{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T02:09:00Z","timestamp":1780452540987,"version":"3.54.1"},"reference-count":60,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,13]],"date-time":"2020-12-13T00:00:00Z","timestamp":1607817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007210","name":"Varian Medical Systems","doi-asserted-by":"publisher","award":["Role of adenosine mediated immunosuppression for radiotherapy of melanoma"],"award-info":[{"award-number":["Role of adenosine mediated immunosuppression for radiotherapy of melanoma"]}],"id":[{"id":"10.13039\/100007210","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Following the introduction of immune checkpoint inhibitors, a substantial prolongation of the overall survival has been achieved for many patients with multiple brain metastases from melanoma. However, heterogeneity between individual tumor responses is incompletely understood. In order to determine the impact of the individual tumor phenotype on the prognosis of melanoma patients, we examined surgical sections from 33 patients who were treated with radiotherapy (whole-brain radiotherapy, WBRT, stereotactic radiotherapy, STX, or both) and Ipilimumab. We analyzed multiplex staining of the hypoxia marker GLUT-1, the adenosine (ADO)-associated enzymes CD73 and CD39, and CD8, a marker of cytotoxic T lymphocytes (CTL) on a single-cell basis using QuPath. Additionally, the MOSAIC interaction analysis algorithm was used to explore the hypothesis that CTL systematically avoid GLUT-1high tumor areas. Our results revealed, that a strong GLUT-1 expression, low numbers of CTL, or exclusion of CTL from the tumor were correlated with significant prognostic detriment. Hypoxic tumors overall have smaller amounts of CTL, and spatial analysis revealed a repellent effect of hypoxia on CTL. In contrast to in vitro studies, specific upregulation of ADO-related enzymes CD73 and CD39 in GLUT-1high tumor regions was never observed. In this study, we could show direct in vivo evidence for hypoxia-mediated immunosuppression in melanoma. Moreover, this study suggests a significant prognostic relevance of the tumor immune phenotype, the strength of CD8 infiltration in the tumor, and the expression of hypoxia marker GLUT-1 on melanoma cells. Last, our results suggest a temporal stability of the microenvironment-mediated immunosuppressive phenotype in melanoma.<\/jats:p>","DOI":"10.3390\/cancers12123753","type":"journal-article","created":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T00:45:36Z","timestamp":1607906736000},"page":"3753","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Role of Hypoxia and the Adenosine System in Immune Evasion and Prognosis of Patients with Brain Metastases of Melanoma: A Multiplex Whole Slide Immunofluorescence Study"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3101-9180","authenticated-orcid":false,"given":"Arnulf","family":"Mayer","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6720-7570","authenticated-orcid":false,"given":"Maximilian","family":"Haist","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"},{"name":"Department of Dermatology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Loquai","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6863-8719","authenticated-orcid":false,"given":"Stephan","family":"Grabbe","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Rapp","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilfried","family":"Roth","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4238-3188","authenticated-orcid":false,"given":"Peter","family":"Vaupel","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0647-8884","authenticated-orcid":false,"given":"Heinz","family":"Schmidberger","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1002\/cncr.10426","article-title":"Survival by radiation therapy oncology group recursive partitioning analysis class and treatment modality in patients with brain metastases from malignant melanoma: A retrospective study","volume":"94","author":"Buchsbaum","year":"2002","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1038\/sj.bjc.6605622","article-title":"Determinants of survival in patients with brain metastases from cutaneous melanoma","volume":"102","author":"Staudt","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1002\/cncr.25634","article-title":"Prognostic factors for survival in melanoma patients with brain metastases","volume":"117","author":"Davies","year":"2011","journal-title":"Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved survival with ipilimumab in patients with metastatic melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1056\/NEJMoa1104621","article-title":"Ipilimumab plus dacarbazine for previously untreated metastatic melanoma","volume":"364","author":"Robert","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1007\/s00066-018-1356-5","article-title":"Long-term survival of patients after ipilimumab and hypofractionated brain radiotherapy for brain metastases of malignant melanoma: Sequence matters","volume":"194","author":"Schmidberger","year":"2018","journal-title":"Strahlenther. Onkol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1200\/JCO.18.00204","article-title":"Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial","volume":"37","author":"Kluger","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s11060-018-2795-7","article-title":"The impact of timing of immunotherapy with cranial irradiation in melanoma patients with brain metastases: Intracranial progression, survival and toxicity","volume":"138","author":"Rahman","year":"2018","journal-title":"J. Neurooncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"227","DOI":"10.3171\/2012.5.JNS111929","article-title":"Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival","volume":"117","author":"Knisely","year":"2012","journal-title":"J. Neurosurg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"297","DOI":"10.2217\/imt-2018-0149","article-title":"Immunotherapy plus surgery\/radiosurgery is associated with favorable survival in patients with melanoma brain metastasis","volume":"11","author":"Amaral","year":"2019","journal-title":"Immunotherapy"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Vosoughi, E., Lee, J.M., Miller, J.R., Nosrati, M., Minor, D.R., Abendroth, R., Lee, J.W., Andrews, B.T., Leng, L.Z., and Wu, M. (2018). Survival and clinical outcomes of patients with melanoma brain metastasis in the era of checkpoint inhibitors and targeted therapies. