Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node―Negative Cervical Cancer
We compared the prognostic significance of ectodomain isoforms of the epidermal growth factor receptor (EGFR), which lack the tyrosine kinase (TK) domain, with that of the full-length receptor and its autophosphorylation status in cervical cancers treated with conventional chemoradiotherapy. Express...
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| Veröffentlicht in: | Clinical cancer research 2011-08, Vol.17 (16), p.5501-5512 |
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| creator | HALLE, Cathinka LANDO, Malin SVENDSRUD, Debbie Hege CLANCY, Trevor HOLDEN, Marit SUNDFØR, Kolbein KRISTENSEN, Gunnar B HOLM, Ruth LYNG, Heidi |
| description | We compared the prognostic significance of ectodomain isoforms of the epidermal growth factor receptor (EGFR), which lack the tyrosine kinase (TK) domain, with that of the full-length receptor and its autophosphorylation status in cervical cancers treated with conventional chemoradiotherapy.
Expression of EGFR isoforms was assessed by immunohistochemistry in a prospectively collected cohort of 178 patients with squamous cell cervical carcinoma, and their detection was confirmed with Western blotting and reverse transcriptase PCR. A proximity ligation immunohistochemistry assay was used to assess EGFR-specific autophosphorylation. Pathways associated with the expression of ectodomain isoforms were studied by gene expression analysis with Illumina beadarrays in 110 patients and validated in an independent cohort of 41 patients.
Membranous expression of ectodomain isoforms alone, without the coexpression of the full-length receptor, showed correlations to poor clinical outcome that were highly significant for lymph node-negative patients (locoregional control, P = 0.0002; progression-free survival, P < 0.0001; disease-specific survival, P = 0.005 in the log-rank test) and independent of clinical variables. The ectodomain isoforms were primarily 60-kD products of alternative EGFR transcripts. Their membranous expression correlated with transcriptional regulation of oncogenic pathways including activation of MYC and MAX, which was significantly associated with poor outcome. This aggressive phenotype of ectodomain EGFR expressing tumors was confirmed in the independent cohort. Neither total nor full-length EGFR protein level, or autophosphorylation status, showed prognostic significance.
Membranous expression of ectodomain EGFR isoforms, and not TK activation, predicts poor outcome after chemoradiotherapy for patients with lymph node-negative cervical cancer. |
| doi_str_mv | 10.1158/1078-0432.CCR-11-0297 |
| format | Article |
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Expression of EGFR isoforms was assessed by immunohistochemistry in a prospectively collected cohort of 178 patients with squamous cell cervical carcinoma, and their detection was confirmed with Western blotting and reverse transcriptase PCR. A proximity ligation immunohistochemistry assay was used to assess EGFR-specific autophosphorylation. Pathways associated with the expression of ectodomain isoforms were studied by gene expression analysis with Illumina beadarrays in 110 patients and validated in an independent cohort of 41 patients.
Membranous expression of ectodomain isoforms alone, without the coexpression of the full-length receptor, showed correlations to poor clinical outcome that were highly significant for lymph node-negative patients (locoregional control, P = 0.0002; progression-free survival, P < 0.0001; disease-specific survival, P = 0.005 in the log-rank test) and independent of clinical variables. The ectodomain isoforms were primarily 60-kD products of alternative EGFR transcripts. Their membranous expression correlated with transcriptional regulation of oncogenic pathways including activation of MYC and MAX, which was significantly associated with poor outcome. This aggressive phenotype of ectodomain EGFR expressing tumors was confirmed in the independent cohort. Neither total nor full-length EGFR protein level, or autophosphorylation status, showed prognostic significance.
