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Efficacy of cidofovir versus bevacizumab in recurrent respiratory papillomatosis: A randomized, double-blind, placebo-controlled pilot study
Eficacia de cidofovir frente a bevacizumab en la papilomatosis respiratoria recurrente: estudio piloto aleatorizado, doble ciego y controlado por placebo
Yuria Ablanedo-Terrazasa,
Corresponding author
yuria.ablanedo@gmail.com

Corresponding author.
, Oscar Estrada-Camachob, Claudia Alvarado-de la Barrerac, Arturo Ramírez-Garcíab, Gabriel Tona-Acedob, Daniel Bross-Sorianoa, José Schimelmitz-Idia
a Práctica Médica Grupal en Otorrinolaringología, Centro Médico ABC, Campus Santa Fe. Avenida Carlos Graef Fernández 154, Colonia Tlaxala, Cuajimalpa 05330, Ciudad de México, Mexico
b Departamento de Otorrinolaringología, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calzada de Tlalpan 4502, Colonia Sección XVI, Tlalpan 14080, Ciudad de México, Mexico
c Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calzada de Tlalpan 4502, Colonia Sección XVI, Tlalpan 14080, Ciudad de México, Mexico
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or acute respiratory distress&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">3</span></a> The estimated incidence of RRP is approximately 4 per 100&#44;000 in children and 2 per 100&#44;000 in adults&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">4&#44;5</span></a> Two forms of the disease are generally recognized&#44; being the juvenile-onset RRP more aggressive and usually diagnosed before 12 years of age&#59; and the adult-onset RRP a less aggressive form of the disease&#44; developed at later stages of life&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">There is no cure for RRP&#46; The current standard of care is surgical resection of papillomas aimed at clearing the airway with preservation of normal structures&#46; Adjuvant therapy may be recommended in addition to surgery for RRP control&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">6</span></a> Current adjuvant therapies have a range of actions including immunomodulation&#44; disruption of HPV replication&#44; control of inflammation and prevention of angiogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">7</span></a> In 2006&#44; the FDA approved the quadrivalent HPV vaccine containing HPV-6&#44; 11&#44; 16 and 18 &#40;Gardasil&#174;&#41;&#46; Besides its main effect in the prevention of HPV infection&#44; some doctors have attempted to administer the vaccine in patients with RRP as an adjuvant treatment&#46; A significant reduction in the number of surgical procedures has been observed&#44; nevertheless&#44; all of these studies are limited by their small sample sizes and the absence of randomized controls&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Cidofovir&#44; an acyclic nucleoside phosphonate that inhibits HPV replication by inhibition of DNA polymerase&#44; is the antiviral most commonly used in medical adjuvant treatment for RRP despite it is not currently approved by the US Food and Drug Administration &#40;FDA&#41; for this indication&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">10</span></a> In prospective studies&#44; adjuvant intralesional cidofovir has resulted in partial to complete regression of papillomas and decreased need for surgery&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">11&#8211;17</span></a> Intralesional administration has the advantage of maintaining plasma levels below those leading to toxicity&#44; with no local side effect&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">17</span></a> Bevacizumab&#44; a recombinant humanized monoclonal immunoglobulin antibody that inhibits angiogenesis via binding and inhibiting vascular endothelial growth factor&#44; is also a promising adjuvant treatment for RRP&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">10</span></a> Although not currently approved by the FDA for RRP&#44; small study series and case reports have reported better RRP control using the combination of KTP laser and bevacizumab&#44; with minimal complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">18&#8211;22</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">We performed a prospective&#44; double-blind&#44; placebo-controlled&#44; longitudinal adjuvant therapy trial aimed at comparing the efficacy of cidofovir versus bevacizumab in the treatment of RRP&#46; This is the first controlled clinical trial exploring the efficacy of bevacizumab in RRP&#46; We hypothesized that administration of intralesional cidofovir or intralesional bevacizumab would significantly decrease severity of RRP&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study population</span><p id="par0025" class="elsevierStylePara elsevierViewall">This randomized&#44; double-blind&#44; placebo-controlled clinical trial was conducted at a national referral center for respiratory diseases&#46; The study was performed during the period between March 2015 and February 2016 &#40;Clinicaltrials&#46;gov Identifier <a href="ctgov:NCT02555800">NCT02555800</a>&#41;&#46; The protocol and the informed consent were approved by the local Institutional Review Board &#40;IRB&#41;&#47;Ethics Committee &#40;Approval No&#46; C-48-14&#41;&#46; The study was conducted in accordance with the principles contained in the Declaration of Helsinki&#46; Consecutive adult or pediatric patients with a diagnosis of RRP&#44; who met inclusion&#47;exclusion criteria were invited to participate&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Inclusion and exclusion criteria</span><p id="par0030" class="elsevierStylePara elsevierViewall">To be considered for inclusion&#44; patients should have histopathologic