Fatty acids metabolism affects the therapeutic effect of anti-PD-1/PD-L1 in tumor immune microenvironment in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a highly invasive and metastatic subtype of kidney malignancy and is correlated with metabolic reprogramming for adaptation to the tumor microenvironment comprising infiltrated immune cells and immunomodulatory molecules. The role of immune cells in the tumor microenvironment (TME) and their association with abnormal fatty acids metabolism in ccRCC remains poorly understood. METHOD: RNA-seq and clinical data of KIRC from The Cancer Genome Atlas (TCGA) and E-MTAB-1980 from the ArrayExpress dataset. The Nivolumab group and Everolimus group of the CheckMate 025 study, the Atezolizumab arm of IMmotion150 and the Atezolizumab plus Bevacizumab group of IMmotion151 cohort were obtained for subsequent analysis. After differential expression genes identification, the signature was constructed through univariate Cox proportional hazard regression and simultaneously the least absolute shrinkage and selection operator (Lasso) analysis and the predictive performance of our signature was assessed by using receiver operating characteristic (ROC), Kaplan-Meier (KM) survival analysis, nomogram, drug sensitivity analysis, immunotherapeutic effect analysis and enrichment analysis. Immunohistochemistry (IHC), qPCR and western blot were performed to measure related mRNA or protein expression. Biological features were evaluated by wound healing, cell migration and invasion assays and colony formation test and analyzed using coculture assay and flow cytometry. RESULTS: Twenty fatty acids metabolism-related mRNA signatures were constructed in TCGA and possessed a strong predictive performance demonstrated through time-dependent ROC and KM survival analysis. Notably, the high-risk group exhibited an impaired response to anti-PD-1/PD-L1 (Programmed death-1 receptor/Programmed death-1 receptor-ligand) therapy compared to the low-risk group. The overall levels of the immune score were higher in the high-risk group. Additionally, drug sensitivity analysis observed that the model could effectively predict efficacy and sensitivity to chemotherapy. Enrichment analysis revealed that the IL6-JAK-STAT3 signaling pathway was a major pathway. IL4I1 could promote ccRCC cells' malignant features through JAK1/STAT3 signaling pathway and M2-like macrophage polarization. CONCLUSION: The study elucidates that targeting fatty acids metabolism can affect the therapeutic effect of PD-1/PD-L1 in TME and related signal pathways. The model can effectively predict the response to several treatment options, underscoring its potential clinical utility.

A novel 7-chemokine-genes predictive signature for prognosis and therapeutic response in renal clear cell carcinoma.

Background: Renal clear cell carcinoma (ccRCC) is one of the most prevailing type of malignancies, which is affected by chemokines. Chemokines can form a local network to regulate the movement of immune cells and are essential for tumor proliferation and metastasis as well as for the interaction between tumor cells and mesenchymal cells. Establishing a chemokine genes signature to assess prognosis and therapy responsiveness in ccRCC is the goal of this effort. Methods: mRNA sequencing data and clinicopathological data on 526 individuals with ccRCC were gathered from the The Cancer Genome Atlas database for this investigation (263 training group samples and 263 validation group samples). Utilizing the LASSO algorithm in conjunction with univariate Cox analysis, the gene signature was constructed. The Gene Expression Omnibus (GEO) database provided the single cell RNA sequencing (scRNA-seq) data, and the R package "Seurat" was applied to analyze the scRNA-seq data. In addition, the enrichment scores of 28 immune cells in the tumor microenvironment (TME) were calculated using the "ssGSEA" algorithm. In order to develop possible medications for patients with high-risk ccRCC, the "pRRophetic" package is employed. Results: High-risk patients had lower overall survival in this model for predicting prognosis, which was supported by the validation cohort. In both cohorts, it served as an independent prognostic factor. Annotation of the predicted signature's biological function revealed that it was correlated with immune-related pathways, and the riskscore was positively correlated with immune cell infiltration and several immune checkpoints (ICs), including CD47, PDCD1, TIGIT, and LAG-3, while it was negatively correlated with TNFRSF14. The CXCL2, CXCL12, and CX3CL1 genes of this signature were shown to be significantly expressed in monocytes and cancer cells, according to scRNA-seq analysis. Furthermore, the high expression of CD47 in cancer cells suggested us that this could be a promising immune checkpoint. For patients who had high riskscore, we predicted 12 potential medications. Conclusion: Overall, our findings show that a putative 7-chemokine-gene signature might predict a patient's prognosis for ccRCC and reflect the disease's complicated immunological environment. Additionally, it offers suggestions on how to treat ccRCC using precision treatment and focused risk assessment.

Neoadjuvant and adjuvant chemotherapy share equivalent efficacy in improving overall survival and cancer-specific survival among muscle invasive bladder cancer patients who undergo radical cystectomy: a retrospective cohort study based on SEER database.