Membranous expression of ectodomain EGFR isoforms, and not TK activation, predicts poor outcome after chemoradiotherapy for patients with lymph node-negative cervical cancer.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-11-0297</identifier><identifier>PMID: 21737508</identifier><identifier>CODEN: CCREF4</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adult ; Aged ; Antineoplastic agents ; Biological and medical sciences ; Blotting, Western ; Carcinoma, Squamous Cell - genetics ; Carcinoma, Squamous Cell - metabolism ; Carcinoma, Squamous Cell - therapy ; Cell Membrane - metabolism ; Chemoradiotherapy ; Cohort Studies ; Female ; Female genital diseases ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks ; Gynecology. Andrology. Obstetrics ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Lymph Nodes - metabolism ; Lymph Nodes - pathology ; Medical sciences ; Middle Aged ; Pharmacology. Drug treatments ; Phosphorylation ; Prognosis ; Protein Isoforms - genetics ; Protein Isoforms - metabolism ; Receptor, Epidermal Growth Factor - genetics ; Receptor, Epidermal Growth Factor - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Treatment Outcome ; Tumors ; Uterine Cervical Neoplasms - genetics ; Uterine Cervical Neoplasms - metabolism ; Uterine Cervical Neoplasms - therapy</subject><ispartof>Clinical cancer research, 2011-08, Vol.17 (16), p.5501-5512</ispartof><rights>2015 INIST-CNRS</rights><rights>2011 AACR.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c385t-ea01eb6085e03ed1063149682cee39b97505d04996051d4236a3e6bac2a391383</citedby><cites>FETCH-LOGICAL-c385t-ea01eb6085e03ed1063149682cee39b97505d04996051d4236a3e6bac2a391383</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24443864$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21737508$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>HALLE, Cathinka</creatorcontrib><creatorcontrib>LANDO, Malin</creatorcontrib><creatorcontrib>SVENDSRUD, Debbie Hege</creatorcontrib><creatorcontrib>CLANCY, Trevor</creatorcontrib><creatorcontrib>HOLDEN, Marit</creatorcontrib><creatorcontrib>SUNDFØR, Kolbein</creatorcontrib><creatorcontrib>KRISTENSEN, Gunnar B</creatorcontrib><creatorcontrib>HOLM, Ruth</creatorcontrib><creatorcontrib>LYNG, Heidi</creatorcontrib><title>Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node―Negative Cervical Cancer</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>We compared the prognostic significance of ectodomain isoforms of the epidermal growth factor receptor (EGFR), which lack the tyrosine kinase (TK) domain, with that of the full-length receptor and its autophosphorylation status in cervical cancers treated with conventional chemoradiotherapy.
Expression of EGFR isoforms was assessed by immunohistochemistry in a prospectively collected cohort of 178 patients with squamous cell cervical carcinoma, and their detection was confirmed with Western blotting and reverse transcriptase PCR. A proximity ligation immunohistochemistry assay was used to assess EGFR-specific autophosphorylation. Pathways associated with the expression of ectodomain isoforms were studied by gene expression analysis with Illumina beadarrays in 110 patients and validated in an independent cohort of 41 patients.
Membranous expression of ectodomain isoforms alone, without the coexpression of the full-length receptor, showed correlations to poor clinical outcome that were highly significant for lymph node-negative patients (locoregional control, P = 0.0002; progression-free survival, P < 0.0001; disease-specific survival, P = 0.005 in the log-rank test) and independent of clinical variables. The ectodomain isoforms were primarily 60-kD products of alternative EGFR transcripts. Their membranous expression correlated with transcriptional regulation of oncogenic pathways including activation of MYC and MAX, which was significantly associated with poor outcome. This aggressive phenotype of ectodomain EGFR expressing tumors was confirmed in the independent cohort. Neither total nor full-length EGFR protein level, or autophosphorylation status, showed prognostic significance.
