Purpose: Immunotherapy offers a second-line option for patients with metastatic urothelial carcinoma (mUC) who failed standard therapy, but the biomarkers for predicting response remain to be explored. This study aims to evaluate the safety, efficacy, and correlative biomarker of toripalimab in patients with previously treated mUC. Patients and Methods: Patients with mUC received toripalimab 3 mg/kg Q2W. Clinical response was assessed every 8 weeks by an independent review committee per RECIST v1.1. Tumor PD-L1 expression, tumor mutational burden (TMB), and other biomarkers were evaluated. Results: Among the intention-to-treat population (n = 151), 85% of the patients experienced treatment-related adverse event (TRAE) and 20% experienced grade 3 and above TRAE. The objective response rate (ORR) was 26% with a disease control rate (DCR) of 45%. The median duration of response, progression-free survival (PFS), and overall survival (OS) were 19.7 months [95% confidence interval (CI): 13.9–not estimable], 2.3 months (95% CI, 1.8–3.6), and 14.4 months (95% CI, 9.3–23.1), respectively. Both PD-L1+ and TMB-high (10 mutations/Mb as the cutoff) patients had better ORR than PD-L1− patients (42% vs. 17%, P = 0.002) and TMB-low patients (48% vs. 22%, P = 0.014), respectively. The TMB-high group also showed better PFS (12.9 vs. 1.8 months, P < 0.001) and OS (not reached versus 10.0 months, P = 0.018) than the TMB-low group. Conclusions: Toripalimab has demonstrated encouraging clinical activity in the second-line treatment of mUC with a manageable safety profile. PD-L1 expression and TMB were two independent biomarkers in the study.
Urine metabolomics have been used to identify biomarkers for clinical diseases. However, inter-individual variations and effect factors need to be further evaluated. In our study, we explored the urine metabolome in a cohort of 203 health adults, 6 patients with benign bladder lesions, and 53 patients with bladder cancer (BCa) using liquid chromatography coupled with high resolution mass spectrometry. Inter-individual analysis of both healthy controls and BCa patients showed that the urine metabolome was relatively stable. Further analysis indicated that sex and age affect inter-individual variations in urine metabolome. Metabolic pathways such as tryptophan metabolism, the citrate cycle, and pantothenate and CoA biosynthesis were found to be related to sex and age. To eliminate age and sex interference, additional BCa urine metabolomic biomarkers were explored using age and sex-matched urine samples (Test group: 44 health adults vs. 33 patients with BCa). Metabolic profiling of urine could significantly differentiate the cases with cancer from the controls and high-grade from low-grade BCa. A metabolite panel consisting of trans-2-dodecenoylcarnitine, serinyl-valine, feruloyl-2-hydroxyputrescine, and 3-hydroxynonanoyl carnitine were discovered to have good predictive ability for BCa with an area under the curve (AUC) of 0.956 (cross validation: AUC = 0.924). A panel of indolylacryloylglycine, N -galacturonyl-L-lysine, and aspartyl-glutamate was used to establish a robust model for high- and low-grade BCa distinction with AUC of 0.937 (cross validation: AUC = 0.891). External sample (26 control vs. 20 BCa) validation verified the acceptable accuracy of these models for BCa detection. Our study showed that urinary metabolomics is a useful strategy for differential analysis and biomarker discovery.
Recent studies have demonstrated that microRNA-154 (miR-154) is involved in tumorigenesis, progression, invasion and metastasis in several types of human cancer. However, whether it plays a role in bladder cancer (BC) is unclear. The aim of the present study was to determine miR-154 levels in human BC tissues and investigate the correlation between miR-154 levels and clinicopathological characteristics as well as patient outcome. Using RT-qPCR, we found that the expression levels of miR-154 were significantly lower in BC tissues compared to adjacent normal tissues. We also demonstrated that downregulation of miR-154 was associated with advanced clinicopathological features and worse prognoses for patients with BC. Using a variety of integrated approaches, we demonstrated that both runt-related transcription factor 2 (RUNX2) and remodeling and spacing factor 1 (RSF1) were miR-154 targets. Notably, there was an inverse correlation between RSF1, RUNX2 and miR-154 expression in BC tissues. The biological functions of miR-154 were examined in vitro using Cell Counting Kit-8 (CCK-8), wound healing, and Transwell assays with T24 human bladder carcinoma cells transfected with miR-154 mimics or negative controls. These assays demonstrated that miR-154 significantly suppressed proliferation, migration and invasion of T24 cells (P<0.05). Furthermore, overexpression of RSF1 and RUNX2 rescued miR-154-induced inhibition of these aggressive behaviors. Our results indicated that miR-154, and its downstream targets RSF1 and RUNX2, are promising options for future BC therapies.
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