Background: Although neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) have been reported an 6% absolute improvement in 5-year overall survival (OS) for muscle invasive bladder cancer (MIBC), criticism still exists including the delay of surgery and the lack of accurate pathological evidence guidance. Trials have instead focused on adjuvant chemotherapy (AC) but encountered with many difficulties. Convincing data directly compared the treatment efficacy of these 2 strategies are lacking. Methods: We conducted a retrospective cohort study to compare the effectiveness of NAC versus AC among patients with T2-4N0-3M0 bladder cancer using the Surveillance, Epidemiology, and End Results (SEER) database. OS and cancer-specific survival (CSS) were compared using Kaplan-Meier (KM) survival estimators and univariate Cox proportional hazards regression models adjusted for inverse probability of treatment weighting (IPTW). The baseline between groups were compared using standardized mean differences (SMD) approach and kernel density plot. Sensitivity analysis was performed to test the robustness of our results. Results: In total, 1,620 (38.9%) of all eligible patients (4,169) received NAC and 2,549 (61.1%) received AC. After adjusted for propensity score, all baseline characteristics were balanced with SMD <10%. The IPTW-adjusted survival analyses revealed no significant difference in OS between the 2 groups [adjusted hazard ratio (AHR) 1.09, 95% confidence interval (CI): 0.99-1.20, P=0.1]. Exploratory subgroup analysis indicated longer OS among lymph node-negative patients treated with NAC (AHR 1.25, 95% CI: 1.1-1.4, P=0.001), whereas lymph node-positive patients were in favor of AC (AHR 0.85, 95% CI: 0.72-0.99, P=0.043). This treatment heterogeneity according to lymph node status is associated with better prognosis in Stage II (T2N0) patients receiving NAC (AHR 1.28, 95% CI: 1.1-1.6, P=0.014). Meanwhile, in stage III-IV (T3-T4 and/or N+) diseases, NAC shares similar treatment efficacy to AC (AHR 0.98, 95% CI: 0.87-1.1, P=0.762). The analyses of CSS yielded similar, robust results on the effect of potential unmeasured confounding variables. Conclusions: Our population-based study suggests that NAC and AC might be interchangeable in MIBC management, especially in patients with Stage III-IV (T3-T4 and/or N+) diseases. However, this conclusion needs further validation from powerful, robust randomized trials.

LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway.

LZTFL1 is a tumor suppressor located in chromosomal region 3p21.3 that is deleted frequently and early in various cancer types including the kidney cancer. However, its role in kidney tumorigenesis remains unknown. Here we hypothesized a tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC) and its mechanism of action based on extensive bioinformatics analysis of patients' tumor data and validated it using both gain- and loss-functional studies in kidney tumor cell lines and patient-derive xenograft (PDX) model systems. Our studies indicated that LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway and inducing cell cycle arrest at G1. Clinically, we found that LZTFL1 is frequently deleted in ccRCC. Downregulation of LZTFL1 is associated with a poor ccRCC outcome and may be used as prognostic maker. Furthermore, we show that overexpression of LZTFL1 in PDX via lentiviral delivery suppressed PDX growth, suggesting that re-expression of LZTFL1 may be a therapeutic strategy against ccRCC.

Is Retzius-sparing robot-assisted radical prostatectomy associated with better functional and oncological outcomes? Literature review and meta-analysis.

OBJECTIVE: To evaluate the efficiency, safety and clinical outcomes of Retzius-sparing robot-assisted radical prostatectomy (RS-RARP) in comparison with the standard RARP. METHODS: A systematic search from Web of Science, PubMed, EMBase, Cochrane Library and Google Scholar was performed using the terms "Retzius-sparing", "Bocciardi approach" and "robot-assisted radical prostatectomy". Video articles and abstract papers for academic conferences were excluded. Meta-analysis of interested outcomes such as positive surgical margins (PSMs) and continence recovery was undertaken. A comprehensive literature review of all studies regarding Retzius-sparing (RS) approach was conducted and summarized. RESULTS: From 2010 to 2017, 11 original articles about RS-RARP approach were retrieved. Of that, only four studies comparing the RS-RARP approach to the conventional RARP were comparable for meta-analysis. Faster overall continence recovery within 1 month after the surgery was noted in the RS group (61% vs. 43%; p = 0.004). PSMs of pT2 and pT3 stages were not significantly different between the groups (10.0% vs. 7.4%; p = 0.39 and 13.1% vs. 9.5%, p = 0.56, respectively). Of all the studies, only one reported sexual recovery outcomes after RS treatment in which 40% of the participants achieved sexual intercourse within the first month. CONCLUSION: Though more technically demanding than the conventional RARP, the RS technique is a safe and feasible approach. This meta-analysis and literature review indicates that RS technique, as opposed to the conventional approach, is associated with a faster continence recovery while PSMs were comparable between the two groups. The limitations of observational studies and the small data in our meta-analysis may prevent an ultimate conclusion. Future well-designed RCTs are needed to validate and confirm our findings.