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Original article
Survival analysis of patients with prostate cancer and unfavorable risk factors treated with radical prostatectomy and salvage radiotherapy after biochemical recurrence and persistence
Análisis de supervivencia de los pacientes con cáncer de próstata con factores patológicos desfavorables tratados con prostatectomía radical y radioterapia de rescate tras la recidiva y persistencia bioquímica
G. Barbas Bernardosa,
Corresponding author
guillermobarbas@gmail.com

Corresponding author.
, F. Herranz Amoa, C. González San Segundob, J. Caño Velascoa, D. Subirá Ríosa, M. Moralejo Gáratea, J. Mayor de Castroa, J. Aragón Chamizoa, C. Hernández Fernándeza
a Servicio de Urología, H.G.U. Gregorio Marañón, Madrid, Spain
b Servicio de Oncología Radioterápica, H.G.U. Gregorio Marañón, Madrid, Spain
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        "titulo" => "An&#225;lisis de supervivencia de los pacientes con c&#225;ncer de pr&#243;stata con factores patol&#243;gicos desfavorables tratados con prostatectom&#237;a radical y radioterapia de rescate tras la recidiva y persistencia bioqu&#237;mica"
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          "en" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Recurrence-free survival &#40;RFS&#41;&#46; &#40;A&#41; RFS of the series after prostatectomy&#46; &#40;B&#41; RFS according to the number of unfavorable pathological factors&#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">Patients with high-risk prostate cancer &#40;PCa&#41; are more likely to have biochemical recurrence &#40;BR&#41; or persistent elevated PSA after primary treatment&#44; require second-line treatments&#44; present metastatic progression or dye from PCa&#46; However&#44; not all patients in this subgroup behave in the same way after radical prostatectomy &#40;RP&#41;&#44; with highly heterogeneous prognoses based on various pathological factors&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">When managed with non-curative intent therapies&#44; this type of tumor has cancer-specific mortality rates at 10 and 15 years which range between 29&#37; and 35&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In addition&#44; metastasis-free survival rates in high-risk PCa patients treated with RP without salvage treatment at 5 and 10 years are around 67&#37; and 48&#37;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">3</span></a> These data&#44; together with the fact that between 27&#37; and 53&#37; of these patients will present PSA recurrence after RP&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a> and that many of them will not have evidence of clinical or radiological disease at the time of BR&#44; with subsequent progression to metastasis if salvage treatment is not administered&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">5</span></a> corroborate the need to establish the post-RP management of patients with PCa with unfavorable pathological factors &#40;UPF&#41;&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The 2019 clinical guidelines of the European Association of Urology<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a> recommend salvage radiotherapy &#40;SRD&#41; in case of BR in patients with UPF &#40;PSA-DT<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>1 year or ISUP grade 4&#8211;5&#41; after RP&#44; with surveillance as an option available for patients with PSADT &#62;12 months&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The objective of this study is to analyze the oncological evolution of patients with UPF who had been treated with RP and SRT when they presented BR&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">From the department&#39;s prostatectomy database &#40;1996&#8211;2015&#41;&#44; the data of patients who presented at least one of the following UPFs have been retrospectively extracted&#58; Gleason score &#8805;8&#44; pathological stage &#8805;pT3 or positive surgical margins &#40;&#43;SM&#41;&#46; A total of 589 patients were extracted&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Patient exclusion after data extraction was as follows&#58; 29 &#40;4&#46;9&#37;&#41; due to follow-up shorter than 12 months&#44; 12 &#40;2&#37;&#41; due to pN&#43; in lymphadenectomy &#40;since most of them were treated with HT or surveillance for having undetectable PSA after RP&#41;&#44; 34 &#40;5&#46;8&#37;&#41; who were not treated after BR &#40;late relapse and&#47;or short life expectancy&#41; and 68 &#40;11&#46;5&#37;&#41; who were treated with hormone therapy &#40;HT&#41; after BR&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Therefore&#44; 446 &#40;75&#46;7&#37;&#41; patients were included in the study&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The diagnosis was made by transrectal ultrasound-guided biopsy and&#44; when indicated&#44; staging CT scan of the abdomen and pelvis&#44; and whole-body bone scintigraphy were performed&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Prostatectomy was performed following the technique described by Walsh<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">6</span></a> in patients who underwent open RP&#46; The indication and extent of pelvic lymphadenectomy were consistent with the corresponding literature recommendations and clinical guidelines during the 19 years of study&#46; Patients