diagnosis of RRP and at least 2 prior surgeries for RRP treatment&#46; The exclusion criteria were pregnancy or plan for pregnancy during study participation&#59; breastfeeding&#59; renal disease&#59; cardiovascular disease&#59; use of nephrotoxic medications&#59; use of adjuvant therapies for HPV in the previous year to study enrolment&#59; history of malignancies&#59; immune deficiency&#59; radiotherapy of the larynx&#44; trachea&#44; bronchi&#44; or lungs&#59; and presence of carcinoma&#46; In addition&#44; patients were excluded if they had a hypersensitivity to cidofovir or bevacizumab&#59; or if laboratory findings were abnormal&#44; including blood biometry&#44; blood chemistry&#44; urine test and electrocardiogram&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Study design and procedures</span><p id="par0035" class="elsevierStylePara elsevierViewall">This is a parallel trial of 3 arms&#44; with an allocation ratio of 1&#58;1&#58;1&#46; Participants were divided into juvenile or adult RRP&#46; A randomization plan for adults and a randomization plan for children were generated&#44; and patients were randomized into blocks of 3 3 3 3 3 3 &#40;please visit <a href="http://www.randomization.com/">http&#58;&#47;&#47;www&#46;randomization&#46;com</a> and use the seed 19&#44;161 to reproduce the plan for adults&#59; and use the seed 21&#44;209 to reproduce the plan for children&#41;&#46; The participants were randomly assigned to either the cidofovir group&#44; the bevacizumab group or the placebo group&#44; according to a predetermined random schedule stratified for adults versus children &#40;generation of random allocation sequence and assignment of interventions&#58; Yuria Ablanedo-Terrazas&#59; enrollment of patients&#58; Oscar Estrada-Camacho&#41;&#46; A double-blind&#44; placebo-controlled experimental design was used&#46; The study participation lasted for 12 months&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Patients were informed about the procedures of the study and provided written informed consent at baseline visit&#46; Parents and legal guardians gave consent for patients under age 18&#46; In addition&#44; the Voice Handicap Index &#40;VHI&#41; was assessed&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">23</span></a> On the next day&#44; the participant&#39;s upper aerodigestive tract was examined using direct microlaringoscopy&#44; and resection of papillomatous lesions was performed with cold instruments&#44; followed by intralesional injection of study drug or placebo&#46; RRP severity was quantified with the Derkay severity score&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">24</span></a> Two surgeons blinded to treatment assignment independently performed Derkay severity score assessments during the surgical procedure&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Direct microlaringoscopy with papilloma resection and administration of study drug or placebo&#44; followed by Derkay score assessments&#44; were performed at 3&#8211;6-week intervals&#44; for a total of 3 visits&#46; VHI questionnaire completion&#44; blood biometry&#44; blood chemistry&#44; urine test and electrocardiogram were performed the day before surgical procedures&#46; Subsequent follow-up visits for VHI questionnaire completion and Derkay score assessment through flexible nasofibrolaryngoscopy were performed at 2-month intervals over the course of one year&#46; Placebo consisted of saline solution 0&#46;9&#37;&#46; Intralesional cidofovir 5<span class="elsevierStyleHsp" style=""></span>mg&#47;mL dissolved in isotonic sodium chloride solution was administered without exceeding the FDA permitted dose of 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#46; Intralesional bevacizumab 25<span class="elsevierStyleHsp" style=""></span>mg&#47;mL was administered without exceeding the FDA permitted dose of 50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#46; The placebo had a colorless physical appearance similar to that of cidofovir and bevacizumab&#44; and all substances were administered by a blinded surgeon&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Statistical methods</span><p id="par0050" class="elsevierStylePara elsevierViewall">Demographic categorical data were compared by using Fisher&#39;s exact test&#46; <span class="elsevierStyleItalic">T</span>-student and ANOVA test was used to compare continuous variables&#46; Values of the Derkay severity score and the VHI score were compared between the cidofovir&#44; the bevacizumab and the placebo groups using the ANOVA test&#46; The within group improvement during follow-up was examined with the paired <span class="elsevierStyleItalic">T</span>-test&#46; A two-sided <span class="elsevierStyleItalic">p</span> value<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 was considered to be significant&#46; All analyses were performed with SPSS version 20 &#40;SPSS Inc&#46;&#44; Chicago&#44; Illinois&#44; USA&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Sample size calculation</span><p id="par0055" class="elsevierStylePara elsevierViewall">For detection of a 50&#37; clinical difference in the Derkay severity score between treatment groups and the placebo group using a two-tailed z test&#44; with a study power of 80&#37; and a confidence level of 95&#37;&#44; the estimated sample size was 15 patients per group&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Baseline characteristics of study population</span><p id="par0060" class="elsevierStylePara elsevierViewall">During the period from March 2015 to February 2016&#44; 16 patients with RRP were screened for eligibility&#46; No patients were excluded from the study&#46; Of the 16 patients included&#44; 