Topical application of mitomycin-C as an adjuvant treatment to bronchoscopic procedures in post-intubation tracheal stenosis

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Moura e Sá" "autores" => array:6 [ 0 => array:4 [ "nombre" => "F." "apellidos" => "Viveiros" "email" => array:1 [ 0 => "fcorreia@chvng.min-saude.pt" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "¿" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Gomes" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Oliveira" ] 3 => array:2 [ "nombre" => "S." "apellidos" => "Neves" ] 4 => array:2 [ "nombre" => "J." "apellidos" => "Almeida" ] 5 => array:2 [ "nombre" => "J." "apellidos" => "Moura e Sá" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Unidade de Broncologia, Serviço de Pneumologia, Centro Hospitalar de Gaia/Espinho, Vila Nova de Gaia, Portugal" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Aplicação tópica de mitomicina-C como adjuvante no tratamento broncoscópico da estenose traqueal pós-entubação" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 978 "Ancho" => 975 "Tamanyo" => 137510 ] ] "descripcion" => array:1 [ "en" => "Case number 11 – <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> and <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. (A) Stenosis (∼75%) with exuberant granulation tissue; (B) APC; (C) MMC application after RB dilatation; and (D) final stenosis (∼25%), with rare granulation tissue 2 months after first MMC session." ] ] ] "textoCompleto" => "IntroductionPost-intubation tracheal stenosis (PITS) is the most common benign cause of upper airway stenosis occurring in 1–4% of ventilated patients.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Management usually involves choosing between endoscopic and open reconstructive procedures.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Surgical resection and anastomosis is considered the definitive treatment. Bronchoscopic intervention is an important therapeutic alternative with some advantages.<a class="elsevierStyleCrossRefs" href="#bib0005">1–4</a> However, in both procedures, recurrence is common (40–70%) over a period of months to years, because of an excessive granulation tissue formation and an insidious process of scar contracture.<a class="elsevierStyleCrossRefs" href="#bib0005">1,5,6</a> Mitomycin-C (MMC) is an antineoplastic antibiotic agent that inhibits fibroblast proliferation, modulating wound healing and scarring.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2,5</a> Its topical application as adjuvant treatment in endoscopic management of stenosis has shown good results,<a class="elsevierStyleCrossRefs" href="#bib0010">2,5–8</a> suggesting that modulation of the wound healing process can play a major role in improving the success rate and reducing the need for frequent procedures in PITS.<a class="elsevierStyleCrossRefs" href="#bib0025">5,9</a> The aim of this study was to evaluate the results of topical MMC application after bronchoscopic dilatation as adjuvant procedure in PITS treatment.MethodsRetrospective selection of patients with PITS observed over the last 6 years (2006–2012) in the Bronchoscopy Unit of Pulmonology Department of the Gaia Hospital Center – Portugal, who had had Rigid Bronchoscopic (RB) dilatation followed by MMC application as adjuvant to endoscopic treatment. RB dilatation from 8.5 to 14mm was performed in all patients. Balloon dilatation was used before RB dilatation in 2 cases of severe stenosis to prevent excessive trauma. Whenever granulation tissue was associated to a fibrotic stricture, radial cuts with Nd-YAG laser or electrocautery were performed at low doses according to the degree of stenosis, before combined RB dilatation and MMC application (RB/MMC treatment). Argon plasma coagulation (APC) and criotherapy were also used, mostly because of exuberant granulation tissue and the benefits of their haemostatic properties. All the described procedures were applied before starting RB/MMC treatment in each patient and also later in selected cases depending on the recurrence of granulation and stenosis characteristics. In each session RB/MMC treatment was the final procedure. MMC was prepared in the Hospital Pharmacy at a 0.4mg/ml concentration, temporarily stored in a syringe, kept inside a cooler which was maintained at 5°C and covered by silvered protection to keep out the light, following the product recommendations. MMC was handled with great care and applied with an impregnated cotton stiletto around the stenotic lesion and granulation tissue for 3min, thereafter cleaned with a cotton stiletto soaked in NaCl 0.9% solution. Any product excess was returned to the pharmacy for appropriate management. All patients were clinically and endoscopically re-evaluated one month after the first MMC session and then monthly for 6 months or until stabilized. More than one RB/MMC session was performed depending on how the process evolved. Besides the interventional techniques performed and results with RB/MMC adjuvant treatment, patients were evaluated for type, location, extension and stenosis diameter (lumen %). RB was performed with the patient's written informed consent and this treatment was approved by the Ethics Committee of our Hospital.ResultsDuring the period studied, MMC was applied as adjuvant to endoscopic treatment in 11 patients with PITS: 6 women and 5 men, with a mean age of 58.4 (±12.7; min 39, max 72) years old. All patients had different degrees of respiratory stridor at initial physical examination. The initial stenosis diameter varied from 25% to 90% of the tracheal lumen, with a median stenosis diameter of 