{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T05:35:37Z","timestamp":1775885737806,"version":"3.50.1"},"reference-count":29,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,7,28]],"date-time":"2024-07-28T00:00:00Z","timestamp":1722124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health of the Czech Republic (RVO)","award":["BBMRI_CZ LM2023033"],"award-info":[{"award-number":["BBMRI_CZ LM2023033"]}]},{"name":"Ministry of Health of the Czech Republic (RVO)","award":["EF16_013\/0001674"],"award-info":[{"award-number":["EF16_013\/0001674"]}]},{"name":"Ministry of Health of the Czech Republic (RVO)","award":["LX22NPO5104"],"award-info":[{"award-number":["LX22NPO5104"]}]},{"name":"Charles University (COOPERATIO, Oncology and Haematology)","award":["BBMRI_CZ LM2023033"],"award-info":[{"award-number":["BBMRI_CZ LM2023033"]}]},{"name":"Charles University (COOPERATIO, Oncology and Haematology)","award":["EF16_013\/0001674"],"award-info":[{"award-number":["EF16_013\/0001674"]}]},{"name":"Charles University (COOPERATIO, Oncology and Haematology)","award":["LX22NPO5104"],"award-info":[{"award-number":["LX22NPO5104"]}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["BBMRI_CZ LM2023033"],"award-info":[{"award-number":["BBMRI_CZ LM2023033"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["EF16_013\/0001674"],"award-info":[{"award-number":["EF16_013\/0001674"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["LX22NPO5104"],"award-info":[{"award-number":["LX22NPO5104"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute for Research of Metabolic and Cardiovascular Diseases","award":["BBMRI_CZ LM2023033"],"award-info":[{"award-number":["BBMRI_CZ LM2023033"]}]},{"name":"National Institute for Research of Metabolic and Cardiovascular Diseases","award":["EF16_013\/0001674"],"award-info":[{"award-number":["EF16_013\/0001674"]}]},{"name":"National Institute for Research of Metabolic and Cardiovascular Diseases","award":["LX22NPO5104"],"award-info":[{"award-number":["LX22NPO5104"]}]},{"name":"European Union\u2014Next Generation EU (LV)","award":["BBMRI_CZ LM2023033"],"award-info":[{"award-number":["BBMRI_CZ LM2023033"]}]},{"name":"European Union\u2014Next Generation EU (LV)","award":["EF16_013\/0001674"],"award-info":[{"award-number":["EF16_013\/0001674"]}]},{"name":"European Union\u2014Next Generation EU (LV)","award":["LX22NPO5104"],"award-info":[{"award-number":["LX22NPO5104"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The significance of extraesophageal reflux as a risk factor in lung adenocarcinoma has been understudied. In this study, we investigated whether extraesophageal reflux leads to higher pepsin concentrations in bronchoalveolar lavage (BAL) in patients with lung adenocarcinoma compared to controls. Subjects were recruited from non-smoker patients (lifelong non-smokers and ex-smokers with more than 5 years of non-smoking history) who had undergone bronchoscopy due to pulmonary abnormalities on a CT scan and met the inclusion criteria. Based on histological verification of the lung process, the patients were divided into three groups: (1) lung adenocarcinoma, (2) pulmonary metastases, and (3) lung sarcoidosis. Lung adenocarcinoma cases were further categorized as central or peripheral. BAL samples collected during bronchoscopy were quantitatively analyzed by enzyme-linked immunosorbent assay (ELISA) to measure pepsin levels. No statistically significant difference in pepsin concentration was observed between the lung adenocarcinoma group and control groups (p = 0.135). After excluding hemorrhagic BAL samples, the pepsin concentration was significantly the lowest in patients with lung adenocarcinoma (p = 0.023) compared to the control groups. The results of the study do not support the hypothesis of a higher occurrence of extraesophageal reflux (evaluated as the amount of pepsin in BAL) in non-smoker patients with lung adenocarcinoma.<\/jats:p>","DOI":"10.3390\/cancers16152687","type":"journal-article","created":{"date-parts":[[2024,7,29]],"date-time":"2024-07-29T09:50:05Z","timestamp":1722246605000},"page":"2687","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Does Extraesophageal Reflux Support the Development of Lung Adenocarcinoma? Analysis of Pepsin in Bronchoalveolar Lavage in Non-Smoker Patients"],"prefix":"10.3390","volume":"16","author":[{"given":"Petra","family":"Zemanova","sequence":"first","affiliation":[{"name":"First Clinic of Tuberculosis and Respiratory Diseases, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, U Nemocnice 2, 12808 Prague, Czech Republic"},{"name":"Department of Oncology, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, U