Bladder cancer (BCa) is one of the most common malignancies worldwide, and its prognostication and treatment remains challenging. The fast growth of various cancer cells requires reprogramming of its energy metabolism using aerobic glycolysis as a major energy source. However, the prognostic and therapeutic value of glycolysis-related genes in BCa remains to be determined. The fused merge dateset from TCGA, GSE13507 and GSE31684 were used for the analysis of glycolysis-related genes expression or subtyping; and corresponding clinical data of these BCa patients were also collected. In the merge cohort, we constructed a 18 multigene signature using the least absolute shrinkage and selection operator (LASSO) Cox regression model. The four external cohorts (i.e., IMvigor210, GSE32894, GSE48276 and GSE48075) of BCa patients were used to validate the accuracy. We evaluated immune infiltration using seven published algorithms: CIBERSORT, QUANTISEQ, XCELL, TIMER, CIBERSORT-ABS, EPIC, and MCPCOUNTER. Subsequently, in order to analyze the correlation between risk groups(scores) and overall survival, recognised immunoregolatory cells or common chemotherapeutic agents, clinicopathological data and immune checkpoint-related genes of BCa patients, Wilcox rank test, chi-square test, cox regression and spearman's correlation were performed. Conspicuously, we could see that CD8+ T, cancer associated fibroblast, macrophage M2, NK, endothelial cells and so on were significantly dysregulated between the two risk groups. In addition, compared with the low-risk group, high-risk group predicted poor prognosis and relatively weak sensitivity of chemotherapy. Additionally, we also found that the expression level of partial genes in the model was significantly correlated with objective responses to anti-PD-1 or anti-PD-L1 treatment in the IMvigor210, GSE111636, GSE176307, GSE78220 or GSE67501 cohort; and its expression level was also varied in different objective response cases receiving tislelizumab combined with low-dose nab-paclitaxel therapy based on our mRNA sequencing (TRUCE-01). According to "GSEA" algorithm of R package "clusterProfiler", the most significantly enriched HALLMARK, KEGG pathway and GO term was separately the 'Epithelial Mesenchymal Transition', 'Ecm Receptor Interaction' and 'MF_Extracellular_matrix_structural_constitunet' in the high- vs. low-risk group. Subsequently, we verified the protein and mRNA expression of interested model-related genes from the Human Protein Atlas (HPA) and 10 paired BCa tissues collected by us. Furthermore, in vitro functional experiments demonstrated that FASN was a functional oncogene in BCa cells through promoting cell proliferation, migration, and invasion abilities. In summary, the glycolysis-associated gene signature established by us exhibited a high predictive performance for the prognosis, immunotherapeutic responsiveness, and chemotherapeutic sensitivity of BCa. And, The model also might function as a chemotherapy and immune checkpoint inhibitor (ICI) treatment guidance.
Background: This study constructs a molecular subtype and prognostic model of bladder cancer (BLCA) through endoplasmic reticulum stress (ERS) related genes, thus helping to clinically guide accurate treatment and prognostic assessment. Methods: The Bladder Cancer (BLCA) gene expression data was downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. We clustered by ERS-related genes which obtained through GeneCards database, results in the establishment of a new molecular typing of bladder cancer. Further, we explored the characteristics of each typology in terms of immune microenvironment, mutations, and drug screening. By analyzing the ERS-related genes with univariate Cox, LASSO and multivariate Cox analyses, we also developed the four-gene signature, while validating the prognostic effect of the model in GSE32894 and GSE13507 cohorts. Finally, we evaluated the prognostic value of the clinical data in the high and low ERS score groups and constructed a prognostic score line graph by Nomogram. Results: We constructed four molecular subtypes (C1- C4) of bladder cancer, in which patients with C2 had a poor prognosis and those with C3 had a better prognosis. The C2 had a high degree of TP53 mutation, significant immune cell infiltration and high immune score. In contrast, C3 had a high degree of FGFR3 mutation, insignificant immune cell infiltration, and reduced immune checkpoint expression. After that, we built ERS-related risk signature to calculate ERS score, including ATP2A3, STIM2, VWF and P4HB. In the GSE32894 and GSE13507, the signature also had good predictive value for prognosis. In addition, ERS scores were shown to correlate well with various clinical features. Finally, we correlated the ERS clusters and ERS score. Patients with high ERS score were more likely to have the C2 phenotype, while patients with low ERS score were C3. Conclusion: In summary, we identified four novel molecular subtypes of BLCA by ERS-related genes which could provide some new insights into precision medicine. Prognostic models constructed from ERS-related genes can be used to predict clinical outcomes. Our study contributes to the study of personalized treatment and mechanisms of BLCA.