Membranous expression of ectodomain EGFR isoforms, and not TK activation, predicts poor outcome after chemoradiotherapy for patients with lymph node-negative cervical cancer.</description><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Carcinoma, Squamous Cell - genetics</subject><subject>Carcinoma, Squamous Cell - metabolism</subject><subject>Carcinoma, Squamous Cell - therapy</subject><subject>Cell Membrane - metabolism</subject><subject>Chemoradiotherapy</subject><subject>Cohort Studies</subject><subject>Female</subject><subject>Female genital diseases</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Regulatory Networks</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Kaplan-Meier Estimate</subject><subject>Lymph Nodes - metabolism</subject><subject>Lymph Nodes - pathology</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Pharmacology. Drug treatments</subject><subject>Phosphorylation</subject><subject>Prognosis</subject><subject>Protein Isoforms - genetics</subject><subject>Protein Isoforms - metabolism</subject><subject>Receptor, Epidermal Growth Factor - genetics</subject><subject>Receptor, Epidermal Growth Factor - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Treatment Outcome</subject><subject>Tumors</subject><subject>Uterine Cervical Neoplasms - genetics</subject><subject>Uterine Cervical Neoplasms - metabolism</subject><subject>Uterine Cervical Neoplasms - therapy</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkc9u1DAQxi0EoqXwCCBfEKcUO_4T54iibam0tFVVzpFjT1ijdRxsb-ne-hK8Ag_Gk-CoWzjNaPSbbzTfh9BbSk4pFeojJY2qCGf1adfdVJRWpG6bZ-iYCtFUrJbieemfmCP0KqXvhFBOCX-JjmrasEYQdYx-fwE_RD2FXcKr-zlCSi5MOIx4ZXKwwWs34YsUxhB9WsZ5A3g1OwvR6y0-j-Fn3uAzXeCIb8DAvDTXEawzOeGrXTbBA9Zjhoi7DfgQtXWhqEQ97xfB9d7PG3wZLPx5-HUJ33R2d4A7iHfOlAudngzE1-jFqLcJ3hzqCfp6trrtPlfrq_OL7tO6MkyJXIEmFAZJlADCwFIiGeWtVLUBYO3Qlp-FJbxtJRHU8ppJzUAO2tSatZQpdoI-POrOMfzYQcq9d8nAdqsnKBb1SnFaM0JlIcUjaWJIKcLYz9F5Hfc9Jf2SUL-43y_u9yWhMuqXhMreu8OF3eDB_tt6iqQA7w-ATsWAsYRjXPrPcc6Zkpz9BacLnJY</recordid><startdate>20110815</startdate><enddate>20110815</enddate><creator>HALLE, Cathinka</creator><creator>LANDO, Malin</creator><creator>SVENDSRUD, Debbie Hege</creator><creator>CLANCY, Trevor</creator><creator>HOLDEN, Marit</creator><creator>SUNDFØR, Kolbein</creator><creator>KRISTENSEN, Gunnar B</creator><creator>HOLM, Ruth</creator><creator>LYNG, Heidi</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20110815</creationdate><title>Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node―Negative Cervical Cancer</title><author>HALLE, Cathinka ; LANDO, Malin ; SVENDSRUD, Debbie Hege ; CLANCY, Trevor ; HOLDEN, Marit ; SUNDFØR, Kolbein ; KRISTENSEN, Gunnar B ; HOLM, Ruth ; LYNG, Heidi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c385t-ea01eb6085e03ed1063149682cee39b97505d04996051d4236a3e6bac2a391383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Carcinoma, Squamous Cell - genetics</topic><topic>Carcinoma, Squamous Cell - metabolism</topic><topic>Carcinoma, Squamous Cell - therapy</topic><topic>Cell Membrane - metabolism</topic><topic>Chemoradiotherapy</topic><topic>Cohort Studies</topic><topic>Female</topic><topic>Female genital diseases</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Regulatory Networks</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Kaplan-Meier Estimate</topic><topic>Lymph Nodes - metabolism</topic><topic>Lymph Nodes - pathology</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Pharmacology. Drug treatments</topic><topic>Phosphorylation</topic><topic>Prognosis</topic><topic>Protein Isoforms - genetics</topic><topic>Protein Isoforms - metabolism</topic><topic>Receptor, Epidermal Growth Factor - genetics</topic><topic>Receptor, Epidermal Growth Factor - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Treatment Outcome</topic><topic>Tumors</topic><topic>Uterine Cervical Neoplasms - genetics</topic><topic>Uterine Cervical Neoplasms - metabolism</topic><topic>Uterine Cervical Neoplasms - therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>HALLE, Cathinka</creatorcontrib><creatorcontrib>LANDO, Malin</creatorcontrib><creatorcontrib>SVENDSRUD, Debbie