Androgen Receptor Transcriptionally Inhibits Programmed Death Ligand-1 Expression and Influences Immune Escape in Bladder Cancer.

In multiple clinical trials, immune checkpoint blockade-based immunotherapy has shown significant therapeutic efficacy in bladder cancer (BCa). Sex is closely related to the incidence rate and prognosis of BCa. As one of the sex hormone receptors, the androgen receptor (AR) is a well-known key regulator that promotes the progression of BCa. However, the regulatory mechanism of AR in the immune response of BCa is still unclear. In this study, the expression of AR and programmed death ligand 1 (PD-L1) was negatively correlated in BCa cells, clinical tissues, and tumor data extracted from The Cancer Genome Atlas Bladder Urothelial Carcinoma cohort. A human BCa cell line was transfected to alter the expression of AR. The results show that AR negatively regulated PD-L1 expression by directly binding to AR response elements on the PD-L1 promoter region. In addition, AR overexpression in BCa cells significantly enhanced the antitumor activity of cocultured CD8+ T cells. Injection of anti-PD-L1 monoclonal antibodies into C3H/HeN mice significantly suppressed tumor growth, and stable expression of AR dramatically enhanced the antitumor activity in vivo. In conclusion, this study describes a novel role of AR in regulating the immune response to BCa by targeting PD-L1, thus providing potential therapeutic strategies for immunotherapy in BCa.

Declaration: Novel SLC3A1 mutation in a cystinuria patient with xanthine stones: a case report.

BACKGROUND: Cystinuria and xanthinuria are both rare genetic diseases involving urinary calculi. However, cases combining these two disorders have not yet been reported. CASE PRESENTATION: In this study, we report a case of cystinuria with xanthine stones and hyperuricemia. The 23-year-old male patient was diagnosed with kidney and ureteral stones, solitary functioning kidney and hyperuricemia after admission to the hospital. The stones were removed by surgery and found to be composed of xanthine. CONCLUSION: Genetic testing by next-generation sequencing technology showed that the patient carried the homozygous nonsense mutation c.1113 C> A (p.Tyr371*) in the SLC3A1 gene, which was judged to be a functionally pathogenic variant. Sanger sequencing revealed that the patient's parents carried this heterozygous mutation, which is a pathogenic variant that can cause cystinuria. The 24-h urine metabolism analysis showed that the cystine content was 644 mg (<320 mg/24 h), indicating that the patient had cystinuria, consistent with the genetic test results. This case shows that cystinuria and xanthine stones can occur simultaneously, and provides evidence of a possible connection between the two conditions. Furthermore, our findings demonstrate the potential value of genetic testing using next-generation sequencing to effectively assist in the clinical diagnosis and treatment of patients with urinary calculi.

High perirenal fat thickness predicts a greater risk of recurrence in Chinese patients with unilateral nephrolithiasis.

INTRODUCTION: The aim of this study was to evaluate the association between recurrence-free survival (RFS) and perirenal fat thickness (PFT) in a cohort of Chinese population with unilateral nephrolithiasis. METHODS: We retrospectively reviewed the medical records of 81 patients with unilateral nephrolithiasis in our center from January 2019 to June 2019. PFT measured on computed tomography (CT) scans was evaluated. Kaplan-Meier curves and log-rank tests were used to assess significant differences in RSF between high-PFT and low-PFT groups within sexes. Univariable and multivariable Cox regression analyses were used to evaluate the potential risk factors for renal stone recurrence. RESULTS: High PFT was significantly associated with high BMI and hyperlipidemia (p = .003 and.047, respectively). The PFT of stone-bearing kidney was significantly greater than PFT of non-stone-bearing kidney (0.77 ± 0.60 cm vs. 0.67 ± 0.58 cm, p = .002) . During the follow-up periods (median 31 months), 21 (25.9%) patients experienced ipsilateral renal stone recurrence. In addition, Kaplan-Meier survival curves showed that patients with low PFT had a significant better RFS than those with high PFT (p = .012). In the univariable Cox analyses, male sex and high PFT were significantly associated with a poor RFS (p = .042 and .018, respectively). Moreover, both male sex and high PFT retained significance in the multivariable analyses (p = .045 and .020, respectively). CONCLUSIONS: Our findings suggested that PFT is a noninvasive and feasible parameter, which may help in the risk stratification of renal stone recurrence in the follow-up periods.