e16608 Background: The occurrence PD-1 ICIs brings a new era of treatment for bladder cancer (BC). Although the safety and efficacy of most PD-1 ICIs have been certified progressively, whether they can be used in patients (pts) with renal impairment is always a concern for clinicians. Consequently, we intend to investigate the variation of renal function and efficacy of PD-1 ICIs based immunochemotherapy for pts with muscle invasive bladder cancer (MIBC) and renal insufficiency in short term. Methods: Our study relied on population of the TRUCE-01 trial (NCT04730219), an open-label, single-arm phase II study of tislelizumab based immunochemotherapy in pts with MIBC. Data of pts, including demographic information, imaging and pathological assessment of efficacy, and serum creatinine (SCr) level in baseline, after the first, second and third cycle (C1, C2 and C3) of treatment was collected and analyzed retrospectively. We calculated at estimated glomerular filtration rate (eGFR) according to CKD-EPI formula 2009, and divided pts into different groups according to baseline eGFR, in reference to CKD categories in the K-DIGO 2012 guidelines. Results: 74 pts have been included in our research in total. The median age was 69.5 years (IQR 61.7-75.0) and 56 (75.7%) were male. Median SCr in baseline was 77.4umol/L (IQR 67.8-96.6), while median eGFR was 84.6 (IQR 63.6-94.0) (the unit of eGFR is mL/min/1.73 m 2 ). At baseline, 25 pts were classified as G1 (eGFR≥90), 36 as G2(eGFR <90 and≥60), 12 as G3 (eGFR <60 and ≥30), and 1 as G4 (eGFR <30 and≥15). No significant difference was found in eGFR between pts with CKD G1-2 in comparison to baseline and after C1, C2, C3 of treatment (All p>0.05). In pts with CKD G3-4, it is notable that eGFR may improve when the C1, C2 and C3 completed, in comparison to the baseline (p=0.087, p=0.046, p=0.114 in Wilcoxson test, p=0.082 in Repeated Measures ANOVA). 48 (64.9%) pts received 3 cycles of ICIs and underwent an operation. 24 of 48 (50%) pts received radical cystectomy (RC) and others were treated by maximal TURBT. All of them have conducted efficacy evaluation by both radiographic test and pathology. It is noted that no statistical difference in outcomes between Group G1-2 and G3-4 (p=0.772). Conclusions: Despite renal impairment is common in pts with MIBC, PD-1 immunotherapy is generally safe for kidney of MIBC patients with renal insufficiency and have no influence on efficacy in the short term. The potential improvement in eGFR of patients with worse renal function and its mechanism is essential to be revealed and verified. [Table: see text]
e16609 Background: Urothelial carcinomas (UCs) are the sixth most common tumor. Among them, UTUCs are uncommon, accounting for only 5-10% of UCs. Currently, radical nephroureterectomy (RNU) remains the gold standard of treatment for UTUC. Neoadjuvant chemotherapy treatment can be used for specific UTUC patients, especially for highly staged and/or grade tumors, such as kidneys with potentially decreased renal function after RNU. Neoadjuvant therapy is a series of treatments administered preoperatively for UTUC, mainly chemotherapy, and in recent years, novel therapies of immunotherapy have emerged. Since conventional cisplatin neoadjuvant regimens also require high preoperative renal function, neoadjuvant chemotherapy regimens such as immunotherapy provide more effective and feasible treatments for patients who are intolerant to current cisplatin chemotherapy regimens. However, there is a lack of valuable studies worldwide on novel regimens such as immunotherapy for UTUC. The aim of this study was to explore a novel preoperative neoadjuvant regimen of immunotherapy combined with chemotherapy for UTUC. To further observe the feasibility and effectiveness of this regimen in the field. Methods: 9 high-risk UTUC patients were included in this study. Among them, 7 had unilateral ureteral tumors. 1 had a unilateral renal pelvic tumor. 1 had unilateral pelvic ureteral tumor. Among them, 2 were combined with bladder tumor. All patients were given 3 cycles of tislelizumab 200 mg combined with albumin paclitaxel 200 mg after a thorough evaluation. The treatment cycles were 21 days. Imaging evaluation and surgical resection were given within 15-20 days after the end of the last treatment cycle. Results: 3 patients underwent radical nephroureterectomy with postoperative pathology suggesting SD status of the tumor. 1 patient underwent ureteral reimplantation with tumor-negative postoperative pathology (cCR) and 2 patients underwent ureteroscopic biopsy, 1 of whom had tumor-negative pathology (cCR). 2 patients declined surgical treatment with RNU, one patient had imaging confirmation that the tumor was in SD, and the other showed no evidence of tumor presence on imaging and cytology (cCR). 1 patient was treated intermittently for grade 2 myocardial adverse effects (the remaining patients had adverse effects mostly limited to grade 1, with alopecia and malaise as common symptoms). Conclusions: The characteristics of epithelial carcinoma of the upper urinary tract have led to a reduced intention of some patients to undergo RNU treatment after the completion of NAC treatment. Although the present study failed to obtain ideal pathological information after RNU, the clinical treatment effect (cCR 30%) presented in combination with imaging and cytological results reveals to some extent the promising prospect of future UTUC patients treated with NAC.
