The role of BUD31 in clear cell renal cell carcinoma: prognostic significance, alternative splicing, and tumor immune environment.

BUD31, a splicing factor, is linked to various cancers. This study examines BUD31's expression, prognostic value, mutation profile, genomic instability, tumor immune environment, and role in clear cell renal cell carcinoma (ccRCC), focusing on cell cycle regulation via alternative splicing. BUD31 expression was analyzed using TCGA and GTEx databases across 33 cancers. Techniques included IHC staining, survival analysis, Cox regression, and nomogram construction. Mutation landscape, genomic instability, and tumor immune microenvironment were evaluated. Functional assays on ccRCC cell lines involved BUD31 knockdown, RNA sequencing, and alternative splicing analysis. BUD31 was upregulated in multiple tumors, including ccRCC. High BUD31 expression correlated with worse survival outcomes and was identified as an independent predictor of poor prognosis in ccRCC. High BUD31 expression also correlated with increased genomic instability and a less active immune microenvironment. BUD31 knockdown inhibited cell proliferation, migration, and invasion in vitro and reduced tumor growth in vivo. RNA sequencing identified 390 alternative splicing events regulated by BUD31, including 17 cell cycle-related genes. KEGG analysis highlighted pathways involved in cell cycle regulation, indicating BUD31's role in promoting cell cycle progression through alternative splicing. BUD31 is upregulated in various tumors and is associated with poor outcomes, increased genomic instability, and a suppressed immune microenvironment in ccRCC. BUD31 promotes cell cycle progression via alternative splicing, suggesting it as a prognostic biomarker and potential therapeutic target in ccRCC.

A prognostic signature based on genes associated with m6A/m5C/m1A/m7G modifications and its immunological characteristics in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is characterized by a high incidence and mortality rate. Despite advancements in therapeutic interventions, the prognosis for renal cancer patients remains suboptimal. Of late, methylation modifications have emerged as promising molecular targets for tumor assessment and treatment, yet their potential has not been fully investigated in the context of ccRCC. Transcriptomic and clinical data were extracted from The Cancer Genome Atlas, Gene Expression Omnibus, and ArrayExpress databases, leading to the identification of 57 methylation-related genes (MRGs). Utilizing DESeq2 analysis, Cox regression analysis, and the LASSO regression algorithm, a Methylation-Related Risk Score (MARS) was constructed. Cluster analysis, Gene Ontology (GO) analysis, clinical feature analysis, immune infiltration analysis, and mutation analysis were further employed to evaluate the model. Our investigation identified six pivotal prognostic MRGs and established a risk score predicated on m6A/m5C/m1A/m7G regulatory factors. This score was validated across two external cohorts and can be utilized to assess individual immune infiltration statuses and predict responses to immunotherapy. Moreover, cluster analysis delineated two distinct m6A/m5C/m1A/m7G gene clusters. We have developed and validated a robust prognostic signature based on genes associated with m6A, m5C, m1A, and m7G modifications. This gene signature demonstrates significant prognostic value in assessing survival outcomes, clinical characteristics, immune infiltration, and responses to immunotherapy in ccRCC patients. This finding provides valuable insights for refining precision treatment strategies.

Impact of tumor multiplicity on the prognosis of patients with primary renal cell carcinoma: a SEER database analysis.

To compare clinical characteristics and survival outcomes of patients with multiple renal cell carcinoma versus single renal cell carcinoma. Develop a prognostic model for predicting prognosis in patients with multiple tumors and analyze prognostic factors. Patients with primary multiple renal cell carcinoma were selected from the Surveillance, Epidemiology, and End Results database (2004-2015). They were divided into single-tumor and multiple-tumor groups. Survival analysis was conducted using the Kaplan-Meier method and log-rank test. A Cox regression model was used to identify potential prognostic factors. A total of 19,489 renal cell carcinoma cases were included, with 947 in the multiple-tumor group and 18,542 in the single-tumor group. The multiple-tumor group had lower cancer-specific survival (P = 0.03, HR = 1.431). Cox regression identified risk factors for the multiple-tumor group including number of tumors, gender, combined summary stage, T stage, N stage, tumor size, and type of surgery. The predicted probabilities showed acceptable agreement with the actual observations at 3-, 5-, and 8-years area under the curve values in both the training and validation cohorts (0.831 vs. 0.605; 0.775 vs. 0.672; and 0.797 vs. 0.699, respectively). Compared with single renal cell carcinoma, multiple renal cell carcinoma is associated with decreased cancer-specific survival. Additionally, we identified several prognostic factors including the number of tumors, T stage, tumor size, and type of surgery. These findings offer valuable insights for selecting appropriate treatment strategies for patients diagnosed with multiple renal cell carcinomas.