were restaged according to the UICC TNM system &#40;7th edition&#41; of 2009&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">7</span></a> Stages were grouped into pT2 and pT3 for multivariate analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">8</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">No patients received adjuvant radiation therapy&#46; Follow-up was performed by PSA 1&#46;5&#8211;2 months after surgery&#44; then every 6 months during the first 5 years and annually thereafter&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">BR was defined as the elevation of PSA above 0&#46;4<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">9</span></a> Patients who did not reach PSA &#60;0&#46;4<span class="elsevierStyleHsp" style=""></span>ng&#47;ml levels after RP were considered as biochemical persistent &#40;BP&#41;&#59; these patients were assigned a disease-free time of 0 months&#46; For the analysis&#44; patients with BP and BR were considered as BR&#46; Patients treated with SRT who reached PSA &#60;0&#46;4<span class="elsevierStyleHsp" style=""></span>ng&#47;ml levels were considered as disease-free&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">SRT was performed in all patients by 3D conformal radiotherapy &#40;RT&#41; with CT planning&#46; The target volume was the prostatectomy bed&#44; following the recommendations of the European &#40;ESTRO&#41;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> and American &#40;RTOG&#41;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a> guidelines on volume delimitation&#46; Patients with absence of lymphadenectomy and&#47;or pT3 with Gleason &#8805;8 had radiation on the pelvic nodes&#46; All patients received 70<span class="elsevierStyleHsp" style=""></span>Gy doses in the prostatectomy bed with 5 sessions of 2<span class="elsevierStyleHsp" style=""></span>Gy&#47;fraction per week&#46; The nodal dose was increased to 74&#8211;76<span class="elsevierStyleHsp" style=""></span>Gy in patients who presented clinical recurrence confirmed by imaging techniques&#46; The dose to the pelvic nodes was 50<span class="elsevierStyleHsp" style=""></span>Gy with identical fractionation&#46; In the absence of published trials on the benefit of SRT<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HT combination during the years when the study patients were treated&#44; the main criteria for adding HT were persistence of elevated PSA &#40;&#62;1<span class="elsevierStyleHsp" style=""></span>ng&#41; prior radiation and Gleason score &#8805;8&#46; The duration of hormone therapy in these patients was 1 year&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Quantitative variables have been represented as median and interquartile range &#40;IQR&#41; and qualitative variables as absolute frequencies and percentages&#46; The Chi-squared test was used for the contrast of qualitative variables and the Student&#39;s <span class="elsevierStyleItalic">t</span> test for numerical variables&#46; The Kaplan&#8211;Meier method was used to assess recurrence-free survival &#40;RFS&#41; and cancer-specific survival &#40;CSS&#41;&#44; with long-rank test to assess the existence of significant differences among categories of the variables&#46; Univariate and multivariate analysis using Cox regression has been used to identify risk factors with a possible influence on the response to SRT and CSS&#46; Statistical significance was considered when there was a <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 value&#46; All calculations have been performed with the statistical program IBM&#174; SPSS&#174; Statistics v&#46;21&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0075" class="elsevierStylePara elsevierViewall">The median age of the 446 patients was 64 &#40;range 59&#8211;68&#41; years&#44; the median PSA at diagnosis was 8 &#40;range 5&#46;6&#8211;11&#41; ng&#47;ml&#44; with 26 patients presenting a PSA equal to or greater than 20<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#46; The most frequent clinical stage was cT1c&#44; with 248 &#40;55&#46;6&#37;&#41; patients&#44; Gleason score 6 was the most frequent in 194 &#40;43&#46;5&#37;&#41; and the most frequent D&#8217;Amico risk group was intermediate&#44; with 200 &#40;44&#46;8&#37;&#41; patients&#46; Prostatectomy was performed through an open approach in 361 &#40;80&#46;9&#37;&#41; patients&#44; and the remaining patients were treated with a laparoscopic procedure&#46; Staging lymphadenectomy was performed in 163 &#40;36&#46;5&#37;&#41; patients&#46; Clinical variables are detailed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">After pathological evaluation of the specimen&#44; the most frequent stage was pT2c in 186 &#40;41&#46;7&#37;&#41; patients&#44; Gleason score 7 &#40;3<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>4&#41; was observed in 142 &#40;31&#46;9&#37;&#41;&#44; 275 &#40;61&#46;7&#37;&#41; patients had positive surgical margins&#44; and 375 &#40;84&#46;1&#37;&#41; presented perineural invasion&#46; Only one UPF was observed in 61&#46;4&#37; &#40;274&#41; of the patients&#44; while all UPFs &#40;three&#41; were present in 10&#46;8&#37; &#40;48&#41; of the patients&#46; The most frequent combination of two UPFs was pT3<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#43;SM in 59 &#40;13&#46;2&#37;&#41; patients&#46; Pathological variables are detailed