{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T04:45:42Z","timestamp":1721796342548},"reference-count":37,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2015,9,13]],"date-time":"2015-09-13T00:00:00Z","timestamp":1442102400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Clin Investigation"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Cancer of unknown primary (<jats:styled-content style=\"fixed-case\">CUP<\/jats:styled-content>) possesses distinct biology and peculiar natural history, in which the roles of the winged and hedgehog signalling pathways are unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>We constructed tissue microarrays and studied the immunohistochemical (<jats:styled-content style=\"fixed-case\">IHC<\/jats:styled-content>) expression of \u03b2\u2010catenin, smoothened (<jats:styled-content style=\"fixed-case\">SMO<\/jats:styled-content>) and the transcription factors <jats:styled-content style=\"fixed-case\">TCF<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> LEF<\/jats:styled-content>,<jats:styled-content style=\"fixed-case\"> GLI<\/jats:styled-content>1 in 87 <jats:styled-content style=\"fixed-case\">CUP<\/jats:styled-content> cases for prognostic significance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A low rate of <jats:styled-content style=\"fixed-case\">IHC<\/jats:styled-content> expression of proteins was seen, the cut\u2010off used being any expression in \u2265\u00a01% of tumour cells. At univariate analysis, only nuclear <jats:styled-content style=\"fixed-case\">IHC SMO<\/jats:styled-content> expression displayed a statistically significant association with favourable outcome [median Overall survival (<jats:styled-content style=\"fixed-case\">OS<\/jats:styled-content>) of 19\u00a0months in <jats:styled-content style=\"fixed-case\">SMO<\/jats:styled-content>\u2010positive vs. 12\u00a0months in <jats:styled-content style=\"fixed-case\">SMO<\/jats:styled-content>\u2010negative cases, <jats:italic>P<\/jats:italic>\u00a0=\u00a00\u00b701]. An activated Wnt pathway, defined as <jats:styled-content style=\"fixed-case\">IHC<\/jats:styled-content> expression of any of nuclear \u03b2\u2010catenin, <jats:styled-content style=\"fixed-case\">TCF<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">LEF<\/jats:styled-content>, was significantly associated with favourable progression free survival (median 9 vs. 5\u00a0months, <jats:italic>P<\/jats:italic>\u00a0=\u00a00\u00b7037) and <jats:styled-content style=\"fixed-case\">OS<\/jats:styled-content> (median 19 vs. 13\u00a0months, <jats:italic>P<\/jats:italic>\u00a0=\u00a00\u00b704). This prognostic impact on <jats:styled-content style=\"fixed-case\">OS<\/jats:styled-content> was mainly driven by nuclear expression of <jats:styled-content style=\"fixed-case\">TCF<\/jats:styled-content> and\/or <jats:styled-content style=\"fixed-case\">LEF<\/jats:styled-content> (<jats:italic>P<\/jats:italic>\u00a0=\u00a00\u00b703). No prognostic significance of the hedgehog pathway activation status, defined as <jats:styled-content style=\"fixed-case\">IHC<\/jats:styled-content> expression of <jats:styled-content style=\"fixed-case\">SMO<\/jats:styled-content> or nuclear <jats:styled-content style=\"fixed-case\">GLI<\/jats:styled-content>1, could be established. A favourable prognostic impact of the concurrent activation of both pathways was observed. A trend for association of activated Wnt with response to chemotherapy (responders 67% among activated Wnt cases vs. 35% among nonactivated Wnt cases, <jats:italic>P<\/jats:italic>\u00a0=\u00a00\u00b707) was observed in <jats:styled-content style=\"fixed-case\">CUP<\/jats:styled-content> adenocarcinomas.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Activation of the Wnt pathway was a positive prognostic factor in a small <jats:styled-content style=\"fixed-case\">CUP<\/jats:styled-content> series, possibly via enhanced chemosensitivity. Independent validation is warranted.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.12518","type":"journal-article","created":{"date-parts":[[2015,8,13]],"date-time":"2015-08-13T05:38:55Z","timestamp":1439444335000},"page":"1145-1152","source":"Crossref","is-referenced-by-count":4,"title":["Prognostic significance of <scp>WNT<\/scp> and hedgehog pathway activation markers in cancer of unknown primary"],"prefix":"10.1111","volume":"45","author":[{"given":"George","family":"Fotopoulos","sequence":"first","affiliation":[{"name":"Department of Medical Oncology Medical School University of Ioannina Ioannina Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Gousia","sequence":"additional","affiliation":[{"name":"Department of Pathology Medical School University of Ioannina Ioannina Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleni","family":"Bareta","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Medical School University of Ioannina Ioannina Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Epameinondas","family":"Koumpis","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Medical School University of Ioannina Ioannina Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofia","family":"Chrisafi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Medical School Papageorgiou Hospital Aristotle University of Thessaloniki Thessaloniki Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthaios","family":"Bobos","sequence":"additional","affiliation":[{"name":"Department of Pathology Medical School Aristotle University of Thessaloniki Thessaloniki Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vassiliki","family":"Malamou\u2010Mitsi","sequence":"additional","affiliation":[{"name":"Department of Pathology Medical School University of Ioannina Ioannina Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Fountzilas","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Medical School Papageorgiou Hospital Aristotle University of Thessaloniki Thessaloniki Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Pavlidis","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Medical School University of Ioannina Ioannina Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Pentheroudakis","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Medical School University of Ioannina Ioannina Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2015,9,13]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-8049(03)00547-1"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1746-1596-5-3"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2008.10.003"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.12-4-418"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/00313020410001671957"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.219840"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-10-101"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2009.06.016"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.4161\/org.4.2.5851"},{"key":"e_1_2_6_11_1","first-page":"73","article-title":"Hedgehog signaling pathway","volume":"1","author":"Reddy MA","year":"2010","journal-title":"Ann Biol Res"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature00989"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20050941"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2000.18.3.632"},{"key":"e_1_2_6_15_1","first-page":"2563","article-title":"Overexpression of Cmyc, nRas and C\u2010erbB\u20102 oncoproteins in carcinoma of unknown primary origin","volume":"15","author":"Pavlidis N","year":"1995","journal-title":"Anticancer Res"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10585-007-9055-0"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-007-0341-7"},{"key":"e_1_2_6_18_1","first-page":"1907","article-title":"Bcl2 and p53 protein expression in metastatic carcinoma of unknown primary origin: biological and clinical implications. 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