5 were children and 11 were adults&#46; Four patients were assigned to receive cidofovir &#40;1 child and 3 adults&#41;&#46; Six patients were assigned to receive bevacizumab &#40;2 children and 4 adults&#41;&#46; Six patients were assigned to receive placebo &#40;2 children and 4 adults&#41;&#46; Enrollment was terminated when all patients with RRP attending our institution were assessed for eligibility&#46; A total of 3 patients were excluded from the analysis because they did not complete the entire three injection treatment &#40;one adult discontinued cidofovir&#44; one adult discontinued bevacizumab and one child discontinued placebo&#41;&#46; Thus&#44; a total of 13 patients were included in the analysis &#40;1 child and 2 adults treated with cidofovir&#59; 2 children and 3 adults treated with bevacizumab&#59; and 1 child and 4 adults treated with placebo&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The annual surgery rate before treatment was 1 surgery per year &#40;IQR&#44; 0&#46;39&#8211;2&#46;3&#41;&#59; and the median time from diagnosis was 6 years &#40;IQR&#44; 2&#46;5&#8211;20&#46;5&#41;&#46; In the group with juvenile RRP&#44; the median age was 5 years &#40;IQR&#44; 3&#46;5&#8211;9&#46;5&#41;&#59; the median age on diagnosis was 2 years &#40;IQR&#44; 2&#8211;4&#46;25&#41;&#59; the median number of resection surgeries before enrollment was 7&#46;5 &#40;IQR&#44; 3&#46;5&#8211;13&#46;75&#41;&#59; and the annual surgery rate was 2&#46;3 surgeries per year &#40;IQR&#44; 1&#46;6&#8211;4&#46;5&#41;&#46; In the group with adult RRP&#44; the median age was 39 years &#40;IQR&#44; 20&#8211;56&#41;&#59; the median age on diagnosis was 21 years &#40;IQR&#44; 8&#8211;38&#41;&#59; and the median number of resection surgeries before enrollment was 6 &#40;IQR&#44; 2&#8211;11&#41;&#46; The annual surgery rate in this group was 0&#46;5 surgeries per year &#40;IQR&#44; 0&#46;3&#8211;1&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">On baseline assessment&#44; no significant differences were found between treatment arms regarding the median number of resection surgeries before enrollment&#44; the annual surgery rate&#44; the Derkay severity score and the VHI score &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; However&#44; distribution of subjects by gender was asymmetric across treatment groups &#40;placebo&#44; 4 females and 1 male&#59; cidofovir&#44; 1 female and 2 males&#59; bevacizumab&#44; 0 females and 5 males&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;033&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Derkay severity score</span><p id="par0075" class="elsevierStylePara elsevierViewall">After one year of treatment&#44; we observed a significant decrease in the Derkay severity score of the group treated with cidofovir &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;027&#44; post-hoc Tukey test <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;043&#41;&#46; We calculated a study power of 70&#46;8&#37; through a post hoc power analysis&#46; This group also had a higher decrease in the annual surgery rate &#40;median&#44; 3&#46;46 on baseline vs&#46; 0 surgeries after treatment&#41; than the group treated with bevacizumab &#40;median&#44; 1 on baseline vs&#46; 0 surgeries after treatment&#41; and the placebo group &#40;median&#44; 0&#46;5 on baseline vs&#46; 0 surgeries after treatment&#44; but these differences were not statistically significant&#59; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Voice Handicap Index</span><p id="par0080" class="elsevierStylePara elsevierViewall">There was a significant decrease in the VHI score in all treatment groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; after one year&#59; and no significant difference was observed between groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;32&#41;&#46; No significant differences in VHI scores were observed when juvenile RRP vs&#46; adult RRP patients of the 3 treatment groups were compared&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Safety</span><p id="par0085" class="elsevierStylePara elsevierViewall">There were no drug-related or placebo-related adverse events in the study&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">Our study showed a statistically significant decrease in the Derkay severity score after one year of intralesional injection with cidofovir&#44; while no significant changes were observed with intralesional bevacizumab or placebo&#46; No difference between treatment arms was observed in the annual surgery rate&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">The decreasing VHI score throughout the study in all treatment groups was attributed to resection of papillomatous lesions&#46; However&#44; the lack of significant differences between all treatment groups indicated that adjuvant treatment with intralesional cidofovir or with intralesional bevacizumab were unable to enhance phonatory function&#46; This may be partially explained by the fact that repeated surgery procedures cause irreversible fibrosis in the Reinke&#39;s space&#44; leading to poor quality of voice&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Since RRP is a rare disease&#44; most information has been obtained from case control studies and case series involving limited number of patients&#46; If no placebo control group is included&#44; the unpredictable periods of RRP reactivation and remission are not easily distinguished from the effects of the tested treatments&#46; To our knowledge&#44; only one randomized&#44; double-blind&#44; placebo-controlled study exploring the efficacy of an adjuvant treatment in RRP has been performed&#46; That trial showed no advantage of intralesional cidofovir over