{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T13:15:53Z","timestamp":1778505353638,"version":"3.51.4"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T00:00:00Z","timestamp":1679356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005357","name":"Agent\u00fara na Podporu V\u00fdskumu a V\u00fdvoja","doi-asserted-by":"publisher","award":["15-0086, 19-0411"],"award-info":[{"award-number":["15-0086, 19-0411"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006109","name":"Vedeck\u00e1 Grantov\u00e1 Agent\u00fara M\u0160VVa\u0160 SR a SAV","doi-asserted-by":"publisher","award":["1\/0327\/19 , 1\/0174\/19,  1\/0043\/18"],"award-info":[{"award-number":["1\/0327\/19 , 1\/0174\/19,  1\/0043\/18"]}],"id":[{"id":"10.13039\/501100006109","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Survivors of testicular germ cell tumors (GCT) may suffer from late cognitive impairment. We hypothesized that disruption of intestinal barrier during chemotherapy and\/or radiotherapy may be a contributing factor of cognitive dysfunction within the gut-blood-brain axis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>GCT survivors (N = 142) from National Cancer Institute of Slovakia completed the Functional Assessment of Cancer Therapy Cognitive Function questionnaires during their annual follow-up visit at 9-year median (range 4-32). Biomarkers of gut microbial translocation and dysbiosis high mobility group box-1 (HMGB-1), lipopolysaccharide, d-lactate and sCD14 were measured from peripheral blood obtained during the same visit. Each questionnaire score was correlated with biomarkers. Survivors were treated with orchiectomy only (N = 17), cisplatin-based chemotherapy (N = 108), radiotherapy to the retroperitoneum (N = 11) or both (N = 6).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>GCT survivors with higher sCD14 (above median) had worse cognitive function perceived by others (CogOth domain) (mean \u00b1 SEM; 14.6 \u00b1 0.25 vs 15.4 \u00b1 0.25, p = 0.019), lower perceived cognitive abilities (CogPCA domain) (20.0 \u00b1 0.74 vs 23.4 \u00b1 0.73, p = 0.025) and lower overall cognitive function score (109.2 \u00b1 0.74 vs 116.7 \u00b1 1.90, p = 0.021). There were no significant cognitive declines associated with HMGB-1, d-lactate and lipopolysaccharide. Survivors treated with \u2265 400mg\/m2 vs &amp;lt; 400mg\/m2 of cisplatin-based chemotherapy had a higher lipopolysaccharide (567.8 \u03bcg\/L \u00b1 42.7 vs 462.9 \u03bcg\/L \u00b1 51.9, (p = 0.03).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>sCD14 is a marker of monocytic activation by lipopolysaccharide and may also serve as a promising biomarker of cognitive impairment in long-term cancer survivors. While chemotherapy and radiotherapy-induced intestinal injury may be the underlying mechanism, further research using animal models and larger patient cohorts are needed to explore the pathogenesis of cognitive impairment in GCT survivors within the gut-brain axis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2023.1146032","type":"journal-article","created":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T05:01:40Z","timestamp":1679374900000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Cognitive impairment and biomarkers of gut microbial translocation in testicular germ cell tumor survivors"],"prefix":"10.3389","volume":"13","author":[{"given":"Michal","family":"Chovanec","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katarina","family":"Kalavska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jana","family":"Obertova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrik","family":"Palacka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katarina","family":"Rejlekova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuzana","family":"Sycova-Mila","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuzana","family":"Orszaghova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Lesko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"De Angelis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Vasilkova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Svetlovska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beata","family":"Mladosievicova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jozef","family":"Mardiak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"Pastorek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbora","family":"Vlkova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Celec","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michal","family":"Mego","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1990.8.11.1777","article-title":"Treatment of testicular cancer: A new and improved model","volume":"8","author":"Einhorn","year":"1990","journal-title":"J