Targeted gene sequencing reveals disparate genomic mutations between young and older adults in renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is a type of cancer that can develop at any point in adulthood, spanning the range of age-related changes that occur in the body. However, the specific molecular mechanisms underlying the connections between age and genetic mutations in RCC have not been extensively investigated. METHODS: Clinical and genetic data from patients diagnosed with RCC were collected from two prominent medical centers in China as well as the TCGA dataset. The patients were categorized into two groups based on their prognosticated age: young adults (YAs) and older adults (OAs). Univariate and multivariate analysis were employed to evaluate the relationships between age and genetic mutations. Furthermore, a mediation analysis was conducted to assess the association between age and overall survival, with genetic disparities serving as a mediator. RESULTS: Our analysis revealed significant differences in clinical presentation between YAs and OAs with RCC, including histopathological types, histopathological tumor stage, and sarcomatoid differentiation. YAs were found to have lower mutation burden and significantly mutated genes (SMGs) of RCC. However, we did not observe any significant differences between the two groups in terms of 10 canonical oncogenic signaling pathways-related genes mutation, telomerase-related genes (TRGs) mutation, copy number changes, and genetic mutations associated with clinically actionable targeted drugs. Importantly, we demonstrate superior survival outcomes in YAs, and we confirmed the mediating effect of genetic disparities on these survival outcome differences between YAs and OAs. CONCLUSION: Our findings reveal previously unrecognized associations between age and the molecular underpinnings of RCC. These associations may serve as valuable insights to guide precision diagnostics and treatments for RCC.

Nc-RNA-mediated low expression of AZIN1 correlated with unfavorable prognosis in kidney renal clear cell carcinoma.

OBJECTIVE: Kidney renal clear cell carcinoma (KIRC, ccRCC) is the most common type of renal cancer with high recurrence and mortality. It has long been recognized that Antizyme inhibitor 1 (AZIN1) serves as a pro-oncogenic molecule in multiple cancers. However, the clinicopathological features of AZIN1 in KIRC remain unexplored. MATERIALS AND METHODS: The Cancer Genome Atlas (TCGA, TIMER, and GEPIA) were employed for pan-cancer expression and survival analysis of AZIN1, indicating the unique anti-tumor role of AZIN1 in KIRC. The expression and clinical characteristics of AZIN1 in KIRC were further proven via Human Protein Atlas and TCGA. single-sample GSEA was employed to investigate the immune infiltration of AZIN1. Then the downstream pathways were illustrated via the LinkedOmics, Metascape, and Cytoscape databases. The possible upper regulating noncoding RNAs (ncRNAs) were analyzed from five programs-TargetScan, StarBase, miRanda, PITA, and miRmap. RESULTS: AZIN1 is downregulated in KIRC patients. Lower levels of AZIN1 were linked with unfavorable outcomes in KIRC patients. The AZIN1 expression was positively related to immune cell infiltration in KIRC. We also elucidated a possible upstream regulatory ncRNA of AZIN1 in KIRC namely STK4-AS1/AC068338.2-miR-106b-5p-AZIN1 axis as well as the downstream signaling pathways. CONCLUSION: This study illustrated the unique anti-tumor role of AZIN1 in KIRC and provided potential value for guiding immunotherapy and targeted therapy.

Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma.

