Age and sex have no impact on expression levels of markers of immune cell infiltration and immune checkpoint pathways in patients with muscle-invasive urothelial carcinoma of the bladder treated with radical cystectomy

2019 ◽  
Vol 68 (6) ◽  
pp. 991-997 ◽  
Author(s):  
Bradley C. Holland ◽  
Akshay Sood ◽  
Kristin Delfino ◽  
Danuta I. Dynda ◽  
Sophia Ran ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Radical Cystectomy ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Expression Levels ◽  
Carcinoma Of The Bladder ◽  
Muscle Invasive ◽  
Age And Sex

Contemporary utilization trends and survival outcomes in patients undergoing radical cystectomy and bladder preservation therapy for muscle invasive bladder cancer.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 387-387
Author(s):  
David Cahn ◽  
Elizabeth Handorf ◽  
Michael Nordsiek ◽  
Thomas M. Churilla ◽  
Eric M. Horwitz ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Radical Cystectomy ◽  
Selection Criteria ◽  
Cox Regression ◽  
External Beam Radiotherapy ◽  
Stage Ii ◽  
Bladder Preservation ◽  
Carcinoma Of The Bladder ◽  
Muscle Invasive

387 Background: To compare overall survival (OS) in patients undergoing radical cystectomy (RC) and bladder preservation therapy (BPT) for muscle invasive urothelial carcinoma of the bladder. Methods: We conducted a retrospective, observational cohort study in which we reviewed the National Cancer Database (NCDB) to identify patients with analytic stage II-III (N0M0) urothelial carcinoma of the bladder from 2003-2011. BPT patients were stratified as any external beam radiotherapy (EBRT), definitive radiotherapy (RT) [50-80Gy], and definitive RT + chemotherapy. Treatment trends were evaluated using Pearson Chi-square tests. OS was compared between RC and BPT using unadjusted Kaplan Meier curves and Cox regression models adjusted for year of treatment, hospital volume, and patient/tumor characteristics using increasingly stringent selection criteria to identify those undergoing BPT. Results: Of the 603,298 patients with bladder cancer captured in the NCDB from 2003-2011, 9% (n = 54,518) had analytic stage II-III with urothelial histology. 51.1% (n = 27,843) of these patients were treated with RC (70.9%, n = 19,745) or BPT (29.1%, n = 8,098). Of the patients undergoing BPT, stratified by selection criteria, 26.9% (n = 2,176) and 15.0% (n = 1,215) were treated with definitive RT and definitive RT + chemotherapy, respectively. Following adjustment, improved survival in patients undergoing RC was noted regardless of BPT definition employed in multivariate analysis. However, we noted attenuated differences in OS using increasingly stringent definitions for BPT (EBRT: HR 2.2 [CI 2.15-2.29]; definitive RT: HR 1.94 [CI 1.74-2.14]; definitive RT + chemotherapy: HR 1.56 [CI 1.45-1.68]). Conclusions: In the NCDB, receipt of BPT was associated with decreased OS compared to RC in all patients with stage II-III urothelial carcinoma, in part due to selection biases. However, the use of increasingly stringent definitions of BPT attenuated the observed survival differences. Further randomized prospective controlled trials are needed to compare trimodal BPT to RC to identify optimal candidates for bladder preservation.

Surgical outcome of pre-operative atezolizumab before radical cystectomy for muscle-invasive urothelial carcinoma of the bladder

2019 ◽  
Vol 18 (1) ◽  
pp. e1516
Author(s):  
B. Szabados ◽  
I. Duran ◽  
S.J. Crabb ◽  
M.S. Van Der Heijden ◽  
A. Font Pous ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Radical Cystectomy ◽  
Surgical Outcome ◽  
Carcinoma Of The Bladder ◽  
Muscle Invasive

scholarly journals Novel mechanism in cardiac injury: immune checkpoints

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E.M Screever ◽  
M.L Axelrod ◽  
M.A Blair ◽  
D.Z Trykall ◽  
J.V Barnett ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Troponin I ◽  
Immune Cell ◽  
Cardiac Injury ◽  
Cell Infiltration ◽  
Immune Checkpoints ◽  
Funding Source ◽  
Immune Cell Infiltration ◽  
Isolated Cardiomyocytes