Long noncoding RNA (MEG3) in urinal exosomes functions as a biomarker for the diagnosis of Hunner-type interstitial cystitis (HIC).

BACKGROUND: Toll-like receptor-7 (TLR7) is functionally involved in the pathogenesis of Hunner-type interstitial cystitis (HIC). In addition, maternally expressed gene 3 (MEG3) is implicated in many urethral diseases. In this study, we aimed to verify the hypothesis that exosomal MEG3 in urine can be used as a novel diagnostic biomarker for HIC. METHODS: Electron microscopy was utilized to observe the distribution of urinary exosomes between the case group and the control group. Receiver operating characteristic analysis was utilized to compare the diagnostic values of MEG3 and miR-19a-3p. Computational analysis and luciferase assay were conducted to identify the correlation between MEG3 and miR-19a-3p as well as between TLR7 and miR-19a-3p. In addition, real-time polymerase chain reaction and Western blot were performed to establish the signaling pathways implicated in the pathogenesis of HIC. RESULTS: When age and gender distributions are excluded, urinary exosomes were equally distributed between case and control groups. The area under the curve of MEG3 was larger than that of miR-19a-3p, indicating that MEG3 has a better value in the diagnosis of HIC. In addition, patients with HIC showed elevated MEG3 expression and inhibited miR-19a-3p expression, thus establishing a negative correlation between MEG3 and miR-19a-3p. MEG3 and TLR7 were both identified as targets of miR-19a-3p, establishing a MEG3/miR-19a-3p/TLR7 signaling pathway, in which MEG3 enhances the expression of TLR7 via inhibiting the expression of miR-19a-3p. CONCLUSION: MEG3 level was upregulated in patients with HIC. In addition, MEG3 downregulated miR-19a-3p expression while upregulating TLR7 expression. Furthermore, MEG3 contributes to the pathogenesis of HIC. Therefore, exosomal MEG3 in urine can be used as a biomarker for HIC diagnosis.

Retrograde en bloc resection for non-muscle invasive bladder tumor can reduce the risk of seeding cancer cells into the peripheral circulation.

OBJECTIVE: To ascertain whether en bloc resection could reduce the risk of seeding cancer cells into the circulation during the resection of non-muscle invasive bladder cancer (NMIBC). METHODS: Patients with primary NMIBC were enrolled in this prospective study from October 2017 to May 2018. Patients were allocated to receive conventional transurethral resection of the bladder (TURB) or retrograde en bloc resection technique of the bladder tumor (RERBT). Blood samples (1 ml) for circulating tumor cell (CTC) enumeration were drawn from the peripheral vein prior to resection (PV1), immediately after resection of the tumor base (PV2), and at 12 h after resection (PV3). Intra-group comparisons of the changes in the number of CTCs identified among the PV1, PV2, and PV3 blood samples were performed in each group. RESULTS: A total of 21 patients (12 in the RERBT group and 9 in the TURB group) were recruited. For patients receiving TURB, the level of CTCs identified in PV3 was significantly higher than that in PV1 (p = 0.047). However, there was no significant difference in CTC counts before and after resection in the RERBT group. CONCLUSION: RERBT did not increase the number of tumor cells in the bloodstream.

A machine learning framework for accurately recognizing circular RNAs for clinical decision-supporting.