BACKGROUND: Belzutifan, a hypoxia-inducible factor 2α inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies. METHODS: In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival. The key secondary end point was the occurrence of an objective response (a confirmed complete or partial response). RESULTS: A total of 374 participants were assigned to belzutifan, and 372 to everolimus. At the first interim analysis (median follow-up, 18.4 months), the median progression-free survival was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided P = 0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the participants (95% confidence interval [CI], 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI, 1.9 to 5.9) in the everolimus group (P<0.001, which met the prespecified significance criterion). At the second interim analysis (median follow-up, 25.7 months), the median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group; at 18 months, 55.2% and 50.6% of the participants, respectively, were alive (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P = 0.20, which did not meet the prespecified significance criterion). Grade 3 or higher adverse events of any cause occurred in 61.8% of the participants in the belzutifan group (grade 5 in 3.5%) and in 62.5% in the everolimus group (grade 5 in 5.3%). Adverse events led to discontinuation of treatment in 5.9% and 14.7% of the participants, respectively. CONCLUSIONS: Belzutifan showed a significant benefit over everolimus with respect to progression-free survival and objective response in participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies. Belzutifan was associated with no new safety signals. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; LITESPARK-005 ClinicalTrials.gov number, NCT04195750.).

Baseline neutrophil-to-eosinophil-ratio and outcome in metastatic clear-cell renal cell carcinoma treated with nivolumab or ipilimumab/nivolumab.

BACKGROUND AND PURPOSE: This study aims to evaluate neutrophil-to-eosinophil ratio (NER) as a prognostic and/or predictive biomarker in metastatic clear cell renal cell carcinoma (m-ccRCC) treated with nivolumab or ipilimumab/nivolumab. PATIENTS/MATERIALS AND METHODS: We performed a retrospective study on m-ccRCC patients treated with nivolumab or ipilimumab/nivolumab (2012-2022). Baseline NER was calculated and correlated with clinical outcomes: response rate (RR), progression free survival (PFS) and overall survival (OS). Corresponding transcriptomic data were analysed. RESULTS: We included 201 m-ccRCC patients, 76 treated with ipilimumab/nivolumab and 125 with nivolumab. Baseline NER was statistically significantly associated with International Metastatic RCC Database Consortium (IMDC) risk groups. Increased NER was associated with shorter PFS and OS in the total patient series and nivolumab-treated patients. In patients treated with ipilimumab/nivolumab, increased NER was only statistically significantly associated with shorter OS. The impact of baseline NER on PFS and OS was independent of IMDC risk stratification. No clear correlation was found between baseline NER and RECIST response or maximal tumour shrinkage. In two additional databases, NER was also associated with PFS and OS in first-line vascular-endothelial-growth-factor-receptor tyrosine-kinase-inhibitors (VEGFR-TKIs), but not to disease-free survival in the post-nephrectomy setting. Lower NER was associated with intratumoural molecular features possibly associated with better outcome on immune checkpoint inhibitors. INTERPRETATION: Lower baseline NER is associated with better PFS and OS, independent of IMDC risk score, in m-ccRCC patients treated with ipilimumab/nivolumab or nivolumab. It correlates with intratumoural molecular features possibly associated with better outcome on immune checkpoint inhibitors. The predictive power of this biomarker is probably limited and insufficient for patient selection.

Validation and Comparison of Prognostic Models in Renal Carcinoma in a Tertiary Hospital.

BACKGROUND: Renal cell carcinoma (RCC) is the third most frequent urological neoplasia. Proper risk stratification is essential for adequate management. Various calculators are available. This project aims to evaluate the accuracy of the calculators applied to our patients. METHODS: We performed a retrospective study of the nephrectomies due to RCC performed from January 2008 to December 2013. We applied the most widely used predictive models (University of California, Los Angeles Integrated Staging System (UISS), Stage, Size, Grade and Necrosis (SSIGN), Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic RCC Database Consortium (IMDC)) to stratify patients in different risk groups. We evaluated progression-free survival (PFS) or death caused by RCC (cancer-specific survival (CSS)) or other causes (overall survival (OS)). RESULTS: We analysed 238 patients. The 5-year OS, CSS and PFS were 76%, 85% and 83%, whereas the 10-year OS, CSS and PFS were 47%, 75% and 77%, respectively. The 5-year survival analysis by risk groups according to the prognostic models showed that the PFS was 0% and 20.4% in high- and intermediate-risk metastatic RCC (mRCC). Moreover, the PFS was 90%, 95.2% and 98.9% in localised high-, intermediate- and low-risk RCC according to the UISS (area under the receiver operating characteristics curve (AUC): 0.93). The SSIGN model showed a CSS of 99% for the group with the lowest score and 5.3% for the group with the worst prognosis (AUC: 0.91). The OS of mRCC showed medians of 13.25 and 87 months according to MSKCC (AUC: 0.75) and 16, 23 and 85 months according to IMDC (AUC: 0.71) (high risk, intermediate and low). CONCLUSIONS: The validation of the predictive models carried out with our patients showed consistency in many of the results. Risk stratification should be implemented.