Hege</creatorcontrib><creatorcontrib>CLANCY, Trevor</creatorcontrib><creatorcontrib>HOLDEN, Marit</creatorcontrib><creatorcontrib>SUNDFØR, Kolbein</creatorcontrib><creatorcontrib>KRISTENSEN, Gunnar B</creatorcontrib><creatorcontrib>HOLM, Ruth</creatorcontrib><creatorcontrib>LYNG, Heidi</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>HALLE, Cathinka</au><au>LANDO, Malin</au><au>SVENDSRUD, Debbie Hege</au><au>CLANCY, Trevor</au><au>HOLDEN, Marit</au><au>SUNDFØR, Kolbein</au><au>KRISTENSEN, Gunnar B</au><au>HOLM, Ruth</au><au>LYNG, Heidi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node―Negative Cervical Cancer</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2011-08-15</date><risdate>2011</risdate><volume>17</volume><issue>16</issue><spage>5501</spage><epage>5512</epage><pages>5501-5512</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><coden>CCREF4</coden><abstract>We compared the prognostic significance of ectodomain isoforms of the epidermal growth factor receptor (EGFR), which lack the tyrosine kinase (TK) domain, with that of the full-length receptor and its autophosphorylation status in cervical cancers treated with conventional chemoradiotherapy.
Expression of EGFR isoforms was assessed by immunohistochemistry in a prospectively collected cohort of 178 patients with squamous cell cervical carcinoma, and their detection was confirmed with Western blotting and reverse transcriptase PCR. A proximity ligation immunohistochemistry assay was used to assess EGFR-specific autophosphorylation. Pathways associated with the expression of ectodomain isoforms were studied by gene expression analysis with Illumina beadarrays in 110 patients and validated in an independent cohort of 41 patients.
Membranous expression of ectodomain isoforms alone, without the coexpression of the full-length receptor, showed correlations to poor clinical outcome that were highly significant for lymph node-negative patients (locoregional control, P = 0.0002; progression-free survival, P < 0.0001; disease-specific survival, P = 0.005 in the log-rank test) and independent of clinical variables. The ectodomain isoforms were primarily 60-kD products of alternative EGFR transcripts. Their membranous expression correlated with transcriptional regulation of oncogenic pathways including activation of MYC and MAX, which was significantly associated with poor outcome. This aggressive phenotype of ectodomain EGFR expressing tumors was confirmed in the independent cohort. Neither total nor full-length EGFR protein level, or autophosphorylation status, showed prognostic significance.
Membranous expression of ectodomain EGFR isoforms, and not TK activation, predicts poor outcome after chemoradiotherapy for patients with lymph node-negative cervical cancer.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>21737508</pmid><doi>10.1158/1078-0432.CCR-11-0297</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical cancer research, 2011-08, Vol.17 (16), p.5501-5512 |
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| subjects | Adult Aged Antineoplastic agents Biological and medical sciences Blotting, Western Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - therapy Cell Membrane - metabolism Chemoradiotherapy Cohort Studies Female Female genital diseases Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Regulatory Networks Gynecology. Andrology. Obstetrics Humans Immunohistochemistry Kaplan-Meier Estimate Lymph Nodes - metabolism Lymph Nodes - pathology Medical sciences Middle Aged Pharmacology. Drug treatments Phosphorylation Prognosis Protein Isoforms - genetics Protein Isoforms - metabolism Receptor, Epidermal Growth Factor - genetics Receptor, Epidermal Growth Factor - metabolism Reverse Transcriptase Polymerase Chain Reaction Treatment Outcome Tumors Uterine Cervical Neoplasms - genetics Uterine Cervical Neoplasms - metabolism Uterine Cervical Neoplasms - therapy |
| title | Membranous Expression of Ectodomain Isoforms of the Epidermal Growth Factor Receptor Predicts Outcome after Chemoradiotherapy of Lymph Node―Negative Cervical Cancer |
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