in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">The median follow-up of the series was 72 &#40;range 37&#8211;122&#41; months&#46; BP was observed in 34 &#40;7&#46;6&#37;&#41; patients and BR during follow-up in 128 &#40;28&#46;7&#37;&#41; patients&#46; The median time until recurrence was 42 &#40;range 20&#8211;112&#41; months&#46; The median PSA at the diagnosis of recurrence was 0&#46;56 &#40;range 0&#46;43&#8211;0&#46;96&#41;&#59; this value was 0&#46;86 &#40;range 0&#46;60&#8211;1&#46;48&#41; in patients with BP&#44; and 0&#46;52 &#40;range 0&#46;41&#8211;0&#46;90&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;35&#41; in patients with BR&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The overall estimation of RFS in the series according to Kaplan&#8211;Meier at 3&#44; 5&#44; 8 and 10 years was 72&#46;8&#44; 65&#46;4&#44; 60&#46;2&#37; and 57&#46;7&#37;&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46; The RFS rate decreased according to the number of UPFs &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46; In the group of patients with only one UPF&#44; the most unfavorable for RFS was the existence of &#43;SM &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;06&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#46; No significant differences were observed in terms of RFS &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;36&#41; in the group of patients with two UPFs &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">A multivariate analysis &#40;Cox regression&#41; was performed with the pathological variables that could affect BR &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The combinations of the following UPFs were identified as independent predictive variables of BR&#58; GS &#8805;8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>pT3 &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;34&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#44; pT3<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#43;SM &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;66&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41; and GS &#8805;8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>pT3<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#43;SM &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4&#46;42&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41;&#46; The existence of perineural invasion also behaved as an independent predictive factor &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;69&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;048&#41;&#46; The performance of lymphadenectomy behaved as an independent protective factor of BR &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;53&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Of the 162 patients who presented BR&#47;BP&#44; 130 &#40;80&#46;2&#37;&#41; were treated with SRT and 32 &#40;19&#46;8&#37;&#41; with SRT<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HT&#46; Biochemical response was presented by 121 &#40;74&#46;7&#37;&#41; patients&#44; no significant differences were observed &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;83&#41; according to the salvage therapy administered&#44; nor according to whether it was BP or BR &#40;BP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>73&#46;5&#37; and BR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>74&#46;8&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;88&#41;&#46; The estimation of RFS after SRT at 3&#44; 5&#44; 8 and 10 years was 95&#46;7&#44; 92&#46;3&#44; 87&#46;9 and 85&#37;&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46; No significant differences were observed &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;54&#41; based on having BP or BR&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">A multivariate analysis was carried out with the following variables&#58; PSA at BR&#47;BP &#40;&#8804;1 or &#62;1<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">12</span></a> time to BR &#40;&#8804;24 months or &#62;24 months&#41; and type of SRT &#40;SRT alone or SRT<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HT&#41;&#46; The UPF variable was excluded&#44; since it was not significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;23&#41; in the univariate analysis&#46; Only time until BR of &#8804;24 months &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;55&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; behaved as an independent predictor of decreased RFS after SRT &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The status of the patients at the end of follow-up is described in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46; Disease-free and deceased were the status in 80&#46;3&#37; &#40;358&#41; and 11&#46;2&#37; &#40;50&#41; of the patients&#44; respectively&#59; although only 1&#46;6&#37; &#40;7&#41; had died from PCa&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">Overall survival at 5&#44; 10&#44; and 15 years was estimated as 95&#46;6&#44; 86&#46;5&#44; and 73&#46;5&#37;&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#46; The estimate of CSS at 5&#44; 10 and 15 years was 99&#46;1&#44; 98&#46;1 and 96&#46;6&#37;&#44; respectively &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">In this retrospective study we have analyzed the oncological evolution of PCa patients with UPFs who were treated with