Targeted therapies in children with renal cell carcinoma (RCC): An International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG)-related retrospective descriptive study.

INTRODUCTION: Introduction: Renal cell carcinoma (RCC) is a very rare pediatric renal tumor. Robust evidence to guide treatment is lacking and knowledge on targeted therapies and immunotherapy is mainly based on adult studies. Currently, the International Society of Pediatric Oncology-Renal Tumor Study Group (SIOP-RTSG) 2016 UMBRELLA protocol recommends sunitinib for metastatic or unresectable RCC. METHODS: This retrospective study describes the effects of tyrosine kinase inhibitors (TKI), anti-programmed cell death 1 (PD-(L)1) monoclonal antibodies, and immunotherapeutic regimens in advanced-stage and relapsed pediatric RCC. RESULTS: Of the 31 identified patients (0-18 years) with histologically proven RCC, 3/31 presented with TNM stage I/II, 8/31 with TNM stage III, and 20/31 with TNM stage IV at diagnosis. The majority were diagnosed with translocation type RCC (MiT-RCC) (21/31) and the remaining patients mainly presented with papillary or clear-cell RCC. Treatment in a neoadjuvant or adjuvant setting, or upon relapse or progression, included mono- or combination therapy with a large variety of drugs, illustrating center specific choices in most patients. Sunitinib was often administered as first choice and predominantly resulted in stable disease (53%). Other frequently used drugs included axitinib, cabozantinib, sorafenib, and nivolumab; however, no treatment seemed more promising than sunitinib. Overall, 15/31 patients died of disease, 12/31 are alive with active disease, and only four patients had a complete response. The sample size and heterogeneity of this cohort only allowed descriptive statistical analysis. CONCLUSION: This study provides an overview of a unique series of clinical and treatment characteristics of pediatric patients with RCC treated with targeted therapies.

Survival characteristics of Wilms Tumor, a reference developed from a longitudinal cohort study.

BACKGROUND: Wilms tumor (WT) survival has been affected by the evolution in clinical and biological prognostic factors. Significant differences in survival rates indicate the need for further efforts to reduce these disparities. This study aims to evaluate the clinicopathological data impact on survival among patients after Wilm's diagnosis. METHODS: The study utilized the SEERStat Database to identify Wilms tumor patients, applying SEERStat software version 8.3.9.2 for data extraction. Selection criteria involved specific codes based on the International Classification of Diseases for Oncology (ICDO-3), excluding cases with unknown SEER stage, incomplete survival data, unknown size, or lymph node status. Statistical analyses, including Kaplan-Meier estimates and Cox regression models, were conducted using R software version 3.5. Standardized mortality ratios (SMR) were computed with SEER*Stat software, and relative and conditional survival analyses were performed to evaluate long-term survival outcomes. RESULTS: Of 2273 patients diagnosed with Wilms tumor, (1219 patients, 53.6% were females with an average age group of 3-8 years (50.2%). The overall mean survival after five years of diagnosis was 93.6% (2.6-94.7), and the overall mean survival rate was 92.5% (91.3-93.8) after ten years of diagnosis. Renal cancers were identified as the leading cause of death (77.3%), followed by nonrenal cancers (11%) and noncancer causes (11%). Additionally, robust relative survival rates of 98.10%, 92.80%, and 91.3% at one, five, and ten years, respectively, were observed, with corresponding five-year conditional survival rates indicating an increasing likelihood of survival with each additional year post-diagnosis. Univariate Cox regression identified significant prognostic factors: superior CSS for patients below 3 years (cHR 0.48) and poorer CSS for those older than 15 years (cHR 2.72), distant spread (cHR 10.24), regional spread (cHR 3.09), and unknown stage (cHR 4.97). In the multivariate model, age was not a significant predictor, but distant spread (aHR 9.22), regional spread (aHR 2.84), and unknown stage (aHR 4.98) were associated with worse CSS compared to localized tumors. CONCLUSION: This study delving into WT survival dynamics reveals a multifaceted landscape influenced by clinicopathological variables. This comprehensive understanding emphasizes the imperative for ongoing research and personalized interventions to refine survival rates and address nuanced challenges across age, stage, and tumor spread in WT patients.

