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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">HPV-16 infection modifies overall survival of Puerto Rican HNSCC patients</title><author><name sortKey="Rivera Pe A, Bianca" sort="Rivera Pe A, Bianca" uniqKey="Rivera Pe A B" first="Bianca" last="Rivera-Pe A">Bianca Rivera-Pe A</name><affiliation><nlm:aff id="Aff1">Department of Biology, Natural Sciences Faculty, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico</nlm:aff></affiliation></author><author><name sortKey="Ruiz Fullana, Francisco J" sort="Ruiz Fullana, Francisco J" uniqKey="Ruiz Fullana F" first="Francisco J." last="Ruíz-Fullana">Francisco J. Ruíz-Fullana</name><affiliation><nlm:aff id="Aff2">Department of Otolaryngology, Head and Neck Surgery Section, University of Puerto Rico, School of Medicine, PO Box 365067, San Juan, 00936 Puerto Rico</nlm:aff></affiliation></author><author><name sortKey="Velez Reyes, German L" sort="Velez Reyes, German L" uniqKey="Velez Reyes G" first="Germán L." last="Vélez-Reyes">Germán L. Vélez-Reyes</name><affiliation><nlm:aff id="Aff1">Department of Biology, Natural Sciences Faculty, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico</nlm:aff></affiliation></author><author><name sortKey="Rodriguez Benitez, Rosa J" sort="Rodriguez Benitez, Rosa J" uniqKey="Rodriguez Benitez R" first="Rosa J." last="Rodriguez-Benitez">Rosa J. Rodriguez-Benitez</name><affiliation><nlm:aff id="Aff3">Department of General Social Sciences, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico</nlm:aff></affiliation></author><author><name sortKey="Marcos Martinez, Maria J" sort="Marcos Martinez, Maria J" uniqKey="Marcos Martinez M" first="María J." last="Marcos-Martínez">María J. Marcos-Martínez</name><affiliation><nlm:aff id="Aff4">Department of Pathology and Laboratory Medicine, University of Puerto Rico, School of Medicine, San Juan, Puerto Rico</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5">Medical Services Administration, San Juan, Puerto Rico</nlm:aff></affiliation></author><author><name sortKey="Trinidad Pinedo, Juan" sort="Trinidad Pinedo, Juan" uniqKey="Trinidad Pinedo J" first="Juan" last="Trinidad-Pinedo">Juan Trinidad-Pinedo</name><affiliation><nlm:aff id="Aff2">Department of Otolaryngology, Head and Neck Surgery Section, University of Puerto Rico, School of Medicine, PO Box 365067, San Juan, 00936 Puerto Rico</nlm:aff></affiliation></author><author><name sortKey="Baez, Adriana" sort="Baez, Adriana" uniqKey="Baez A" first="Adriana" last="Báez">Adriana Báez</name><affiliation><nlm:aff id="Aff2">Department of Otolaryngology, Head and Neck Surgery Section, University of Puerto Rico, School of Medicine, PO Box 365067, San Juan, 00936 Puerto Rico</nlm:aff></affiliation><affiliation><nlm:aff id="Aff6">Department of Pharmacology and Toxicology, University of Puerto Rico, School of Medicine, San Juan, Puerto Rico</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27559359</idno><idno type="pmc">4995614</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995614</idno><idno type="RBID">PMC:4995614</idno><idno type="doi">10.1186/s13027-016-0095-4</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000044</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000044</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">HPV-16 infection modifies overall survival of Puerto Rican HNSCC patients</title><author><name sortKey="Rivera Pe A, Bianca" sort="Rivera Pe A, Bianca" uniqKey="Rivera Pe A B" first="Bianca" last="Rivera-Pe A">Bianca Rivera-Pe A</name><affiliation><nlm:aff id="Aff1">Department of Biology, Natural Sciences Faculty, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico</nlm:aff></affiliation></author><author><name sortKey="Ruiz Fullana, Francisco J" sort="Ruiz Fullana, Francisco J" uniqKey="Ruiz Fullana F" first="Francisco J." last="Ruíz-Fullana">Francisco J. Ruíz-Fullana</name><affiliation><nlm:aff id="Aff2">Department of Otolaryngology, Head and Neck Surgery Section, University of Puerto Rico, School of Medicine, PO Box 365067, San Juan, 00936 Puerto Rico</nlm:aff></affiliation></author><author><name sortKey="Velez Reyes, German L" sort="Velez Reyes, German L" uniqKey="Velez Reyes G" first="Germán L." last="Vélez-Reyes">Germán L. Vélez-Reyes</name><affiliation><nlm:aff id="Aff1">Department of Biology, Natural Sciences Faculty, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico</nlm:aff></affiliation></author><author><name sortKey="Rodriguez Benitez, Rosa J" sort="Rodriguez Benitez, Rosa J" uniqKey="Rodriguez Benitez R" first="Rosa J." last="Rodriguez-Benitez">Rosa J. Rodriguez-Benitez</name><affiliation><nlm:aff id="Aff3">Department of General Social Sciences, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico</nlm:aff></affiliation></author><author><name sortKey="Marcos Martinez, Maria J" sort="Marcos Martinez, Maria J" uniqKey="Marcos Martinez M" first="María J." last="Marcos-Martínez">María J. Marcos-Martínez</name><affiliation><nlm:aff id="Aff4">Department of Pathology and Laboratory Medicine, University of Puerto Rico, School of Medicine, San Juan, Puerto Rico</nlm:aff></affiliation><affiliation><nlm:aff id="Aff5">Medical Services Administration, San Juan, Puerto Rico</nlm:aff></affiliation></author><author><name sortKey="Trinidad Pinedo, Juan" sort="Trinidad Pinedo, Juan" uniqKey="Trinidad Pinedo J" first="Juan" last="Trinidad-Pinedo">Juan Trinidad-Pinedo</name><affiliation><nlm:aff id="Aff2">Department of Otolaryngology, Head and Neck Surgery Section, University of Puerto Rico, School of Medicine, PO Box 365067, San Juan, 00936 Puerto Rico</nlm:aff></affiliation></author><author><name sortKey="Baez, Adriana" sort="Baez, Adriana" uniqKey="Baez A" first="Adriana" last="Báez">Adriana Báez</name><affiliation><nlm:aff id="Aff2">Department of Otolaryngology, Head and Neck Surgery Section, University of Puerto Rico, School of Medicine, PO Box 365067, San Juan, 00936 Puerto Rico</nlm:aff></affiliation><affiliation><nlm:aff id="Aff6">Department of Pharmacology and Toxicology, University of Puerto Rico, School of Medicine, San Juan, Puerto Rico</nlm:aff></affiliation></author></analytic><series><title level="j">Infectious Agents and Cancer</title><idno type="eISSN">1750-9378</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>HPV-16 modifies the overall survival (OS) of patients with oropharyngeal cancer (OPSCC). HPV-16 has been established as risk factor for OPSCC, but HPV-16 infection may also reside in the larynx and oral cavity. We evaluated HPV-16 status on OS of Head and Neck Squamous Cell Carcinoma (HNSCC) patients.</p></sec><sec><title>Methods</title><p>HPV-16 infection was confirmed by amplification of E6 and E7 viral oncogenes through PCR assay and E6 IHC in 185 HNSCC samples. Associations between HPV-16 status and clinicopathological parameters were performed using Fisher’s exact test and x<sup>2</sup>. Survival analysis was completed using Kaplan-Meier estimator and multivariate Cox regression analysis.</p></sec><sec><title>Results</title><p>OS of HPV-16 positive patients was longer compared to HPV-16 negative patients (<italic>P</italic> = 0.002). HPV-16 positive tumors of the larynx (LSCC) and pharynx (PSCC) showed improved OS compared to HPV-16 negative tumors. Also, HPV-16 positive patients exposed to radiotherapy presented a better survival.</p></sec><sec><title>Conclusions</title><p>HPV-16 status has a positive prognostic value in HNSCC. Addition of HPV-16 status to the TNM staging can provide better assessment in prognosis and guide treatment for HNSCC patients.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ferlay, J" uniqKey="Ferlay J">J Ferlay</name></author><author><name sortKey="Shin, Hr" uniqKey="Shin H">HR Shin</name></author><author><name sortKey="Bray, F" uniqKey="Bray F">F Bray</name></author><author><name sortKey="Forman, D" uniqKey="Forman D">D Forman</name></author><author><name sortKey="Mathers, C" uniqKey="Mathers C">C Mathers</name></author><author><name sortKey="Parkin, Dm" uniqKey="Parkin D">DM Parkin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="O Orke, Ma" uniqKey="O Orke M">MA O’Rorke</name></author><author><name sortKey="Ellison, Mv" uniqKey="Ellison M">MV Ellison</name></author><author><name sortKey="Murray, Lj" uniqKey="Murray L">LJ Murray</name></author><author><name sortKey="Moran, M" uniqKey="Moran M">M Moran</name></author><author><name sortKey="James, J" uniqKey="James J">J James</name></author><author><name sortKey="Anderson, La" uniqKey="Anderson L">LA Anderson</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Shiboski, Ch" uniqKey="Shiboski C">CH Shiboski</name></author><author><name sortKey="Schmidt, Bl" uniqKey="Schmidt B">BL Schmidt</name></author><author><name sortKey="Jordan, Rc" uniqKey="Jordan R">RC Jordan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baez, A" uniqKey="Baez A">A Báez</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pulte, D" uniqKey="Pulte D">D Pulte</name></author><author><name sortKey="Brenner, H" uniqKey="Brenner H">H Brenner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Figueroa, Nr" uniqKey="Figueroa N">NR Figueroa</name></author><author><name sortKey="Ortiz, Kj" uniqKey="Ortiz K">KJ Ortiz</name></author><author><name sortKey="Perez, N" uniqKey="Perez N">N Pérez</name></author><author><name sortKey="Villanueva, E" uniqKey="Villanueva E">E Villanueva</name></author><author><name sortKey="Traverso, M" uniqKey="Traverso M">M Traverso</name></author><author><name sortKey="Torres, Cr" uniqKey="Torres C">CR Torres</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Blot, Wj" uniqKey="Blot W">WJ Blot</name></author><author><name sortKey="Mclaughlin, Jk" uniqKey="Mclaughlin J">JK McLaughlin</name></author><author><name sortKey="Winn, Dm" uniqKey="Winn D">DM Winn</name></author><author><name sortKey="Austin, Df" uniqKey="Austin D">DF Austin</name></author><author><name sortKey="Greenberg, Rs" uniqKey="Greenberg R">RS Greenberg</name></author><author><name sortKey="Preston Martin, S" uniqKey="Preston Martin S">S Preston-Martin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Saracci, R" uniqKey="Saracci R">R Saracci</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hashibe, M" uniqKey="Hashibe M">M Hashibe</name></author><author><name sortKey="Brennan, P" uniqKey="Brennan P">P Brennan</name></author><author><name sortKey="Benhamou, S" uniqKey="Benhamou S">S Benhamou</name></author><author><name sortKey="Castellsague, X" uniqKey="Castellsague X">X Castellsague</name></author><author><name sortKey="Chen, C" uniqKey="Chen C">C Chen</name></author><author><name sortKey="Curado, Mp" uniqKey="Curado M">MP Curado</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gillison, Ml" uniqKey="Gillison M">ML Gillison</name></author><author><name sortKey="Koch, Wm" uniqKey="Koch W">WM Koch</name></author><author><name sortKey="Capone, Rb" uniqKey="Capone R">RB Capone</name></author><author><name sortKey="Spafford, M" uniqKey="Spafford M">M Spafford</name></author><author><name sortKey="Westra, Wh" uniqKey="Westra W">WH Westra</name></author><author><name sortKey="Wu, L" uniqKey="Wu L">L Wu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mork, J" uniqKey="Mork J">J Mork</name></author><author><name sortKey="Lie, Ak" uniqKey="Lie A">AK Lie</name></author><author><name sortKey="Glattre, E" uniqKey="Glattre E">E Glattre</name></author><author><name sortKey="Hallmans, G" uniqKey="Hallmans