RP in monotherapy and with SRT when they presented BR&#44; obtaining promising data for this subgroup of patients with a poor prognosis that are rarely studied separately from the other risk groups when approaching the management of relapse&#46; We obtained post-RT RFS rates at 10 years &#62;85&#37;&#44; OS &#62;73&#37; at 15 years and CSS &#62;96&#37; at 15 years&#46; The following UPFs combinations were identified as independent predictive variables of BR&#58; GS &#8805;8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>pT3&#44; pT3<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#43;SM and GS &#8805;8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>pT3<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>&#43;SM&#44; in addition to the existence of perineural invasion and absence of lymphadenectomy performance&#46; Patients with BR and SRT for a period of &#8804;2 years after RP had a worse response to SRT&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">There was not much literature related to RT in patients undergoing RP before 2005&#8211;2006&#44; and it presented disparate and often contradictory results&#44; and was mostly based on retrospective studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">13&#8211;15</span></a> Subsequently&#44; the first results of prospective randomized studies began to appear&#44; such as the EORTC 22911&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">16</span></a> the SWOG 8794<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> and the German ARO 96-02&#47;AUO AP 09&#47;95<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a> trials&#46; These provided the first conclusive data in favor of adjuvant RT in patients with PCa and UPFs&#44; demonstrating an increase in BR-free survival&#46; With the posterior publication of long-term results&#44; it was even possible to demonstrate a significant improvement in overall survival and metastasis-free survival&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">19</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The data of our series confirm the fact that approximately half of the patients with PCa and UPFs treated with RP will present relapse within the 10 years following RP&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">4</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The post-SRT RFS rates of our study compared to the previously mentioned clinical trials are more optimistic &#40;85&#37; at 10 years in our study compared to 75&#37; in the SWOG&#44; 56&#37; in the ARO 96-02&#47;AUO AP 09&#47;95 and 65&#37; in the EORTC&#41;&#46; The OS rate of 86&#37; at 10 years is also higher than the rates described in the only trial that managed to demonstrate significant differences &#40;74&#37; at 10 years&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">However&#44; it is important to highlight&#44; in addition to the limitations of our study&#44; that our data cannot be fully extrapolated to those of these trials&#44; due to several factors&#46; First&#44; they do not have the exact same inclusion criteria in terms of UPFs&#46; Second&#44; management with posterior RT is heterogeneous among them&#46; Third&#44; keeping with the proposed objective&#44; we evaluated salvage RT exclusively and not adjuvant RT globally&#44; analyzing together patients with BR&#44; BP&#44; and patients treated with SRT alone or in combination with HT&#44; as has been described in the corresponding section&#46; Finally&#44; we must highlight that these results may also be conditioned by the fact that most of the patients have been treated in the last 6 years according to follow-up data&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Regarding the predictive factors of response to SRT&#44; nomograms with utility in clinical practice in the prediction of the efficacy of SRT have been published in the literature&#44; such as the Stephenson et al&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">20</span></a> nomogram &#40;with patients treated after BR with PSA &#62;0&#46;2&#41; or the one created by Tendulkar et al&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">21</span></a> &#40;including patients with pre-RT PSA &#60;0&#46;2&#41;&#46; These nomograms highlight that higher pre-RT PSA level&#44; lower RT dose&#44; absence of HT and invasion of seminal vesicles behave as predictive factors of recurrence&#46; In our series&#44; neither the PSA level in relapse nor the use of HT obtained significance&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Despite the data published in the 3 large trials mentioned above and the increasing evidence on the benefits of adjuvant RT in patients with UPFs&#44; there have been studies published which have shown that the indication for this treatment is not increasing&#44; but even decreasing&#46; The hypotheses postulated on the possible causes include the following&#58; patient preferences&#44; concern about adverse effects&#44; and lack of clear evidence of benefit in terms of overall and cancer-specific survival with respect to early salvage RT treatments &#40;PSA figures &#8804;0&#46;6&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">22&#8211;24</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">With this work we aim to provide data in relation to this subgroup of patients treated with RP and UPFs who require a consensus on their postoperative management