Radiomics nomogram based on CT radiomics features and clinical factors for prediction of Ki-67 expression and prognosis in clear cell renal cell carcinoma: a two-center study.

OBJECTIVES: To develop and validate a radiomics nomogram combining radiomics features and clinical factors for preoperative evaluation of Ki-67 expression status and prognostic prediction in clear cell renal cell carcinoma (ccRCC). METHODS: Two medical centers of 185 ccRCC patients were included, and each of them formed a training group (n = 130) and a validation group (n = 55). The independent predictor of Ki-67 expression status was identified by univariate and multivariate regression, and radiomics features were extracted from the preoperative CT images. The maximum relevance minimum redundancy (mRMR) and the least absolute shrinkage and selection operator algorithm (LASSO) were used to identify the radiomics features that were most relevant for high Ki-67 expression. Subsequently, clinical model, radiomics signature (RS), and radiomics nomogram were established. The performance for prediction of Ki-67 expression status was validated using area under curve (AUC), calibration curve, Delong test, decision curve analysis (DCA). Prognostic prediction was assessed by survival curve and concordance index (C-index). RESULTS: Tumour size was the only independent predictor of Ki-67 expression status. Five radiomics features were finally identified to construct the RS (AUC: training group, 0.821; validation group, 0.799). The radiomics nomogram achieved a higher AUC (training group, 0.841; validation group, 0.814) and clinical net benefit. Besides, the radiomics nomogram provided a highest C-index (training group, 0.841; validation group, 0.820) in predicting prognosis for ccRCC patients. CONCLUSIONS: The radiomics nomogram can accurately predict the Ki-67 expression status and exhibit a great capacity for prognostic prediction in patients with ccRCC and may provide value for tailoring personalized treatment strategies and facilitating comprehensive clinical monitoring for ccRCC patients.

Comprehensive pan-cancer analysis of ZNF337 as a potential diagnostic, immunological, and prognostic biomarker.

BACKGROUND: Zinc Finger Protein 337 (ZNF337) is a novel Zinc Finger (ZNF) protein family member. However, the roles of ZNF337 in human cancers have not yet been investigated. METHODS: In this study, with the aid of TCGA databases, GTEx databases, and online websites, we determined the expression levels of ZNF337 in pan-cancer and its potential value as a diagnostic and prognostic marker for pan-cancer and analyzed the relationship between ZNF337 expression and immune cell infiltration and immune checkpoint genes. We then focused our research on the potential of ZNF337 as a biomarker for diagnostic and prognostic in KIRC (kidney renal clear cell carcinoma) and validated in the E-MTAB-1980 database. Moreover, the expression of ZNF337 was detected through qRT-PCR and Western blotting (WB). CCK-8 experiment, colony formation experiment, and EDU experiment were performed to evaluate cell proliferation ability. Wound healing assay and transwell assay were used to analyze its migration ability. The qRT-PCR and WB were used to detect the expression of ZNF337 in tumor tissues and paracancerous tissues of KIRC patients. RESULTS: The pan-cancer analysis revealed that abnormal ZNF337 expression was found in multiple human cancer types. ZNF337 had a high diagnostic value in pan-cancer and a significant association with the prognosis of certain cancers, indicating that ZNF337 may be a valuable prognostic biomarker for multiple cancers. Further analysis demonstrated that the expression level of ZNF337 displayed significant correlations with cancer-associated fibroblasts, immune cell infiltration, and immune checkpoint genes in many tumors. Additionally, ZNF337 was observed to have a high expression in KIRC. Its expression was significantly associated with poor prognosis [overall survival (OS), disease-specific survival (DSS)], age, TNM stage, histologic grade, and pathologic stage. The high ZNF337 expression was associated with poor prognosis in the E-MTAB-1980 validation cohort. The in vitro experiments suggested that the expression of ZNF337 in KIRC tumor tissues was higher than in adjacent tissues, and ZNF337 knockdown inhibited the proliferation and migration of KIRC cells, whereas overexpression of ZNF337 had the opposite effects. CONCLUSIONS: ZNF337 might be an important prognostic and immunotherapeutic biomarker for pan-cancer, especially in KIRC.