BACKGROUND: Circular RNAs (circRNAs) are those RNA molecules that lack the poly (A) tails, which present the closed-loop structure. Recent studies emphasized that some circRNAs imply different functions from canonical transcripts, and further associated with complex diseases. Several computational methods have been developed for detecting circRNAs from RNA-seq data. However, the existing methods prefer to high sensitivity strategies, which always introduce many false positives. Thus, in clinical decision-supporting system, a comprehensive filtering approach is needed for accurately recognizing real circRNAs for decision models. METHODS: In this paper, we first reviewed the detection strategies of the existing methods. According to the features from RNA-seq data, we showed that any single feature (data signal) selected by the existing strategies cannot accurately distinguish a circRNA. However, we found that some combinations of those features (data signals) could be used as signatures for recognizing circRNAs. To avoid the high computational complexity of the combinational optimization problem, we present CIRCPlus2, which adopts a machine learning framework to recognize real circRNAs according to multiple data signals captured from RNA-seq data. By comparing multiple machine learning frameworks, CIRCPlus2 adopts a Gradient Boosting Decision Tree (GBDT) framework. RESULTS: Given a set of candidate circRNAs, reported by any existing detection tool(s), the features of each candidate are extracted from the aligned reads. The GBDT framework can be trained by a training dataset. By applying the selected features on the framework, the predictions on true/false positives are reported. To verify the performance of the proposed approach, we conducted several groups of experiments on both real RNA-seq datasets and a series of simulation datasets with different preset configurations. The results demonstrated that CIRCPlus2 clearly improved the specificities, while it also maintained high levels of sensitivities. CONCLUSIONS: Filtering false positives is quite important in RNA-seq data analysis pipeline. Machine learning framework is suitable for solving this filtering problem. CIRCPlus2 is an efficient approach to identify the false positive circRNAs from the real ones.

HAO2 inhibits malignancy of clear cell renal cell carcinoma by promoting lipid catabolic process.

Hydroxy acid oxidase 2 (HAO2) has been reported to inhibit tumor progression through metabolic pathway. The current study was designed to evaluate the prognostic significance and probable mechanism of HAO2 in patients with clear cell renal cell carcinoma (ccRCC). The study screened The Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) database for patients with ccRCC having complete clinical information and HAO2 expression. Low HAO2 was associated with shorter overall survival (OS) and shorter disease-free survival (DFS). Gene set enrichment analysis (GSEA) showed HAO2 was associated with neutral lipid catabolic process, metabolic process, lipid oxidation, epithelial-mesenchymal transition (EMT), and Kirsten rat sarcoma viral oncogene signaling (KRAS). Western blot analysis and immunohistochemistry analysis checked HAO2 expression in ccRCC cancer tissues, normal tissues, and renal cancer cell lines. HAO2 was downregulated in ccRCC cancer tissues and ccRCC cell lines when compared with their control group. Overexpression of HAO2 by plasmid promoted lipid catabolic process, eliminated lipid accumulation, inhibited KRAS expression, controlled the proliferation, migration, and invasion activity of ccRCC tumor cells. Our results indicated that HAO2 inhibits malignancy ccRCC by promoting lipid catabolic process, HAO2 could be an effective molecular marker and treatment for ccRCC.

Serum exosomal miR-210 as a potential biomarker for clear cell renal cell carcinoma.

Exosomal microRNAs (miRNAs) are suggested to reflect molecular changes occurring in their cells of origin and are potential indicators in the early detection of cancers. This study aimed to determine whether certain exosomal miRNAs from tumor tissue can be used as noninvasive biomarkers for clear cell renal cell carcinoma (ccRCC). Based on ccRCC miRNA expression profiles and the literature, we selected six miRNAs (miR-210, miR-224, miR-452, miR-155, miR-21, and miR-34a) and analyzed their expression in tissues, sera, and serum exosomes through quantitative real-time polymerase chain reaction in hypoxia-induced (with CoCl2 ) renal cell lines. miR-210, miR-224, miR-452, miR-155, and miR-21 were upregulated in tumor tissues compared with normal tissues. Serum miR-210 and miR-155 levels were higher in patients with ccRCC than in healthy controls (HCs). Furthermore, only exosomal miR-210 was significantly upregulated in patients with ccRCC than in HCs. Moreover, receiver operating characteristic (ROC) curve analysis revealed an area under the ROC curve of 0.8779 (95% confidence interval, 0.7987-0.9571) and a sensitivity and specificity of 82.5% and 80.0%, respectively. Moreover, exosomal miR-210 was upregulated at an advanced stage, and Fuhrman grade and metastasis decreased significantly one month after surgery. Acute hypoxia exposure activates miR-210 and release of exosomes with upregulated miR-210 in both normal and tumor RCC cell lines and interferes with vacuole membrane protein 1 mRNA expression, especially in the metastatic ccRCC cell line. In conclusion, Serum exosomal miR-210 originating from tumor tissue has potential as a novel noninvasive biomarker for the detection and prognosis of ccRCC.