75%. Stricture was mostly located 1–3cm below vocal chords, with involvement of 1–3 tracheal rings. A fibrous ring conformation (complex stenosis) was observed in 9 cases and 2 presented with half ring (simple stenosis) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). RB dilatation and topical MMC application was performed as described in all patients. All patients were prescribed systemic steroids (prednisolone dose of 0.5mg/kg/day) for 7 days after procedure to help control inflammation. Depending on the stenosis characteristics – presence of granulation tissue and/or fibrosis – Nd-YAG laser was performed on 7 patients, electrocautery in 4, APC in 3 and criotherapy in 2 selected cases (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Dumon tracheal stent 16mm/4cm (Novatech.SA; La Ciotat, France) was placed in 2 patients (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>); one because of cartilage destruction with tracheomalacia and another because of recurrent granulation tissue related to permanent tracheostomy. The mean number of MMC sessions/patient was 3.5 (min 1; max 10), with prolonged decrease in granulation tissue in 6 (55%) cases, moderate in 2 (18%) and relapse in 3 (27%). As demonstrated in graphic 1 there was a reduction in stenosis diameter in all patients, with a noticeable improvement in granulation tissue formation after RB/MMC treatment (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). In 4 cases we observed 50% reduction in stenosis diameter (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>), in 2 patients 40% and 3 improved by 25–30%. The median of final airway diameter was 75% of the lumen, with a stenosis total mean improvement of 34%. The mean time from decrease in granulation to clinical improvement was 27.5 months (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia>DiscussionNo therapeutic option gives 100% result in PITS and all procedures can cause additional injury particularly restenosis by granulation tissue formation and fibrosis.<a class="elsevierStyleCrossRefs" href="#bib0005">1,4,7,9</a> Relapse is relatively frequent and is the main long-term problem.<a class="elsevierStyleCrossRefs" href="#bib0005">1,4,7</a> In recent years the search for alternative procedures focussed on the modulation of scar formation has increased.<a class="elsevierStyleCrossRefs" href="#bib0015">3,7</a> MMC is an anti-proliferative agent which decreases fibroblast proliferation and recurrence of granulation tissue.<a class="elsevierStyleCrossRefs" href="#bib0005">1,4,5</a> Repeated MMC applications have shown better results than a single application.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2,10</a> The utility of the described doses for tracheal stenosis vary between concentrations of 0.4mg/ml and 2mg/ml,<a class="elsevierStyleCrossRefs" href="#bib0015">3,7,10</a> applied for 1–5min.<a class="elsevierStyleCrossRefs" href="#bib0020">4,9,10</a> Most studies have demonstrated efficacy and safety of topical MMC at 0.4mg/ml concentration in PITS treatment<a class="elsevierStyleCrossRefs" href="#bib0005">1,3,4,7,10</a> and the evidence suggests that the effects of topical application remain localized, with a minimal impact on the surrounding tissue.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Doses of 1mg/ml have also been associated with improvement in recent analysis<a class="elsevierStyleCrossRefs" href="#bib0005">1,3</a> and a less traumatic airway injury from BR dilatation or laser before MMC application seems to be beneficial.<a class="elsevierStyleCrossRefs" href="#bib0005">1,4,9</a>Some studies suggest that early stenosis responds better to MMC than mature fibrotic stenosis.<a class="elsevierStyleCrossRefs" href="#bib0015">3,10</a> When fibrosis is present a combination of procedures is usually needed for treatment.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Our case series suggests that RB dilatation followed by MMC application (0.4mg/ml) for 3min can be beneficial in the wound healing modulation, delaying and decreasing granulation tissue formation. As verified in other studies,<a class="elsevierStyleCrossRefs" href="#bib0005">1,5,6,9,10</a> we observed a clinical improvement, with a better and longer lasting response in patients treated with MMC.RB dilatation followed by MMC application was then performed for all patients .We used a combined treatment approach with additional interventional techniques according to the presence of fibrosis, hemorrhagic risk and for management of exuberant granulation tissue. In our experience, from the first MMC application, there was a general improvement within the first 6 months.Definitive conclusions cannot be drawn from this study because of the small size of our population and the absence of patient randomization or a control group. However, topical MMC (0.4mg/ml) application after RB dilatation as adjuvant in bronchoscopic management of PITS seems to produce good results: a decrease in granulation tissue formation and sustained improvement in lumen diameter. Further research and randomized prospective clinical trials are needed to determine the most effective concentration, time and frequency of exposure to MMC. Exploring the possibility of using MMC earlier in PITS treatment algorithm could lead to improvements for granulation tissue management in the future.Ethical disclosuresProtection of human and animal subjectsThe authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).Confidentiality of dataThe authors declare that no patient data appear in this article.Right to privacy and informed consentThe authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "xres295768" "titulo" => array:5 [ 0 => "Abstract" 1 => "Introduction" 2 => "Methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec279559" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres295769" "titulo" => array:5 [ 0 => "Resumo" 1 => "Introdução" 2 => "Métodos" 3 => "Resultados" 4 => "Conclusões" ] ] 3 => array:2 [ "identificador" => "xpalclavsec279558" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:3 [ "identificador" => "sec0025" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Right to privacy and informed consent" ] ] ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-01-17" "fechaAceptado" => "2013-06-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec279559" "palabras" => array:3 [ 0 => "Post-intubation tracheal stenosis" 1 => "Rigid bronchoscopy" 2 => "Mitomycin-C" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec279558" "palabras" => array:3 [ 0 => "Estenose traqueal pós-entubação" 1 => "Broncoscopia rígida" 2 => "Mitomicina-C" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "IntroductionPost-intubation tracheal stenosis (PITS) continues to be challenging in terms of diagnosis, management and prevention. Recurrence is common because of excessive granulation tissue formation and an insidious process of scar contracture. Topical application of mitomycin-C (MMC) as an adjuvant treatment for endoscopic management of stenosis has shown good results. The authors aimed to evaluate the results of MMC topical application following bronchoscopic dilatation as an adjuvant in PITS treatment. MethodsRetrospectively selected patients with PITS who had had rigid bronchoscopy (RB) dilatation followed by MMC application as adjuvant to endoscopic treatment. MMC in a concentration of 0.4mg/ml was applied with a cotton stiletto around the stenotic lesion and granulation tissue for 3min. ResultsEleven patients with PITS, with a median initial tracheal stenosis of 75% of the lumen, underwent RB/MMC treatment. Mean MMC sessions performed/patient was 3.5, with good response and prolonged decrease in granulation tissue formation in 55% of cases, moderate in 18% and relapse in 27%. Mean stenosis improvement was 34%. ConclusionsTopical MMC application at 0.4mg/ml concentration seems to be associated with good results as adjuvant in PITS management with decrease in granulation tissue and sustained improvement in lumen diameter." ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "IntroduçãoO diagnóstico, tratamento e prevenção da estenose traqueal pós-entubação (ETPE) continua a ser um desafio. A recorrência é comum devido à formação excessiva de tecido de granulação e a um processo insidioso de cicatrização constritiva. A aplicação tópica de mitomicina-C (MMC) tem mostrado bons resultados como tratamento adjuvante na manipulação endoscópica das estenoses traqueais. Os autores tiveram como objetivo avaliar os resultados da aplicação tópica de MMC, após dilatação broncoscópica, como tratamento adjuvante da ETPE. MétodosDoentes com ETPE selecionados retrospetivamente, nos quais foi efetuada dilatação com broncoscópio rígido (BR) seguida da aplicação tópica de MMC como adjuvante no tratamento endoscópico. A MMC na concentração de 0,4mg/ml foi aplicada com um estilete recoberto com algodão, em redor da lesão estenótica e tecido de granulação, durante 3 minutos. ResultadosEm 11 doentes com ETPE, com mediana de estenose inicial de 75% do diâmetro do lúmen traqueal, foi aplicado o tratamento sucessivo com BR/MMC. A média de sessões com aplicação de MMC efetuada por doente foi de 3,5. Observou-se uma boa resposta e redução duradoura na formação de tecido de granulação em 55% dos casos, moderada em 18% e recorrente em 27%. A melhoria média no diâmetro da estenose foi de 34%. ConclusõesA aplicação tópica de MMC na concentração de 0,4mg/ml parece estar associada a bons resultados quando utilizada como adjuvante no tratamento das ETPE. Esses resultados devem-se à diminuição na formação de tecido de granulação e melhoria sustentada no diâmetro do lúmen traqueal." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Viveiros F, Gomes J, Oliveira A, Neves S, Almeida J, Moura e Sá J. Aplicação tópica de mitomicina-C como adjuvante no tratamento broncoscópico da estenose traqueal pós-entubação. Rev Port Pneumol. 2013;19:276–280." ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 613 "Ancho" => 996 "Tamanyo" => 114344 ] ] "descripcion" => array:1 [ "en" => "Results of RB/MMC treatment presented by percentage of lumen stenosis." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 978 "Ancho" => 975 "Tamanyo" => 137510 ] ] "descripcion" => array:1 [ "en" => "Case number 11 – <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a> and <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. (A) Stenosis (∼75%) with exuberant granulation tissue; (B) APC; (C) MMC application after RB dilatation; and (D) final stenosis (∼25%), with rare granulation tissue 2 months after first MMC session." ] ] 2 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "N°, patient number; C, complex; S, simple; APC, argon plasma coagulation; MMC, mitomycin-C; RB, rigid bronchoscopy; mo, months; Tx, treatment; %, percentage." "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">N° \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Stenosis type \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Electrocautery \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Laser \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">APC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Criotherapy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Tracheal stent \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">MMC sessions (N°) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Follow-up time (mo) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Time since first RB/MMC Tx (mo) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Time since last RB/MMC<a class="elsevierStyleCrossRef" href="#tblfn0010">**</a> Tx (mo) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Time since general improvement<a class="elsevierStyleCrossRef" href="#tblfn0005">*</a> (mo) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">% stenosis improvement \t\t\t\t\t\t\n \t\t\t\t</td></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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">5 \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">3 \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">8 \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="\n \t\t\t\t\ttop\n \t\t\t\t">68 \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="\n \t\t\t\t\ttop\n \t\t\t\t">66 \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="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">61 \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="\n \t\t\t\t\ttop\n \t\t\t\t">50 \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="\n \t\t\t\t\ttop\n \t\t\t\t">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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">3 \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">57 \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="\n \t\t\t\t\ttop\n \t\t\t\t">56 \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="\n \t\t\t\t\ttop\n \t\t\t\t">56 \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="\n \t\t\t\t\ttop\n \t\t\t\t">53 \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="\n \t\t\t\t\ttop\n \t\t\t\t">30<a class="elsevierStyleCrossRef" href="#tblfn0015">***</a> \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="\n \t\t\t\t\ttop\n \t\t\t\t">3 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">48 \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="\n \t\t\t\t\ttop\n \t\t\t\t">47 \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="\n \t\t\t\t\ttop\n \t\t\t\t">47 \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="\n \t\t\t\t\ttop\n \t\t\t\t">37 \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="\n \t\t\t\t\ttop\n \t\t\t\t">40<a class="elsevierStyleCrossRef" href="#tblfn0015">***</a> \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="\n \t\t\t\t\ttop\n \t\t\t\t">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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">7 \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="\n \t\t\t\t\ttop\n \t\t\t\t">3 \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">8 \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="\n \t\t\t\t\ttop\n \t\t\t\t">50 \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="\n \t\t\t\t\ttop\n \t\t\t\t">48 \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="\n \t\t\t\t\ttop\n \t\t\t\t">32 \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="\n \t\t\t\t\ttop\n \t\t\t\t">43 \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="\n \t\t\t\t\ttop\n \t\t\t\t">20 \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="\n \t\t\t\t\ttop\n \t\t\t\t">5<a class="elsevierStyleCrossRef" href="#tblfn0020">†</a> \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">3 \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">3 \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="\n \t\t\t\t\ttop\n \t\t\t\t">20<a class="elsevierStyleCrossRef" href="#tblfn0020">†</a> \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="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40 \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="\n \t\t\t\t\ttop\n \t\t\t\t">6 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">25 \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="\n \t\t\t\t\ttop\n \t\t\t\t">24 \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="\n \t\t\t\t\ttop\n \t\t\t\t">24 \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="\n \t\t\t\t\ttop\n \t\t\t\t">21 \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="\n \t\t\t\t\ttop\n \t\t\t\t">10 \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="\n \t\t\t\t\ttop\n \t\t\t\t">7 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">22 \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="\n \t\t\t\t\ttop\n \t\t\t\t">21 \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="\n \t\t\t\t\ttop\n \t\t\t\t">21 \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="\n \t\t\t\t\ttop\n \t\t\t\t">18 \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="\n \t\t\t\t\ttop\n \t\t\t\t">5 \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="\n \t\t\t\t\ttop\n \t\t\t\t">8 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \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="\n \t\t\t\t\ttop\n \t\t\t\t">6 \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="\n \t\t\t\t\ttop\n \t\t\t\t">8 \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="\n \t\t\t\t\ttop\n \t\t\t\t">50<a class="elsevierStyleCrossRef" href="#tblfn0015">***</a> \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="\n \t\t\t\t\ttop\n \t\t\t\t">9 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">S \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">10 \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="\n \t\t\t\t\ttop\n \t\t\t\t">8 \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="\n \t\t\t\t\ttop\n \t\t\t\t">8 \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="\n \t\t\t\t\ttop\n \t\t\t\t">7 \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="\n \t\t\t\t\ttop\n \t\t\t\t">50<a class="elsevierStyleCrossRef" href="#tblfn0015">***</a> \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="\n \t\t\t\t\ttop\n \t\t\t\t">10 \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">C \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">1 \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">– \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="\n \t\t\t\t\ttop\n \t\t\t\t">10 \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="\n \t\t\t\t\ttop\n \t\t\t\t">18 \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="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \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="\n \t\t\t\t\ttop\n \t\t\t\t">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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25<a class="elsevierStyleCrossRef" href="#tblfn0015">***</a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td 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Topical application of mitomycin-C as an adjuvant treatment to bronchoscopic procedures in post-intubation tracheal stenosis

Aplicação tópica de mitomicina-C como adjuvante no tratamento broncoscópico da estenose traqueal pós-entubação

F. Viveiros

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fcorreia@chvng.min-saude.pt

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, J. Gomes, A. Oliveira, S. Neves, J. Almeida, J. Moura e Sá

Unidade de Broncologia, Serviço de Pneumologia, Centro Hospitalar de Gaia/Espinho, Vila Nova de Gaia, Portugal

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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Case number 11 &#8211; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> and <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; &#40;A&#41; Stenosis &#40;&#8764;75&#37;&#41; with exuberant granulation tissue&#59; &#40;B&#41; APC&#59; &#40;C&#41; MMC application after RB dilatation&#59; and &#40;D&#41; final stenosis &#40;&#8764;25&#37;&#41;&#44; with rare granulation tissue 2 months after first MMC session&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Post-intubation tracheal stenosis &#40;PITS&#41; is the most common benign cause of upper airway stenosis occurring in 1&#8211;4&#37; of ventilated patients&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Management usually involves choosing between endoscopic and open reconstructive procedures&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Surgical resection and anastomosis is considered the definitive treatment&#46; Bronchoscopic intervention is an important therapeutic alternative with some advantages&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;4</span></a> However&#44; in both procedures&#44; recurrence is common &#40;40&#8211;70&#37;&#41; over a period of months to years&#44; because of an excessive granulation tissue formation and an insidious process of scar contracture&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;5&#44;6</span></a> Mitomycin-C &#40;MMC&#41; is an antineoplastic antibiotic agent that inhibits fibroblast proliferation&#44; modulating wound healing and scarring&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;5</span></a> Its topical application as adjuvant treatment in endoscopic management of stenosis has shown good results&#44;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5&#8211;8</span></a> suggesting that modulation of the wound healing process can play a major role in improving the success rate and reducing the need for frequent procedures in PITS&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;9</span></a> The aim of this study was to evaluate the results of topical MMC application after bronchoscopic dilatation as adjuvant procedure in PITS treatment&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0010" class="elsevierStylePara elsevierViewall">Retrospective selection of patients with PITS observed over the last 6 years &#40;2006&#8211;2012&#41; in the Bronchoscopy Unit of Pulmonology Department of the Gaia Hospital Center &#8211; Portugal&#44; who had had Rigid Bronchoscopic &#40;RB&#41; dilatation followed by MMC application as adjuvant to endoscopic treatment&#46; RB dilatation from 8&#46;5 to 14<span class="elsevierStyleHsp" style=""></span>mm was performed in all patients&#46; Balloon dilatation was used before RB dilatation in 2 cases of severe stenosis to prevent excessive trauma&#46; Whenever granulation tissue was associated to a fibrotic stricture&#44; radial cuts with Nd-YAG laser or electrocautery were performed at low doses according to the degree of stenosis&#44; before combined RB dilatation and MMC application &#40;RB&#47;MMC treatment&#41;&#46; Argon plasma coagulation &#40;APC&#41; and criotherapy were also used&#44; mostly because of exuberant granulation tissue and the benefits of their haemostatic properties&#46; All the described procedures were applied before starting RB&#47;MMC treatment in each patient and also later in selected cases depending on the recurrence of granulation and stenosis characteristics&#46; In each session RB&#47;MMC treatment was the final procedure&#46; MMC was prepared in the Hospital Pharmacy at a 0&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;ml concentration&#44; temporarily stored in a syringe&#44; kept inside a cooler which was maintained at 5<span class="elsevierStyleHsp" style=""></span>&#176;C and covered by silvered protection to keep out the light&#44; following the product recommendations&#46; MMC was handled with great care and applied with an impregnated cotton stiletto around the