Construction of a 12-Gene Prognostic Risk Model and Tumor Immune Microenvironment Analysis Based on the Clear Cell Renal Cell Carcinoma Model.

OBJECTIVES: Accurate survival predictions and early interventional therapy are crucial for people with clear cell renal cell carcinoma (ccRCC). METHODS: In this retrospective study, we identified differentially expressed immune-related (DE-IRGs) and oncogenic (DE-OGs) genes from The Cancer Genome Atlas (TCGA) dataset to construct a prognostic risk model using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analysis. We compared the immunogenomic characterization between the high- and low-risk patients in the TCGA and the PUCH cohort, including the immune cell infiltration level, immune score, immune checkpoint, and T-effector cell- and interferon (IFN)-γ-related gene expression. RESULTS: A prognostic risk model was constructed based on 9 DE-IRGs and 3 DE-OGs and validated in the training and testing TCGA datasets. The high-risk group exhibited significantly poor overall survival compared with the low-risk group in the training (P < 0.0001), testing (P = 0.016), and total (P < 0.0001) datasets. The prognostic risk model provided accurate predictive value for ccRCC prognosis in all datasets. Decision curve analysis revealed that the nomogram showed the best net benefit for the 1-, 3-, and 5-year risk predictions. Immunogenomic analyses of the TCGA and PUCH cohorts showed higher immune cell infiltration levels, immune scores, immune checkpoint, and T-effector cell- and IFN-γ-related cytotoxic gene expression in the high-risk group than in the low-risk group. CONCLUSION: The 12-gene prognostic risk model can reliably predict overall survival outcomes and is strongly associated with the tumor immune microenvironment of ccRCC.

AP-2α gene deregulation is associated with renal cell carcinoma patient survival.

BACKGROUND: Renal cell carcinoma (RCC), one of the most fatal urologic tumors, accounts for approximately 3% of all adult cancers and exhibits a high metastatic index at diagnosis and a high rate of relapse. Radical or partial nephrectomy is a curative option for nonmetastatic RCCs. Targeted therapy has been shown to improve the survival of patients with metastatic RCCs. However, the underlying cellular and molecular events associated with RCC pathogenesis are not well known. METHODS: To investigate the clinical role of the transcription factor activator protein (AP)-2α in RCC, methylated CpG island recovery assays and microarray analysis were employed. COBRA and RT‒qPCR assays were performed to assess AP-2α expression in RCC. RESULTS: A negative correlation was noted between AP-2α mRNA expression levels and methylation status. Multivariate analyses showed that AP-2α mRNA was a major risk factor not only for overall and disease-free survival in RCC but also for disease-free survival in clear cell RCC. CONCLUSIONS: Our results indicated that AP-2α expression was deregulated in RCC and associated with overall patient survival and disease-free survival. Such findings suggest that AP-2α might play an important role in the pathogenesis of RCC.

Prognostic value and immune infiltration of the NEK family in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a fatal urological malignancy. Members of the never-in mitosis gene A (NIMA)-related kinase (NEK) family have been found to participate in the progression of several cancers and could be used as target genes to treat corresponding diseases. Nonetheless, the prognostic value and immune infiltration levels of NEK family genes in ccRCC remain unknown. The GSCA, TIMER, and GEPIA databases were utilized to examine the differential expression of NEK family members in ccRCC, and the Kaplan-Meier plotter was utilized to analyze the prognosis. The STRING database was used to construct a protein-protein interaction network. Analysis of function was performed by the Sangerbox tool. In addition, the relationship between NEK family genes and immune cells was explored using the TIMER and TISIDB databases. Finally, we used quantitative real-time PCR (qPCR) and immunohistochemistry (IHC) for experimental verification. Transcriptional levels of NEK2, NEK3, NEK5, NEK6, and NEK11 significantly differed between ccRCC and normal tissues. Moreover, there was a significant correlation between NEK1, NEK2, NEK4, NEK8, NEK9, and NEK10 and their clinicopathological stages in patients with ccRCC. Based on survival analysis, ccRCC patients with high transcriptional levels of NEK2, NEK3, NEK8, and NEK10 and low transcriptional levels of NEK1, NEK4, NEK5, NEK6, NEK7, NEK9, NEK11 had shorter survival times. Additionally, a significant relationship was observed between NEK family members and immune cell infiltration, immune cell markers, and immune subtypes. These results indicate that NEK family members are significantly differentially expressed in ccRCC, and a significant correlation exists between the NEK family and prognosis and immune infiltration. NEK family members may act as therapeutic targets and prognostic indicators in ccRCC.