placebo at 12 months&#46; Nevertheless&#44; the study was limited by a small sample size and a change in the cidofovir concentration midway through the trial&#44; from 0&#46;3<span class="elsevierStyleHsp" style=""></span>mg&#47;ml in children and 0&#46;75<span class="elsevierStyleHsp" style=""></span>mg&#47;ml in adults&#44; to 5<span class="elsevierStyleHsp" style=""></span>mg&#47;ml in both adults and children&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">25</span></a> Our study was limited by a small sample size&#44; particularly from the pediatric group&#46; We were unable to enroll the estimated number of patients&#44; and this may have contributed to the lack of efficacy of intralesional bevacizumab observed here&#46; The limited number of pediatric patients may be related to implementation of vaccination programs&#46; A prospective study of the incidence of juvenile RRP in Australia showed that following an extensive quadrivalent HPV 6&#47;11&#47;16&#47;18 vaccination program of females aged 12&#8211;26 years&#44; the incidence juvenile RRP declined from 0&#46;16 to 0&#46;02 per 100&#44;000 in a 5-years period&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">26</span></a> Uncontrolled case series suggest that the quadrivalent HPV vaccine may also be effective in diminishing the recurrence rate of RRP&#44;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">27&#8211;29</span></a> but a double-blinded randomized controlled trial is needed to evaluate the effect of vaccination on the clinical course&#46; Despite promising results in prevention and treatment of RRP&#44; vaccination is limited by suboptimal rates of acceptance among providers and patient families in countries such as the United States&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">30</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">A potential limitation of our study may be the bevacizumab and the cidofovir dosing used&#46; Since both drugs are not currently approved by the FDA for RRP&#44; there are no accepted protocols for dose&#44; frequency of administration&#44; number of injections and drug concentrations&#46; A systematic review on published dosing regimens of cidofovir as an adjuvant in juvenile and adult RRP showed concentrations of cidofovir ranging from 0&#46;0001 to 37&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#44; with 42&#37; of articles reporting an adopted concentration of 5<span class="elsevierStyleHsp" style=""></span>mg&#47;mL&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">31</span></a> There is also a great variability in the bevacizumab dosing regimens used across studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">18&#44;32</span></a> By consequence&#44; we cannot rule out the possibility of having used bevacizumab and cidofovir suboptimal dosing regimens&#46; Future studies should be performed to better define the dosing details and response rate to intralesional bevacizumab and intralesional cidofovir in RRP&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Preliminary evidence suggests that bevacizumab injections enhance photoangiolytic laser treatment of glottal papillomatosis while enhancing phonatory function&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">33</span></a> However&#44; resection of papillomatous lesions in our patients was performed using cold instruments&#46; By consequence&#44; the lack of efficacy of bevacizumab observed here might be related with the surgical treatment used&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The rarity of RRP&#44; surgical and adjuvant treatment variation among the studies&#44; poor quality of studies due to lack of controls and inadequate follow-up&#44; are some of the variables that have made it difficult to derive cumulative conclusions in the study of RRP&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conclusion</span><p id="par0120" class="elsevierStylePara elsevierViewall">While we observed a significant decrease in the Derkay severity score with intralesional cidofovir&#44; we were unable to provide proof of efficacy of intralesional bevacizumab in the treatment of RRP&#46; There is a need for well-designed placebo-controlled&#44; double-blinded&#44; randomized controlled trials assessing the efficacy of intralesional cidofovir and intralesional bevacizumab therapies for RRP&#46; It is likely that a multi-center trial will be required to include a sufficient number of participants for adequate study power&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Data sharing statement</span><p id="par0125" class="elsevierStylePara elsevierViewall">Raw data of study participants&#44; the informed consent form&#44; the original protocol and the randomization plan would be shared as Supplementary Information with publication&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Funding</span><p id="par0130" class="elsevierStylePara elsevierViewall">This work was funded by a grant from the <span class="elsevierStyleGrantSponsor" id="gs1">Comisi&#243;n de Equidad y G&#233;nero de la Honorable C&#225;mara de Diputados de la LXI Legislatura&#44; M&#233;xico</span>&#46; The funding source had no role in the design and conduct of the study&#59; collection&#44; management&#44; analysis&#44; and interpretation of the data&#59; preparation&#44; review&#44; or approval of the manuscript&#59; and decision to submit the manuscript for publication&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflict of interests</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare that there is no conflict of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">After surgical resection of papilloma&#44; adjuvant therapy may be recommended for the control