stenotic lesion and granulation tissue for 3<span class="elsevierStyleHsp" style=""></span>min&#44; thereafter cleaned with a cotton stiletto soaked in NaCl 0&#46;9&#37; solution&#46; Any product excess was returned to the pharmacy for appropriate management&#46; All patients were clinically and endoscopically re-evaluated one month after the first MMC session and then monthly for 6 months or until stabilized&#46; More than one RB&#47;MMC session was performed depending on how the process evolved&#46; Besides the interventional techniques performed and results with RB&#47;MMC adjuvant treatment&#44; patients were evaluated for type&#44; location&#44; extension and stenosis diameter &#40;lumen &#37;&#41;&#46; RB was performed with the patient&#39;s written informed consent and this treatment was approved by the Ethics Committee of our Hospital&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0015" class="elsevierStylePara elsevierViewall">During the period studied&#44; MMC was applied as adjuvant to endoscopic treatment in 11 patients with PITS&#58; 6 women and 5 men&#44; with a mean age of 58&#46;4 &#40;&#177;12&#46;7&#59; min 39&#44; max 72&#41; years old&#46; All patients had different degrees of respiratory stridor at initial physical examination&#46; The initial stenosis diameter varied from 25&#37; to 90&#37; of the tracheal lumen&#44; with a median stenosis diameter of 75&#37;&#46; Stricture was mostly located 1&#8211;3<span class="elsevierStyleHsp" style=""></span>cm below vocal chords&#44; with involvement of 1&#8211;3 tracheal rings&#46; A fibrous ring conformation &#40;complex stenosis&#41; was observed in 9 cases and 2 presented with half ring &#40;simple stenosis&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; RB dilatation and topical MMC application was performed as described in all patients&#46; All patients were prescribed systemic steroids &#40;prednisolone dose of 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41; for 7 days after procedure to help control inflammation&#46; Depending on the stenosis characteristics &#8211; presence of granulation tissue and&#47;or fibrosis &#8211; Nd-YAG laser was performed on 7 patients&#44; electrocautery in 4&#44; APC in 3 and criotherapy in 2 selected cases &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Dumon tracheal stent 16<span class="elsevierStyleHsp" style=""></span>mm&#47;4<span class="elsevierStyleHsp" style=""></span>cm &#40;Novatech&#46;SA&#59; La Ciotat&#44; France&#41; was placed in 2 patients &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#59; one because of cartilage destruction with tracheomalacia and another because of recurrent granulation tissue related to permanent tracheostomy&#46; The mean number of MMC sessions&#47;patient was 3&#46;5 &#40;min 1&#59; max 10&#41;&#44; with prolonged decrease in granulation tissue in 6 &#40;55&#37;&#41; cases&#44; moderate in 2 &#40;18&#37;&#41; and relapse in 3 &#40;27&#37;&#41;&#46; As demonstrated in graphic 1 there was a reduction in stenosis diameter in all patients&#44; with a noticeable improvement in granulation tissue formation after RB&#47;MMC treatment &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; In 4 cases we observed 50&#37; reduction in stenosis diameter &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#44; in 2 patients 40&#37; and 3 improved by 25&#8211;30&#37;&#46; The median of final airway diameter was 75&#37; of the lumen&#44; with a stenosis total mean improvement of 34&#37;&#46; The mean time from decrease in granulation to clinical improvement was 27&#46;5 months &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0020" class="elsevierStylePara elsevierViewall">No therapeutic option gives 100&#37; result in PITS and all procedures can cause additional injury particularly restenosis by granulation tissue formation and fibrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;7&#44;9</span></a> Relapse is relatively frequent and is the main long-term problem&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;7</span></a> In recent years the search for alternative procedures focussed on the modulation of scar formation has increased&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;7</span></a> MMC is an anti-proliferative agent which decreases fibroblast proliferation and recurrence of granulation tissue&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;5</span></a> Repeated MMC applications have shown better results than a single application&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;10</span></a> The utility of the described doses for tracheal stenosis vary between concentrations of 0&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;ml and 2<span class="elsevierStyleHsp" style=""></span>mg&#47;ml&#44;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;7&#44;10</span></a> applied for 1&#8211;5<span class="elsevierStyleHsp" style=""></span>min&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;9&#44;10</span></a> Most studies have demonstrated efficacy and safety of topical MMC at 0&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;ml concentration in PITS treatment<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3&#44;4&#44;7&#44;10</span></a> and the evidence suggests that the effects of topical application remain localized&#44; with a minimal impact on the surrounding tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Doses of 1<span class="elsevierStyleHsp" style=""></span>mg&#47;ml have also been associated with improvement in recent analysis<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3</span></a> and a less traumatic airway injury