Pioglitazone decreased renal calcium oxalate crystal formation by suppressing M1 macrophage polarization via the PPAR-γ-miR-23 axis.

Interaction of pioglitazone (PGZ) and macrophages (Mps) in renal crystal formation remains unclear. In the present study, we investigated the possible mechanisms involved with Mps of PGZ in suppressing renal crystal formation. Crystal formation in the mouse kidney was detected using polarized light optical microscopy and Pizzolato staining. Gene expression was detected by Western blot analysis, quantitative RT-PCR, immunohistochemistry, immunofluorescence, and ELISA. Mp phenotypes were identified by flow cytometric analysis. Cell apoptosis was detected with TUNEL assay, and tubular injury was detected with periodic acid-Schiff staining. Interaction of peroxisome proliferator-activated receptor (PPAR)-γ and promoter was determined by chromatin immunoprecipitation assay. Luciferase reporter assay was performed to authenticate target genes of miRNA-23 (miR-23). Recombinant adenovirus was used to elucidate the role of miR-23 in vivo. Renal crystal formation, inflammation, tubular injury, and cell apoptosis were significantly marked in glyoxylic acid-treated groups and significantly decreased in PGZ-treated groups. PGZ significantly reduced Mp infiltration and M1 Mp polarization in the kidney. In vitro, PGZ shifted crystal-stimulated M1-predominant Mps to M2-predominant Mps, which were anti-inflammatory. PPAR-γ could directly bind to one PPAR-γ regulatory element in the promoter of pre-miR-23 to promote expression of miR-23 in Mps. We identified two downstream target genes of miR-23, interferon regulatory factor 1 and Pknox1. Moreover, miR-23 decreased crystal deposition, M1 Mp polarization, and injury in the kidney. This study has proven that PGZ decreased renal calcium oxalate crystal formation and renal inflammatory injury by suppressing M1 Mp polarization through a PPAR-γ-miR-23-interferon regulatory factor 1/Pknox1 axis. PGZ is liable to be a potential therapeutic medicine for treating urolithiasis.

Association between calcitonin receptor gene polymorphisms and calcium stone urolithiasis: A meta-analysis.

PURPOSE: It has been reported that calcitonin receptor (CALCR) gene polymorphisms might be associated with calcium stone urolithiasis. Owing to mixed and inconclusive results, we conducted a meta-analysis to summarize and clarify this association. MATERIALS AND METHODS: A systematic search of studies on the association between CALCR gene polymorphisms and calcium stone urolithiasis susceptibility was conducted in databases. RESULTS: Odds ratios and 95% confi dence intervals were used to pool the effect size. Five articles were included in our meta-analysis. CONCLUSIONS: CALCR rs1801197 might be associated with increased risk of calcium stone urolithiasis. There is insufficient data to fully confirm the association between CALCR rs1042138 and calcium stone urolithiasis susceptibility. Well-designed studies with larger sample size and more subgroups are required to validate the risk identified in the current meta-analysis.

Circular RNA CEP128 acts as a sponge of miR-145-5p in promoting the bladder cancer progression via regulating SOX11.

BACKGROUND: This study aimed to investigate the effect of over-expressing circular RNA CEP128 (circCEP128) on cell functions and explore the molecular mechanism of which in bladder carcinoma. METHODS: The differentially expressed circRNAs and mRNAs in bladder carcinoma cells and cells in adjacent tissues were screened out using microarray analysis. Expression levels of circRNAs and mRNAs in tissues and cells were determined by qRT-PCR. Expression of SOX11 was detected by western blot. Luciferase reporter assay and RNA pull-down assay were used to investigate the interactions between the specific circRNA, miRNA and mRNA. Cell cycle and apoptosis were measured using flow cytometry after transfection. MTT assay was also performed to detect the cell proliferation. RESULTS: In present study, circCEP128 and SOX11 were observed significantly up-regulated in bladder cancer tissues, while the expression of miR-145-5p was decreased in cancer samples compared to normal samples. Cytoscape was used to visualize circCEP128-miRNA-target gene interactions based on the TargetScan and circular RNA interactome, which revealed that circCEP128 served as a sponge of miR-145-5p and indirectly regulated SOX11. Knockdown of circCEP128 induced the inhibition of cell proliferation and the increased bladder cancer cell apoptosis rate. CONCLUSIONS: CircCEP128 functions as a ceRNA for miR-145-5p, which could up regulates SOX11 and further promotes cell proliferation and inhibits cell apoptosis of bladder cancer.

