scholarly journals Immune Cell-Associated Protein Expression Helps to Predict Survival in Muscle-Invasive Urothelial Bladder Cancer Patients after Radical Cystectomy and Optional Adjuvant Chemotherapy

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 159
Author(s):  
Helge Taubert ◽  
Markus Eckstein ◽  
Elena Epple ◽  
Rudolf Jung ◽  
Katrin Weigelt ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Immune Cell ◽  
Tumor Stage ◽  
Immune Markers ◽  
Nodal Stage ◽  
Macrophage Marker ◽  
Muscle Invasive ◽  
Marker Cluster ◽  
Cluster Of Differentiation ◽  
Low Expression

Bladder cancer (BCa) is the tenth most commonly diagnosed malignant cancer worldwide. Although adjuvant chemotherapy following radical cystectomy is a common therapy for muscle invasive bladder cancer patients, no applicable biomarkers exist to predict which patients will benefit from chemotherapy. In this study, we examined three immune cell markers, the chemokine CC motif ligand 2 (CCL2), the pan macrophage marker cluster of differentiation 68 (CD68) and the M2 macrophage marker cluster of differentiation 163 (CD163), using immunohistochemistry to determine their predictive value for the chemotherapy response in different nodal stage (pN0 vs. pN1 + 2) and tumor stage subgroups (pT2 vs. pT3 + 4). The prognosis was studied in terms of the overall survival (OS), disease-specific survival (DSS), and recurrence-free-survival (RFS) in 168 muscle invasive BCa patients. Chemotherapy was associated with a poorer prognosis in patients with a higher expression of the immune markers CCL2 (RFS), CD68 (DSS and RFS), and CD163 (DSS and RFS) in the N0 group and with poorer survival in patients with a higher expression of the immune markers CCL2 (OS, DSS, and RFS), CD68 (OS, DSS, and RFS), and CD163 (OS, DSS, and RFS) in the pT2 group when compared with treatments without chemotherapy. In contrast, chemotherapy was associated with a better prognosis in patients with a low expression of the immune markers CCL2 (DSS and RFS), CD68 (OS, DSS, and RFS), and CD163 (OS) in the N1 + 2 group. In addition, chemotherapy was associated with improved survival in patients with a low expression of the immune marker CD68 (OS and DSS) and there was a trend for a better prognosis in patients with a low expression of CD163 (OS) in the pT3 + 4 group compared to patients not treated with chemotherapy. Interestingly, CD68 appeared to be the most applicable immune marker to stratify patients by the outcome of chemotherapy in the nodal stage and tumor stage groups. Overall, we suggest that, in addition to the clinical factors of tumor stage and nodal stage, it is also meaningful to consider the abundance of immune cells, such as macrophages, to better predict the response to chemotherapy for BCa patients after radical treatment.

scholarly journals High Apelin Level Indicates a Poor Prognostic Factor in Muscle-Invasive Bladder Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Long Yang ◽  
Yan-Lei Li ◽  
Xiao-Qing Li ◽  
Zheng Zhang
Keyword(s):  
Bladder Cancer ◽  
Cancer Patients ◽  
Vascular Invasion ◽  
Tumor Stage ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Kaplan Meier ◽  
Tumor Tissues ◽  
High Tumor Stage ◽  
Muscle Invasive

Purpose. To compare the expression level of apelin in muscle-invasive bladder cancer and matched paracarcinoma tissues and investigate the relationship between apelin and clinical prognosis in the patients. Methods. To assess apelin expression by using immunohistochemical method compared with bladder tumors and matched paracarcinoma tissues. Subsequently, the correlation of apelin expression with the clinicopathological features of bladder cancer patients was analyzed. Kaplan-Meier survival curves method was used to analyze apelin prognostic significance for muscle-invasive bladder cancer patients (including 404 muscle-invasive bladder cancer patients and 28 normal bladder tissues, in TCGA dataset). Results. Apelin protein level was overexpressed in bladder tumor tissues compared with paracarcinoma tissues. Furthermore, high apelin expression was associated with high tumor stage (P<0.05), distant metastasis (P<0.05), and vascular invasion (P<0.05). Kaplan-Meier curve analyses showed that the overexpression of apelin was a potential predictor of overall survival and disease-free survival. Conclusion. Apelin was upregulated in bladder tumor tissues compared with matched adjacent noncancer tissues, especially in the high tumor stage, distant metastasis, and vascular invasion. What is more, high expression of apelin in muscle-invasive bladder cancer indicates the poor prognosis. These data suggested that apelin might be a therapeutic potential biomarker in muscle-invasive bladder cancer patients.

