => array:2 [ "identificador" => "cesec40" "titulo" => "Fluorescence in situ hybridization (FISH)" ] 2 => array:2 [ "identificador" => "cesec50" "titulo" => "Immunohistochemistry" ] ] ] 2 => array:2 [ "identificador" => "cesec60" "titulo" => "RESULTS" ] 3 => array:2 [ "identificador" => "cesec70" "titulo" => "DISCUSSION" ] 4 => array:2 [ "identificador" => "cesec80" "titulo" => "AUTHOR CONTRIBUTIONS" ] 5 => array:1 [ "titulo" => "REFERENCES" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:1 [ "nota" => "<p class="elsevierStyleNotepara" id="cenpara10">No potential conflict of interest was reported.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig1" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 325 "Ancho" => 664 "Tamanyo" => 90322 ] ] "descripcion" => array:1 [ "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">ALK</span>-rearranged NSCLCs. <span class="elsevierStyleBold">A.</span> Invasive adenocarcinoma, acinar predominant with papillary areas, in a 36-year-old male patient (case 1). <span class="elsevierStyleBold">B.</span> FISH of case 1 showing one isolated orange signal along with one fusion signal (positive for <span class="elsevierStyleItalic">ALK</span> rearrangement). <span class="elsevierStyleBold">C.</span><span class="elsevierStyleItalic">ALK</span> expression in case 1: diffuse and intense cytoplasmic immunostaining. <span class="elsevierStyleBold">D.</span> Invasive adenocarcinoma, acinar predominant with mucinous areas, in a 45-year-old male patient (case 2). <span class="elsevierStyleBold">E.</span> FISH of case 2 showing split orange and green signals along with one fusion signal (positive for <span class="elsevierStyleItalic">ALK</span> rearrangement). <span class="elsevierStyleBold">F.</span> ALK expression in case 2: intense cytoplasmic immunostaining in virtually all tumor cells.</p>" ] ] 1 => array:7 [ "identificador" => "tbl1" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Authors, year of publication \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Country \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">ALK</span>-rearranged tumors \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">Soda et al., 2007 (2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">Japan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">6.7% (n = 75) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">Rodig et al., 2009 (17) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">5.6% (n = 358) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">Wong et al., 2009 (4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">China \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">4.9% (n = 266) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">Sakairi et al., 2010 (19) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">Japan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">6.4% (n = 109) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">Takahashi et al., 2010 (16) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">Japan \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">2.4% (n = 211) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">Sun et al., 2010 (15) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">China \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">5.7% (n = 52) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">Paik et al., 2011 (11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">Korea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">3.8% (n = 735) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">Li et al., 2011 (12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">China \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">5% (n = 202) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">Kim et al., 2011 (13) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">Korea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">3.7% (n = 449) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">Paik et al., 2011 (14) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">Korea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">4.2% (n = 453) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">Yang et al., 2012 (23) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">USA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">8.2% (n = 300) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="top">Lopes et al. (present study) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="center" valign="top">Brazil \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="top">3.2% (n = 62) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Prevalence of <span class="elsevierStyleItalic">ALK</span>-rearranged NSCLC in different countries.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "REFERENCES" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "cebibsec10" "bibliografiaReferencia" => array:41 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths" "autores" => array:1 [ 0 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| Year/Month | Html | Total | |
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| 2024 November | 5 | 1 | 6 |
| 2024 October | 32 | 25 | 57 |
| 2024 September | 16 | 13 | 29 |
| 2024 August | 32 | 21 | 53 |
| 2024 July | 23 | 17 | 40 |
| 2024 June | 26 | 10 | 36 |
| 2024 May | 40 | 11 | 51 |
| 2024 April | 31 | 13 | 44 |
| 2024 March | 51 | 13 | 64 |
| 2024 February | 35 | 14 | 49 |
| 2024 January | 16 | 9 | 25 |
| 2023 December | 9 | 19 | 28 |
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| 2023 September | 13 | 17 | 30 |
| 2023 August | 17 | 6 | 23 |
| 2023 July | 8 | 11 | 19 |
| 2023 June | 13 | 13 | 26 |
| 2023 May | 44 | 0 | 44 |
| 2023 April | 32 | 1 | 33 |
| 2023 March | 33 | 3 | 36 |
| 2023 February | 25 | 6 | 31 |
| 2023 January | 14 | 4 | 18 |
| 2022 December | 14 | 5 | 19 |
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