{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T14:49:22Z","timestamp":1791470962037,"version":"4.3.4"},"reference-count":44,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T00:00:00Z","timestamp":1638144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007655","name":"Aichi Cancer Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007655","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["19cm0106301h0004"],"award-info":[{"award-number":["19cm0106301h0004"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["20cm0106301h0005"],"award-info":[{"award-number":["20cm0106301h0005"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>CD28, one of the costimulatory molecules, has a pivotal role in T\u2010cell activation, and its expression is strictly regulated in normal T cells. Gain\u2010of\u2010function genetic alterations involving <jats:italic>CD28<\/jats:italic> have been frequently observed in adult T\u2010cell leukemia\/lymphoma (ATLL). These abnormalities, such as <jats:italic>CD28<\/jats:italic> fusions and copy number variations, may not only confer continuous, prolonged, and enhanced CD28 signaling to downstream pathways but also induce overexpression of the CD28 protein. In this study, 120 ATLL cases were examined by immunohistochemistry for CD28 and its ligands CD80 and CD86, and their expression on tumor cells was semiquantitatively evaluated. CD28 was overexpressed in 55 (46%) cases, and CD80 or CD86 (CD80\/CD86) was infrequently overexpressed in 12 (11%). Compared with non\u2010overexpressers, CD28 overexpressers showed a higher frequency of <jats:italic>CD28<\/jats:italic> genetic alterations and had an increased number of CD80\/CD86\u2010positive non\u2010neoplastic cells infiltrating tumor microenvironment. In the entire ATLL patient cohort, CD28 overexpressers showed a significantly poorer overall survival (OS) compared with non\u2010overexpressers (<jats:italic>P\u00a0<\/jats:italic>=\u00a0.001). The same was true for a subgroup who were treated with multidrug regimens with or without mogamulizumab. CD28 overexpression had no prognostic impact in the group who received allogeneic hematopoietic stem cell transplantation. In the multivariate analysis for OS, CD28 overexpression was selected as an independent risk factor. These results suggest ATLL patients with CD28 overexpression have more aggressive clinical course and are more refractory to treatment with multidrug chemotherapy. CD28 overexpression appears to be a novel unfavorable prognostic marker in ATLL patients, and further prospective studies are warranted to establish its prognostic significance.<\/jats:p>","DOI":"10.1111\/cas.15191","type":"journal-article","created":{"date-parts":[[2021,11,5]],"date-time":"2021-11-05T12:29:37Z","timestamp":1636115377000},"page":"349-361","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Clinicopathological significance of CD28 overexpression in adult T\u2010cell leukemia\/lymphoma"],"prefix":"10.1111","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9916-4862","authenticated-orcid":false,"given":"Yuma","family":"Sakamoto","sequence":"first","affiliation":[{"name":"Department of Pathology and Molecular Diagnostics Graduate School of Medical Sciences Nagoya City University Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1060-0777","authenticated-orcid":false,"given":"Takashi","family":"Ishida","sequence":"additional","affiliation":[{"name":"Department of Immunology Nagoya University Graduate School of Medicine Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Masaki","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Diagnostics Graduate School of Medical Sciences Nagoya City University Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morishige","family":"Takeshita","sequence":"additional","affiliation":[{"name":"Department of Pathology Faculty of Medicine Fukuoka University Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Department of Hematology National Hospital Organization Kyushu Medical Center Fukuoka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Yonekura","sequence":"additional","affiliation":[{"name":"Department of Dermatology Imamura General Hospital Kagoshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukie","family":"Tashiro","sequence":"additional","affiliation":[{"name":"Department of Pathology Imamura General Hospital Kagoshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asahi","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medical Sciences Nagoya City University Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Kusumoto","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medical Sciences Nagoya City University Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4951-960X","authenticated-orcid":false,"given":"Shinsuke","family":"Iida","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medical Sciences Nagoya City University Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atae","family":"Utsunomiya","sequence":"additional","affiliation":[{"name":"Department of Hematology Imamura General Hospital Kagoshima Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuzo","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Tumor Immunology School of Medicine Aichi Medical University Nagakute Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6157-636X","authenticated-orcid":false,"given":"Hiroshi","family":"Inagaki","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Diagnostics Graduate School of Medical Sciences Nagoya City University Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2009.00770.x"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3405"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa8172"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.04.020"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp068082"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa063842"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3415"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.357"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.186767"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3370"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3356"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-019-0473-1"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-02-698977"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3444"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V50.3.481.481"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.1991.tb08051.x"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2111"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(14)70202-5"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.17211"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2017.07.002"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2015.139253"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019001815"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00277-020-03967-x"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2001.02737.x"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.11.9958"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-03-414490"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2013.09.014"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.02235"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-2697"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.37.3472"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.13338"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.67.7732"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/cjp2.180"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64012-6"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3800781"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-02-835991"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.1999.01685.x"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-1489"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-05-159624"},{"key":"e_1_2_11_41_1","first-page":"1521","article-title":"CD28, a marker associated with tumoral expansion in multiple myeloma","volume":"4","author":"Robillard N","year":"1998","journal-title":"Clin Cancer Res"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-03-012542"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100016"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-10-530964"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-09-242347"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.15191","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cas.15191","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.15191","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,27]],"date-time":"2023-08-27T04:14:37Z","timestamp":1693109677000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.15191"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,29]]},"references-count":44,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,1]]}},"alternative-id":["10.1111\/cas.15191"],"URL":"https:\/\/doi.org\/10.1111\/cas.15191","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,29]]},"assertion":[{"value":"2021-06-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-10-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-11-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}