Presence of lymphocytic infiltrate cytotoxic T lymphocyte CD3+, CD8+, and immunoscore as prognostic marker in patients after radical cystectomy.

Tumor-Infiltrating Lymphocytes (TILs) has been shown to be essential to predict disease outcome in several types of cancers. Moreover, the distribution of cytotoxic T lymphocytes (CD8+) and T cells in general (CD3+) have been used to establish an Immunoscore, as a new cancer prognosticator for survival in colon and lung cancer. In bladder cancer, immune activation has been shown to be associated with genomic subtypes of muscle invasive bladder cancer (MIBC). We sought to evaluate the prognostic impact of these immune cell types in MIBC patients treated with radical cystectomy. For this purpose, cystectomy sections (n = 67) with identifiable invasive margin were selected and stained for CD8+ and CD3+ tumour infiltrating lymphocytes (TILs); both tumor core (CT) and invasive margin (IM) were assessed. Immunoscore was calculated based on previously defined criteria and used to illustrate differences in survival. High density of CD8IM TILs was associated with better disease-free (DFS) (P = 0.01) and overall survival (OS) (P = 0.02) whereas CD3IM TILs were associated with better OS (P = 0.05). Immunoscore was associated with improved DFS (P = 0.02) and OS (P = 0.05). The expression of cytotoxic T cells (CD8+ T cells) in TCGA bladder cancer was also investigated from RNA-Seq profiles of 344 cases. T cell cytotoxicity associated genes (n = 113) were derived from MSig GSEA database. Luminal (n = 121) and basal (n = 68) samples were used to evaluate expression differences. Differential expression (P<0.05) of cytotoxic T cell genes was noted across different molecular subsets of bladder cancer within TCGA analysis. Our data suggests host immune system appears to play a valuable prognostic role in MIBC.

Prognostic pathological factors in radical cystectomy after neoadjuvant chemotherapy.

AIMS: We undertook a systematic evaluation of the prognostic value of numerous histological factors in 165 radical cystectomies (RCs) of patients with invasive urothelial carcinoma (UC) who underwent surgery after neoadjuvant chemotherapy (NAC). METHODS AND RESULTS: Tumour regression grade (TRG) and therapy-related stromal and epithelial changes were also recorded. Locally advanced disease (≥pT2 and/or pN+) was present in 64% of patients, 22% had no evidence of residual carcinoma (pT0 + pN0), and 28% had no evidence of residual muscle-invasive carcinoma (≤pT1 + N0). TRG1, TRG2 and TRG3 were found in 32%, 15% and 50% of patients, respectively. Histological variants of UC were reported in 25% of cases. The most common therapy-related stromal change was fibroblastic reaction (78%), and the most common epithelial change in residual UC was smudgy and poorly preserved chromatin (28%). Prominent stromal and epithelial changes were noted in 41% and 5% of RCs, respectively. Progression was found in 45% of patients, and cancer-related deaths occurred in 30%. Multivariate analysis showed that the only independent prognostic parameters for progression were T stage, N stage, lymphovascular invasion, and margin status. Similarly, only T stage, N stage and margin status correlated with cancer-related deaths. Neither TRG nor any of the stromal-related or epithelial-related variables correlated with outcome. CONCLUSIONS: We confirm that the traditional and routinely reported histological parameters in RC post-NAC remain the most powerful prognosticators of disease course. The significance of TRG in the bladder remains unconfirmed.

A General Framework for Interrogation of mRNA Stability Programs Identifies RNA-Binding Proteins that Govern Cancer Transcriptomes.

Widespread remodeling of the transcriptome is a signature of cancer; however, little is known about the post-transcriptional regulatory factors, including RNA-binding proteins (RBPs) that regulate mRNA stability, and the extent to which RBPs contribute to cancer-associated pathways. Here, by modeling the global change in gene expression based on the effect of sequence-specific RBPs on mRNA stability, we show that RBP-mediated stability programs are recurrently deregulated in cancerous tissues. Particularly, we uncovered several RBPs that contribute to the abnormal transcriptome of renal cell carcinoma (RCC), including PCBP2, ESRP2, and MBNL2. Modulation of these proteins in cancer cell lines alters the expression of pathways that are central to the disease and highlights RBPs as driving master regulators of RCC transcriptome. This study presents a framework for the screening of RBP activities based on computational modeling of mRNA stability programs in cancer and highlights the role of post-transcriptional gene dysregulation in RCC.

Neoadjuvant chemotherapy-related histologic changes in radical cystectomy: assessment accuracy and prediction of response.

We evaluated the spectrum of histologic changes associated with neoadjuvant chemotherapy (NAC) and compared them with those resulting from transurethral resection (TUR). Twenty-five patients who received NAC were divided based on both their preoperative clinical/radiographic findings (clinical stage, hydronephrosis, palpable mass) and the cystectomy (RC) findings into NAC respondents (advanced clinical stage and