G">G Hallmans</name></author><author><name sortKey="Jellum, E" uniqKey="Jellum E">E Jellum</name></author><author><name sortKey="Koskela, P" uniqKey="Koskela P">P Koskela</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baez, A" uniqKey="Baez A">A Báez</name></author><author><name sortKey="Almod Var, Ji" uniqKey="Almod Var J">JI Almodóvar</name></author><author><name sortKey="Cantor, A" uniqKey="Cantor A">A Cantor</name></author><author><name sortKey="Celestin, F" uniqKey="Celestin F">F Celestin</name></author><author><name sortKey="Cruz Cruz, L" uniqKey="Cruz Cruz L">L Cruz-Cruz</name></author><author><name sortKey="Fonseca, S" uniqKey="Fonseca S">S Fonseca</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Van Doorslaer, K" uniqKey="Van Doorslaer K">K Van Doorslaer</name></author><author><name sortKey="Tan, Q" uniqKey="Tan Q">Q Tan</name></author><author><name sortKey="Xirasagar, S" uniqKey="Xirasagar S">S Xirasagar</name></author><author><name sortKey="Bandaru, S" uniqKey="Bandaru S">S Bandaru</name></author><author><name sortKey="Gopalan, V" uniqKey="Gopalan V">V Gopalan</name></author><author><name sortKey="Mohamoud, Y" uniqKey="Mohamoud Y">Y Mohamoud</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Scheffner, M" uniqKey="Scheffner M">M Scheffner</name></author><author><name sortKey="Werness, Ba" uniqKey="Werness B">BA Werness</name></author><author><name sortKey="Huibregtse, Jm" uniqKey="Huibregtse J">JM Huibregtse</name></author><author><name sortKey="Levine, Aj" uniqKey="Levine A">AJ Levine</name></author><author><name sortKey="Howley, Pm" uniqKey="Howley P">PM Howley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dyson, N" uniqKey="Dyson N">N Dyson</name></author><author><name sortKey="Howley, Pm" uniqKey="Howley P">PM Howley</name></author><author><name sortKey="Munger, K" uniqKey="Munger K">K Münger</name></author><author><name sortKey="Harlow, E" uniqKey="Harlow E">E Harlow</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gillison, Ml" uniqKey="Gillison M">ML Gillison</name></author><author><name sortKey="Shah, Kv" uniqKey="Shah K">KV Shah</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fakhry, C" uniqKey="Fakhry C">C Fakhry</name></author><author><name sortKey="Zhang, Q" uniqKey="Zhang Q">Q Zhang</name></author><author><name sortKey="Nguyen Tan, Pf" uniqKey="Nguyen Tan P">PF Nguyen-Tan</name></author><author><name sortKey="Rosenthal, D" uniqKey="Rosenthal D">D Rosenthal</name></author><author><name sortKey="El Naggar, A" uniqKey="El Naggar A">A El-Naggar</name></author><author><name sortKey="Garden, As" uniqKey="Garden A">AS Garden</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gillison, Ml" uniqKey="Gillison M">ML Gillison</name></author><author><name sortKey="D Ouza, G" uniqKey="D Ouza G">G D’Souza</name></author><author><name sortKey="Westra, W" uniqKey="Westra W">W Westra</name></author><author><name sortKey="Sugar, E" uniqKey="Sugar E">E Sugar</name></author><author><name sortKey="Xiao, W" uniqKey="Xiao W">W Xiao</name></author><author><name sortKey="Begum, S" uniqKey="Begum S">S Begum</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Deschler, Dg" uniqKey="Deschler D">DG Deschler</name></author><author><name sortKey="Richmon, Jd" uniqKey="Richmon J">JD Richmon</name></author><author><name sortKey="Khariwala, Ss" uniqKey="Khariwala S">SS Khariwala</name></author><author><name sortKey="Ferris, Rl" uniqKey="Ferris R">RL Ferris</name></author><author><name sortKey="Wang, Mb" uniqKey="Wang M">MB Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goldenberg, D" uniqKey="Goldenberg D">D Goldenberg</name></author><author><name sortKey="Begum, S" uniqKey="Begum S">S Begum</name></author><author><name sortKey="Westra, Wh" uniqKey="Westra W">WH Westra</name></author><author><name sortKey="Khan, Z" uniqKey="Khan Z">Z Khan</name></author><author><name sortKey="Sciubba, J" uniqKey="Sciubba J">J Sciubba</name></author><author><name sortKey="Pai, Si" uniqKey="Pai S">SI Pai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schwartz, Sr" uniqKey="Schwartz S">SR Schwartz</name></author><author><name sortKey="Yueh, B" uniqKey="Yueh B">B Yueh</name></author><author><name sortKey="Mcdougall, Jk" uniqKey="Mcdougall J">JK McDougall</name></author><author><name sortKey="Daling, Jr" uniqKey="Daling J">JR Daling</name></author><author><name sortKey="Schwartz, Sm" uniqKey="Schwartz S">SM Schwartz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dayyani, F" uniqKey="Dayyani F">F Dayyani</name></author><author><name sortKey="Etzel, Cj" uniqKey="Etzel C">CJ Etzel</name></author><author><name sortKey="Liu, M" uniqKey="Liu M">M Liu</name></author><author><name sortKey="Ho, Ch" uniqKey="Ho C">CH Ho</name></author><author><name sortKey="Lippman, Sm" uniqKey="Lippman S">SM Lippman</name></author><author><name sortKey="Tsao, As" uniqKey="Tsao A">AS Tsao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stadler, Me" uniqKey="Stadler M">ME Stadler</name></author><author><name sortKey="Patel, Mr" uniqKey="Patel M">MR Patel</name></author><author><name sortKey="Couch, Me" uniqKey="Couch M">ME Couch</name></author><author><name sortKey="Hayes, Dn" uniqKey="Hayes D">DN Hayes</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="De Roda Husman, Am" uniqKey="De Roda Husman A">AM de Roda Husman</name></author><author><name sortKey="Walboomers, Jm" uniqKey="Walboomers J">JM Walboomers</name></author><author><name sortKey="Van Den Brule, Aj" uniqKey="Van Den Brule A">AJ van den Brule</name></author><author><name sortKey="Meijer, Cj" uniqKey="Meijer C">CJ Meijer</name></author><author><name sortKey="Snijders, Pj" uniqKey="Snijders P">PJ Snijders</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baez, A" uniqKey="Baez A">A Báez</name></author><author><name sortKey="Cantor, A" uniqKey="Cantor A">A Cantor</name></author><author><name sortKey="Fonseca, S" uniqKey="Fonseca S">S Fonseca</name></author><author><name sortKey="Marcos Martinez, M" uniqKey="Marcos Martinez M">M Marcos-Martinez</name></author><author><name sortKey="Mathews, La" uniqKey="Mathews L">LA Mathews</name></author><author><name sortKey="Muro Cacho, Ca" uniqKey="Muro Cacho C">CA Muro-Cacho</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Bol, V" uniqKey="Bol V">V Bol</name></author><author><name sortKey="Gregoire, V" uniqKey="Gregoire V">V Grégoire</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fakhry, C" uniqKey="Fakhry C">C Fakhry</name></author><author><name sortKey="Westra, Wh" uniqKey="Westra W">WH Westra</name></author><author><name sortKey="Li, S" uniqKey="Li S">S Li</name></author><author><name sortKey="Cmelak, A" uniqKey="Cmelak A">A Cmelak</name></author><author><name sortKey="Ridge, Ja" uniqKey="Ridge J">JA Ridge</name></author><author><name sortKey="Pinto, H" uniqKey="Pinto H">H Pinto</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Annertz, K" uniqKey="Annertz K">K Annertz</name></author><author><name sortKey="Rosenquist, K" uniqKey="Rosenquist K">K Rosenquist</name></author><author><name sortKey="Andersson, G" uniqKey="Andersson G">G Andersson</name></author><author><name sortKey="Jacobsson, H" uniqKey="Jacobsson H">H Jacobsson</name></author><author><name sortKey="Hansson, Bg" uniqKey="Hansson B">BG Hansson</name></author><author><name sortKey="Wennerberg, J" uniqKey="Wennerberg J">J Wennerberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nagel, R" uniqKey="Nagel R">R Nagel</name></author><author><name sortKey="Martens De Kemp, Sr" uniqKey="Martens De Kemp S">SR Martens-de Kemp</name></author><author><name sortKey="Buijze, M" uniqKey="Buijze M">M Buijze</name></author><author><name sortKey="Jacobs, G" uniqKey="Jacobs G">G Jacobs</name></author><author><name sortKey="Braakhuis, Bj" uniqKey="Braakhuis B">BJ Braakhuis</name></author><author><name sortKey="Brakenhoff, Rh" uniqKey="Brakenhoff R">RH Brakenhoff</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smeets, Sj" uniqKey="Smeets S">SJ Smeets</name></author><author><name sortKey="Braakhuis, Bj" uniqKey="Braakhuis B">BJ Braakhuis</name></author><author><name sortKey="Abbas, S" uniqKey="Abbas S">S Abbas</name></author><author><name sortKey="Snijders, Pj" uniqKey="Snijders P">PJ Snijders</name></author><author><name sortKey="Ylstra, B" uniqKey="Ylstra B">B Ylstra</name></author><author><name sortKey="Van De Wiel, Ma" uniqKey="Van De Wiel M">MA van de Wiel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sepiashvili, L" uniqKey="Sepiashvili L">L Sepiashvili</name></author><author><name sortKey="Bruce, Jp" uniqKey="Bruce J">JP Bruce</name></author><author><name sortKey="Huang, Sh" uniqKey="Huang S">SH Huang</name></author><author><name sortKey="O Ullivan, B" uniqKey="O Ullivan B">B O’Sullivan</name></author><author><name sortKey="Liu, Ff" uniqKey="Liu F">FF Liu</name></author><author><name sortKey="Kislinger, T" uniqKey="Kislinger T">T Kislinger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Perez Ordonez, B" uniqKey="Perez Ordonez B">B Perez-Ordonez</name></author><author><name sortKey="Beauchemin, M" uniqKey="Beauchemin M">M Beauchemin</name></author><author><name sortKey="Jordan, Rc" uniqKey="Jordan R">RC Jordan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Braakhuis, Bj" uniqKey="Braakhuis B">BJ Braakhuis</name></author><author><name sortKey="Snijders, Pj" uniqKey="Snijders P">PJ Snijders</name></author><author><name sortKey="Keune, Wj" uniqKey="Keune W">WJ Keune</name></author><author><name sortKey="Meijer, C" uniqKey="Meijer C">C Meijer</name></author><author><name sortKey="Ruijter Schippers, Hj" uniqKey="Ruijter Schippers H">HJ Ruijter-Schippers</name></author><author><name sortKey="Leemans, C" uniqKey="Leemans C">C Leemans</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ramshankar, V" uniqKey="Ramshankar V">V Ramshankar</name></author><author><name sortKey="Krishnamurthy, A" uniqKey="Krishnamurthy A">A Krishnamurthy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ang, Kk" uniqKey="Ang K">KK Ang</name></author><author><name sortKey="Harris, J" uniqKey="Harris J">J Harris</name></author><author><name sortKey="Wheeler, R" uniqKey="Wheeler R">R Wheeler</name></author><author><name sortKey="Weber, R" uniqKey="Weber R">R Weber</name></author><author><name sortKey="Rosenthal, Di" uniqKey="Rosenthal D">DI Rosenthal</name></author><author><name sortKey="Nguyen Tan, Pf" uniqKey="Nguyen Tan P">PF Nguyen-Tân</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rieckmann, T" uniqKey="Rieckmann T">T Rieckmann</name></author><author><name sortKey="Tribius, S" uniqKey="Tribius S">S Tribius</name></author><author><name sortKey="Grob, Tj" uniqKey="Grob T">TJ Grob</name></author><author><name sortKey="Meyer, F" uniqKey="Meyer F">F Meyer</name></author><author><name sortKey="Busch, Cj" uniqKey="Busch C">CJ Busch</name></author><author><name sortKey="Petersen, C" uniqKey="Petersen C">C Petersen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smith, Em" uniqKey="Smith E">EM Smith</name></author><author><name sortKey="Rubenstein, Lm" uniqKey="Rubenstein L">LM Rubenstein</name></author><author><name sortKey="Haugen, Th" uniqKey="Haugen T">TH Haugen</name></author><author><name sortKey="Pawlita, M" uniqKey="Pawlita M">M Pawlita</name></author><author><name sortKey="Turek, Lp" uniqKey="Turek L">LP Turek</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Young, Rj" uniqKey="Young R">RJ Young</name></author><author><name sortKey="Rischin, D" uniqKey="Rischin D">D Rischin</name></author><author><name sortKey="Fisher, R" uniqKey="Fisher R">R Fisher</name></author><author><name sortKey="Mcarthur, Ga" uniqKey="Mcarthur G">GA McArthur</name></author><author><name sortKey="Fox, Sb" uniqKey="Fox S">SB Fox</name></author><author><name sortKey="Peters, Lj" uniqKey="Peters L">LJ Peters</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Infect Agent Cancer</journal-id><journal-id journal-id-type="iso-abbrev">Infect. Agents Cancer</journal-id><journal-title-group><journal-title>Infectious Agents and Cancer</journal-title></journal-title-group><issn pub-type="epub">1750-9378</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27559359</article-id><article-id pub-id-type="pmc">4995614</article-id><article-id pub-id-type="publisher-id">95</article-id><article-id pub-id-type="doi">10.1186/s13027-016-0095-4</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>HPV-16 infection modifies overall survival of Puerto Rican HNSCC patients</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes" equal-contrib="yes"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0001-8821-0210</contrib-id><name><surname>Rivera-Peña</surname><given-names>Bianca</given-names></name><address><phone>787-758-2525</phone><email>bianca.rivera@upr.edu</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Ruíz-Fullana</surname><given-names>Francisco J.