Tumor Subtyping: Making Sense of Heterogeneity with a Goal Toward Treatment

2020 ◽  
pp. 1-11
Author(s):  
Joshua J. Meeks ◽  
Gottfrid Sjödahl ◽  
Seth P. Lerner ◽  
Arighno Das ◽  
David J. McConkey ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Immune Cell ◽  
Response To Therapy ◽  
Genomic Diversity ◽  
Intrinsic Resistance ◽  
Making Sense ◽  
Search Terms ◽  
Muscle Invasive ◽  
Next Generation Sequencing Ngs ◽  
Descriptive Feature

BACKGROUND: Bladder cancers have high total mutation burdens resulting in genomic diversity and intra- and inter-tumor heterogeneity that may impact the diversity of gene expression, biologic aggressiveness, and potentially response to therapy. To compare bladder cancers among patients, an organizational structure is necessary that describes the tumor at the histologic and molecular level. These “molecular subtypes”, or “expression subtypes” of bladder cancer were originally described in 2010 and continue to evolve secondary to next generation sequencing (NGS) and an increasing public repository of well-annotated cohorts. OBJECTIVE: To review the history and methodology of expression-based subtyping of non-muscle invasive (NMIBC) and muscle invasive bladder cancer (MIBC). METHODS: A literature review was performed of primary papers from PubMed that described subtyping methods and their descriptive feature including search terms of “subtype”, and “bladder cancer”. RESULTS: 21 papers were identified for review. Tumor subtyping developed from N = 2 to N = 6 subtyping schemes with most subtypes comprised of at least luminal and basal tumors. Most NMIBCs are luminal cancers and luminal MIBCs may be associated with less aggressive features, while one study of basal tumors identified a better clinical outcome with systemic chemotherapy. Tumors with a 53-like signature may have intrinsic resistance to chemotherapy. The heterogeneity of tumors, which is likely derived from stromal components and immune cell infiltration, affect subtype calls. CONCLUSION: Subtyping, while still evolving, is ready for testing in clinical trials. Improved patient selection with tumor subtyping may help with tumor classification and potentially match patient or tumor to therapy.

scholarly journals Analysis of CXCL9, PD1 and PD-L1 mRNA in Stage T1 Non-Muscle Invasive Bladder Cancer and Their Association with Prognosis

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2794 ◽  
Author(s):  
Jennifer Kubon ◽  
Danijel Sikic ◽  
Markus Eckstein ◽  
Veronika Weyerer ◽  
Robert Stöhr ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Regression Analysis ◽  
Prognostic Factor ◽  
Patient Group ◽  
Independent Prognostic Factor ◽  
Invasive Bladder Cancer ◽  
Immune Markers ◽  
Muscle Invasive Bladder Cancer ◽  
Cox's Regression ◽  
Muscle Invasive

Non-muscle invasive bladder cancer (NMIBC), which is characterized by a recurrence rate of approximately 30% and very long treatment times, remains a major unresolved problem for patients and the health care system. The immunological interplay between tumor cells and the immune environment is important for tumor development. Therefore, we analyzed the mRNA of three immune markers, CXCL9, PD1 and PD-L1, in NMIBC by qRT-PCR. The results were subsequently correlated with clinicopathological parameters and prognostic data. Altogether, as expected, higher age was an independent prognostic factor for overall survival (OS) and disease-specific survival (DSS), but not for recurrence-free survival (RFS). Lower CXCL9 mRNA was observed in multivariate Cox’s regression analysis to be an independent prognostic parameter for reduced OS (relative risk; RR = 2.08; p = 0.049), DSS (RR = 4.49; p = 0.006) and RFS (RR = 2.69; p = 0.005). In addition, PD-L1 mRNA was an independent prognostic factor for DSS (RR = 5.02; p = 0.042) and RFS (RR = 2.07; p = 0.044). Moreover, in univariate Cox’s regression analysis, the stratification of patients revealed that low CXCL9 or low PD1 mRNA was associated with reduced RFS in the younger patient group (≤71 years), but not in the older patient group (>71 years). In addition, low CXCL9 or low PD-L1 was associated with shorter RFS in patients with higher tumor cell proliferation and in patients without instillation therapy. In conclusion, the characterization of mRNA levels of immune markers differentiates NIMBC patients with respect to prognosis.