Clin Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.03292","article-title":"Survival and new prognosticators in metastatic seminoma: Results from the IGCCCG-update consortium","volume":"39","author":"Beyer","year":"2021","journal-title":"J Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.03296","article-title":"Predicting outcomes in men with metastatic nonseminomatous germ cell tumors (NSGCT): Results from the IGCCCG update consortium","volume":"39","author":"Gillessen","year":"2021","journal-title":"J Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41585-021-00440-w","article-title":"Late adverse effects and quality of life in survivors of testicular germ cell tumour","volume":"18","author":"Chovanec","year":"2021","journal-title":"Nat Rev Urol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2017-0457","article-title":"Long-term cognitive functioning in testicular germ-cell tumor survivors","volume":"23","author":"Chovanec","year":"2018","journal-title":"Oncologist"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s00520-015-2663-3","article-title":"Cognitive impairment in testicular cancer survivors 2 to 7 years after treatment","volume":"23","author":"Amidi","year":"2015","journal-title":"Support Care Cancer"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.1240537","article-title":"The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide","volume":"342","author":"Viaud","year":"2013","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-1259","article-title":"Cyclophosphamide induces differentiation of Th17 cells in cancer patients","volume":"71","author":"Viaud","year":"2011","journal-title":"Cancer Res"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2015.00306","article-title":"Abnormal lipopolysaccharide binding protein as marker of gastrointestinal inflammation in Parkinson disease","volume":"9","author":"Pal","year":"2015","journal-title":"Front Neurosci"},{"key":"B10","first-page":"89","article-title":"Immunity and inflammation in neurodegenerative diseases","volume":"2","author":"Cappellano","year":"2013","journal-title":"Am J Neurodegener Dis"},{"key":"B11","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1111\/j.1600-065X.2007.00579.x","article-title":"The grateful dead: Damage-associated molecular pattern molecules and reduction\/oxidation regulate immunity","volume":"220","author":"Lotze","year":"2007","journal-title":"Immunol Rev"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nri1594","article-title":"High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal","volume":"5","author":"Lotze","year":"2005","journal-title":"Nat Rev Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s40168-018-0441-4","article-title":"Gut-dependent microbial translocation induces inflammation and cardiovascular events after ST-elevation myocardial infarction","volume":"6","author":"Zhou","year":"2018","journal-title":"Microbiome"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-317726","article-title":"Increased levels of systemic LPS-positive bacterial extracellular vesicles in patients with intestinal barrier dysfunction","volume":"69","author":"Tulkens","year":"2020","journal-title":"Gut"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000000735","article-title":"Soluble CD14 is a nonspecific marker of monocyte activation","volume":"29","author":"Shive","year":"2015","journal-title":"AIDS"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.3390\/pathogens10101235","article-title":"Targeting inflammation driven by HMGB1 in bacterial keratitis-a review","volume":"10","author":"Hazlett","year":"2021","journal-title":"Pathogens"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v3.i4.225","article-title":"Plasma d (-)-lactate as a new marker for diagnosis of acute intestinal injury following ischemia-reperfusion","volume":"3","author":"Yao","year":"1997","journal-title":"World J Gastroenterol"},{"key":"B18","article-title":"Increased d-lactic acid intestinal bacteria in patients with chronic fatigue syndrome","volume":"23","author":"Sheedy","year":"2009","journal-title":"Vivo"},{"key":"B19","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1186\/s12885-020-07301-6","article-title":"Long-term sexual functioning in germ-cell tumor survivors","volume":"20","author":"Chovanec","year":"2020","journal-title":"BMC Cancer"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djab027","article-title":"Measuring patient self-reported cognitive function: Development of the functional assessment of cancer therapy\u2013cognitive function instrument","volume":"7","author":"Wagner","year":"2009","journal-title":"J Support Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1136\/bmj-2022-070499","article-title":"Advances in diagnosis and treatment of testicular