</given-names></name><address><email>fjruiz77@gmail.com</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Vélez-Reyes</surname><given-names>Germán L.</given-names></name><address><email>velez192009@gmail.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Rodriguez-Benitez</surname><given-names>Rosa J.</given-names></name><address><email>rosa.rodriguez12@upr.edu</email></address><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Marcos-Martínez</surname><given-names>María J.</given-names></name><address><email>maria.marcos@upr.edu</email></address><xref ref-type="aff" rid="Aff4">4</xref><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Trinidad-Pinedo</surname><given-names>Juan</given-names></name><address><email>jtrinidadpi@hotmail.com</email></address><xref ref-type="aff" rid="Aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Báez</surname><given-names>Adriana</given-names></name><address><email>adriana.baez@upr.edu</email></address><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff6">6</xref></contrib><aff id="Aff1"><label>1</label>Department of Biology, Natural Sciences Faculty, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico</aff><aff id="Aff2"><label>2</label>Department of Otolaryngology, Head and Neck Surgery Section, University of Puerto Rico, School of Medicine, PO Box 365067, San Juan, 00936 Puerto Rico</aff><aff id="Aff3"><label>3</label>Department of General Social Sciences, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico</aff><aff id="Aff4"><label>4</label>Department of Pathology and Laboratory Medicine, University of Puerto Rico, School of Medicine, San Juan, Puerto Rico</aff><aff id="Aff5"><label>5</label>Medical Services Administration, San Juan, Puerto Rico</aff><aff id="Aff6"><label>6</label>Department of Pharmacology and Toxicology, University of Puerto Rico, School of Medicine, San Juan, Puerto Rico</aff></contrib-group><pub-date pub-type="epub"><day>24</day><month>8</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>24</day><month>8</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>11</volume><issue>1</issue><elocation-id>47</elocation-id><history><date date-type="received"><day>14</day><month>5</month><year>2016</year></date><date date-type="accepted"><day>29</day><month>7</month><year>2016</year></date></history><permissions><copyright-statement>© The Author(s). 2016</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold>This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><sec><title>Background</title><p>HPV-16 modifies the overall survival (OS) of patients with oropharyngeal cancer (OPSCC). HPV-16 has been established as risk factor for OPSCC, but HPV-16 infection may also reside in the larynx and oral cavity. We evaluated HPV-16 status on OS of Head and Neck Squamous Cell Carcinoma (HNSCC) patients.</p></sec><sec><title>Methods</title><p>HPV-16 infection was confirmed by amplification of E6 and E7 viral oncogenes through PCR assay and E6 IHC in 185 HNSCC samples. Associations between HPV-16 status and clinicopathological parameters were performed using Fisher’s exact test and x<sup>2</sup>. Survival analysis was completed using Kaplan-Meier estimator and multivariate Cox regression analysis.</p></sec><sec><title>Results</title><p>OS of HPV-16 positive patients was longer compared to HPV-16 negative patients (<italic>P</italic> = 0.002). HPV-16 positive tumors of the larynx (LSCC) and pharynx (PSCC) showed improved OS compared to HPV-16 negative tumors. Also, HPV-16 positive patients exposed to radiotherapy presented a better survival.</p></sec><sec><title>Conclusions</title><p>HPV-16 status has a positive prognostic value in HNSCC. Addition of HPV-16 status to the TNM staging can provide better assessment in prognosis and guide treatment for HNSCC patients.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Head and neck squamous cell carcinoma</kwd><kwd>Human Papillomavirus (HPV)</kwd><kwd>Overall Survival (OS)</kwd><kwd>TNM</kwd><kwd>Biomarker</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100000054</institution-id><institution>National Cancer Institute</institution></institution-wrap></funding-source><award-id>P20CA91402</award-id><award-id>U54CA96297</award-id></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100000057</institution-id><institution>National Institute of General Medical Sciences</institution></institution-wrap></funding-source><award-id>S06GM8224</award-id></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/http://dx.doi.org/10.13039/100000097</institution-id><institution>National Center for Research Resources</institution></institution-wrap></funding-source><award-id>G12RR03051</award-id></award-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/http://dx.doi.org/10.13039/100006545</institution-id><institution>National Institute on Minority Health and Health Disparities</institution></institution-wrap></funding-source><award-id>8G12MD007600</award-id></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2016</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Background</title><p>HNSCC is the seventh most common type of cancer diagnosed, and it is ranked as the eighth cause of cancer death worldwide [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR2">2</xref>]. This cancer includes tumors from the oral cavity (OSCC) (ICD-10-C14.8), pharynx (PSCC) (ICD-10-C14.0), larynx (LSCC) (ICD-10-C32.9), and the paranasal sinuses (ICD-10-C31.9) [<xref ref-type="bibr" rid="CR3">3</xref>]. HNSCC is predominantly diagnosed in patients over 60 years old; however, a growing number of HNSCC patients are being diagnosed at younger ages [<xref ref-type="bibr" rid="CR4">4</xref>]. Historically, HNSCC has been more frequently diagnosed in men, with a male–female ratio of about 4:1. However, this ratio is rapidly changing because more women are exposing themselves to tobacco and alcohol [<xref ref-type="bibr" rid="CR5">5</xref>]. The overall-5-year survival (OS) for HNSCC patients is 65.9 %, for all HNSCC sites and stages [<xref ref-type="bibr" rid="CR6">6</xref>], with a median survival of 2.5 years after treatment.</p><p>In the United States, Puerto Rican Hispanics, African-Americans, and economically disadvantaged Whites are at greater risk of developing HNSCC. The incidence of HNSCC in Puerto Ricans is 2.5 higher than Hispanics in the US [<xref ref-type="bibr" rid="CR7">7</xref>]. The incidence of OSCC or PSCC is approximately 72 % higher in Puerto Ricans than in US Hispanics. Similarly, the incidence rate of LSCC is 51 % higher than among Hispanics living in the Unites States [<xref ref-type="bibr" rid="CR7">7</xref>].</p><p>The etiology of HNSCC involves a variety of toxic, environmental, and viral agents [<xref ref-type="bibr" rid="CR5">5</xref>]. Studies have established that smoking and alcohol consumption are the major risk factors for the development of HNSCC [<xref ref-type="bibr" rid="CR8">8</xref>–<xref ref-type="bibr" rid="CR10">10</xref>]. Currently, human papillomavirus (HPV) infection has also been recognized as a risk factor for HNSCC, particularly for OPSCC [<xref ref-type="bibr" rid="CR11">11</xref>–<xref ref-type="bibr" rid="CR13">13</xref>]. There are more than 180 types of HPVs described, of which 30 types are considered high risk, including HPV-16 and HPV-18 [<xref ref-type="bibr" rid="CR14">14</xref>, <xref ref-type="bibr" rid="CR15">15</xref>]. The malignant transformation of HPV integration is mediated by HPV oncoproteins E6 and E7 [<xref ref-type="bibr" rid="CR14">14</xref>]. HPV-16 E6 protein has been associated to the abnormal degradation of the p53 protein, leading to a disruption in G1/S cell cycle control [<xref ref-type="bibr" rid="CR16">16</xref>]. Also, HPV-16 E7 oncoprotein binds to the phosphorylated form of pRb protein, which inactivates pRb and a disruption in the G1/S transition occurs [<xref ref-type="bibr" rid="CR17">17</xref>]. Both events cause an abnormal promotion of cell proliferation due to disruptions in the cell cycle control mechanisms. HPV-16 DNA has been detected in almost 35 % of HNSCC patients, and evidence has accumulated showing that HPV is etiologic for OPSCC [<xref ref-type="bibr" rid="CR18">18</xref>, <xref ref-type="bibr" rid="CR19">19</xref>]. It has been proposed that HPV-16 positive HNSCC patients have a distinct cancer progression and prognosis than HPV-16 negative HNSCC patients [<xref ref-type="bibr" rid="CR20">20</xref>]. HPV-16 positive patients tend to be diagnosed at a younger age when compared to HPV-16 negative patients [<xref ref-type="bibr" rid="CR20">20</xref>, <xref ref-type="bibr" rid="CR21">21</xref>]. Additionally, the presence of HPV-16 in HNSCC patients has been correlated to the presence of local metastases, positive lymph nodes, and a more advanced tumor stage at the time of diagnosis [<xref ref-type="bibr" rid="CR22">22</xref>]. Clinically, HPV-16 positive HNSCC patients have a better prognosis than HPV-16 negative patients [<xref ref-type="bibr" rid="CR11">11</xref>, <xref ref-type="bibr" rid="CR13">13</xref>, <xref ref-type="bibr" rid="CR23">23</xref>, <xref ref-type="bibr" rid="CR24">24</xref>].</p><p>The complex anatomical structure of the head and neck area makes it very challenging for clinicians to determine the primary site of HNSCC [<xref ref-type="bibr" rid="CR25">25</xref>]. Detection of HNSCC involves clinical and histological examinations of suspicious tissue, but, at times, unnoticed malignant lesions remain undetected. HNSCC tumors arising from each anatomical site have a unique progression, epidemiology, and therapeutic approach. HNSCC prognostication is based on the TNM Classification of Malignant Tumors (TNM) according to the sub-site [<xref ref-type="bibr" rid="CR26">26</xref>]. The TNM system is useful to describe the extent of the disease, estimate the likely prognosis, and plan treatment. Treatment strategies rely on TNM, possible side effects, and the patient’s preferences and overall health. Since HNSCC is often discovered in advance stages (III and IV), the most urgent problem is the need to identify an effective diagnostic marker for early detection, and prediction of outcome. Therefore, the purpose of this study was to evaluate whether addition of HPV-16 status to the TNM staging system will help predict better the OS of HNSCC Puerto Rican patients.