of recurrent respiratory papillomatosis &#40;RRP&#41;&#46; As the efficacy of adjuvant therapy remains unproven&#44; the aim of this study was to compare the efficacy of cidofovir versus bevacizumab used as adjuvant therapies for the control of RRP&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">This randomized&#44; double-blind&#44; placebo-controlled pilot study was performed in a national respiratory disease referral centre&#46; Patients with RRP were recruited prospectively and were divided into juvenile or adult RRP&#46; Participants were randomly assigned to receive adjuvant therapy with cidofovir&#44; bevacizumab or placebo&#46; The study drug or placebo was administered after direct microlaryngoscopy with papilloma resection using cold instruments&#46; The Derkay severity score and the Voice Handicap Index &#40;VHI&#41; were assessed at 3&#8211;6-week intervals&#44; for a total of 3 visits&#46; Follow-up included VHI and Derkay score assessments at 2-month intervals over the course of one year&#46; Annual rates before and after surgical treatment were compared&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Five children and 11 adults were enrolled in the study&#46; After one year&#44; the group treated with cidofovir had a significant decrease in Derkay score &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;027&#41;&#46; No difference between treatment arms was observed in the annual surgery rate&#46; There was a significant decrease in the VHI score in all treatment groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#44; and no significant difference was observed between groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;32&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">While we observed a significant decrease in RRP severity with intralesional cidofovir&#44; we were unable to provide proof of efficacy of intralesional bevacizumab&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Clinicaltrials&#46;gov Identifier&#58; <span class="elsevierStyleInterRef" id="intr0005" href="ctgov:NCT02555800">NCT02555800</span>&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Objectives"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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          3 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Conclusion"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Tras la extirpaci&#243;n quir&#250;rgica de los papilomas&#44; puede recomendarse terapia adyuvante para el control de la papilomatosis respiratoria recurrente &#40;PRR&#41;&#46; Como la eficacia de la terapia adyuvante no est&#225; demostrada&#44; el objetivo de este estudio fue comparar la eficacia de cidofovir frente a bevacizumab&#44; utilizados como terapias adyuvantes para el control de PRR&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Estudio piloto aleatorizado&#44; doble ciego y controlado por placebo&#44; realizado en un centro nacional de referencia de enfermedades respiratorias&#46; Se reclut&#243; prospectivamente a los pacientes con PRR&#44; y se dividieron en 2 grupos&#58; PRR de j&#243;venes y PRR de adultos&#46; A los participantes se les asign&#243; aleatoriamente la administraci&#243;n de terapia adyuvante de cidofovir&#44; bevacizumab o placebo&#46; La administraci&#243;n de los f&#225;rmacos de estudio o placebo se realiz&#243; tras practicar microlaringoscopia directa con extirpaci&#243;n de papilomas&#44; utilizando instrumental fr&#237;o&#46; Se llevaron a cabo evaluaciones utilizando la puntuaci&#243;n de gravedad de Derkay y la escala VHI &#40;Voice Handicap Index&#41; a intervalos de 3 a 6 semanas&#44; con un total de 3 visitas&#46; El seguimiento incluy&#243; evaluaci&#243;n de las escalas VHI y Derkay a intervalos de 2 meses&#44; durante el curso de un a&#241;o&#46; Se compararon las tasas anuales pre- y postratamiento quir&#250;rgico&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">El estudio incluy&#243; 5 ni&#241;os y 11 adultos&#46; Transcurrido un a&#241;o&#44; el grupo tratado con cidofovir reflej&#243; una reducci&#243;n significativa en la escala Derkay &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;027&#41;&#46; No se observ&#243; diferencia alguna entre las ramas terap&#233;uticas en la tasa quir&#250;rgica anual&#46; Se vio una reducci&#243;n significativa en la puntuaci&#243;n VHI en todos los grupos terap&#233;uticos &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; y no se observ&#243; diferencia significativa entre los grupos &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;32&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">A pesar de verse una reducci&#243;n significativa de la gravedad de PRR con la administraci&#243;n de cidofovir intralesional&#44; no pudimos probar la eficacia de bevacizumab intralesional&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Objetivos"
          ]
          1 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "M&#233;todos"
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          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusi&#243;n"
          ]
        ]
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    "multimedia" => array:3 [
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        "identificador" => "fig0005"
        "etiqueta" => "Figure 1"
        "tipo" => "MULTIMEDIAFIGURA"
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">CONSORT flow diagram of the study&#46; Numbers of study participants assessed for eligibility&#44; randomized&#44; followed-up through 12 months and included in the analysis&#46;</p>"
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        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
