Identification of an immunogenic cell death-related gene signature predicts survival and sensitivity to immunotherapy in clear cell renal carcinoma.

Immunogenic cell death (ICD) is the trigger of adaptive immune responses. However, the role of ICD-related genes in clear cell renal carcinoma (ccRCC) remains unclear. We aimed to identify biomarkers associated with ICD and develop an ICD-related predictive model that predicts the immune microenvironment, prognosis, and response to immunotherapy in ccRCC. Our study included 739 patients (603 in the training set and 136 in the validation set) with clinicopathologic information and transcriptome sequencing data. Consensus clustering, principal component analysis (PCA), weighted gene co-expression network analysis (WGCNA), univariate COX analysis, multivariate COX analysis, and the Lasso-Cox algorithm were applied to shrink predictors and construct a predictive signature of overall survival (OS). We used CIBERSORT, ESTIMATE, and TIMER in the R package IOBR to evaluate the tumor microenvironment and immune infiltration pattern of each sample. Finally, the single cell sequencing results of immune cells in ccRCC were used to verify the results of immune infiltration analysis, and the performance of the prognostic model was evaluated by calibration curves and c-index. This study revealed that inability of the initial immune response and primary immunodeficiency were significantly enriched in the ICD subgroup with poor prognosis. We found that the ten candidate ICD genes (CALR, ENTPD1, FOXP3, HSP90AA1, IFNB1, IFNG, IL6, LY96, PIK3CA, and TLR4) could affect the prognosis of ccRCC (p < 0.05). The prediction model (PRE) we constructed can not only predict the long-term survival probability but also evaluate the landscape of immune infiltration in ccRCC. Our study demonstrated that low infiltration of dendritic cells in ccRCC implies a poor prognosis, whereas the degree of CTL infiltration is less important. An individualized prediction model was created to predict the 1-, 2-, 3-, and 5-year survival and responsiveness of ccRCC patients to immunotherapy, which may serve as a potent tool for clinicians to make better treatment decisions and thus improve the overall survival (OS) of ccRCC patients in the future.

Selective arterial embolization of renal angiomyolipoma: comparing ethanol-lipiodol emulsion and polyvinyl alcohol particles as embolic agents.

PURPOSE: To examine the effectiveness and safety of two embolic agents, an ethanol-lipiodol emulsion and polyvinyl alcohol (PVA) particles, for selective arterial embolization (SAE) of renal angiomyolipoma (AML). METHODS: Retrospectively, we reviewed the medical records and imaging data of renal AML patients who received SAE in our hospitals between July 2007 and January 2018. Among those eligible for analysis were patients with complete medical information, preoperative and postoperative contrast-enhanced computed tomography scans, and follow-up data. An ethanol-lipiodol emulsion was used to embolize 15 AMLs, and PVA particles were used to embolize 16 AMLs. We compared the tumor responses and adverse events between the two embolization-agent groups. RESULTS: After embolization, no significant differences were observed in the shrinkage rates: 34.2% ± 3.4% for the ethanol-lipiodol emulsion group and 26.3% ± 3.0% for the PVA particles group (P = 0.090). Minor post-embolization complications were also similar between the groups, and there were no severe adverse events. The length of hospital stay after SAE was 2.5 ± 0.5 days for the ethanol-lipiodol emulsion group and 1.9 ± 0.5 days for the PVA particles group and was not significantly different (P = 0.425). CONCLUSION: The results showed that SAE with ethanol-lipiodol emulsion or PVA particles was safe and efficient in decreasing tumor size and controlling renal AML hemorrhage.

Cystic Renal Masses: Old and New Paradigms.

Cystic renal masses describe a spectrum of lesions with benign and/or malignant features. Cystic renal masses are most often identified incidentally with the Bosniak classification system stratifying their malignant potential. Solid enhancing components most often represent clear cell renal cell carcinoma yet display an indolent natural history relative to pure solid renal masses. This has led to an increased adoption of active surveillance as a management strategy in those who are poor surgical candidates. This article provides a contemporary overview of historical and emerging clinical paradigms in the diagnosis and management of this distinct clinical entity.