</p></sec><sec id="Sec2"><title>Methods</title><sec id="Sec3"><title>Study design</title><p>This is a retrospective study where patients meeting the following criteria were eligible for inclusion: histologically proven squamous cell carcinoma arising from the pharynx (hypopharynx, oropharynx), oral cavity, and larynx treated surgically between 1993 and 2005. Fresh-frozen tumor tissue was collected from all HNSCC accrued patients. Additionally, genomic DNA of HNSCC patients had been previously tested for HPV-16 status by Gp5+/6+ primer region within the L1 gene consensus PCR [<xref ref-type="bibr" rid="CR27">27</xref>], HPV-16 E6/E7 type-specific PCR, and E6 immunohistochemical (IHC) staining [<xref ref-type="bibr" rid="CR13">13</xref>, <xref ref-type="bibr" rid="CR28">28</xref>, <xref ref-type="bibr" rid="CR29">29</xref>]. The cohort consisted of 185 HNSCC and their clinicopathological parameters are shown in Table <xref rid="Tab1" ref-type="table">1</xref>. All procedures have the approval of the University of Puerto Rico-Medical Sciences Campus IRB (MSC-IRB Protocol 2770103). Relevant diagnostic information including tumor site, tumor grade, and histology were obtained from medical records and pathological reports. Treatment of choice was surgery followed by postoperative radiotherapy. Follow-up information was prospectively collected from hospital, pathological records and the Puerto Rican Cancer Registry.<table-wrap id="Tab1"><label>Table 1</label><caption><p>Study cohort clinicopathological characteristics</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Characteristics</th><th><italic>N</italic> = 185</th></tr></thead><tbody><tr><td colspan="2">Age (y)</td></tr><tr><td> Mean ± SD</td><td>62.72 ± 12.13</td></tr><tr><td> Range</td><td>24-98</td></tr><tr><td colspan="2">Sex, n (%)</td></tr><tr><td> Male</td><td>164 (88.6)</td></tr><tr><td> Female</td><td>21 (11.4)</td></tr><tr><td colspan="2">Primary Tumor Site, n (%)</td></tr><tr><td> Larynx</td><td>83 (44.9)</td></tr><tr><td> Oral Cavity</td><td>68 (36.7)</td></tr><tr><td> Oropharynx</td><td>17 (9.2)</td></tr><tr><td> Hypopharynx</td><td>17 (9.2)</td></tr><tr><td colspan="2">HPV-16 Status, n (%)*</td></tr><tr><td> HPV-16 +</td><td>97 (52.4)</td></tr><tr><td> HPV-16 -</td><td>88 (47.6)</td></tr><tr><td colspan="2">Tumor Stage, n (%)</td></tr><tr><td> I, II</td><td>47 (25.4)</td></tr><tr><td> III, IV</td><td>138 (74.6)</td></tr><tr><td colspan="2">Tumor Grade, n (%)</td></tr><tr><td> Well</td><td>43 (23.2)</td></tr><tr><td> Moderate</td><td>107 (57.8)</td></tr><tr><td> Poor</td><td>16 (8.7)</td></tr><tr><td> SCC</td><td>19 (10.3)</td></tr><tr><td colspan="2">Nodal Involvement</td></tr><tr><td> Yes</td><td>64 (34.6)</td></tr><tr><td> No</td><td>121 (65.4)</td></tr><tr><td>Heavy Smoking, n (%)</td><td>163 (88.1)</td></tr><tr><td>Heavy Drinking, n (%)</td><td>154 (83.2)</td></tr></tbody></table><table-wrap-foot><p>*HPV-16 + = human papillomavirus type 16 positive; HPV-16 - = human papillomavirus type 16 negative</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec4"><title>DNA extraction</title><p>Genomic DNA from all tumor samples was isolated using the DNA Isolation kit for Cells and Tissues (Roche, Indianapolis, IN) according to the manufacturer instructions. DNA concentration was measured with NanoDrop 8000 UV–vis Spectrophotometer (Thermo Scientific, Waltham, MA).</p></sec><sec id="Sec5"><title>Detection of HPV16 DNA</title><p>HPV-16 status had been pre-screened by Gp5+/6+ consensus PCR followed by HPV-16 E6/E7 type-specific PCR, and results were confirmed for this study with a TaqMan-based qPCR targeted at HPV-16 E6 and E7 viral oncogenes. The HPV-16 E6 specific primer set included a forward primer 5′-gcacagagctgcaaacaactataca-3′, a reverse primer 5′-tcccgaaaagcaaagtcatatacc-3′, and a probe oligo 5′-tgtactgcaagcaacagttactgcgacgt-3′. The HPV-16 E7 specific primer set included a forward primer 5′-gatgaaatagatggtccagc-3′, a reverse primer 5′-gctttgtacgcaaccgaagc-3′, and a probe oligo 5′-cggacagagcccattacaatattgtaacc-3′. Quality and amount of input DNA samples were tested in each qPCR assay with <italic>β-actin</italic> gene primers with a forward primer 5′-gcccatctacgaggggta-3′, a reverse primer 5′-ccttaatgtcacgcacga-3′, and a probe oligo 5′-accaccacggccgagcgg-3′. Reaction mixtures with SiHa DNA (1–2 copies of HPV-16) and K562 DNA (HPV-16 negative) were used as positive and negative control, respectively. qPCR reactions were carried out in a 96-well optical tray with a final volume of 25 μL. Each reaction consisted of 600 nM of each primer, 200 nM of each probe (Taqman, Applied Biosystems, Grand Island, NY), 1X of TaqMan Universal PCR Master Mix (Applied Biosystems), which contains the Taq Polymerase, dNTPs, and ROX reference dye, and 75 ng of genomic DNA. DNA was amplified in a 7500 Real Time PCR System (Applied Biosystems, Grand Island, NY). Thermal cycling conditions were: 50 °C for 2 min, 95 °C for 10 min, followed by 40 cycles of 95 °C for 15 s and an annealing temperature of 60 °C for 1 min. All HNSCC samples classified as HPV-16 positive had amplification of E6 and E7 viral oncogenes through qPCR assay.</p></sec><sec id="Sec6"><title>Statistical analysis</title><p>Data from independent groups was compared using Fisher exact test or x<sup>2</sup>, as appropriate. Odds ratio (OR) calculations for clinicopathological parameters were performed using binary logistic. Overall survival (OS) was measured in months from the date of diagnosis until death, if occurred. Survival analyses were performed using Kaplan-Meier curves. Log-rank Mantel-Cox and Gehan-Breslow Wilcoxon tests were used to determine the significance between two survival curves. Established prognostic factors having an impact on HNSCC survival were analyzed in a multivariate Cox regression analysis. Statistical significance was established to be <italic>p</italic> ≤ 0.05. Statistical analyses were performed using IBM SPSS Version 22 (IBM Corp; Armonk, NY).</p></sec></sec><sec id="Sec7"><title>Results</title><sec id="Sec8"><title>HPV-16 status in a cohort of HNSCC Puerto Rican patients</title><p>Patient characteristics are shown in Table <xref rid="Tab1" ref-type="table">1</xref>. The mean age was 62.72 years (range 24–98 SD: 12.13). Of the 185 HNSCC patients included in the study, 88.6 % were male and 11.4 % were female. Three-quarters (74.6 %) of the patients presented tumors with advance staging (III and IV) and 25.4 % were in early stages (I and II) of the disease. The HNSCC sub-site distribution was 44.9 % LSCC, 36.7 % OSCC and 18.4 % PSCC. The PSCC sub-site includes cases from the oropharynx and hypopharynx. Patients with oropharyngeal and hypopharyngeal cancers were combined under PSCC for the statistical analysis in view of the relatively small number of cases of each sub-site in our study cohort. However, the distribution of oropharyngeal and hypopharyngeal cancers is shown in Table <xref rid="Tab1" ref-type="table">1</xref>. Smoking and drinking habits of our study cohort were defined according to the substance usage reported by each consented patient. Heavy smoking patients reported smoking a pack or more of cigarettes per day and heavy drinking patients reported 15 drinks or more per week. The majority of our HNSCC patients were heavy smokers (88.1 %) and heavy drinkers (83.2 %).</p><p>When we distribute the study cohort by HPV-16 status, 52.4 % were HPV-16 positive and 47.6 % were HPV-16 negative. The HNSCC sub-site distribution of the HPV-16 positive patients was 42.3 % LSCC, 37.1 % were OSCC and 20.6 % were PSCC. No statistically significant association was found between HPV-16 status and gender, age, risk factors and staging (Table <xref rid="Tab2" ref-type="table">2</xref>).<table-wrap id="Tab2"><label>Table 2</label><caption><p>Adjusted OR’s and 95 % CIs of HNSCC patients according to HPV-16 status and clinicopathological parameters</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Variable</th><th colspan="2">HPV-16 + (<italic>N</italic> = 97)</th><th colspan="2">HPV-16 - (<italic>N</italic> = 88)</th><th>OR value, 95 % CI</th><th><italic>P</italic> value</th></tr><tr><th></th><th>No.</th><th>Percent</th><th>No.</th><th>Percent</th><th></th><th></th></tr></thead><tbody><tr><td colspan="7">Age (y)</td></tr><tr><td> ≤ 60</td><td>45</td><td>46.4</td><td>38</td><td>43.2</td><td></td><td></td></tr><tr><td> > 60</td><td>52</td><td>53.6</td><td>50</td><td>56.8</td><td>1.14 [0.637 – 2.035]</td><td>0.767</td></tr><tr><td colspan="7">Sex</td></tr><tr><td> Male</td><td>89</td><td>91.8</td><td>75</td><td>85.2</td><td></td><td></td></tr><tr><td> Female</td><td>8</td><td>8.2</td><td>13</td><td>14.8</td><td>1.93 [0.759 – 4.902]</td><td>0.173</td></tr><tr><td colspan="7">Tumor site</td></tr><tr><td> Larynx</td><td>41</td><td>42.3</td><td>42</td><td>47.7</td><td>0.866 [0.304 – 2.470]</td><td>0.788</td></tr><tr><td> Oral Cavity</td><td>36</td><td>37.1</td><td>32</td><td>36.4</td><td>0.998 [0.338 – 2.942]</td><td>0.996</td></tr><tr><td> Pharynx</td><td>20</td><td>20.6</td><td>14</td><td>15.9</td><td>1.675 [0.420 – 6.681]</td><td>0.465</td></tr><tr><td colspan="7">Stage of Disease</td></tr><tr><td> I,II</td><td>30</td><td>30.9</td><td>17</td><td>19.3</td><td></td><td></td></tr><tr><td> III,IV</td><td>67</td><td>69.1</td><td>71</td><td>80.7</td><td>1.87 [0.945 – 3.700]</td><td>0.091</td></tr><tr><td colspan="7">Tumor grade</td></tr><tr><td> SCC</td><td>11</td><td>11.3</td><td>8</td><td>9.1</td><td></td><td></td></tr><tr><td> Well</td><td>22</td><td>22.7</td><td>21</td><td>23.9</td><td>0.875 [0.226 – 3.385]</td><td>0.847</td></tr><tr><td> Moderate</td><td>55</td><td>56.7</td><td>52</td><td>59.1</td><td>0.729 [0.269 – 1.973]</td><td>0.534</td></tr><tr><td> Poor</td><td>9</td><td>9.3</td><td>7</td><td>7.9</td><td>0.720 [0.240 – 2.161]</td><td>0.558</td></tr><tr><td colspan="7">Nodal involvement</td></tr><tr><td> Yes</td><td>30</td><td>16.2</td><td>34</td><td>18.4</td><td></td><td></td></tr><tr><td> No</td><td>67</td><td>36.2</td><td>54</td><td>29.2</td><td>0.711 [0.387-1.306]</td><td>0.272</td></tr><tr><td colspan="7">Tobacco status</td></tr><tr><td> Yes</td><td>88</td><td>90.7</td><td>75</td><td>85.2</td><td></td><td></td></tr><tr><td> No</td><td>9</td><td>9.3</td><td>13</td><td>14.8</td><td>1.70 [0.686 – 4.186]</td><td>0.265</td></tr><tr><td colspan="7">Alcohol status</td></tr><tr><td> Yes</td><td>82</td><td>84.5</td><td>72</td><td>81.8</td><td></td><td></td></tr><tr><td> No</td><td>15</td><td>15.5</td><td>16</td><td>18.2</td><td>1.22 [0.561 – 2.630]</td><td>0.695</td></tr></tbody></table><table-wrap-foot><p><italic>HPV-16 +</italic> human papillomavirus type 16 positive, <italic>HPV-16 -</italic> human papillomavirus type 16 negative, <italic>OR</italic> odds ratio, <italic>95 % CI</italic> 95 % confidence interval</p></table-wrap-foot></table-wrap></p></sec><sec id="Sec9"><title>Survival analysis of HNSCC patients according to HPV-16 status</title><p>HNSCC patients with HPV-16 positive status had a better OS compared to HPV-16 negative patients for all sites and stages (Fig. <xref rid="Fig1" ref-type="fig">1</xref>). HPV-16 positive patients had a median survival of 102.8 months compared to HPV-16 negative tumors, which had a 63.1 months median survival (<italic>P</italic> = 0.002). Cox regression analysis was performed and showed that HPV-16 positive HNSCC patients have an improved survival compared to HPV-16 negative patients after adjustment for established prognostic factors such as nodal status, tumor stage, cell differentiation, tumor site, heavy smoking and heavy drinking usage, age, and sex (Table <xref rid="Tab3" ref-type="table">3</xref>).