Trends in genitourinary cancer mortality in the United States: analysis of the CDC-WONDER database 1999-2020.

Introduction: Sociodemographic disparities in genitourinary cancer-related mortality have been insufficiently studied, particularly across multiple cancer types. This study aimed to investigate gender, racial, and geographic disparities in mortality rates for the most common genitourinary cancers in the United States. Methods: Mortality data for prostate, bladder, kidney, and testicular cancers were obtained from the Centers for Disease Control and Prevention (CDC) WONDER database between 1999 and 2020. Age-adjusted mortality rates (AAMRs) were analyzed by year, gender, race, urban-rural status, and geographic region using a significance level of p < 0.05. Results: Overall, AAMRs for prostate, bladder, and kidney cancer declined significantly, while testicular cancer-related mortality remained stable. Bladder and kidney cancer AAMRs were 3-4 times higher in males than females. Prostate cancer mortality was highest in black individuals/African Americans and began increasing after 2015. Bladder cancer mortality decreased significantly in White individuals, Black individuals, African Americans, and Asians/Pacific Islanders but remained stable in American Indian/Alaska Natives. Kidney cancer-related mortality was highest in White individuals but declined significantly in other races. Testicular cancer mortality increased significantly in White individuals but remained stable in Black individuals and African Americans. Genitourinary cancer mortality decreased in metropolitan areas but either increased (bladder and testicular cancer) or remained stable (kidney cancer) in non-metropolitan areas. Prostate and kidney cancer mortality was highest in the Midwest, bladder cancer in the South, and testicular cancer in the West. Discussion: Significant sociodemographic disparities exist in the mortality trends of genitourinary cancers in the United States. These findings highlight the need for targeted interventions and further research to address these disparities and improve outcomes for all populations affected by genitourinary cancers.

Clinical outcome predictors for metastatic renal cell carcinoma: a retrospective multicenter real-life case series.

Over the last decades, the therapeutic armamentarium of metastatic renal cell carcinoma (mRCC) has been revolutionized by the advent of tyrosin-kinase inhibitors (TKI), immune-checkpoint inhibitors (ICI), and immune-combinations. RCC is heterogeneous, and even the most used validated prognostic systems, fail to describe its evolution in real-life scenarios. Our aim is to identify potential easily-accessible clinical factors and design a disease course prediction system. Medical records of 453 patients with mRCC receiving sequential systemic therapy in two high-volume oncological centres were reviewed. The Kaplan-Meier method and Cox proportional hazard model were used to estimate and compare survival between groups. As first-line treatment 366 patients received TKI monotherapy and 64 patients received ICI, alone or in combination. The mean number of therapy lines was 2.5. A high Systemic Inflammation Index, a BMI under 25 Kg/m2, the presence of bone metastases before systemic therapy start, age over 65 years at the first diagnosis, non-clear-cell histology and sarcomatoid component were correlated with a worse OS. No significant OS difference was observed between patients receiving combination therapies and those receiving exclusively monotherapies in the treatment sequence. Our relapse prediction system based on pathological stage and histological grade was effective in predicting the time between nephrectomy and systemic treatment. Our multicentric retrospective analysis reveals additional potential prognostic factors for mRCC, not included in current validated prognostic systems, suggests a model for disease course prediction and describes the outcomes of the most common therapeutic strategies currently available.

Sodium levels and immunotherapy efficacy in mRCC patients with bone metastases: sub analysis of Meet-Uro 15 study.