Nemocnice 2, Prague 2, 12808 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9386-657X","authenticated-orcid":false,"given":"Michal","family":"Vocka","sequence":"additional","affiliation":[{"name":"Department of Oncology, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, U Nemocnice 2, Prague 2, 12808 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zdislava","family":"Vanickova","sequence":"additional","affiliation":[{"name":"Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, U Nemocnice 2, 12808 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frantisek","family":"Liska","sequence":"additional","affiliation":[{"name":"Institute of Biology and Medical Genetics, Purkyne Institute, First Faculty of Medicine, Charles University in Prague, Albertov 4, 12800 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ludmila","family":"Krizova","sequence":"additional","affiliation":[{"name":"Department of Oncology, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, U Nemocnice 2, Prague 2, 12808 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0641-3068","authenticated-orcid":false,"given":"Josef","family":"Kalab","sequence":"additional","affiliation":[{"name":"First Clinic of Tuberculosis and Respiratory Diseases, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, U Nemocnice 2, 12808 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiri","family":"Votruba","sequence":"additional","affiliation":[{"name":"First Clinic of Tuberculosis and Respiratory Diseases, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, U Nemocnice 2, 12808 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1136\/gut.2004.053025","article-title":"Extraoesophageal manifestations of gastro-oesophageal reflux","volume":"54","author":"Poelmans","year":"2005","journal-title":"Gut"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"115","DOI":"10.4103\/1817-1737.53347","article-title":"Pulmonary manifestations of gastroesophageal reflux disease","volume":"4","author":"Gaude","year":"2009","journal-title":"Ann. Thorac. Med."},{"key":"ref_3","first-page":"1","article-title":"Review article: Reflux and its consequences\u2014The laryngeal, pulmonary and oesophageal manifestations","volume":"33","author":"Pearson","year":"2011","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.3748\/wjg.v30.i16.2209","article-title":"Laryngopharyngeal reflux disease: Updated examination of mechanisms, pathophysiology, treatment, and association with gastroesophageal reflux disease","volume":"30","author":"Cui","year":"2024","journal-title":"World J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"27","DOI":"10.14309\/ajg.0000000000001538","article-title":"ACG Clinical Guideline for the Diagnosis and Management of Gastroesophageal Reflux Disease","volume":"117","author":"Katz","year":"2022","journal-title":"Am. J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1007\/s00018-002-8423-9","article-title":"Pepsinogens, progastricsins, and prochymosins: Structure, function, evolution, and development","volume":"59","author":"Kageyama","year":"2002","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1097\/MLG.0b013e31804154c3","article-title":"Activity\/stability of human pepsin: Implications for reflux attributed laryngeal disease","volume":"117","author":"Johnston","year":"2007","journal-title":"Laryngoscope"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0016-5085(69)80121-6","article-title":"Role of acid and pepsin in acute experimental esophagitis","volume":"56","author":"Goldberg","year":"1969","journal-title":"Gastroenterology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1177\/000348940811700911","article-title":"Mucin gene expression in human laryngeal epithelia: Effect of laryngopharyngeal reflux","volume":"117","author":"Samuels","year":"2008","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1097\/01.mlg.0000149445.07146.03","article-title":"Pepsin and carbonic anhydrase isoenzyme III as diagnostic markers for laryngopharyngeal reflux disease","volume":"114","author":"Johnston","year":"2004","journal-title":"Laryngoscope"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1177\/000348940611500108","article-title":"Effect of pepsin on laryngeal stress protein (Sep70, Sep53, and Hsp70) response: Role in laryngopharyngeal reflux disease","volume":"115","author":"Johnston","year":"2006","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1177\/000348940711601211","article-title":"Receptor-mediated uptake of pepsin by laryngeal epithelial cells","volume":"116","author":"Johnston","year":"2007","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5598","DOI":"10.3748\/wjg.v19.i34.5598","article-title":"Epidemiology