<fig id="Fig1"><label>Fig. 1</label><caption><p>Overall survival of HNSCC patients according to HPV-16 status. Kaplan-Meier survival curve analysis of HNSCC patients according to HPV-16 status. Analysis includes all 185 HNSCC patients for all anatomical sub-sites and stages</p></caption><graphic xlink:href="13027_2016_95_Fig1_HTML" id="MO1"></graphic></fig><table-wrap id="Tab3"><label>Table 3</label><caption><p>Multivariate Cox analysis</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Covariate</th><th>Coefficient</th><th>Standard error</th><th><italic>P</italic> value</th><th>HR value, 95 % CI</th></tr></thead><tbody><tr><td>Positive nodal status</td><td>0.308</td><td>0.209</td><td>0.141</td><td>1.361 [0.903 – 2.052]</td></tr><tr><td>Tumor stage</td><td>0.034</td><td>0.099</td><td>0.733</td><td>1.034 [0.852 – 1.257]</td></tr><tr><td colspan="5">Tumor grade</td></tr><tr><td> Well</td><td>0.089</td><td>0.442</td><td>0.841</td><td>1.093 [0.460 – 2.598]</td></tr><tr><td> Moderate</td><td>0.348</td><td>0.322</td><td>0.279</td><td>1.417 [0.754 – 2.662]</td></tr><tr><td> Poor</td><td>0.496</td><td>0.344</td><td>0.149</td><td>1.642 [0.837 – 3.222]</td></tr><tr><td colspan="5">Tumor site</td></tr><tr><td> Larynx</td><td>- 0.170</td><td>0.337</td><td>0.614</td><td>0.844 [0.436 – 1.634]</td></tr><tr><td> Oral Cavity</td><td>- 0.176</td><td>0.350</td><td>0.616</td><td>0.839 [0.423 – 1.665]</td></tr><tr><td> Pharynx</td><td>0.237</td><td>0.423</td><td>0.575</td><td>1.267 [0.554 – 2.901]</td></tr><tr><td> Heavy smoking</td><td>0.202</td><td>0.329</td><td>0.539</td><td>1.224 [0.642 – 2.333]</td></tr><tr><td> Heavy drinking</td><td>0.217</td><td>0.249</td><td>0.384</td><td>1.242 [0.762 – 2.024]</td></tr><tr><td> HPV-16</td><td>0.555</td><td>0.182</td><td>0.002</td><td>1.742 [1.219 – 2.488]</td></tr><tr><td> Sex</td><td>- 0.247</td><td>0.324</td><td>0.447</td><td>0.781 [0.414 – 1.475]</td></tr><tr><td> Age</td><td>0.026</td><td>0.007</td><td>0.000</td><td>1.026 [1.011 – 1.041]</td></tr></tbody></table><table-wrap-foot><p>(−2 Log Likelihood): 1051.086, <italic>HR</italic> hazard ratio, <italic>95 % CI</italic> 95 % confidence interval, <italic>HPV-16</italic> human papillomavirus type 16</p></table-wrap-foot></table-wrap></p><p>LSCC and PSCC patients with HPV-16 positive tumors had a better OS compared to HPV-16 negative patients (Fig. <xref rid="Fig2" ref-type="fig">2a</xref>, <xref rid="Fig2" ref-type="fig">2b</xref>). The median survival of HPV-16 positive LSCC patients was 118 months compared to HPV-16 negative cases which had a median survival of 58.1 months (<italic>P</italic> = <0.001). As well, the OS of PSCC patients improves in HPV-16 positive cases (129.2 months) compared to HPV-16 negative cases (20.4 months) (<italic>P</italic> = <0.001). In contrast, the OS of OSCC patients was not significantly different between HPV-16 positive and HPV-16 negative cases (Fig. <xref rid="Fig2" ref-type="fig">2c</xref>).<fig id="Fig2"><label>Fig. 2</label><caption><p>Overall survival of HNSCC patients according to HPV-16 status in each HNSCC anatomical sub-sites. Kaplan-Meier survival curve analysis of HPV-16 positive patients versus HPV-16 negative patients according to HNSCC anatomical sub-site. <bold>a</bold> Larynx (LSCC); <bold>b</bold> Pharynx (PSCC); <bold>c</bold> Oral Cavity (OSCC)</p></caption><graphic xlink:href="13027_2016_95_Fig2_HTML" id="MO2"></graphic></fig></p><p>Since HPV-16 positive patients showed a better survival, we evaluated the effect of HPV-16 presence on OS in HNSCC tumor staging. As shown in Fig. <xref rid="Fig3" ref-type="fig">3</xref>, HPV-16 positive patients have a better OS than HPV-16 negative patients regardless of the tumor staging. HPV-16 positive early stage tumors had an improved OS of 106.8 months as compared to HPV-16 negative tumors, which had a median OS of 63.2 months (<italic>P</italic> = 0.056) (Fig. <xref rid="Fig3" ref-type="fig">3a</xref>). Likewise, late stage tumors that were HPV-16 positive had a better OS (95.2 months) compared to late stages HPV-16 negative tumors, whose median OS was 60.1 months (<italic>P</italic> = 0.011) (Fig. <xref rid="Fig3" ref-type="fig">3b</xref>).<fig id="Fig3"><label>Fig. 3</label><caption><p>Overall survival of HNSCC patients according to HPV-16 status and tumor staging. Kaplan-Meier survival curve analysis of HNSCC HPV-16 positive patients versus HPV-16 negative patients distributed by tumor staging. <bold>a</bold> Early Stages (I and II); <bold>b</bold> Late Stages (III and IV)</p></caption><graphic xlink:href="13027_2016_95_Fig3_HTML" id="MO3"></graphic></fig></p><p>Recent studies have observed that HPV-16 positivity is a strong prognostic marker for OS in patients treated with primary radio-chemotherapy [<xref ref-type="bibr" rid="CR30">30</xref>]. We compared the OS of HNSCC patients, of all sub-sites and tumor stages, which were treated with radiotherapy adjuvant to surgery. We found that HPV-16 positive patients exposed to radiotherapy after surgery had an improved survival compared to HPV-16 negative patients (Fig. <xref rid="Fig4" ref-type="fig">4a</xref>). Furthermore, when we sub-divide HNSCC patients by tumor site and radiotherapy treatment, HPV-16 positive LSCC and PSCC patients showed a better OS than HPV-16 negative patients (Fig. <xref rid="Fig4" ref-type="fig">4b</xref>, <xref rid="Fig4" ref-type="fig">4c</xref>). In contrast, OSCC patients, treated with adjuvant radiotherapy, do not show difference in OS in the presence or absence of HPV-16 (Fig. <xref rid="Fig4" ref-type="fig">4d</xref>).<fig id="Fig4"><label>Fig. 4</label><caption><p>Overall survival of HNSCC patients exposed to radiation according to HPV-16 status and HNSCC sub-sites. Kaplan-Meier survival curve analysis of HNSCC patients exposed to radiotherapy (RTX) adjuvant to surgery. Patients were distributed by HPV-16 status and anatomical sub-site. <bold>a</bold> All RTX patients, which includes all HNSCC sub-sites and stages; <bold>b</bold> Larynx RTX patients; <bold>c</bold> Pharynx RTX patients; <bold>d</bold> Oral Cavity RTX patients</p></caption><graphic xlink:href="13027_2016_95_Fig4_HTML" id="MO4"></graphic></fig></p><p>Since our study cohort was mostly composed of heavy smokers (88 %), we evaluated if HPV-16 status affects the OS of a HNSCC smoker population. As shown on Fig. <xref rid="Fig5" ref-type="fig">5</xref>, HPV-16 positive heavy smokers had a better OS (104.2 months) compared to HPV-16 negative heavy smokers (57.3 months) (<italic>P</italic> = <0.001). Likewise, the OS of HPV-16 positive patients with a history of heavy alcohol consumption was better (99.9 months) than HPV-16 negative patients (65.1 months) (<italic>P</italic> = 0.012) (Fig. <xref rid="Fig6" ref-type="fig">6</xref>).<fig id="Fig5"><label>Fig. 5</label><caption><p>Overall survival of HNSCC patients with heavy smoking history according to HPV-16 status. Kaplan-Meier survival curve analysis of HPV-16 positive versus HPV-16 negative HNSCC patients with a history of heavy smoking</p></caption><graphic xlink:href="13027_2016_95_Fig5_HTML" id="MO5"></graphic></fig><fig id="Fig6"><label>Fig. 6</label><caption><p>Overall survival of HNSCC patients with heavy alcohol consumption history according to HPV-16 status. Kaplan-Meier survival curve analysis of HPV-16 positive versus HPV-16 negative HNSCC patients with a history of heavy alcohol consumption</p></caption><graphic xlink:href="13027_2016_95_Fig6_HTML" id="MO6"></graphic></fig></p></sec></sec><sec id="Sec10"><title>Discussion</title><p>Our study shows that HPV-16 positivity modifies the OS of HNSCC patients in two anatomical sub-sites, PSCC and LSCC, but not in OSCC (Fig. <xref rid="Fig2" ref-type="fig">2</xref>). Previous studies have shown that HPV-16 infection in LSCC and PSCC increased the survival of HNSCC patients [<xref ref-type="bibr" rid="CR11">11</xref>, <xref ref-type="bibr" rid="CR31">31</xref>]. In contrast, a recent study shows that HPV-16 infection in OSCC does not cause an increase in survival, supporting our findings [<xref ref-type="bibr" rid="CR32">32</xref>].</p><p>The key mechanism for which HPV-16 infection gives a better prognosis to HNSCC patients is still unknown. However, it has been proposed that HPV-16 positive cells have an increased sensitivity to cancer therapies, a slower cellular growth rate, an enhanced immune response towards the virus, or a combination of these factors [<xref ref-type="bibr" rid="CR33">33</xref>]. Additionally, it has been shown that HPV-16 positive cells have fewer DNA copy number alterations, less genome-wide hypomethylation, less <italic>TP53</italic> mutations, and lower expression of <italic>EGFR</italic> [<xref ref-type="bibr" rid="CR34">34</xref>]. Because of those differences, two HNSCC carcinogenesis models have being proposed. The first model suggests that progression of HNSCC, not infected by HPV-16, may be due to the amplification or loss of large parts of chromosome arms 3p, 9p, 11p and 17p [<xref ref-type="bibr" rid="CR35">35</xref>–<xref ref-type="bibr" rid="CR37">37</xref>]. In contrast, the second model of HNSCC carcinogenesis suggests that tumors infected with HPV-16 have a lower level of chromosomal loss at these regions, which may be the cause for a better survival in these patients [<xref ref-type="bibr" rid="CR37">37</xref>].</p><p>It has been proposed that HPV-16 positivity in HNSCC produces distinct tumor sub-site differences when exposure risks are combined, suggesting that different molecular pathways are involved [<xref ref-type="bibr" rid="CR38">38</xref>]. When we evaluated HPV-16 presence in each HNSCC anatomic sub-site, we demonstrated that HPV-16 status has a unique impact in the patient’s survival. HPV-16 positive LSCC and PSCC patients have an improved survival, in contrast to OSCC patients which did not show an improved survival. This difference may arise due to smoking and drinking habits of our study population. Our study cohort is composed of heavy smokers (88.1 %) and heavy drinkers (83.2 %). It has been proposed that HNSCC carcinogenesis in HPV-16 positive tumors, with a history of heavy smoking, may arise upon HPV-16 infection in pre-neoplastic tissue already having a number of genetic alterations, for instance, <italic>p53</italic> mutations or an increase in <italic>EGFR</italic> expression [<xref ref-type="bibr" rid="CR39">39</xref>]. If such alterations are acquired prior to HPV-16 infection, it may impart some of the molecular characteristics of HPV-16 negative tumors, thus resulting in poor outcome and prognosis [<xref ref-type="bibr" rid="CR40">40</xref>]. Also, it has been suggested that tobacco, alcohol and HPV-16 are independent risk factors for HNSCC, producing distinct tumor groups with different prognosis and guide of treatment [<xref ref-type="bibr" rid="CR41">41</xref>].