Abstract Background Recent studies indicate exosomes play an important role in cell-to-cell communication, cancer metastasis, neovascularization, the regulation of the tumor immune microenvironment, and drug resistance in various tumors. However, the prognostic and therapeutic value of exosome-related genes in bladder cancer (BCa) remains to be determined. Hence, the goal of this study was to identify and validate a novel prognostic model based on exosome-associated genes for BCa patients Methods Differentially expressed exosome-related genes (DEGs) were analyzed using the Cancer Genome Atlas (TCGA) databases. DEGs closely associated with BCa patient survival prognosis were identified using Cox regression; and these genes are used for molecular typing. Moreover, we constructed a 17 multigene model using the least absolute shrinkage and selection operator (LASSO) Cox regression model. The five external cohorts (i.e., GSE13507, GSE32894, GSE31684, GSE48075, and IMvigor210) of BCa patients were used to validate the accuracy by KM plot, ROC and calibration curves. Subsequently, we assessed immune infiltration using seven published algorithms: TIMER, CIBERSORT, CIBERSORT-ABS, QUANTISEQ, MCPCOUNTER, XCELL, and EPIC. Furthermore, the correlation results between risk groups (scores) and overall survival, recognised immunoregolatory cells or common chemotherapeutic agents, clinicopathological data and immune checkpoint-related genes of BCa patients, were analyzed based on wilcox rank test, chi-square test, cox regression and spearman's correlation method. Additionally, we also preformed that the expression level of partial modeled genes was significantly associated with objective responses to anti-PD-1/PD-L1 treatment in the IMvigor210, GSE111636, GSE176307 or our Truce01 cohort. Results In BC patients, 156 exosome-related prognostic DEGs were identified, and were clustered into three classes. Subtypes C3 predicts worse OS, DSS, and PFS in patients with BCa. The prognostic model of 17 exosome-related genes showed good prediction performance by the TCGA training set, internal test set and five external verification sets. Our study also additionally confirmed that model riskscore was closely related with drug susceptibility, immune cell infiltration, and the prediction of immunotherapy efficacy. The high-risk group was characterized by a higher number of infiltrating macrophages M2 cells, and cancer-associated fibroblasts (CAFs). Lastly, we verified the protein and mRNA expression of six interested model-related genes (including AKR1B1, CGB5, CSPG4, P4HB, POLR3G and RAC3) from the Human Protein Atlas (HPA) and 10 paired BCa tissues collected by us. Conclusions In summary, the exosome-associated gene signature established by us exhibited a high predictive performance for the prognosis, immunotherapeutic responsiveness, and chemotherapeutic sensitivity of BCa. And, The model also might function as a chemotherapy and immune checkpoint inhibitor (ICI) treatment guidance.
Transient receptor potential cation channel subfamily V (TRPV) play an essential in cancer initiation, progression, and treatment. TRPV expression alteration are shown relate to multiple cancers prognosis and treatment of cancers but are less-studied in pan-cancer. In this study, we characterize the clinical prediction value of TRPV at pan-cancer level.Several databases were used to examine the transcript expression difference in tumor vs. normal tissue, copy-number variant (CNV) and single nucleotide polymorphisms (SNP) mutation of each TRPV members in pan-cancer, including The Cancer Genome Atlas (TCGA) and cBioPortal. We performed K-M survival curve and univariate Cox regression analyses to identify survival and prognosis value of TRPV. CellMiner were selected to explore drug sensitivity. We also analyzed association between tumor mutation burden (TMB), microsatellite instability (MSI), tumor immune microenvironment and TRPV family genes expression. Moreover, we investigated the relationship between TRPVs expression and effectiveness of immunotherapy in multiple cohorts, including one melanoma (GSE78220), one renal cell carcinoma (GSE67501), and three bladder cancer cohorts (GSE111636, IMvigor210, GSE176307 and our own sequencing dataset (TRUCE-01)), and further analyzed the changes of TRPVs expression before and after treatment (tislelizumab combined with nab-paclitaxel) of bladder cancer. Next, we made a special effort to investigate and study biological functions of TRPV in bladder cancer using gene set enrichment analysis (GSEA), and conducted immune infiltration analysis with TRPVs family genes expression, copy number or somatic mutations of bladder cancer by TIMER 2.0. Finally, real-time PCR and protein expression validation of TRPVs within 10 paired cancer and para-carcinoma tissue samples, were also performed in bladder cancer.Only TRPV2 expression was lower in most cancer types among TRPV family genes. All TRPVs were correlated with survival changes. Amplification was the significant gene alternation in all TRPVs. Next, analysis between TRPVs and clinical traits showed that TRPVs were related to pathologic stage, TNM stage and first course treatment outcome. Moreover, TRPV expression was highly correlated with MSI and TMB. Immunotherapy is a research hotspot at present, our result showed the significant association between TRPVs expression and immune infiltration indicated that TRPV expression alternation could be used to guide prognosis. In addition, we also discovered that the expression level of TRPV1/2/3/4/6 was positively or negatively correlated with objective responses to anti-PD-1/PD-L1 across multiple immunotherapy cohort. Further analysis of drug sensitivity showed the value to treatment. Based on the above analysis, we next focused on TRPV family in bladder cancer. The result demonstrated TRPV also played an important role in bladder cancer. Finally, qPCR assay verified our analysis in bladder cancer.Our study firstly revealed expression and genome alternation of TRPV in pan-cancer. TRPV could be used to predict prognosis or instructing treatment of human cancers, especially bladder cancer.
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