Enhanced recovery after surgery for radical cystectomy with ileal urinary diversion: a multi-institutional, randomized, controlled trial from the Chinese bladder cancer consortium.

PURPOSE: Enhanced recovery after surgery (ERAS) has played an important role in recovery management for radical cystectomy with ileal urinary diversion (RC-IUD). This study is to evaluate ERAS compared with the conventional recovery after surgery (CRAS) for RC-IUD. METHODS: From October 2014 and July 2016, bladder cancer patients scheduled for curative treatment from 25 centers of Chinese Bladder Cancer Consortium were randomly assigned to either ERAS or CRAS group. Primary endpoint was the 30-day complication rate. Secondary endpoints included recovery of fluid and regular diet, flatus, bowel movement, ambulation, and length of stay (LOS) postoperatively. Follow-up period was 30-day postoperatively. RESULTS: There were 144 ERAS and 145 CRAS patients. Postoperative complications occurred in 25.7 and 30.3% of the ERAS and CRAS patients with 55 complications in each group, respectively (p = 0.40). There was no significant difference between groups in major complications (p = 0.82), or type of complications (p = 0.99). The ERAS group had faster recovery of bowel movements (median 88 versus 100 h, p = 0.01), fluid diet tolerance (68 versus 96 h, p < 0.001), regular diet tolerance (125 versus 168 h, p = 0.004), and ambulation (64 versus 72 h, p = 0.047) than the CRAS group, but similar time to flatus and LOS. CONCLUSIONS: ERAS did not increase 30-day complications compared with CRAS after RC. ERAS may be better than CRAS in terms of bowel movement, tolerance of fluid and regular diet, and ambulation.

Association between MPO-463G > A polymorphism and chronic kidney disease: a meta-analysis.

BACKGROUND/OBJECTIVE: Previous studies have shown that MPO -463G > A (rs2333227) might be associated with chronic kidney disease (CKD) susceptibility, but sample sizes of those studies are relatively small. Hence, we decided to perform a meta-analysis to evaluate the association. Methods/main results: Two investigators search databases systematically and independently. Odds ratios and 95% confidence intervals were used to pool the effect size. Four articles with 618 cases and 932 controls in total were included in our meta-analysis. CONCLUSIONS: MPO -463G > A was not associated with CKD susceptibility in recessive model and homozygote comparison. MPO -463G > A was associated with increased risk of CKD in allelic comparison, heterozygote comparison and dominant model, however, the results lacked stability. Owing to insufficient data, the association between MPO -463G > A and CKD cannot be fully confirmed.

Conformational stabilization of FOX-DNA complex architecture to sensitize prostate cancer chemotherapy.

The forkhead box (FOX) transcription factor is a family of tumor suppressors that negatively regulates the tumorigenesis activity of prostate cancer; stabilization of FOX-DNA complex architecture has been recognized as a new and promising strategy for sensitizing cancer chemotherapy. Here, we described a systematic method that combined in silico analysis and in vitro assay to investigate the intermolecular interaction between FOX DNA-binding domain (DBD) and its cognate DNA partner. The structural and energetic information harvested from the molecular investigation were used to guide high-throughput virtual screening against a structurally diverse, nonredundant library of natural product compounds, aiming at discovery of novel small-molecule medicines that can conformationally stabilize and promote FOX-DNA recognition and interaction. The screening identified a number of theoretically promising hits, which were then examined by using fluorescence anisotropy assay to determine their binding potency for FOX DBD domain. The antitumor activity of identified high-affinity compounds was also tested at cellular level. Structural dynamics analysis found that the small-molecule stabilizers can shift the conformational equilibrium of FOX DBD to DNA-bound state, thus promoting the protein domain to bind tightly with its DNA partner.

Development of Therapeutic dsP21-322 for Cancer Treatment.