Abstract Background Immune checkpoint inhibitors (ICI), specifically directed against CTLA-4 and PD-1, have revolutionized cancer therapy but are associated with immune-related adverse events, including fulminant myocarditis. The mechanisms are unknown, but one possibility is that CTLA-4 and PD-1 play a critical role in cardiovascular homeostasis. Purpose The purpose of this study is to investigate the role of these immune checkpoints in cardiac injury. We hypothesize that cardiomyocytes can express immune checkpoint ligands in response to stress and that CTLA-4 and/or PD-1 play a key role in cardiac response to injury. Methods We measured expression levels of CTLA-4 ligands (Cd80, Cd86) and PD-1 ligands (Pdcdl1, Pdcdl2) in in vitro and in vivo models of cardiac injury, including iPSC-derived cardiomyocytes (iPSC-CM) and diseased human cardiac samples. Immunofluorescent staining and multiplex immunohistochemistry were used to derive more granular data on cell type expressing specific immune checkpoint associated proteins. To determine the functional role of CTLA-4 and PD-1 in cardiac injury, myocardial infarction (MI) was induced in C57Bl/6 mice treated with anti-CTLA-4 or in mice with a genetic knock-out of CTLA-4 and PD-1 (Pdcd1−/−Ctla4+/+ and Pdcd1−/−Ctla4+/−). Flow cytometry was performed 2-days post-MI to determine immune cell infiltration, echocardiography was performed 7-days and 28-days post-MI and plasma samples were analyzed for ANP and Troponin I. Results Doxorubicin or hypoxia increased expression of Cd80, Cd86, Pdcdl1 and Pdcdl2 in iPSC-CM. After MI, isolated cardiomyocytes from the ischemic/border zone area yielded significant increased expression of both Cd80 and Cd86, which was confirmed at the protein level. However, pharmacologic inhibition of CTLA-4 during MI resulted in better survival compared to no treatment (p<0.007). No differences were seen in immune cell infiltration, troponin I and ANP levels and echocardiography. Pdcd1−/-Ctla4+/+ and Pdcd1−/−Ctla4+/− mice showed a decrease in immune cell infiltration. Conclusions Whole hearts, isolated cardiomyocytes and iPSC-CM from both mice and humans express immune checkpoint ligands in response to cardiac injury. Pharmacologic or genetic inhibition of CTLA-4 and PD-1 in MI did not result in adverse effects regarding survival, cardiac function, immune cell infiltration and heart enzyme levels in mice. These data support the hypothesis that immune checkpoint pathways play a role in cardiac injury and in these preliminary studies immune checkpoint inhibition during cardiac ischemic injury did not result in adverse effects. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health grants R56 HL141466 and R01 HL141466

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 Transcriptional expression of ZICs as an independent indicator of survival in gliomas

2020 ◽  
Author(s):  
Zhao cheng Han ◽  
Jingnan Jia ◽  
Yangting Lv ◽  
Rongyanqi Wang ◽  
Kegang Cao
Keyword(s):  
Immune Cell ◽  
Cox Regression ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
Cell Infiltration ◽  
Low Grade ◽  
Immune Cell Infiltration ◽  
Expression Levels ◽  
Ppi Networks

Abstract Background: The functional significance of the zinc-finger of the cerebellum (ZIC) gene family in gliomas remains to be elucidated. Methods: Clinical data from patients with gliomas, containing expression levels of ZIC genes, were extracted from CCLE, GEPIA2 and The Human Protein Atlas(HPA). Univariate survival analysis adjusted by Cox regression via OncoLnc was used to determine the prognostic significance of ZIC expression. We used cBioPortal to explore the correlation between gene mutations and overall survival (OS). ZIC expression was found to be related to immune cell infiltration in gliomas via TIMER analysis. GO term and KEGG pathway enrichment analyses were performed with Metascape. PPI networks were constructed using STRING. Result: The expression levels of ZIC1/2/4 in gliomas were significantly different from those in normal samples. High expression levels of ZIC1/2/5 were associated with poor OS in brain low-grade glioma (LGG) patients, while low ZIC3 expression combined with high ZIC4 expression was related to favourable OS in glioblastoma multiforme (GBM). ZIC mutations were associated with poor prognosis in LGG patients and related to favourable prognosis in GBM patients. We observed that the expression of ZICs was related to immune cell infiltration in glioma patients. ZICs were enriched in several pathways and biological processes involving arrhythmogenic right ventricular cardiomyopathy (ARVC) and tissue morphogenesis. The PPI network revealed that some coexpressed proteins of ZICs played a role in the pathogenesis of gliomas. Conclusions: Differences in the expression levels of ZIC genes could provide a significant marker for predicting prognosis in gliomas.

scholarly journals C3aR1 Correlates With Immune Cell Infiltration and Serves as Prognostic and Therapeutic Biomarker in Gastric Cancer