One year overall survival of wilms tumor cases and its predictors, among children diagnosed at a teaching hospital in South Western Uganda: a retrospective cohort study.

BACKGROUND: Wilms tumor (WT) is the second most common solid tumor in Africa with both low overall survival (OS) and event-free survival (EFS) rates. However, no known factors are predicting this poor overall survival. OBJECTIVE: The study was to determine the one-year overall survival of WT cases and its predictors among children diagnosed in the pediatric oncology and surgical units of Mbarara regional referral hospital (MRRH), western Uganda. METHODOLOGY: Children's treatment charts and files diagnosed and managed for WT were retrospectively followed up for the period between January 2017 to January 2021. Charts of children with histologically confirmed diagnoses were reviewed for demographics, clinical and histological characteristics, as well as treatment modalities. RESULTS: One-year overall survival was found to be 59.3% (95% CI: 40.7-73.3), with tumor size greater than 15 cm (p 0.021) and unfavorable WT type (p 0.012) being the predominant predictors. CONCLUSION: Overall survival (OS) of WT at MRRH was found to be 59.3%, and predictive factors noted were unfavorable histology and tumor size greater than 115 cm.

Top 100 most-cited articles on renal cell carcinoma: A bibliometric analysis.

BACKGROUND: To analyze the top 100 most-cited articles on renal cell carcinoma (RCC) using bibliometric methods based on the Web of Science core collection database and to explore the research status, hotspots, and emerging trends in RCC. METHODS: The literature on RCC was searched in the Web of Science core collection database using a specific search strategy, and the types of literature were limited to articles and reviews, with no restrictions to language and publication date. The top 100 articles with the highest number of citations were extracted after the manual screening. The publication year, the number of citations, authors, country, institution, journal, and keywords of these articles were collected and analyzed. Descriptive statistics and visual analysis were performed using Microsoft Excel, VOSviewer, CiteSpace, R, and SPSS. RESULTS: The number of citations of the top 100 articles varied from 541 to 4530, with a median citation count of 807.5, and the citation rates ranged from 13.8 to 448.4 citations per year. Motzer RJ (n = 22), Escudier B (n = 13), Rini BI (n = 13), and Hutson TE (n = 11) were major contributors to this research area, with Motzer RJ publishing 16 articles as the first author. The US (n = 73), France (n = 5), Canada (n = 4), and Sweden (n = 4) were the leading countries for RCC studies. MEMORIAL SLOAN KETTERING CANCER CENTER (n = 22) was the institution with the highest number of publications. These 100 articles were derived from 24 journals, and the New England Journal of Medicine had the largest number of articles published (n = 18, impact factor = 91.245). The keyword co-occurrence network analysis showed that research hotspots in this field included molecular mechanisms of RCC development and progression, surgical treatment, targeted drug-related clinical trials, and immunotherapy. CONCLUSION: We analyzed the top 100 articles with the highest number of citations in the field of RCC and identified the influential authors, countries, institutions, and journals in this field. This study also presented the current research status, hotspots, and future trends in RCC.

The emerging landscape of neo/adjuvant immunotherapy in renal cell carcinoma.

Adjuvant and neoadjuvant therapies that reduce the risk of renal cell carcinoma (RCC) recurrence remain an area of unmet need. Advances have been made in metastatic RCC recently by leveraging PD-1/PD-L1 immune checkpoint inhibitors (ICIs). These agents are currently being investigated in the adjuvant and neoadjuvant settings to determine if intervention early in the disease trajectory offers a clinically meaningful benefit. While a disease-free survival benefit has been demonstrated with pembrolizumab, results from other ICI studies have not been positive to date. More mature data from these studies are needed to determine whether there is a survival benefit to ICIs in the curative-intent setting. The success of ICIs has also ushered a new wave of studies combining ICIs with other agents such as targeted therapies and vaccines, which are in early stages of investigation. We review the current state of adjuvant/neoadjuvant therapy in RCC and highlight opportunities for ongoing study.

Radiomics to predict immunotherapy efficacy in advanced renal cell carcinoma: A retrospective study.