scholarly journals RNA Expression of DNA Damage Response Genes in Muscle-Invasive Bladder Cancer: Influence on Outcome and Response to Adjuvant Cisplatin-Based Chemotherapy

2021 ◽  
Vol 22 (8) ◽  
pp. 4188
Author(s):  
Jonas Herrmann ◽  
Helena Schmidt ◽  
Katja Nitschke ◽  
Cleo-Aron Weis ◽  
Philipp Nuhn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Bladder Cancer ◽  
Dna Damage Response ◽  
Invasive Bladder Cancer ◽  
Rna Expression ◽  
Muscle Invasive Bladder Cancer ◽  
Damage Response ◽  
Muscle Invasive ◽  
Low Expression

Background: Perioperative cisplatin-based chemotherapy (CBC) can improve the outcome of patients with muscle-invasive bladder cancer (MIBC), but it is still to be defined which patients benefit. Mutations in DNA damage response genes (DDRG) can predict the response to CBC. The value of DDRG expression as a marker of CBC treatment effect remains unclear. Material and methods: RNA expression of the nine key DDRG (BCL2, BRCA1, BRCA2, ERCC2, ERCC6, FOXM1, RAD50, RAD51, and RAD52) was assessed by qRT-PCR in a cohort of 61 MICB patients (median age 66 y, 48 males, 13 females) who underwent radical cystectomy in a tertiary care center. The results were validated in the The Cancer Genome Atlas (TCGA) cohort of MIBC (n = 383). Gene expression was correlated with disease-free survival (DFS) and overall survival (OS). Subgroup analyses were performed in patients who received adjuvant cisplatin-based chemotherapy (ACBC) (Mannheim n = 20 and TCGA n = 75). Results: Low expression of RAD52 was associated with low DFS in both the Mannheim and the TCGA cohorts (Mannheim: p = 0.039; TCGA: p = 0.017). This was especially apparent in subgroups treated with ACBC (Mannheim: p = 0.0059; TCGA: p = 0.012). Several other genes showed an influence on DFS in the Mannheim cohort (BRCA2, ERCC2, FOXM1) where low expression was associated with poor DFS (p < 0.05 for all). This finding was not fully supported by the data in the TCGA cohort, where high expression of FOXM1 and BRCA2 correlated with poor DFS. Conclusion: Low expression of RAD52 correlated with decreased DFS in the Mannheim and the TCGA cohort. This effect was especially pronounced in the subset of patients who received ACBC, making it a promising indicator for response to ACBC on the level of gene expression.

scholarly journals An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sia Viborg Lindskrog ◽  
Frederik Prip ◽  
Philippe Lamy ◽  
Ann Taber ◽  
Clarice S. Groeneveld ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Chromosomal Instability ◽  
Prognostic Value ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Invasive Bladder Cancer ◽  
Immune Cell Infiltration ◽  
Muscle Invasive Bladder Cancer ◽  
Omics Analysis ◽  
Muscle Invasive

AbstractThe molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

scholarly journals Antibody Targeting of B7-H4 Enhances the Immune Response in Urothelial Carcinoma

2019 ◽  
Author(s):  
Joseph R. Podojil ◽  
Alexander P. Glaser ◽  
Dylan Baker ◽  
Elise T. Courtois ◽  
Damiano Fantini ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cell ◽  
Urothelial Carcinoma ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Locally Advanced ◽  
Human Monocyte ◽  
Tumor Stage ◽  
Immune Checkpoints ◽  
Ifn Γ