of esophageal cancer","volume":"19","author":"Zhang","year":"2013","journal-title":"World J. Gastroenterol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1111\/j.1572-0241.2001.03934.x","article-title":"Gastroesophageal reflux disease is a risk factor for laryngeal and pharyngeal cancer","volume":"96","author":"Hepworth","year":"2001","journal-title":"Am. J. Gastroenterol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1111\/j.1365-2273.2004.00851.x","article-title":"Effects of gastroesophageal reflux disease in laryngeal carcinoma","volume":"29","author":"Bacciu","year":"2004","journal-title":"Clin. Otolaryngol. Allied Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3342\/ceo.2011.4.2.101","article-title":"The role of laryngopharyngeal reflux as a risk factor in laryngeal cancer: A preliminary report","volume":"4","author":"Tae","year":"2011","journal-title":"Clin. Exp. Otorhinolaryngol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1158\/1055-9965.EPI-13-0183","article-title":"Gastric reflux is an independent risk factor for laryngopharyngeal carcinoma","volume":"22","author":"Langevin","year":"2013","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.cgh.2018.10.028","article-title":"Gastroesophageal and Laryngopharyngeal Reflux Associated with Laryngeal Malignancy: A Systematic Review and Meta-analysis","volume":"17","author":"Parsel","year":"2019","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1177\/000348940311200601","article-title":"Cell Biology of Laryngeal Epithelial Defenses in Health and Disease: Further Studies","volume":"112","author":"Johnston","year":"2003","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e2753","DOI":"10.7717\/peerj.2753","article-title":"Risk of lung cancer in patients with gastro-esophageal reflux disease: A population-based cohort study","volume":"4","author":"Hsu","year":"2016","journal-title":"PeerJ"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7552","DOI":"10.1002\/cam4.5498","article-title":"Causal associations between gastroesophageal reflux disease and lung cancer risk: A Mendelian randomization study","volume":"12","author":"Li","year":"2023","journal-title":"Cancer Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1111\/j.1442-2050.2007.00796.x","article-title":"Gastroesophageal reflux disease and non-small cell lung cancer. Results of a pilot study","volume":"21","author":"Vereczkei","year":"2008","journal-title":"Dis. Esophagus"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"173","DOI":"10.14740\/gr1537","article-title":"The Association between Gastroesophageal Reflux Disease and Non-Small Cell Lung Cancer: A Retrospective Case-Control Study","volume":"15","author":"Amarnath","year":"2022","journal-title":"Gastroenterol. Res."},{"key":"ref_24","unstructured":"R Core Team (2022). R: A Language and Environment for Statistical Computing (Version 4.2.2), R Foundation for Statistical Computing. Available online: https:\/\/www.R-project.org."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"176","DOI":"10.12998\/wjcc.v6.i8.176","article-title":"Risk factors for gastroesophageal reflux disease and analysis of genetic contributors","volume":"6","author":"Argyrou","year":"2018","journal-title":"World J. Clin. Cases"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e32899","DOI":"10.1097\/MD.0000000000032899","article-title":"Non-small cell lung cancer (NSCLC): A review of risk factors, diagnosis, and treatment","volume":"102","author":"Alduais","year":"2023","journal-title":"Medicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1183\/09031936.00144012","article-title":"Lung adenocarcinoma subtypes based on expression of human airway basal cell genes","volume":"42","author":"Fukui","year":"2013","journal-title":"Eur. Respir. J."},{"key":"ref_28","unstructured":"(2021, April 22). Human Pepsin (PP) Elisa Kit. Available online: https:\/\/www.elisakit.cc\/uploads\/file\/e01p0699-human-pp-c.pdf."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1183\/09031936.00050911","article-title":"Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis","volume":"39","author":"Lee","year":"2012","journal-title":"Eur. Respir. J."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/15\/2687\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:25:19Z","timestamp":1760109919000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/15\/2687"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,28]]},"references-count":29,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["cancers16152687"],"URL":"https:\/\/doi.org\/10.3390\/cancers16152687","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,28]]}}}