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Background: Urothelial bladder cancers (UBCs) are distinct in two main molecular subtypes, namely basal and luminal type. Subtypes are also diverse in term of immune contexture, providing a rationale for patient selection to immunotherapy. Methods: By digital microscopy analysis of a muscle-invasive BC (MIBC) cohort, we explored the density and clinical significance of CD66b+ tumor-associated-neutrophils (TAN) and CD3+ T cells. Bioinformatics analysis of UBC datasets and gene expression analysis of UBC cell lines were additionally performed. Results: Basal type BC contained a significantly higher density of CD66b+ TAN compared to the luminal type. This finding was validated on TCGA, GSE32894 and GSE124305 datasets by computing a neutrophil signature. Of note, basal-type MIBC display a significantly higher level of chemokines (CKs) attracting neutrophils. Moreover, pro-inflammatory stimuli significantly up-regulate CXCL1, CXCL2 and CXCL8 in 5637 and RT4 UBC cell lines and induce neutrophil chemotaxis. In term of survival, a high density of T cells and TAN was significantly associated to a better outcome, with TAN density showing a more limited statistical power and following a non-linear predicting model. Conclusions: TAN are recruited in basal type MIBC by pro-inflammatory CKs. This finding establishes a groundwork for a better understanding of the UBC immunity and its relevance. [ABSTRACT FROM AUTHOR]

Urothelial bladder cancer (UBC) are classified into luminal and basal subtypes showing distinct molecular features and clinical behaviour. Recent in silico data have proposed the activation on the Signal Transducer and Activator of Transcription 3 (STAT3) as relevant transcription factor in UBC. To answer this question, we have combined the retrospective analysis of clinical samples, functional assays on cell lines, interrogation of public UBC datasets and a murine model of basal-type UBC. Immunohistochemistry on a retrospective UBC cohort uncovered that STAT3 Y705 phosphorylation (pSTAT3) is significantly increased in infiltrating basal-type UBC compared to luminal UBC. In vitro, STAT3 silencing in UBC cell lines significantly reduced tumor cell viability and invasion. Gene expression profile of UBC cell lines combined with the analysis of the Cancer Genome Atlas (TCGA) and GSE32894 UBC datasets showed that increased expression of a set of STAT3 targets predicts basal-type, propensity to local progression and worse prognosis. MYC and FOSL1 represent relevant STAT3 downstream targets, as validated by their co-localization in pSTAT3+ UBC cancer cells. These findings were largely reproduced in the BBN-induced murine model of basal-type UBC. Of note, FOSL1 protein resulted strongly expressed in the non-papillary UBC pathway and FOSL1-regulated transcripts were significantly enriched in the transition from NMIBC to MIBC, as indicated by the interrogation of the GSE32894 dataset. The blockade of the STAT3 pathway might represent a novel treatment option for these neoplasms. Monitoring pSTAT3 and the downstream targets, particularly FOSL1, could provide meaningful levels of UBC stratification. [ABSTRACT FROM AUTHOR]

Background: According to International Guidelines radical cystectomy (RC) should not be delayed over 90 days to prevent the risk of intercurrent progression and worse survival. Nevertheless, such a recommendation relies on a few retrospective studies reaching non-univocal conclusions. Aim of the present study was to investigate if the latency between diagnosis and cystectomy (LDC) is related to prognosis after RC., Methods: Retrospective analysis of database collecting complete information on patients undergone RC at single institution since 2004. The cases with an LDC <15 or >360 days or submitted to neo-adjuvant chemotherapy or with distant metastasis were excluded. Uni- and multivariate analyses assessed the relationship between LDC upstaging, progression-free and overall survival., Results: The data of 376 patients were analyzed; mean/median LDC was 83/76 days and 124 patients (33%) had LDC>90 days. LDC was shorter in younger patients with first diagnosis of more advanced BC at clinical staging; accordingly, patients with LDC<90 days had more advanced disease also at final pathology. Prevalence of pathological upstaging was 37%; in case of upstaging LDC was 75 days vs. 72 days (P=0.4629). Multivariable regression models adjusted for pathological local and lymph nodal stage showed that LDC, continuous or dichotomized at 30/60/90/120/180/240 days was not related to progression-free or overall survival. The retrospective design of study is the main limitation of the study., Conclusions: In our experience nor the risk of upstaging, neither survival after RC were related to LDC. Even if these results should not discourage any effort to perform surgery expeditiously, the window of opportunity for RC might not be delimited by a predetermined threshold.