{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:45:02Z","timestamp":1791233102565,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,27]],"date-time":"2024-04-27T00:00:00Z","timestamp":1714176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004504","name":"Research Council of Lithuania","doi-asserted-by":"publisher","award":["S-MIP-21-31"],"award-info":[{"award-number":["S-MIP-21-31"]}],"id":[{"id":"10.13039\/501100004504","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Non-muscle-invasive papillary urothelial carcinoma (NMIPUC) of the urinary bladder is the most common type of bladder cancer. Intravesical Bacille Calmette\u2013Guerin (BCG) immunotherapy is applied in patients with a high risk of recurrence and progression of NMIPUC to muscle-invasive disease. However, the tumor relapses in about 30% of patients despite the treatment, raising the need for better risk stratification. We explored the potential of spatial distributions of immune cell subtypes (CD20, CD11c, CD163, ICOS, and CD8) within the tumor microenvironment to predict NMIPUC recurrence following BCG immunotherapy. Based on analyses of digital whole-slide images, we assessed the densities of the immune cells in the epithelial\u2013stromal interface zone compartments and their distribution, represented by an epithelial\u2013stromal interface density ratio (IDR). While the densities of any cell type did not predict recurrence, a higher IDR of CD11c (HR: 0.0012, p-value = 0.0002), CD8 (HR: 0.0379, p-value = 0.005), and ICOS (HR: 0.0768, p-value = 0.0388) was associated with longer recurrence-free survival (RFS) based on the univariate Cox regression. The history of positive repeated TUR (re-TUR) (HR: 4.93, p-value = 0.0001) and T1 tumor stage (HR: 2.04, p-value = 0.0159) were associated with shorter RFS, while G3 tumor grade according to the 1973 WHO classification showed borderline significance (HR: 1.83, p-value = 0.0522). In a multivariate analysis, the two models with a concordance index exceeding 0.7 included the CD11c IDR in combination with either a history of positive re-TUR or tumor stage. We conclude that the CD11c IDR is the most informative predictor of NMIPUC recurrence after BCG immunotherapy. Our findings highlight the importance of assessment of the spatial distribution of immune cells in the tumor microenvironment.<\/jats:p>","DOI":"10.3390\/ijms25094776","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T08:02:22Z","timestamp":1714723342000},"page":"4776","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Spatial Distribution of Macrophage and Lymphocyte Subtypes within Tumor Microenvironment to Predict Recurrence of Non-Muscle-Invasive Papillary Urothelial Carcinoma after BCG Immunotherapy"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4818-8316","authenticated-orcid":false,"given":"Julius","family":"Drachneris","sequence":"first","affiliation":[{"name":"Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania"},{"name":"National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Klinikos, 08406 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1360-6533","authenticated-orcid":false,"given":"Mindaugas","family":"Morkunas","sequence":"additional","affiliation":[{"name":"Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 08406 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mantas","family":"Fabijonavicius","sequence":"additional","affiliation":[{"name":"Center of Urology, Vilnius University Hospital Santaros Klinikos, 08406 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albertas","family":"Cekauskas","sequence":"additional","affiliation":[{"name":"Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 08406 Vilnius, Lithuania"},{"name":"Center of Urology, Vilnius University Hospital Santaros Klinikos, 08406 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feliksas","family":"Jankevicius","sequence":"additional","affiliation":[{"name":"Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, 08406 Vilnius, Lithuania"},{"name":"Center of Urology, Vilnius University Hospital Santaros Klinikos, 08406 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9232-1730","authenticated-orcid":false,"given":"Arvydas","family":"Laurinavicius","sequence":"additional","affiliation":[{"name":"Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania"},{"name":"National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Klinikos, 08406 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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