Background: Immune-checkpoint inhibitors (ICIs) have significantly improved metastatic renal cell carcinoma (mRCC) prognosis, although their efficacy in patients with bone metastases (BMs) remains poorly understood. We investigated the prognostic role of natremia in pretreated RCC patients with BMs receiving immunotherapy. Materials and methods: This retrospective multicenter study included RCC patients with BMs receiving nivolumab as second-line therapy or beyond. Inclusion criteria involved baseline sodium levels (pre-ICI) and sodium levels after 4 weeks of nivolumab initiation (post-ICI). The population was divided into two groups based on the median value, and response rates, progression-free survival (PFS), and overall survival (OS) were assessed. Results: Among 120 eligible patients, those with pre-treatment sodium levels ≥140 mEq/L showed longer OS (18.7 vs. 12.0 months, p=0.04). Pre-treatment sodium levels ≥140 mEq/L were associated with better OS compared to levels <140 mE/L (18.7 vs. 12.0, p=0.04). Post-treatment sodium levels ≥140 mEq/L were associated with improved PFS (9.6 vs. 3.2 months) and OS (25.1 vs. 8.8 months) (p=0.05 and p<0.01, respectively). Patients with consistent sodium levels ≥140 mEq/L at both time points exhibited the best outcomes compared to those with lower values (PFS 11.5 vs. 3.3 months and OS 42.2 vs. 9.0 months, respectively, p<0.01). Disease control rate was significantly higher in the latter group (p<0.01). Multivariate analysis confirmed the prognostic significance of sodium levels. Conclusion: Elevated sodium levels (≥140 mEq/L) pre- and post-ICI treatment correlate with better survival outcomes in mRCC patients with BMs. This finding suggests sodium level assessment as a potential prognostic factor in these patients and warrants further investigation, particularly in combination immunotherapy settings.

Real-world implementation of North American and SIOP strategies for the treatment of Wilms tumor in Uruguay.

Wilms tumor has been selected as an index tumor by the WHO Global Initiative for Childhood Cancer with the aim to improve cure rates worldwide. Nevertheless, there is a scarcity of published data on outcomes beyond those of the major cooperative groups. Therefore, we conducted a retrospective analysis including all patients with Wilms tumor treated at our referral center in Uruguay between 1995 and 2020. Treatment consisted of North American (NA) strategies in 23 cases (1995-2004), followed by the SIOP strategy in 35 cases thereafter. Staging included: I-II = 28, III = 7, IV = 14, and V = 9. There were no major surgical or medical complications; however, a delay in the administration of local radiotherapy was observed (median of 21 days after surgery). There were no cases of toxicity- or surgery-related deaths or treatment abandonment. Five-year probability of overall survival was 0.72 and 0.92 for the NA and SIOP groups, respectively. We conclude that outcomes were better for the SIOP strategy with no unexpected toxicities and high treatment compliance in both strategies. Timely implementation of radiotherapy was challenging.

Long-term responders to nivolumab in previously treated advanced renal cell carcinoma: a sub-analysis of meet-URO15 study.

BACKGROUND: Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of long-term responses are still to be determined. This study aims to investigate clinical and pathological characteristics of mRCC patients who achieved long-term responses during nivolumab treatment. MATERIALS AND METHODS: A retrospective analysis was performed on mRCC patients receiving nivolumab as second or further therapy line between May 2016 and January 2019 in 34 Italian Oncology Centres. Outcome assessments and logistic regression were performed to evaluate factors influencing long-term responses. RESULTS: A total of 571 patients with a median age of 61 years (range 17-85) were included in the analysis. With a median follow-up of 22.1 (1.0-89.0) months, 23.1% of patients were 2-year progression-free on treatment with nivolumab, hence they were categorized as long-term responders. Baseline characteristics, including age, gender, and histology, were similar between long- and short-term responders. Karnofsky Performance Status ≥ 80% was significantly associated with long-term response (p = 0.02), while bone metastases (p = 0.03), International mRCC Database Consortium intermediate-poor risk (p < 0.01) and Neutrophil-to-Lymphocyte Ratio ≥ 3.2 (p = 0.02) were associate with short-term responses. Long-term responders exhibited a median progression-free survival of 55.0 months versus 4.0 months of the short-term responders. The median OS was not reached in long-term responders while it was 17.0 months for short*term responders. CONCLUSION: This retrospective analysis sheds light on factors associated with long-term response to nivolumab in mRCC. Understanding these clinical features will be essential for selecting patients who may mostly benefit from immunotherapy.