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BC and UTUC are characterized by distinct phenotypical and genotypical features as well as specific gene- and protein- expression profiles, which result in a diverse natural history of the tumor. With respect to BC, UTUC tends to be diagnosed in a later stage and displays poorer clinical outcome. In the present review, we seek to highlight the individuality of UTUC from a biological, immunological, genetic-molecular, and clinical standpoint, also reporting the most recent evidence on UTUC treatment. In this regard, while the role of surgery in nonmetastatic UTUC is undebated, solid data on adjuvant or neoadjuvant chemotherapy are still an unmet need, not permitting a definite paradigm shift in the standard treatment. In advanced setting, evidence is mainly based on BC literature and retrospective studies and confirms platinum-based combination regimens as bedrock of first-line treatment. Recently, immunotherapy and target therapy are gaining a foothold in the treatment of metastatic disease, with pembrolizumab and atezolizumab showing encouraging results in combination with chemotherapy as a first-line strategy. Moreover, atezolizumab performed well as a maintenance treatment, while pembrolizumab as a single agent achieved promising outcomes in second-line setting. Regarding the target therapy, erdafitinib, a fibroblast growth factor receptor inhibitor, and enfortumab vedotin, an antibody-drug conjugate, proved to have a strong antitumor property, likely due to the distinctive immune-genetic background of UTUC. In this context, great efforts have been addressed to uncover the biological, immunological, and clinical grounds in UTUC patients in order to achieve a personalized treatment.<\/jats:p>","DOI":"10.1177\/15330338231159753","type":"journal-article","created":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T02:35:13Z","timestamp":1677638113000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Upper Tract Urinary Carcinoma: A Unique Immuno-Molecular Entity and a Clinical Challenge in the Current Therapeutic Scenario"],"prefix":"10.1177","volume":"22","author":[{"given":"Giulia","family":"Mazzaschi","sequence":"first","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8541-1655","authenticated-orcid":false,"given":"Giulia Claire","family":"Giudice","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matilde","family":"Corian\u00f2","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2072-114X","authenticated-orcid":false,"given":"Davide","family":"Campobasso","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospital of Parma, Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Perrone","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Maffezzoli","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Testi","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Isella","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umberto","family":"Maestroni","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospital of Parma, Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Buti","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, University Hospital of Parma, Parma, Italy"},{"name":"Department of Medicine and Surgery, University of Parma, Parma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2023,2,28]]},"reference":[{"key":"bibr1-15330338231159753","unstructured":"Kidney and Renal Pelvis Cancer \u2014 Cancer Stat Facts. https:\/\/seer.cancer.gov\/statfacts\/html\/kidrp.html. 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