at the time of recurrence&#46; SRT is presented as an option that is becoming more effective every day&#44; taking into account the encouraging survival figures obtained&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">In the historical series of our center&#44; with more than 1500 prostatectomies&#44; only 65&#37; of the patients with BR and only 62&#37; of the patients with BP were treated with SRT&#46; The good results obtained have meant a change in the usual practice with our patients&#44; in such a way that&#44; at present&#44; SRT is systematically assessed in all BRs&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">The limitations of our study include its observational&#44; retrospective design&#44; its limited population&#44; in which the patients included were not evaluated&#44; treated and followed in a strictly uniform and prospective manner&#46; Additionally&#44; it would be necessary to delve into various aspects related to SRT&#44; such as the simultaneous use of HT&#44; the evaluation of its side effects or its comparison with the adjuvant RT modality&#44; aspects that were not among the objectives of this study&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">It should be noted that there are at least three prospective clinical trials underway in this regard &#40;RADICALS&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">25</span></a> GETUG-AFU 16<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">26</span></a> and RAVES<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">27</span></a>&#41; whose preliminary results were presented at the Congress of the European Society for Medical Oncology &#40;ESMO&#41; 2019&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">28&#44;29</span></a> These trials seem to show that adjuvant radiotherapy does not present a clear superiority in terms of oncological control compared to observation and eventual SRT after elevated PSA&#46; Instead&#44; the first option seems to be associated with greater genitourinary morbidity &#40;incontinence&#44; urethral stricture&#44; &#8230;&#41;&#46; However&#44; long-term follow-up data are still required in order to draw more robust conclusions about the best time sequence for SRT administration&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusion</span><p id="par0175" class="elsevierStylePara elsevierViewall">In patients with PCa and UPFs&#44; RP only achieves control of the disease at 10 years in approximately half of the cases&#46; Sequential multimodal treatment &#40;prostatectomy and SRT when required&#41; increases this control to over 85&#37;&#44; achieving long CSS&#46; Patients with a time to relapse greater than 24 months responded better to salvage therapy&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicts of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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            0 => "C&#225;ncer de pr&#243;stata"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Survival analysis of patients with prostate cancer &#40;PCa&#41; with adverse prognostic factors &#40;APF&#41; treated with radical prostatectomy &#40;RP&#41; and salvage radiotherapy &#40;SRT&#41; after biochemical recurrence &#40;BR&#41; or biochemical persistence &#40;BP&#41;&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Retrospective analysis of 446 patients with at least one of the following APF&#58; Gleason score &#8805;8&#44; pathologic stage &#8805;pT3 and&#47;or positive surgical margins&#46; BR criteria used was PSA level over 0&#46;4<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">A survival analysis using Kaplan&#8211;Meier was performed to compare the different variable categories with log-rank test&#46; In order to identify risk factors for SRT response and cancer specific survival &#40;CSS&#41; we performed univariate and multivariate analyses using Cox regression&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Mean follow up&#58; 72 &#40;IQR 27&#8211;122&#41; months&#44; mean time to BR&#58; 42 &#40;IQR 20&#8211;112&#41; months&#44; mean PSA level at BR&#58; 0&#46;56 &#40;IQR 0&#46;42&#8211;0&#46;96&#41;&#46; BR was present in 36&#46;3&#37; of the patients&#46; Biochemical response to SRT was observed in 121 &#40;75&#46;7&#37;&#41; patients&#46;</p><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Recurrence-free survival &#40;RFS&#41; rates after SRT at 3&#44; 5&#44; 8 and 10 years were 95&#46;7&#37;&#44; 92&#46;3&#37;&#44; 87&#46;9&#37;&#44; and 85&#37;&#59; overall survival &#40;OS&#41; rates after 5&#44; 10 and 15 years was 95&#46;6&#37;&#44; 86&#46;5&#37; and 73&#46;5&#37;&#44; respectively&#46; CSS rates at 5&#44; 10 and 15 years were 99&#46;1&#37;&#44; 98&#46;1&#37; and 96&#46;6&#37;&#46;</p><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Only time to BR &#60;24 months &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;55&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;01&#41; was identified as an independent risk factor for RFS after SRT&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">In these patients&#44; RP only controls the disease in approximately half of the cases&#46; Multimodal sequential treatment &#40;RP<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SRT when needed&#41; increases this control&#44; achieving high CSS rates and biochemical control in over 87&#37; of the patients&#46; Patients with