Small activating RNAs (saRNAs) are a class of artificially designed short duplex RNAs targeted at the promoter of a particular gene to upregulate its expression via a mechanism known as RNA activation (RNAa) and hold great promise for treating a wide variety of diseases including those undruggable by conventional therapies. The therapeutic benefits of saRNAs have been demonstrated in a number of preclinical studies carried out in different disease models including cancer. With many tumor suppressor genes (TSGs) downregulated due to either epigenetic mechanisms or haploinsufficiency resulting from deletion/mutation, cancer is an ideal disease space for saRNA therapeutics which can restore the expression of TSGs via epigenetic reprogramming. The p21WAF1/CIP gene is a TSG frequently downregulated in cancer and an saRNA for p21WAF1/CIP known as dsP21-322 has been identified to be a sequence-specific p21WAF1/CIP activator in a number of cancer types. In this chapter, we review preclinical development of medicinal dsP21-322 for cancer, especially prostate cancer and bladder cancer, and highlight its potential for further clinical development.

A novel transurethral resection technique for superficial bladder tumor: retrograde en bloc resection.

BACKGROUND: Transurethral resection of bladder tumor (TURBT) is the standard approach to bladder tumors but suffers from several disadvantages. The aim of this study was to evaluate the safety and efficacy of a novel procedure of retrograde en bloc resection of bladder tumor (RERBT) with conventional monopolar resection electrode for the treatment of superficial bladder tumors. METHODS: RERBT and conventional TURBT (C-TURBT) were conducted, respectively, in 40 and 50 patients diagnosed with superficial papillary bladder tumors. In the RERBT group, the tumors were en bloc removed retrogradely under direct vision using a conventional monopolar electrode. Patients' clinicopathological, intraoperative, and postoperative data were compared retrospectively between the RERBT and C-TURBT groups. RESULTS: Of the 90 patients, 40 underwent RERBT and 50 underwent C-TURBT. Both groups were comparable in clinicopathological characteristic. RERBT could be performed as safely and effectively as C-TURBT. There were no significant differences in operative time and surgical complications. The cumulative recurrence rates between groups were similar during up to 18 months follow-up. The detrusor muscle could be identified pathologically in 100% of RERBT tumor specimens and the biopsy of tumor bases, but only in 54 and 70%, respectively, of C-TURBT samples (P < 0.01). CONCLUSIONS: The RERBT technique is feasible and safe for superficial bladder tumors using conventional monopolar resection setting, with the advantages of adequate tumor resection and the ability to collect good quality tumor specimens for pathological diagnosis and staging compared to conventional TURBT.

Association Between Klotho Gene Polymorphisms and Urolithiasis: A Meta-Analysis.

Former studies have suggested that urolithiasis is related to Klotho gene polymorphisms. The aim of this meta-analysis was to investigate this relationship. Studies on the association between urolithiasis susceptibility and Klotho gene polymorphisms were systematically searched for in databases. Odds ratios and 95% confidence intervals were pooled as the effect size. This meta-analysis incorporated ten articles. Klotho rs1207568 adenine (A) may be related to a decreased urolithiasis risk in Caucasians. The results showed that Klotho rs3752472 may not be related to urolithiasis risk in the Han Asian subgroup. Klotho rs564481 may not be related to urolithiasis risk in Asians or Caucasians, and Klotho rs650439 may not be related to urolithiasis risk in Asians. Key Words: Klotho, Single-nucleotide polymorphism, Urolithiasis, Meta-analysis.

Methuosis Inducer SGI-1027 Cooperates with Everolimus to Promote Apoptosis and Pyroptosis by Triggering Lysosomal Membrane Permeability in Renal Cancer.

The mTOR inhibitor everolimus has been approved as a sequential or second-line therapy for renal cell carcinoma (RCC). However, the development of drug resistance limits its clinical applications. This study aims to address the challenge of everolimus resistance and provide new insights into the treatment of advanced RCC. Here, the cytotoxicity of the DNA methyltransferase 1 (DNMT1) inhibitor SGI-1027 in inducing cell vacuolation and methuosis is discovered and demonstrated for the first time. Additionally, SGI-1027 exerts synergistic effects with everolimus, as their combination suppresses the growth, migration, and invasion of renal cancer cells. Mechanistically, apoptosis and GSDME-dependent pyroptosis triggered by lysosomal membrane permeability (LMP) are observed. The upregulation of GSDME expression and increased lysosomal activity in renal cancer cells provide a therapeutic window for the combination of these two drugs to treat renal cancer. The combination treatment exhibits effective anti-tumor activity and is well tolerated in a subcutaneous tumor model. Overall, this study validates and reveals the specific cytotoxicity property of SGI-1027 and its potent synergistic effect with everolimus, offering new insights into advanced RCC therapy and everolimus-resistance overcoming.