2021 ◽  
Author(s):  
weifeng liu ◽  
Zhijie Chu ◽  
Cheng Yang ◽  
Tianbao Yang ◽  
Yanhui Yang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cell ◽  
Differentially Expressed Genes ◽  
Tumor Tissue ◽  
Immune Cell ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Expression Levels

Abstract As the fourth most common malignancy worldwide, gastric cancer can lead more than 720 000 patient death every year. Precisely therapeutic intervention can significantly improve patients’ survival status underlying the precise clarification by molecular indexes. Identifying the biomarkers highly associated with disease prognosis will be helpful to guide the clinical therapy. C3ar1 is an essential receptor in the complement system, and participates in various biological processes associated with immunological responses. To identify the crucial roles of C3AR1 in gastric cancer tmorigenesis, we determined the mRNA profile, protein expression levels and the clinicopathological indexes using cBioportal, Kaplan-Meier plotter and the Human Protein Atlas databases. To identify the molecular network in C3AR1-expressed gastric cancer, we obtained the differentially expressed genes using the GEPIA database compared with normal stomach tissues. Furthermore, we analyzed the biological impact of these differentially expressed genes using protein-protein interaction network and gene set enrichment analysis, in which we identified the hub genes and critical pathways influenced by over-expressed C3AR1 in gastric cancer. Finally, we evaluated the correlation between the C3AR1 expression levels and immune cell infiltration levels utilizing the Tumor Immunoassay Resource database. Our results revealed that the higher expression level of C3AR1 can lead higher infiltration of T cell CD8+, T cell CD4+, macrophage, neutrophil, B cell and myeloid dendritic cells into tumor tissue. Moreover, we also found that higher infiltration of macrophage cells into tumor tissue can worsen the survival of patients with gastric cancer, which may be highly associated with the polarization states of macrophages (TAM and M2 status). Our investigation suggest that C3AR1 can be as an efficient diagnostic biomarkers for gastric cancer therapy.

scholarly journals Ferroptosis Regulators and Tumor Microenvironment Immune Cell Infiltration Characterization in Adrenocortical Carcinoma

2022 ◽  
Author(s):  
Chengquan Shen ◽  
Jing Liu ◽  
Ye Liang ◽  
Zhijuan Liang ◽  
Liping Wang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Signaling Pathway ◽  
Immune Checkpoint ◽  
Adrenocortical Carcinoma ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Genes Expression ◽  
Receptor Signaling Pathway ◽  
Checkpoint Genes

Abstract Background Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and lacking effective systemic treatment options. Recent studies showed that ferroptosis play a prominent role in the initiation and development of cancer. Nonetheless, the potential roles of ferroptosis regulators in the prognosis and tumor microenvironment immunomodulator factors expression remain not fully study. Methods TCGA and GEO ACC datasets were used to investigate the relationship between ferroptosis regulators with prognosis and clinical features. Consensus clustering analysis was performed to divided ACC patients into different ferroptosis subgroups. A ferroptosis scoring system was established for individual ACC using principal component analysis algorithms. The correlation between ferroptosis score and tumor microenvironment immune cell infiltration was analyzed. Results Twenty ferroptosis regulators were differentially expressed in ACC and 17 ferroptosis regulators were closely related to the prognosis of ACC. Three ferroptosis subgroups (Cluster A, B, and C) were determined based on the expression of ferroptosis regulators. Cluster C is preferentially associated with favorable OS, PFS, upregulated antigen-presenting genes expression, and higher immune cell infiltration. GSEA also indicated that Cluster C was prominently related to immune fully activation including chemokine signaling pathway, natural killer cell-mediated cytotoxicity, T cell receptor signaling pathway, and Toll-like receptor signaling pathway. A ferroptosis scoring system was constructed and it could serve as an independent prognostic factor for ACC. The ferroptosis scores were significantly correlated with TMB, immune-checkpoint genes expression, and tumor microenvironment immune cell infiltration in ACC. Further analyses indicated that the ferroptosis score integrated with TMB, immune-checkpoint genes expression, and CD4+ T cell infiltration, could predict the prognosis of ACC. Furthermore, a nomogram was constructed to monitor the prognosis of individual ACC patient. RNA isolation and reverse transcription‑quantitative PCR (RT-qPCR) demonstrated significant differences in the expression levels of ACSL4, FANCD2 and SLC7A1 between ACC and normal tissues. Conclusion Our study demonstrated ferroptosis regulators were significantly associated with the prognosis, clinical characteristics, immune-checkpoint genes expression, and tumor microenvironment immune cell infiltration in ACC. This current study provided comprehensive evidence for further research on ferroptosis regulators in ACC and provides new enlightenment for epigenetic regulation of antitumor immune response.

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