time to recurrence &#62;24 months responded better to rescue treatment&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Analizar la supervivencia de los pacientes con c&#225;ncer de pr&#243;stata &#40;CP&#41; con factores pron&#243;sticos desfavorables &#40;FPD&#41; tratados con PR y radioterapia de rescate &#40;RTR&#41; tras recidiva bioqu&#237;mica &#40;RB&#41; y persistencia bioqu&#237;mica &#40;PB&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todo</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">An&#225;lisis retrospectivo de 446 pacientes con al menos uno de los siguientes FPD&#58; score de Gleason &#8805;8&#44; estadio patol&#243;gico &#8805;pT3 y&#47;o m&#225;rgenes quir&#250;rgicos positivos &#40;MQ<span class="elsevierStyleMonospace">&#43;</span>&#41;&#46; El criterio de RB fue la elevaci&#243;n del PSA por encima de 0&#44;4<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Evaluaci&#243;n de supervivencia mediante Kaplan-Meier y log-rank&#46; Para identificar factores de riesgo con posible influencia en la respuesta a RTR y la supervivencia causa-espec&#237;fica &#40;SCE&#41; se us&#243; an&#225;lisis uni y multivariable &#40;regresi&#243;n de Cox&#41;&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Mediana de seguimiento&#58; 72 &#40;rango 37-122&#41; meses&#44; mediana de tiempo hasta RB&#58; 42 &#40;rango 20-112&#41; meses&#46; El 36&#44;3&#37; presentaron RB&#46; Presentaron respuesta bioqu&#237;mica a la RTR 121 &#40;74&#44;7&#37;&#41; pacientes&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La supervivencia libre de reca&#237;da &#40;SLR&#41; despu&#233;s de la RTR a los 3&#44; 5&#44; 8 y 10 a&#241;os fue del 95&#44;7&#44; del 92&#44;3&#44; del 87&#44;9 y del 85&#37;&#44; la SG a los 5&#44; 10 y 15 a&#241;os fue del 95&#44;6&#44; del 86&#44;5 y del 73&#44;5&#37;&#46; La SCE a los 5&#44; 10 y 15 a&#241;os fue del 99&#44;1&#44; del 98&#44;1 y del 96&#44;6&#37;&#44; respectivamente&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Solo el tiempo hasta la RB &#60;24 meses &#40;HR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44;55&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;01&#41; se comport&#243; como un factor predictor independiente de SLR despu&#233;s de RTR&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La PR solo consigue control de la enfermedad a los 10 a&#241;os en aproximadamente la mitad de los casos&#46; El tratamiento multimodal secuencial &#40;PR<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>RTR cuando precise&#41; aumenta este control bioqu&#237;mico hasta &#62;87&#37;&#44; logr&#225;ndose una larga SCE&#46; Los pacientes con un tiempo hasta recidiva &#62;24 meses respondieron mejor al tratamiento de rescate&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Barbas Bernardos G&#44; Herranz Amo F&#44; Gonz&#225;lez San Segundo C&#44; Ca&#241;o Velasco J&#44; Subir&#225; R&#237;os D&#44; Moralejo G&#225;rate M&#44; et al&#46; An&#225;lisis de supervivencia de los pacientes con c&#225;ncer de pr&#243;stata con factores patol&#243;gicos desfavorables tratados con prostatectom&#237;a radical y radioterapia de rescate tras la recidiva y persistencia bioqu&#237;mica&#46; Actas Urol Esp&#46; 2020&#59;44&#58;701&#8211;707&#46;</p>"
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>cT2b&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">32 &#40;7&#46;2&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>cT2c&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">25 &#40;5&#46;6&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>cT3a&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">3 &#40;0&#46;7&#37;&#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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Gleason score</span></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"><span class="elsevierStyleHsp" style=""></span>6&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">194 &#40;43&#46;5&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>7&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">171 &#40;38&#46;3&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>8&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">48 &#40;10&#46;8&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>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">33 &#40;7&#46;4&#37;&#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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">D&#8217;Amico risk groups</span></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"><span class="elsevierStyleHsp" style=""></span>Low&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">139 &#40;31&#46;2&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>Intermediate&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">200 &#40;44&#46;8&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>High&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">107 &#40;24&#37;&#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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Pathological stage</span></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"><span class="elsevierStyleHsp" style=""></span>pT2a&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">41 &#40;9&#46;2&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>pT2b&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">6 &#40;1&#46;3&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>pT2c&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">186 &#40;41&#46;7&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>pT3a&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">144 &#40;32&#46;3&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>pT3b&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">69 &#40;15&#46;5&#37;&#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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Gleason score</span></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"><span class="elsevierStyleHsp" style=""></span>6&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">55 &#40;12&#46;3&#41;&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"><span class="elsevierStyleHsp" style=""></span>7 &#40;3<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>4&#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">142 &#40;31&#46;9&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>7 &#40;4<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>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
                  \t\t\t\t\ttop\n
                  \t\t\t\t">71 &#40;15&#46;9&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>8&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">104 &#40;23&#46;3&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>9 and 10&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">74 &#40;16&#46;6&#37;&#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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Surgical margins</span></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"><span class="elsevierStyleHsp" style=""></span>Negative&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">171 &#40;38&#46;3&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>Positive&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">275 &#40;61&#46;7&#37;&#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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Perineural invasion</span></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"><span class="elsevierStyleHsp" style=""></span>No&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">71 &#40;15&#46;9&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>Yes&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">375 &#40;84&#46;1&#37;&#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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Unfavorable pathological factors</span></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"><span class="elsevierStyleHsp" style=""></span>One&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">274 &#40;61&#46;4&#37;&#41;&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"><span class="elsevierStyleHsp" style=""></span>Two&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">Reference&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"><span class="elsevierStyleHsp" style=""></span>&#62;1<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&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"><span class="elsevierStyleHsp" style=""></span>SM&#43;&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"><span class="elsevierStyleHsp" style=""></span>pT<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>ng&#47;ml 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">0&#46;71&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">0&#46;32&#8211;1&#46;59&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</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>GS<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SM&#43;&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&#46;13&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\ttable-entry\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
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>GS<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>pT3&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">2&#46;34&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">1&#46;23&#8211;4&#46;69&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">0&#46;01&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"><span class="elsevierStyleHsp" style=""></span>pT3<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SM&#43;&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\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>GS<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>8<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>pT3<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>SM&#43;&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\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Treatment for recurrence</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">0&#46;50&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"><span class="elsevierStyleItalic">Perineural invasion</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \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
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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">Reference&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="" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&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">Reference&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">&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
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