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                  <table border="0" frame="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment group&nbsp;\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="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
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                  \t\t\t\t">Placebo</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">F&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">16&#47;16&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  " align="char" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">60&nbsp;\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
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                  \t\t\t\t">F&nbsp;\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
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                  \t\t\t\t">13&#47;14&nbsp;\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">82&nbsp;\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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\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
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                  \t\t\t\t">53&nbsp;\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
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                  \t\t\t\t">F&nbsp;\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
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                  \t\t\t\t">14&#47;15&nbsp;\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">58&nbsp;\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="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">20&nbsp;\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">F&nbsp;\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
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                  \t\t\t\t">6&#47;3&nbsp;\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
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                  \t\t\t\t">41&nbsp;\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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\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">59&nbsp;\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">M&nbsp;\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">14&#47;14&nbsp;\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">70&nbsp;\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  " colspan="5" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cidofovir</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&nbsp;\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">M&nbsp;\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">23&#47;24&nbsp;\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">23&nbsp;\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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\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">39&nbsp;\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">F&nbsp;\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">11&#47;11&nbsp;\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">60&nbsp;\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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\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&nbsp;\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">M&nbsp;\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">31&#47;35&nbsp;\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&nbsp;\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
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \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="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">8&#47;10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">M&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">BVZ&#44; bevacizumab&#59; IQR&#44; interquartile range&#59; JRRP&#44; Juvenile recurrent respiratory papillomatosis&#59; ARRP&#44; adult recurrent respiratory papillomatosis&#59; VHI&#44; voice Handicap Index&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Cidofovir &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">BVZ &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41;&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Placebo &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#41;&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>13&#41;&nbsp;\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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span> value&nbsp;\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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#40;median&#41;&nbsp;\t\t\t\t\t\t\n
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                  \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">17&nbsp;\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">20&nbsp;\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">53&nbsp;\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">20 &#40;IQR&#44; 8&#8211;48&#41;&nbsp;\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">0&#46;342&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Male&#47;female&nbsp;\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">2&#47;1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#47;0&nbsp;\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">1&#47;4&nbsp;\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">8&#47;5&nbsp;\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">0&#46;033<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;</a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">JRRP&#47;ARRP&nbsp;\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">1&#47;2&nbsp;\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">2&#47;3&nbsp;\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">1&#47;4&nbsp;\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">4&#47;9&nbsp;\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">0&#46;786&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total