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4374-x"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Passarelli, A., Tucci, M., Mannavola, F., Felici, C., and Silvestris, F. (2019). The metabolic milieu in melanoma: Role of immune suppression by CD73\/adenosine. Tumour Biol., 42.","DOI":"10.1177\/1010428319837138"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Najjar, Y.G., Menk, A.V., Sander, C., Rao, U., Karunamurthy, A., Bhatia, R., Zhai, S., Kirkwood, J.M., and Delgoffe, G.M. (2019). Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma. JCI Insight, 4.","DOI":"10.1172\/jci.insight.124989"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.ejso.2016.07.145","article-title":"Immunotherapy in melanoma: Recent advances and future directions","volume":"43","author":"Franklin","year":"2017","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1038\/2201352a0","article-title":"Cellular and humoral immunity to different types of human neoplasms","volume":"220","author":"Hellstrom","year":"1968","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"13003","DOI":"10.1073\/pnas.0805599105","article-title":"Rapid tolerization of virus-activated tumor-specific CD8+ T cells in prostate tumors of TRAMP mice","volume":"105","author":"Bai","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","first-page":"3011","article-title":"Interleukin 2 activation of cytotoxic T-lymphocytes infiltrating into human metastatic melanomas","volume":"46","author":"Itoh","year":"1986","journal-title":"Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s10555-007-9055-1","article-title":"Hypoxia in cancer: Significance and impact on clinical outcome","volume":"26","author":"Vaupel","year":"2007","journal-title":"Cancer Metastasis Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/978-1-4939-3023-4_22","article-title":"Hypoxia-Driven Adenosine Accumulation: A Crucial Microenvironmental Factor Promoting Tumor Progression","volume":"876","author":"Vaupel","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.3389\/fimmu.2018.01591","article-title":"Hypoxia-Driven Immunosuppressive Metabolites in the Tumor Microenvironment: New Approaches for Combinational Immunotherapy","volume":"9","author":"Li","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1097\/00008390-199710000-00006","article-title":"Intratumoral oxygen tension in metastatic melanoma","volume":"7","author":"Lartigau","year":"1997","journal-title":"Melanoma Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.immuni.2015.09.001","article-title":"Metabolic Reprogramming of Immune Cells in Cancer Progression","volume":"43","author":"Biswas","year":"2015","journal-title":"Immunity"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/nrc.2017.86","article-title":"Targeting immunosuppressive adenosine in cancer","volume":"17","author":"Vijayan","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"25602","DOI":"10.18632\/oncotarget.4693","article-title":"A non-canonical adenosinergic pathway led by CD38 in human melanoma cells induces suppression of T cell proliferation","volume":"6","author":"Morandi","year":"2015","journal-title":"Oncotarget"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1007\/s00262-014-1553-8","article-title":"Extracellular adenosine metabolism in immune cells in melanoma","volume":"63","author":"Umansky","year":"2014","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.coph.2016.04.001","article-title":"Immunosuppressive activities of adenosine in cancer","volume":"29","author":"Allard","year":"2016","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nature14011","article-title":"Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients","volume":"515","author":"Herbst","year":"2014","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"26659","DOI":"10.18632\/oncotarget.25426","article-title":"CD73 expression and clinical significance in human metastatic melanoma","volume":"9","author":"Monteiro","year":"2018","journal-title":"Oncotarget"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1158\/2326-6066.CIR-14-0018","article-title":"Inhibition of CD39 enzymatic function at the surface of tumor cells alleviates their immunosuppressive activity","volume":"3","author":"Bastid","year":"2015","journal-title":"Cancer Immunol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1172\/JCI0215337","article-title":"Ecto-5\u2032-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia","volume":"110","author":"Synnestvedt","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1111\/pcmr.12371","article-title":"Prognostic and predictive significance of immune cells infiltrating cutaneous melanoma","volume":"28","author":"Ladanyi","year":"2015","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_32","first-page":"7066","article-title":"Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer","volume":"62","author":"Kaanders","year":"2002","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0167-8140(97)01920-8","article-title":"Oxygen tension in human tumours measured with polarographic needle electrodes and its relationship to vascular density, necrosis and hypoxia","volume":"44","author":"Lyng","year":"1997","journal-title":"Radiother. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1089\/ars.2007.1628","article-title":"Detection and characterization of tumor hypoxia using pO2 histography","volume":"9","author":"Vaupel","year":"2007","journal-title":"Antioxid. Redox Signal."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Gaustad, J.V., Simonsen, T.G., Leinaas, M.N., and Rofstad, E.K. (2012). Sunitinib treatment does not improve blood supply but induces hypoxia in human melanoma xenografts. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-388"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Mihic-Probst, D., Ikenberg, K., Tinguely, M., Schraml, P., Behnke, S., Seifert, B., Civenni, G., Sommer, L., Moch, H., and Dummer, R. (2012). Tumor cell plasticity and angiogenesis in human melanomas. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033571"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s12253-017-0363-7","article-title":"Expression of Glut-1 in Malignant Melanoma and Melanocytic Nevi: An Immunohistochemical Study of 400 Cases","volume":"25","author":"Dura","year":"2019","journal-title":"Pathol. Oncol. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4719","DOI":"10.1158\/0008-5472.CAN-07-6339","article-title":"Lack of hypoxic response in uterine leiomyomas despite severe tissue hypoxia","volume":"68","author":"Mayer","year":"2008","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"32748","DOI":"10.18632\/oncotarget.4977","article-title":"Glucose transporter isoform 1 expression enhances metastasis of malignant melanoma cells","volume":"6","author":"Koch","year":"2015","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1593806","DOI":"10.1080\/2162402X.2019.1593806","article-title":"Prognostic value of tumor-infiltrating lymphocytes in melanoma: A systematic review and meta-analysis","volume":"8","author":"Fu","year":"2019","journal-title":"Oncoimmunology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5315","DOI":"10.1158\/1078-0432.CCR-18-3314","article-title":"Development and Validation of a Combined Hypoxia and Immune Prognostic Classifier for Head and Neck Cancer","volume":"25","author":"Brooks","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1002\/ijc.25543","article-title":"Warburg phenotype in renal cell carcinoma: High expression of glucose-transporter 1 (GLUT-1) correlates with low CD8(+) T-cell infiltration in the tumor","volume":"128","author":"Singer","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"277ra230","DOI":"10.1126\/scitranslmed.aaa1260","article-title":"Immunological mechanisms of the antitumor effects of supplemental oxygenation","volume":"7","author":"Hatfield","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Pilla, L., Alberti, A., Di Mauro, P., Gemelli, M., Cogliati, V., Cazzaniga, M.E., Bidoli, P., and Maccalli, C. (2020). Molecular and Immune Biomarkers for Cutaneous Melanoma: Current Status and Future Prospects. Cancers, 12.","DOI":"10.3390\/cancers12113456"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3447","DOI":"10.1172\/JCI87324","article-title":"Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma","volume":"126","author":"Daud","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e1071007","DOI":"10.1080\/2162402X.2015.1071007","article-title":"Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study","volume":"5","author":"Maccalli","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/s43018-019-0022-x","article-title":"Immune-awakening revealed by peripheral T cell dynamics after one cycle of immunotherapy","volume":"1","author":"Valpione","year":"2020","journal-title":"Nat. Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/nature13954","article-title":"PD-1 blockade induces responses by inhibiting adaptive immune resistance","volume":"515","author":"Tumeh","year":"2014","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nature21349","article-title":"Elements of cancer immunity and the cancer-immune set point","volume":"541","author":"Chen","year":"2017","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"981","DOI":"10.3109\/09553000903232843","article-title":"Solid tumours arising from differently pre-oxygenated cells: Comparable growth rates despite dissimilar tissue oxygenation","volume":"85","author":"Mayer","year":"2009","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"8738","DOI":"10.18632\/oncotarget.14434","article-title":"Prognostic impact of CD73 and A2A adenosine receptor expression in non-small-cell lung cancer","volume":"8","author":"Inoue","year":"2017","journal-title":"Oncotarget"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"813","DOI":"10.3389\/fimmu.2018.00813","article-title":"Controlling the Immune Suppressor: Transcription Factors and MicroRNAs Regulating CD73\/NT5E","volume":"9","author":"Kordass","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nature14404","article-title":"Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity","volume":"523","author":"Spranger","year":"2015","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e00506","DOI":"10.1002\/prp2.506","article-title":"Therapeutic potential of adenosine kinase inhibition-Revisited","volume":"7","author":"Jarvis","year":"2019","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1038\/bjc.2016.336","article-title":"Downregulation of EGFR in hypoxic, diffusion-limited areas of squamous cell carcinomas of the head and neck","volume":"115","author":"Mayer","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1369\/jhc.6A7134.2007","article-title":"Simultaneous visualization of multiple antigens with tyramide signal amplification using antibodies from the same species","volume":"55","author":"Toth","year":"2007","journal-title":"J. Histochem. Cytochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1158\/1078-0432.CCR-15-1507","article-title":"The Where, the When, and the How of Immune Monitoring for Cancer Immunotherapies in the Era of Checkpoint Inhibition","volume":"22","author":"Hegde","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_59","unstructured":"Gonciarz, K., Bankhead, P., Otto, M., Schmidberger, H., Sbalzarini, I.F., and Mayer, A. (2018, January 17\u201319). Spatial interaction analysis in QuPath using MOSAICsuite. Proceedings of the Jahrestagung der GBS, Frankfurt, Germany."},{"key":"ref_60","unstructured":"R Core Team (2018). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/12\/3753\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:44:35Z","timestamp":1760179475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/12\/3753"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,13]]},"references-count":60,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["cancers12123753"],"URL":"https:\/\/doi.org\/10.3390\/cancers12123753","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,13]]}}}