</p><p>HPV-16 status is an important factor for establishing the prognosis and treatment of HNSCC. Our results showed that HPV-16 positive patients had a better response to radiotherapy when compared to HPV-16 negative patients. This increase in radiosensitivity could be mediated through wild–type p53-mediated apoptosis in HPV-16 positive cells and a lower chromosomal loss [<xref ref-type="bibr" rid="CR42">42</xref>].</p><p>The primary limitations of this study are the small number of early stages (I and II) HNSCC samples, and a small group of PSCC’s in our study cohort. These limitations may explain why we did not observe a statistical difference in early stage tumors by HPV-16 status. Our HNSCC patient population is composed mostly of late stage tumors (III, IV), predominantly from LSCC and OSCC. This issue occurs because our head and neck cancer service is attached to a supraterciary level hospital care center which is responsible for the management of complex cancer cases for the whole island of Puerto Rico.</p></sec><sec id="Sec11"><title>Conclusions</title><p>In this study we showed that, HPV-16 presence, in HNSCC tumors, causes an increase in OS and increases radiosensitivity of tumor cells. Interestingly, we have shown that HPV-16 is present, not only in OPSCC as previously described, but it was also detected in LSCC and OSCC. Although the TNM classification has been effective for prognostication of HNSCC, HPV-16 detection may serve as a potential biomarker, in combination with the TNM, to better establish the prognosis of LSCC and PSCC and guide treatment. Future work should be directed to understand how HPV-16 affects HNSCC carcinogenesis, and how its infection modifies the disease progression increasing the OS in these patients.</p></sec><sec id="Sec12"><title>Abbreviations</title><p>HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus; IHC, immunohistochemistry; LSCC, larynx squamous cell carcinoma; OPSCC, oropharynx squamous cell carcinoma; OS, overall survival; OSCC, oral cavity squamous cell carcinoma; PSCC, pharynx squamous cell carcinoma; qPCR, quantitative real-time polymerase chain reaction; RTX, radiotherapy; TNM, TNM classification of malignant tumors</p></sec></body><back><ack><title>Acknowledgements</title><p>The research described was supported by the University of Puerto Rico School of Medicine Otolaryngology Section, NIH/National Cancer Institute grants P20CA91402, U54CA96297; NIH/National Institute of General Medical Sciences grant S06GM8224. This research also used core facilities supported by NIH/NCRR G12RR03051 and NIH/NIMHDD 8G12MD007600. Additionally, we want to thank Antonio Arrieta, MSII, for the assistance on the statistical part of this study.</p><sec id="FPar1"><title>Availability of data and materials</title><p>The authors are cognizant and agree to abide to NIH data sharing policies. Raw data from this study will be made accessible only to those who agree to defined conditions of use, and to individuals who meet professional criteria as appropriate.</p></sec><sec id="FPar2"><title>Authors’ contributions</title><p>BR, FR, JT & AB performed the study design. FR, JT & AB consented HNSCC patients to the study and collected all HNSCC tumor samples. MM carried out the histopathological analysis of the samples. BR & GV carried out the DNA extraction and HPV screening using qPCR on all samples. RR, BR & FR performed the statistical analysis. All authors drafted, revised and approved the final manuscript.</p></sec><sec id="FPar3"><title>Competing interests</title><p>The authors declare that they have no competing interests with the presented study.</p></sec><sec id="FPar4"><title>Ethics approval and consent to participate</title><p>All study procedures have the approval of the University of Puerto Rico-Medical Sciences Campus IRB (MSC-IRB Protocol 2770103). Informed consent was obtained from all study participants.</p></sec></ack><ref-list id="Bib1"><title>References</title><ref id="CR1"><label>1.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ferlay</surname><given-names>J</given-names></name><name><surname>Shin</surname><given-names>HR</given-names></name><name><surname>Bray</surname><given-names>F</given-names></name><name><surname>Forman</surname><given-names>D</given-names></name><name><surname>Mathers</surname><given-names>C</given-names></name><name><surname>Parkin</surname><given-names>DM</given-names></name></person-group><article-title>Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008</article-title><source>Int J Cancer</source><year>2010</year><volume>127</volume><issue>12</issue><fpage>2893</fpage><lpage>2917</lpage><pub-id pub-id-type="doi">10.1002/ijc.25516</pub-id><pub-id pub-id-type="pmid">21351269</pub-id></element-citation></ref><ref id="CR2"><label>2.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>O’Rorke</surname><given-names>MA</given-names></name><name><surname>Ellison</surname><given-names>MV</given-names></name><name><surname>Murray</surname><given-names>LJ</given-names></name><name><surname>Moran</surname><given-names>M</given-names></name><name><surname>James</surname><given-names>J</given-names></name><name><surname>Anderson</surname><given-names>LA</given-names></name></person-group><article-title>Human papillomavirus related head and neck cancer survival: A systematic review and meta-analysis</article-title><source>Oral Oncol</source><year>2012</year><volume>48</volume><issue>12</issue><fpage>1191</fpage><lpage>1201</lpage><pub-id pub-id-type="doi">10.1016/j.oraloncology.2012.06.019</pub-id><pub-id pub-id-type="pmid">22841677</pub-id></element-citation></ref><ref id="CR3"><label>3.</label><element-citation publication-type="book"><person-group person-group-type="author"><collab>American Medical Association</collab></person-group><source>ICD-10-CM 2016: The Complete Official Codebook</source><year>2016</year><edition>2016</edition><publisher-loc>Chicago</publisher-loc><publisher-name>American Medical Association</publisher-name></element-citation></ref><ref id="CR4"><label>4.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shiboski</surname><given-names>CH</given-names></name><name><surname>Schmidt</surname><given-names>BL</given-names></name><name><surname>Jordan</surname><given-names>RC</given-names></name></person-group><article-title>Tongue and tonsil carcinoma: increasing trends in the US population ages 20–44 years</article-title><source>Cancer</source><year>2005</year><volume>103</volume><issue>9</issue><fpage>1843</fpage><lpage>49</lpage><pub-id pub-id-type="doi">10.1002/cncr.20998</pub-id><pub-id pub-id-type="pmid">15772957</pub-id></element-citation></ref><ref id="CR5"><label>5.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Báez</surname><given-names>A</given-names></name></person-group><article-title>Genetic and environmental factors in head and neck cancer genesis</article-title><source>J Environ Sci Health C Environ Carcinog Ecotoxicol Rev</source><year>2008</year><volume>26</volume><issue>2</issue><fpage>174</fpage><lpage>200</lpage><pub-id pub-id-type="doi">10.1080/10590500802129431</pub-id><pub-id pub-id-type="pmid">18569329</pub-id></element-citation></ref><ref id="CR6"><label>6.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pulte</surname><given-names>D</given-names></name><name><surname>Brenner</surname><given-names>H</given-names></name></person-group><article-title>Changes in Survival in Head and Neck Cancers in the Late 20th and Early 21st Century: A Period Analysis</article-title><source>Oncologist</source><year>2010</year><volume>15</volume><issue>9</issue><fpage>994</fpage><lpage>1001</lpage><pub-id pub-id-type="doi">10.1634/theoncologist.2009-0289</pub-id><pub-id pub-id-type="pmid">20798198</pub-id></element-citation></ref><ref id="CR7"><label>7.</label><element-citation publication-type="book"><person-group person-group-type="author"><name><surname>Figueroa</surname><given-names>NR</given-names></name><name><surname>Ortiz</surname><given-names>KJ</given-names></name><name><surname>Pérez</surname><given-names>N</given-names></name><name><surname>Villanueva</surname><given-names>E</given-names></name><name><surname>Traverso</surname><given-names>M</given-names></name><name><surname>Torres</surname><given-names>CR</given-names></name><etal></etal></person-group><source>Cancer in Puerto Rico, 2004–2009</source><year>2012</year><publisher-loc>San Juan</publisher-loc><publisher-name>Puerto Rico Central Cancer Registry</publisher-name></element-citation></ref><ref id="CR8"><label>8.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Blot</surname><given-names>WJ</given-names></name><name><surname>McLaughlin</surname><given-names>JK</given-names></name><name><surname>Winn</surname><given-names>DM</given-names></name><name><surname>Austin</surname><given-names>DF</given-names></name><name><surname>Greenberg</surname><given-names>RS</given-names></name><name><surname>Preston-Martin</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Smoking and drinking in relation to oral and pharyngeal cancer</article-title><source>Cancer Res</source><year>1988</year><volume>48</volume><issue>11</issue><fpage>3282</fpage><lpage>7</lpage><pub-id pub-id-type="pmid">3365707</pub-id></element-citation></ref><ref id="CR9"><label>9.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Saracci</surname><given-names>R</given-names></name></person-group><article-title>The interactions of tobacco smoking and other agents in cancer etiology</article-title><source>Epidemiol Rev</source><year>1987</year><volume>9</volume><fpage>175</fpage><lpage>93</lpage><pub-id pub-id-type="pmid">3315716</pub-id></element-citation></ref><ref id="CR10"><label>10.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hashibe</surname><given-names>M</given-names></name><name><surname>Brennan</surname><given-names>P</given-names></name><name><surname>Benhamou</surname><given-names>S</given-names></name><name><surname>Castellsague</surname><given-names>X</given-names></name><name><surname>Chen</surname><given-names>C</given-names></name><name><surname>Curado</surname><given-names>MP</given-names></name><etal></etal></person-group><article-title>Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium</article-title><source>J Natl Cancer Inst</source><year>2007</year><volume>99</volume><issue>10</issue><fpage>777</fpage><lpage>89</lpage><pub-id pub-id-type="doi">10.1093/jnci/djk179</pub-id><pub-id pub-id-type="pmid">17505073</pub-id></element-citation></ref><ref id="CR11"><label>11.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gillison</surname><given-names>ML</given-names></name><name><surname>Koch</surname><given-names>WM</given-names></name><name><surname>Capone</surname><given-names>RB</given-names></name><name><surname>Spafford</surname><given-names>M</given-names></name><name><surname>Westra</surname><given-names>WH</given-names></name><name><surname>Wu</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Evidence for a causal association between human papillomavirus and a subset of head and neck cancers</article-title><source>J Natl Cancer Inst</source><year>2000</year><volume>92</volume><issue>9</issue><fpage>709</fpage><lpage>20</lpage><pub-id pub-id-type="doi">10.1093/jnci/92.9.709</pub-id><pub-id pub-id-type="pmid">10793107</pub-id></element-citation></ref><ref id="CR12"><label>12.