PD-L1 expression and its correlation with tumor biomarkers in Chinese urothelial bladder cancer.

Data on prevalence of programmed death ligand-1 (PD-L1) expression and its correlation with tumor biomarkers in Chinese patients with muscle-invasive urothelial bladder cancer (MIUBC) are scarce. We investigated the prevalence of PD-L1 expression, PD-L1 expression in tumor cells (TC) and immune cells (IC), and its correlation with tumor biomarkers (CD8+ T cells and tumor mutation burden [TMB]) in Chinese patients with newly diagnosed MIUBC (NCT03433924). Of 248 patients enrolled, 229 with PD-L1 data available were analysed. High PD-L1 expression (≥ 25% of TC or IC with PD-L1 expression) was observed in 120 (52.4%) patients. 59 cases showed positive staining in ≥ 25% of TC, and 82 cases had positive staining in ≥ 25% of IC. High expression of CD8+ T cell and TMB (> 10 mutations/megabase) was observed in 44.5% and 54.1% patients, respectively. A positive correlation was observed between percentage of TC with membrane PD-L1 positivity and CD8+ T cells (0.34; P < 0.001) and between IC with membrane PD-L1 positivity and CD8+ T cells (0.44; P < 0.001). There is high prevalence of PD-L1 expression in Chinese patients with MIUBC, suggesting that a sizable subset of patients could benefit from immunotherapy. The correlation of PD-L1 expression with tumor biomarkers provide clues for mechanisms underlying the effects of biomarkers for predicting efficacy.

Correlation of PSA and survival in metastatic hormone-sensitive prostate cancer treated with rezvilutamide plus ADT in the CHART trial.

BACKGROUND: This exploratory analysis of the CHART trial (ClinicalTrials.gov: NCT03520478) investigated prostate-specific antigen (PSA) kinetics and the correlation between PSA and survival outcomes in high-volume, metastatic, hormone-sensitive prostate cancer (mHSPC). METHODS: A total of 654 patients were randomized 1:1 to receive either rezvilutamide plus androgen deprivation therapy (ADT; n = 326) or bicalutamide plus ADT (n = 328). PSA kinetics were evaluated, and the correlation between survival and the achievement of undetectable PSA (≤0.2 ng/mL) or ≥90% PSA reduction (PSA90) was assessed. FINDINGS: The rezvilutamide group exhibited higher proportions of ≥50% PSA reduction (PSA50; 98.2% vs. 87.5%), PSA90 (88.7% vs. 63.1%), and undetectable PSA (38.3% vs. 17.7%) responses compared to the bicalutamide group by 3 months. The rezvilutamide group demonstrated superior efficacy in delaying PSA progression compared to the bicalutamide group (hazard ratio [HR] 0.21, 95% confidence interval 0.16-0.27). The achievement of undetectable PSA and PSA90 by 6 months in the rezvilutamide group was associated with prolonged overall survival (undetectable PSA, HR = 0.34; PSA90, HR = 0.22), radiographic progression-free survival (HR = 0.36, HR = 0.26), time to PSA progression (HR = 0.25, HR = 0.17), and time to castration resistance (HR = 0.34, HR = 0.23) compared to those who did not achieve these PSA milestones. Stratification by baseline PSA level revealed consistent survival improvements with rezvilutamide plus ADT across quartiles. CONCLUSIONS: PSA kinetics is a valuable prognostic factor in mHSPC treated with rezvilutamide plus ADT, and the achievement of undetectable PSA and PSA90 is associated with improved survival. These findings highlight the importance of monitoring PSA kinetics in the management of mHSPC. FUNDING: This study was funded by Jiangsu Hengrui Pharmaceuticals Co., Ltd.