from BR dilatation or laser before MMC application seems to be beneficial&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;9</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Some studies suggest that early stenosis responds better to MMC than mature fibrotic stenosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;10</span></a> When fibrosis is present a combination of procedures is usually needed for treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Our case series suggests that RB dilatation followed by MMC application &#40;0&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;ml&#41; for 3<span class="elsevierStyleHsp" style=""></span>min can be beneficial in the wound healing modulation&#44; delaying and decreasing granulation tissue formation&#46; As verified in other studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;5&#44;6&#44;9&#44;10</span></a> we observed a clinical improvement&#44; with a better and longer lasting response in patients treated with MMC&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">RB dilatation followed by MMC application was then performed for all patients &#46;We used a combined treatment approach with additional interventional techniques according to the presence of fibrosis&#44; hemorrhagic risk and for management of exuberant granulation tissue&#46; In our experience&#44; from the first MMC application&#44; there was a general improvement within the first 6 months&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Definitive conclusions cannot be drawn from this study because of the small size of our population and the absence of patient randomization or a control group&#46; However&#44; topical MMC &#40;0&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;ml&#41; application after RB dilatation as adjuvant in bronchoscopic management of PITS seems to produce good results&#58; a decrease in granulation tissue formation and sustained improvement in lumen diameter&#46; Further research and randomized prospective clinical trials are needed to determine the most effective concentration&#44; time and frequency of exposure to MMC&#46; Exploring the possibility of using MMC earlier in PITS treatment algorithm could lead to improvements for granulation tissue management in the future&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Ethical disclosures</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Protection of human and animal subjects</span><p id="par0040" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association &#40;Declaration of Helsinki&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Confidentiality of data</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Right to privacy and informed consent</span><p id="par0050" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article&#46; The corresponding author is in possession of this document&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflicts of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Post-intubation tracheal stenosis &#40;PITS&#41; continues to be challenging in terms of diagnosis&#44; management and prevention&#46; Recurrence is common because of excessive granulation tissue formation and an insidious process of scar contracture&#46; Topical application of mitomycin-C &#40;MMC&#41; as an adjuvant treatment for endoscopic management of stenosis has shown good results&#46; The authors aimed to evaluate the results of MMC topical application following bronchoscopic dilatation as an adjuvant in PITS treatment&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Retrospectively selected patients with PITS who had had rigid bronchoscopy &#40;RB&#41; dilatation followed by MMC application as adjuvant to endoscopic treatment&#46; MMC in a concentration of 0&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;ml was applied with a cotton stiletto around the stenotic lesion and granulation tissue for 3<span class="elsevierStyleHsp" style=""></span>min&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Eleven patients with PITS&#44; with a median initial tracheal stenosis of 75&#37; of the lumen&#44; underwent RB&#47;MMC treatment&#46; Mean MMC sessions performed&#47;patient was 3&#46;5&#44; with good response and prolonged decrease in granulation tissue formation in 55&#37; of cases&#44; moderate in 18&#37; and relapse in 27&#37;&#46; Mean stenosis improvement was 34&#37;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Topical MMC application at 0&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;ml concentration seems to be associated with good results as adjuvant in PITS management with decrease in granulation tissue and sustained improvement in lumen diameter&#46;</p>"
      ]
      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Introdu&#231;&#227;o</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">O diagn&#243;stico&#44; tratamento e preven&#231;&#227;o da estenose traqueal p&#243;s-entuba&#231;&#227;o &#40;ETPE&#41; continua a ser um desafio&#46; A recorr&#234;ncia &#233; comum devido &#224; forma&#231;&#227;o excessiva de tecido de granula&#231;&#227;o e a um processo insidioso de cicatriza&#231;&#227;o constritiva&#46; A aplica&#231;&#227;o t&#243;pica de mitomicina-C &#40;MMC&#41; tem mostrado bons resultados como tratamento adjuvante na manipula&#231;&#227;o endosc&#243;pica das estenoses traqueais&#46; Os autores tiveram como objetivo avaliar os resultados da aplica&#231;&#227;o t&#243;pica de MMC&#44; ap&#243;s dilata&#231;&#227;o broncosc&#243;pica&#44; como tratamento adjuvante da ETPE&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Doentes com ETPE selecionados