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mork</surname><given-names>J</given-names></name><name><surname>Lie</surname><given-names>AK</given-names></name><name><surname>Glattre</surname><given-names>E</given-names></name><name><surname>Hallmans</surname><given-names>G</given-names></name><name><surname>Jellum</surname><given-names>E</given-names></name><name><surname>Koskela</surname><given-names>P</given-names></name><etal></etal></person-group><article-title>Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck</article-title><source>N Engl J Med</source><year>2001</year><volume>344</volume><issue>15</issue><fpage>1125</fpage><lpage>31</lpage><pub-id pub-id-type="doi">10.1056/NEJM200104123441503</pub-id><pub-id pub-id-type="pmid">11297703</pub-id></element-citation></ref><ref id="CR13"><label>13.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Báez</surname><given-names>A</given-names></name><name><surname>Almodóvar</surname><given-names>JI</given-names></name><name><surname>Cantor</surname><given-names>A</given-names></name><name><surname>Celestin</surname><given-names>F</given-names></name><name><surname>Cruz-Cruz</surname><given-names>L</given-names></name><name><surname>Fonseca</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>High frequency of HPV16-associated head and neck squamous cell carcinoma in the Puerto Rican population</article-title><source>Head Neck</source><year>2004</year><volume>26</volume><issue>9</issue><fpage>778</fpage><lpage>84</lpage><pub-id pub-id-type="doi">10.1002/hed.20046</pub-id><pub-id pub-id-type="pmid">15350023</pub-id></element-citation></ref><ref id="CR14"><label>14.</label><element-citation publication-type="journal"><person-group person-group-type="author"><collab>IARC Monograph</collab></person-group><article-title>Human Papillomaviruses</article-title><source>IARC</source><year>2012</year><volume>100B</volume><fpage>255</fpage><lpage>313</lpage></element-citation></ref><ref id="CR15"><label>15.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Van Doorslaer</surname><given-names>K</given-names></name><name><surname>Tan</surname><given-names>Q</given-names></name><name><surname>Xirasagar</surname><given-names>S</given-names></name><name><surname>Bandaru</surname><given-names>S</given-names></name><name><surname>Gopalan</surname><given-names>V</given-names></name><name><surname>Mohamoud</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>The Papillomavirus Episteme: a central resource for papillomavirus sequence data and analysis</article-title><source>Nucleic Acids Res</source><year>2013</year><volume>41</volume><fpage>D571</fpage><lpage>8</lpage><pub-id pub-id-type="doi">10.1093/nar/gks984</pub-id><pub-id pub-id-type="pmid">23093593</pub-id></element-citation></ref><ref id="CR16"><label>16.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Scheffner</surname><given-names>M</given-names></name><name><surname>Werness</surname><given-names>BA</given-names></name><name><surname>Huibregtse</surname><given-names>JM</given-names></name><name><surname>Levine</surname><given-names>AJ</given-names></name><name><surname>Howley</surname><given-names>PM</given-names></name></person-group><article-title>The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53</article-title><source>Cell</source><year>1990</year><volume>63</volume><issue>6</issue><fpage>1129</fpage><lpage>36</lpage><pub-id pub-id-type="doi">10.1016/0092-8674(90)90409-8</pub-id><pub-id pub-id-type="pmid">2175676</pub-id></element-citation></ref><ref id="CR17"><label>17.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dyson</surname><given-names>N</given-names></name><name><surname>Howley</surname><given-names>PM</given-names></name><name><surname>Münger</surname><given-names>K</given-names></name><name><surname>Harlow</surname><given-names>E</given-names></name></person-group><article-title>The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product</article-title><source>Science</source><year>1989</year><volume>243</volume><issue>4893</issue><fpage>934</fpage><lpage>37</lpage><pub-id pub-id-type="doi">10.1126/science.2537532</pub-id><pub-id pub-id-type="pmid">2537532</pub-id></element-citation></ref><ref id="CR18"><label>18.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gillison</surname><given-names>ML</given-names></name><name><surname>Shah</surname><given-names>KV</given-names></name></person-group><article-title>Human papillomavirus-associated head and neck squamous cell carcinoma: Mounting evidence for an etiologic role for human papillomavirus in a subset of head and neck cancers</article-title><source>Curr Opin Oncol</source><year>2001</year><volume>13</volume><issue>3</issue><fpage>183</fpage><lpage>88</lpage><pub-id pub-id-type="doi">10.1097/00001622-200105000-00009</pub-id><pub-id pub-id-type="pmid">11307062</pub-id></element-citation></ref><ref id="CR19"><label>19.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fakhry</surname><given-names>C</given-names></name><name><surname>Zhang</surname><given-names>Q</given-names></name><name><surname>Nguyen-Tan</surname><given-names>PF</given-names></name><name><surname>Rosenthal</surname><given-names>D</given-names></name><name><surname>El-Naggar</surname><given-names>A</given-names></name><name><surname>Garden</surname><given-names>AS</given-names></name><etal></etal></person-group><article-title>Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma</article-title><source>J Clin Oncol</source><year>2014</year><volume>32</volume><issue>30</issue><fpage>3365</fpage><lpage>73</lpage><pub-id pub-id-type="doi">10.1200/JCO.2014.55.1937</pub-id><pub-id pub-id-type="pmid">24958820</pub-id></element-citation></ref><ref id="CR20"><label>20.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gillison</surname><given-names>ML</given-names></name><name><surname>D’Souza</surname><given-names>G</given-names></name><name><surname>Westra</surname><given-names>W</given-names></name><name><surname>Sugar</surname><given-names>E</given-names></name><name><surname>Xiao</surname><given-names>W</given-names></name><name><surname>Begum</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers</article-title><source>J Natl Cancer Inst</source><year>2008</year><volume>100</volume><issue>6</issue><fpage>407</fpage><lpage>20</lpage><pub-id pub-id-type="doi">10.1093/jnci/djn025</pub-id><pub-id pub-id-type="pmid">18334711</pub-id></element-citation></ref><ref id="CR21"><label>21.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Deschler</surname><given-names>DG</given-names></name><name><surname>Richmon</surname><given-names>JD</given-names></name><name><surname>Khariwala</surname><given-names>SS</given-names></name><name><surname>Ferris</surname><given-names>RL</given-names></name><name><surname>Wang</surname><given-names>MB</given-names></name></person-group><article-title>The “new” head and neck cancer patient-young, nonsmoker, nondrinker, and HPV positive: evaluation</article-title><source>Otolaryngol Head Neck Surg</source><year>2014</year><volume>151</volume><issue>3</issue><fpage>375</fpage><lpage>80</lpage><pub-id pub-id-type="doi">10.1177/0194599814538605</pub-id><pub-id pub-id-type="pmid">24925311</pub-id></element-citation></ref><ref id="CR22"><label>22.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goldenberg</surname><given-names>D</given-names></name><name><surname>Begum</surname><given-names>S</given-names></name><name><surname>Westra</surname><given-names>WH</given-names></name><name><surname>Khan</surname><given-names>Z</given-names></name><name><surname>Sciubba</surname><given-names>J</given-names></name><name><surname>Pai</surname><given-names>SI</given-names></name><etal></etal></person-group><article-title>Cystic lymph node metastasis in patients with head and neck cancer: An HPV-associated phenomenon</article-title><source>Head Neck</source><year>2008</year><volume>30</volume><fpage>898</fpage><lpage>903</lpage><pub-id pub-id-type="doi">10.1002/hed.20796</pub-id><pub-id pub-id-type="pmid">18383529</pub-id></element-citation></ref><ref id="CR23"><label>23.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Schwartz</surname><given-names>SR</given-names></name><name><surname>Yueh</surname><given-names>B</given-names></name><name><surname>McDougall</surname><given-names>JK</given-names></name><name><surname>Daling</surname><given-names>JR</given-names></name><name><surname>Schwartz</surname><given-names>SM</given-names></name></person-group><article-title>Human papillomavirus infection and survival in oral squamous cell cancer: a population-based study</article-title><source>Otolaryngol Head Neck Surg</source><year>2001</year><volume>125</volume><issue>1</issue><fpage>1</fpage><lpage>9</lpage><pub-id pub-id-type="doi">10.1067/mhn.2001.116979</pub-id><pub-id pub-id-type="pmid">11458206</pub-id></element-citation></ref><ref id="CR24"><label>24.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dayyani</surname><given-names>F</given-names></name><name><surname>Etzel</surname><given-names>CJ</given-names></name><name><surname>Liu</surname><given-names>M</given-names></name><name><surname>Ho</surname><given-names>CH</given-names></name><name><surname>Lippman</surname><given-names>SM</given-names></name><name><surname>Tsao</surname><given-names>AS</given-names></name></person-group><article-title>Meta-analysis of the impact of human papillomavirus (HPV) on cancer risk and overall survival in head and neck squamous cell carcinomas (HNSCC)</article-title><source>Head Neck Oncol</source><year>2010</year><volume>2</volume><fpage>2</fpage><lpage>15</lpage><pub-id pub-id-type="doi">10.1186/1758-3284-2-15</pub-id><pub-id pub-id-type="pmid">20205783</pub-id></element-citation></ref><ref id="CR25"><label>25.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stadler</surname><given-names>ME</given-names></name><name><surname>Patel</surname><given-names>MR</given-names></name><name><surname>Couch</surname><given-names>ME</given-names></name><name><surname>Hayes</surname><given-names>DN</given-names></name></person-group><article-title>Molecular biology of head and neck cancer: Risks and pathways</article-title><source>Hematol Oncol Clin North Am</source><year>2008</year><volume>22</volume><issue>6</issue><fpage>1099</fpage><lpage>1124</lpage><pub-id pub-id-type="doi">10.1016/j.hoc.2008.08.007</pub-id><pub-id pub-id-type="pmid">19010262</pub-id></element-citation></ref><ref id="CR26"><label>26.</label><element-citation publication-type="book"><person-group person-group-type="author"><collab>American Joint Committee on Cancer</collab></person-group><source>AJCC Cancer Staging Handbook 7</source><year>2011</year><edition>7</edition><publisher-loc>New York</publisher-loc><publisher-name>Springer</publisher-name></element-citation></ref><ref id="CR27"><label>27.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>de Roda Husman</surname><given-names>AM</given-names></name><name><surname>Walboomers</surname><given-names>JM</given-names></name><name><surname>van den Brule</surname><given-names>AJ</given-names></name><name><surname>Meijer</surname><given-names>CJ</given-names></name><name><surname>Snijders</surname><given-names>PJ</given-names></name></person-group><article-title>The use of general primers GP5 and GP6 elongated at their 3′ ends with adjacent highly conserved sequences improves human papillomavirus detection by PCR</article-title><source>J Gen Virol</source><year>1995</year><volume>76</volume><issue>4</issue><fpage>1057</fpage><lpage>62</lpage><pub-id pub-id-type="doi">10.1099/0022-1317-76-4-1057</pub-id><pub-id pub-id-type="pmid">9049358</pub-id></element-citation></ref><ref id="CR28"><label>28.