resections &#40;median&#41;&nbsp;\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">3&nbsp;\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">15&nbsp;\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">5&nbsp;\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">6 &#40;IQR&#44; 2&#46;5&#8211;11&#41;&nbsp;\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">0&#46;094&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baseline annual surgical rate &#40;median&#41;&nbsp;\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">3&#46;4&nbsp;\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">1&nbsp;\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">0&#46;5&nbsp;\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">1 &#40;IQR&#44; 0&#46;39&#8211;2&#46;33&#41;&nbsp;\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">0&#46;104&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baseline Derkay score &#40;median&#41;&nbsp;\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">23&#46;5&nbsp;\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">9&nbsp;\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">14&nbsp;\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
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                  \t\t\t\t">14 &#40;8&#46;75&#8211;22&#41;&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  " align="char" valign="\n
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                  \t\t\t\t">0&#46;320&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Baseline VHI &#40;median&#41;&nbsp;\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
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                  \t\t\t\t">53&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">50&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">58&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">53 &#40;43&#46;5&#8211;69&#46;5&#41;&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</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Derkay score at 12 months&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&#46;5&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  " align="left" valign="\n
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                  \t\t\t\t">2&#46;5&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  " align="left" valign="\n
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                  \t\t\t\t">2 &#40;0&#46;62&#8211;4&#46;3&#41;&nbsp;\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
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                  \t\t\t\t">0&#46;704&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VHI at 12 months&nbsp;\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
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                  \t\t\t\t">30&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  " align="left" valign="\n
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                  \t\t\t\t">19&nbsp;\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">38&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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&#46;5 &#40;IQR&#44; 30&#8211;39&#41;&nbsp;\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
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                  \t\t\t\t">0&#46;200&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Annual surgical rate at 12 months&nbsp;\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
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                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&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">0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;IQR&#44; 0&#46;39&#8211;2&#46;33&#41;&nbsp;\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
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                  \t\t\t\t">0&#46;914&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Difference in surgical rate<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&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  " align="left" valign="\n
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                  \t\t\t\t">3&#46;4&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  " align="left" valign="\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;35&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  " align="left" valign="\n
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                  \t\t\t\t">0&#46;66 &#40;IQR&#44; 0&#46;34&#8211;2&#46;33&#41;&nbsp;\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
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                  \t\t\t\t">0&#46;104&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Difference in Derkay score<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">9 &#40;IQR&#44; 3&#46;37&#8211;13&#46;62&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;027<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Difference in VHI<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">23&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">23 &#40;IQR&#44; 37&#8211;16&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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Article information
ISSN: 21735735
Original language: English
DOI:10.1016/j.otoeng.2020.12.001
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