AbstractLocally advanced urothelial carcinoma has a poor survival despite a response to immunotherapy in approximately 25% of patients. To develop new therapies targeting other immune checkpoints, we identified increased expression of the T cell inhibitor protein, B7-H4 (VTCN1, B7S1, B7X), during tumor development of murine bladder cancer. Evaluation of B7-H4 in human bladder cancer by single-cell RNA-Seq and immune mass cytometry showed that B7-H4 is expressed by luminal tumors that are not normally responsive to PD-1 inhibitors. Additionally, overexpression B7-H4 was associated with significantly worse patient survival. In support of clinical translation, treatment of human monocyte and T cell co-cultures with a B7-H4 blocking antibody resulted in enhanced IFN-γ secretion by CD4+ and CD8+ T cell. While the study of B7-H4 in mouse cancer models has been difficult using tumor cell lines, our findings show that B7-H4 expression increased at 3 months after exposure to BBN on CD11b+ monocytes/macrophages and delivery of anti-B7-H4 antibody resulted in decreased tumor size and increased CD8 immune cell infiltration with increased CD8+/IFN-γ-producing T cells and a complimentary decrease in tumor infiltrating T regulatory cells (Tregs). Furthermore, treatment with a combination of anti-PD-1 and anti-B7-H4 antibodies resulted in a significant reduction in tumor stage. This data suggests that novel anti-B7-H4 antibodies maybe a viable target for bladder cancers unresponsive to PD-1 checkpoint inhibitors.

Bladder cancer in young adults: Disease and treatment characteristics of patients treated at tertiary cancer center.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16521-e16521
Author(s):  
Ramiz Ahmad Abu-Hijlih ◽  
Samer Salah ◽  
Akram Al-Ibraheem ◽  
Fawzi Abuhijla ◽  
Hashem Abu Serhan ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Urinary Bladder ◽  
Metastatic Disease ◽  
Locally Advanced ◽  
High Volume ◽  
Tumor Stage ◽  
Best Supportive Care ◽  
Cancer Center ◽  
Young Population ◽  
Muscle Invasive

e16521 Background: The incidence of bladder cancer in the Middle East is increasing. The data on young population with urothelial carcinoma (UC) of urinary bladder in the region is scarce. We evaluated clinical and tumor characteristics, in addition to management details in patients younger than 45 years old. Methods: We reviewed of all patients presenting with UC of the urinary bladder from July 2006 to December 2019. Clinical characteristics including demographics, stage at presentation, and treatment outcomes were described. Results: Out of 1,272 new cases of bladder cancer, a total of 112 patients (8.8%) were ≤45 years old. Seven patients (6%) had non-urothelial histology and were excluded. The remaining 105 eligible patients with UC had a median age at presentation was 41 years (35-43). Ninety three patients (88.6%) were males. Tumor stage at presentation: non-muscle invasive disease (Ta-T1), locally advanced muscle invasive bladder cancer (MIBC) (T2-3), and metastatic disease were 14 cases (84.7%), 2.8%, and 12.5%, respectively. All patients with MIBC received neoadjuvant cisplatin-based chemotherapy. Radical cystectomy was performed in 8 cases (7.6%); 3 patients with MIBC and 5 with high volume non-MIBC. Neobladder reconstruction was done in 6 patients. A total of 13 patients with metastatic disease (93%) received palliative chemotherapy (Gemcitabine/Cisplatin), and one (7%) was candidate of best supportive care only. Conclusions: Bladder cancer is relatively rare in young population, though the incidence at our region is higher than other reports in the literature. Most of patients present with early disease. Early diagnosis and multidisciplinary approach are paramount for management of these patients.

scholarly journals An integrated multi-omics analysis identifies clinically relevant molecular subtypes of non-muscle-invasive bladder cancer

2020 ◽  
Author(s):  
Sia Viborg Lindskrog ◽  
Frederik F. Prip ◽  
Philippe Lamy ◽  
Ann Taber ◽  
Clarice S. Groeneveld ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Chromosomal Instability ◽  
Prognostic Value ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Invasive Bladder Cancer ◽  
Immune Cell Infiltration ◽  
Muscle Invasive Bladder Cancer ◽  
Omics Analysis ◽  
Muscle Invasive

AbstractThe molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we performed a large integrative multi-omics analysis of patients diagnosed with NMIBC (n=834). Transcriptomic analysis identified four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provided independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations were significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration was associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirmed the higher infiltration of class 2b tumors and demonstrated an association between higher immune cell infiltration and lower recurrence rates. Finally, a single-sample classification tool was built and the independent prognostic value of the transcriptomic classes was documented in 1306 validation samples. The classifier provides a framework for novel biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

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