retrospetivamente&#44; nos quais foi efetuada dilata&#231;&#227;o com broncosc&#243;pio r&#237;gido &#40;BR&#41; seguida da aplica&#231;&#227;o t&#243;pica de MMC como adjuvante no tratamento endosc&#243;pico&#46; A MMC na concentra&#231;&#227;o de 0&#44;4<span class="elsevierStyleHsp" style=""></span>mg&#47;ml foi aplicada com um estilete recoberto com algod&#227;o&#44; em redor da les&#227;o esten&#243;tica e tecido de granula&#231;&#227;o&#44; durante 3 minutos&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Em 11 doentes com ETPE&#44; com mediana de estenose inicial de 75&#37; do di&#226;metro do l&#250;men traqueal&#44; foi aplicado o tratamento sucessivo com BR&#47;MMC&#46; A m&#233;dia de sess&#245;es com aplica&#231;&#227;o de MMC efetuada por doente foi de 3&#44;5&#46; Observou-se uma boa resposta e redu&#231;&#227;o duradoura na forma&#231;&#227;o de tecido de granula&#231;&#227;o em 55&#37; dos casos&#44; moderada em 18&#37; e recorrente em 27&#37;&#46; A melhoria m&#233;dia no di&#226;metro da estenose foi de 34&#37;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclus&#245;es</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A aplica&#231;&#227;o t&#243;pica de MMC na concentra&#231;&#227;o de 0&#44;4<span class="elsevierStyleHsp" style=""></span>mg&#47;ml parece estar associada a bons resultados quando utilizada como adjuvante no tratamento das ETPE&#46; Esses resultados devem-se &#224; diminui&#231;&#227;o na forma&#231;&#227;o de tecido de granula&#231;&#227;o e melhoria sustentada no di&#226;metro do l&#250;men traqueal&#46;</p>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Please cite this article as&#58; Viveiros F&#44; Gomes J&#44; Oliveira A&#44; Neves S&#44; Almeida J&#44; Moura e S&#225; J&#46; Aplica&#231;&#227;o t&#243;pica de mitomicina-C como adjuvante no tratamento broncosc&#243;pico da estenose traqueal p&#243;s-entuba&#231;&#227;o&#46; Rev Port Pneumol&#46; 2013&#59;19&#58;276&#8211;280&#46;</p>"
      ]
    ]
    "multimedia" => array:3 [
      0 => array:7 [
        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 613
            "Ancho" => 996
            "Tamanyo" => 114344
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        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Results of RB&#47;MMC treatment presented by percentage of lumen stenosis&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Case number 11 &#8211; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> and <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; &#40;A&#41; Stenosis &#40;&#8764;75&#37;&#41; with exuberant granulation tissue&#59; &#40;B&#41; APC&#59; &#40;C&#41; MMC application after RB dilatation&#59; and &#40;D&#41; final stenosis &#40;&#8764;25&#37;&#41;&#44; with rare granulation tissue 2 months after first MMC session&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">N&#176;&#44; patient number&#59; C&#44; complex&#59; S&#44; simple&#59; APC&#44; argon plasma coagulation&#59; MMC&#44; mitomycin-C&#59; RB&#44; rigid bronchoscopy&#59; mo&#44; months&#59; Tx&#44; treatment&#59; &#37;&#44; percentage&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
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                  \t\t\t\t" style="border-bottom: 2px solid black">N&#176;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Stenosis type&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Electrocautery&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Laser&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">APC&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Criotherapy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Tracheal stent&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">MMC sessions &#40;N&#176;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Follow-up time &#40;mo&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Time since first RB&#47;MMC Tx &#40;mo&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Time since last RB&#47;MMC<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;&#42;</span></a> Tx &#40;mo&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Time since general improvement<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a> &#40;mo&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&#37; stenosis improvement&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">30<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#42;&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
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                            1 => "R&#46; Agarwal"
                            2 => "A&#46;N&#46; Aggarwal"
                            3 => "D&#46;L&#46; Gupta"
                          ]
                        ]
                      ]
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                      "doi" => "10.1097/LBR.0b013e3182721290"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Bronchology Interv Pulmonol"
                        "fecha" => "2012"
                        "volumen" => "19"
                        "paginaInicial" => "304"
                        "paginaFinal" => "310"
                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23207530"
                            "web" => "Medline"
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    "identificador" => "9853"
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      "titulo" => "Brief Communication"
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Article information

ISSN: 21735115
Original language: English

DOI:10.1016/j.rppnen.2013.10.003

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