cancer","volume":"379","author":"Chovanec","year":"2022","journal-title":"BMJ"},{"key":"B22","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1053\/j.gastro.2003.12.004","article-title":"Chemotherapy- and radiotherapy-induced intestinal damage is regulated by intestinal trefoil factor","volume":"126","author":"Beck","year":"2004","journal-title":"Gastroenterology"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.11671","article-title":"The burdens of cancer therapy. clinical and economic outcomes of chemotherapy-induced mucositis","volume":"98","author":"Elting","year":"2003","journal-title":"Cancer"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1053\/j.soncn.2003.10.002","article-title":"Scope and epidemiology of cancer therapy-induced oral and gastrointestinal mucositis","volume":"20","author":"Avritscher","year":"2004","journal-title":"Semin Oncol Nurs"},{"key":"B25","article-title":"Intestinal stem cell injury and protection during cancer therapy","volume":"2","author":"Yu","year":"2013","journal-title":"Transl Cancer Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-316723","article-title":"Human gut microbiome: Hopes, threats and promises","volume":"67","author":"Cani","year":"2018","journal-title":"Gut"},{"key":"B27","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1002\/JLB.5HI1117-446RR","article-title":"Frontline science: Microbiota reconstitution restores intestinal integrity after cisplatin therapy","volume":"103","author":"Perales-Puchalt","year":"2018","journal-title":"J Leukoc Biol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(01)00425-0","article-title":"Role of protein kinase cepsilon and protein kinase a in a model of paclitaxel-induced painful peripheral neuropathy in the rat","volume":"108","author":"Dina","year":"2001","journal-title":"Neuroscience"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2009.10.009","article-title":"Methotrexate reduces hippocampal blood vessel density and activates microglia in rats but does not elevate central cytokine release","volume":"207","author":"Seigers","year":"2010","journal-title":"Behav Brain Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0b013e3182237e54","article-title":"Plasma sCD14 is a biomarker associated with impaired neurocognitive test performance in attention and learning domains in HIV infection","volume":"57","author":"Lyons","year":"2011","journal-title":"J Acquir Immune Defic Syndr"},{"key":"B31","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1186\/s12879-016-1510-6","article-title":"Soluble CD14 in cerebrospinal fluid is associated with markers of inflammation and axonal damage in untreated HIV-infected patients: A retrospective cross-sectional study","volume":"16","author":"Jespersen","year":"2016","journal-title":"BMC Infect Dis"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000008682","article-title":"Association of CD14 with incident dementia and markers of brain aging and injury","volume":"94","author":"Pase","year":"2020","journal-title":"Neurology"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.36.1154","article-title":"Inflammation and behavioral symptoms after breast cancer treatment: Do fatigue, depression, and sleep disturbance share a common underlying mechanism","volume":"29","author":"Bower","year":"2011","journal-title":"J Clin Oncol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s40170-021-00260-x","article-title":"Lipopolysaccharide promotes metastasis via acceleration of glycolysis by the nuclear factor-kappaB\/snail\/hexokinase3 signaling axis in colorectal cancer","volume":"9","author":"Wu","year":"2021","journal-title":"Cancer Metab"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/pros.23722","article-title":"Lipopolysaccharide (LPS) enhances prostate cancer metastasis potentially through NF-kappaB activation and recurrent dexamethasone administration fails to suppress it in vivo","volume":"79","author":"Jain","year":"2019","journal-title":"Prostate"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/jncics\/pkac039","article-title":"Bacterial lipopolysaccharide as a negative predictor of adjuvant gemcitabine efficacy in pancreatic cancer","volume":"6","author":"Guenther","year":"2022","journal-title":"JNCI Cancer Spectr"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1146032\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,21]],"date-time":"2023-03-21T05:01:45Z","timestamp":1679374905000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1146032\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,21]]},"references-count":36,"alternative-id":["10.3389\/fonc.2023.1146032"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2023.1146032","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,21]]},"article-number":"1146032"}}