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Báez</surname><given-names>A</given-names></name><name><surname>Cantor</surname><given-names>A</given-names></name><name><surname>Fonseca</surname><given-names>S</given-names></name><name><surname>Marcos-Martinez</surname><given-names>M</given-names></name><name><surname>Mathews</surname><given-names>LA</given-names></name><name><surname>Muro-Cacho</surname><given-names>CA</given-names></name><etal></etal></person-group><article-title>Differences in Smad4 expression in human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck squamous cell carcinoma</article-title><source>Clin Cancer Res</source><year>2005</year><volume>11</volume><issue>9</issue><fpage>3191</fpage><lpage>7</lpage><pub-id pub-id-type="doi">10.1158/1078-0432.CCR-04-1299</pub-id><pub-id pub-id-type="pmid">15867212</pub-id></element-citation></ref><ref id="CR29"><label>29.</label><mixed-citation publication-type="other">Fonseca S. The Incidence, Prognostic and Therapeutic Significance of HPV-16 E6/E7 Oncoproteins in Head and Neck Squamous Cell Carcinoma in Puerto Ricans. [master's thesis]. San Juan: University of Puerto Rico - School of Medicine; 2006. p. 67.</mixed-citation></ref><ref id="CR30"><label>30.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bol</surname><given-names>V</given-names></name><name><surname>Grégoire</surname><given-names>V</given-names></name></person-group><article-title>Biological basis for increased sensitivity to radiation therapy in HPV-positive head and neck cancers</article-title><source>Biomed Res Int</source><year>2014</year><volume>2014</volume><fpage>1</fpage><lpage>6</lpage><pub-id pub-id-type="doi">10.1155/2014/696028</pub-id></element-citation></ref><ref id="CR31"><label>31.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fakhry</surname><given-names>C</given-names></name><name><surname>Westra</surname><given-names>WH</given-names></name><name><surname>Li</surname><given-names>S</given-names></name><name><surname>Cmelak</surname><given-names>A</given-names></name><name><surname>Ridge</surname><given-names>JA</given-names></name><name><surname>Pinto</surname><given-names>H</given-names></name><etal></etal></person-group><article-title>Improved Survival of Patients With Human Papillomavirus – Positive Head and Neck Squamous Cell Carcinoma in a Prospective Clinical Trial</article-title><source>J Natl Cancer Inst</source><year>2008</year><volume>100</volume><issue>4</issue><fpage>261</fpage><lpage>69</lpage><pub-id pub-id-type="doi">10.1093/jnci/djn011</pub-id><pub-id pub-id-type="pmid">18270337</pub-id></element-citation></ref><ref id="CR32"><label>32.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Annertz</surname><given-names>K</given-names></name><name><surname>Rosenquist</surname><given-names>K</given-names></name><name><surname>Andersson</surname><given-names>G</given-names></name><name><surname>Jacobsson</surname><given-names>H</given-names></name><name><surname>Hansson</surname><given-names>BG</given-names></name><name><surname>Wennerberg</surname><given-names>J</given-names></name></person-group><article-title>High-risk HPV and survival in patients with oral and oropharyngeal squamous cell carcinoma – 5-year follow up of a population-based study</article-title><source>Acta Otolaryngol</source><year>2014</year><volume>134</volume><issue>8</issue><fpage>843</fpage><lpage>51</lpage><pub-id pub-id-type="doi">10.3109/00016489.2014.890289</pub-id><pub-id pub-id-type="pmid">24930912</pub-id></element-citation></ref><ref id="CR33"><label>33.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nagel</surname><given-names>R</given-names></name><name><surname>Martens-de Kemp</surname><given-names>SR</given-names></name><name><surname>Buijze</surname><given-names>M</given-names></name><name><surname>Jacobs</surname><given-names>G</given-names></name><name><surname>Braakhuis</surname><given-names>BJ</given-names></name><name><surname>Brakenhoff</surname><given-names>RH</given-names></name></person-group><article-title>Treatment response of HPV-positive and HPV-negative head and neck squamous cell carcinoma cell lines</article-title><source>Oral Oncol</source><year>2013</year><volume>49</volume><issue>6</issue><fpage>560</fpage><lpage>66</lpage><pub-id pub-id-type="doi">10.1016/j.oraloncology.2013.03.446</pub-id><pub-id pub-id-type="pmid">23578372</pub-id></element-citation></ref><ref id="CR34"><label>34.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Smeets</surname><given-names>SJ</given-names></name><name><surname>Braakhuis</surname><given-names>BJ</given-names></name><name><surname>Abbas</surname><given-names>S</given-names></name><name><surname>Snijders</surname><given-names>PJ</given-names></name><name><surname>Ylstra</surname><given-names>B</given-names></name><name><surname>van de Wiel</surname><given-names>MA</given-names></name><etal></etal></person-group><article-title>Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus</article-title><source>Oncogene</source><year>2006</year><volume>25</volume><issue>17</issue><fpage>2558</fpage><lpage>64</lpage><pub-id pub-id-type="doi">10.1038/sj.onc.1209275</pub-id><pub-id pub-id-type="pmid">16314836</pub-id></element-citation></ref><ref id="CR35"><label>35.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sepiashvili</surname><given-names>L</given-names></name><name><surname>Bruce</surname><given-names>JP</given-names></name><name><surname>Huang</surname><given-names>SH</given-names></name><name><surname>O’Sullivan</surname><given-names>B</given-names></name><name><surname>Liu</surname><given-names>FF</given-names></name><name><surname>Kislinger</surname><given-names>T</given-names></name></person-group><article-title>Novel insights into head and neck cancer using next-generation “omic” technologies</article-title><source>Cancer Res</source><year>2015</year><volume>75</volume><issue>3</issue><fpage>480</fpage><lpage>86</lpage><pub-id pub-id-type="doi">10.1158/0008-5472.CAN-14-3124</pub-id><pub-id pub-id-type="pmid">25589349</pub-id></element-citation></ref><ref id="CR36"><label>36.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Perez-Ordonez</surname><given-names>B</given-names></name><name><surname>Beauchemin</surname><given-names>M</given-names></name><name><surname>Jordan</surname><given-names>RC</given-names></name></person-group><article-title>Molecular biology of squamous cell carcinoma of the head and neck</article-title><source>J Clin Pathol</source><year>2006</year><volume>59</volume><issue>5</issue><fpage>445</fpage><lpage>53</lpage><pub-id pub-id-type="doi">10.1136/jcp.2003.007641</pub-id><pub-id pub-id-type="pmid">16644882</pub-id></element-citation></ref><ref id="CR37"><label>37.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Braakhuis</surname><given-names>BJ</given-names></name><name><surname>Snijders</surname><given-names>PJ</given-names></name><name><surname>Keune</surname><given-names>WJ</given-names></name><name><surname>Meijer</surname><given-names>C</given-names></name><name><surname>Ruijter-Schippers</surname><given-names>HJ</given-names></name><name><surname>Leemans</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus</article-title><source>J Natl Cancer Inst</source><year>2004</year><volume>96</volume><issue>13</issue><fpage>998</fpage><lpage>1006</lpage><pub-id pub-id-type="doi">10.1093/jnci/djh183</pub-id><pub-id pub-id-type="pmid">15240783</pub-id></element-citation></ref><ref id="CR38"><label>38.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ramshankar</surname><given-names>V</given-names></name><name><surname>Krishnamurthy</surname><given-names>A</given-names></name></person-group><article-title>Human papilloma virus in head and neck cancers-role and relevance in clinical management</article-title><source>Indian J Surg Oncol</source><year>2013</year><volume>4</volume><issue>1</issue><fpage>59</fpage><lpage>66</lpage><pub-id pub-id-type="doi">10.1007/s13193-012-0196-5</pub-id><pub-id pub-id-type="pmid">24426701</pub-id></element-citation></ref><ref id="CR39"><label>39.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ang</surname><given-names>KK</given-names></name><name><surname>Harris</surname><given-names>J</given-names></name><name><surname>Wheeler</surname><given-names>R</given-names></name><name><surname>Weber</surname><given-names>R</given-names></name><name><surname>Rosenthal</surname><given-names>DI</given-names></name><name><surname>Nguyen-Tân</surname><given-names>PF</given-names></name><etal></etal></person-group><article-title>Human papillomavirus and survival of patients with oropharyngeal cancer</article-title><source>N Engl J Med</source><year>2010</year><volume>363</volume><issue>1</issue><fpage>24</fpage><lpage>35</lpage><pub-id pub-id-type="doi">10.1056/NEJMoa0912217</pub-id><pub-id pub-id-type="pmid">20530316</pub-id></element-citation></ref><ref id="CR40"><label>40.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rieckmann</surname><given-names>T</given-names></name><name><surname>Tribius</surname><given-names>S</given-names></name><name><surname>Grob</surname><given-names>TJ</given-names></name><name><surname>Meyer</surname><given-names>F</given-names></name><name><surname>Busch</surname><given-names>CJ</given-names></name><name><surname>Petersen</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity</article-title><source>Radiother Oncol</source><year>2013</year><volume>107</volume><issue>2</issue><fpage>242</fpage><lpage>46</lpage><pub-id pub-id-type="doi">10.1016/j.radonc.2013.03.013</pub-id><pub-id pub-id-type="pmid">23602369</pub-id></element-citation></ref><ref id="CR41"><label>41.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Smith</surname><given-names>EM</given-names></name><name><surname>Rubenstein</surname><given-names>LM</given-names></name><name><surname>Haugen</surname><given-names>TH</given-names></name><name><surname>Pawlita</surname><given-names>M</given-names></name><name><surname>Turek</surname><given-names>LP</given-names></name></person-group><article-title>Complex etiology underlies risk and survival in head and neck cancer human papillomavirus, tobacco, and alcohol: a case for multifactor disease</article-title><source>J Oncol</source><year>2012</year><volume>2012</volume><issue>57</issue><fpage>1</fpage><lpage>9</lpage><pub-id pub-id-type="doi">10.1155/2012/571862</pub-id></element-citation></ref><ref id="CR42"><label>42.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Young</surname><given-names>RJ</given-names></name><name><surname>Rischin</surname><given-names>D</given-names></name><name><surname>Fisher</surname><given-names>R</given-names></name><name><surname>McArthur</surname><given-names>GA</given-names></name><name><surname>Fox</surname><given-names>SB</given-names></name><name><surname>Peters</surname><given-names>LJ</given-names></name><etal></etal></person-group><article-title>Relationship between epidermal growth factor receptor status, p16(INK4A), and outcome in head and neck squamous cell carcinoma</article-title><source>Cancer Epidemiol Biomarkers Prev</source><year>2011</year><volume>20</volume><issue>6</issue><fpage>1230</fpage><lpage>37</lpage><pub-id pub-id-type="doi">10.1158/1055-9965.EPI-10-1262</pub-id><pub-id pub-id-type="pmid">21467228</pub-id></element-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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