Immunotherapy has become a cornerstone for the treatment of renal cell carcinoma. Nevertheless, some patients are resistant to immune checkpoint inhibitors. The possibility to identify patients who cannot benefit from immunotherapy is a relevant clinical challenge. We analyzed the association between several radiomics features and response to immunotherapy in 53 patients treated with checkpoint inhibitors for advanced renal cell carcinoma. We found that the following features are associated with progression of disease as best tumor response: F_stat.range (p < .0004), F_stat.max (p < .0007), F_stat.var (p < .0016), F_stat.uniformity (p < .0020), F_stat.90thpercentile (p < .0050). Gross tumor volumes characterized by high values of F_stat.var and F_stat.max (greater than 60,000 and greater than 300, respectively) are most likely related to a high risk of progression. Further analyses are warranted to confirm these results. Radiomics, together with other potential predictive factors, such as gut microbiota, genetic features or circulating immune molecules, could allow a personalized treatment for patients with advanced renal cell carcinoma.

Identification and Validation of the Prognostic Panel in Clear Cell Renal Cell Carcinoma Based on Resting Mast Cells for Prediction of Distant Metastasis and Immunotherapy Response.

Clear cell renal cell carcinoma (ccRCC) has a high metastatic rate, and its incidence and mortality are still rising. The aim of this study was to identify the key tumor-infiltrating immune cells (TIICs) affecting the distant metastasis and prognosis of patients with ccRCC and to construct a relevant prognostic panel to predict immunotherapy response. Based on ccRCC bulk RNA sequencing data, resting mast cells (RMCs) were screened and verified using the CIBERSORT algorithm, survival analysis, and expression analysis. Distant metastasis-associated genes were identified using single-cell RNA sequencing data. Subsequently, a three-gene (CFB, PPP1R18, and TOM1L1) panel with superior distant metastatic and prognostic performance was established and validated, which stratified patients into high- and low-risk groups. The high-risk group exhibited lower infiltration of RMCs, higher tumor mutation burden (TMB), and worse prognosis. Therapeutically, the high-risk group was more sensitive to anti-PD-1 and anti-CTLA-4 immunotherapy, whereas the low-risk group displayed a better response to anti-PD-L1 immunotherapy. Furthermore, two immune clusters revealing distinct immune, clinical, and prognosis heterogeneity were distinguished. Immunohistochemistry of ccRCC samples verified the expression patterns of the three key genes. Collectively, the prognostic panel based on RMCs is able to predict distant metastasis and immunotherapy response in patients with ccRCC, providing new insight for the treatment of advanced ccRCC.

Navigating the Current Landscape of Non-Clear Cell Renal Cell Carcinoma: A Review of the Literature.

Non-clear cell renal cell carcinoma (nccRCC) is an entity comprised of a heterogeneous constellation of RCC subtypes. Genomic profiling has broadened our understanding of molecular pathogenic mechanisms unique to individual nccRCC subtypes. To date, clinical trials evaluating the use of immunotherapies and targeted therapies have predominantly been conducted in patients with clear cell histology. A comprehensive review of the literature has been undertaken in order to describe molecular pathogenic mechanisms pertaining to each nccRCC subtype, and concisely summarise findings from therapeutic trials conducted in the nccRCC space.

Cuproptosis-Related LncRNA-Based Prediction of the Prognosis and Immunotherapy Response in Papillary Renal Cell Carcinoma.

Cuproptosis, a new cell death pattern, is promising as an intervention target to treat tumors. Abnormal long non-coding RNA (lncRNA) expression is closely associated with the occurrence and development of papillary renal cell carcinoma (pRCC). However, cuproptosis-related lncRNAs (CRLs) remain largely unknown as prognostic markers for pRCC. We aimed to forecast the prognosis of pRCC patients by constructing models according to CRLs and to examine the correlation between the signatures and the inflammatory microenvironment. From the Cancer Genome Atlas (TCGA), RNA sequencing, genomic mutations and clinical data of TCGA-KIRP (Kidney renal papillary cell carcinoma) were analyzed. Randomly selected pRCC patients were allotted to the training and testing sets. To determine the independent prognostic impact of the training characteristic, the least absolute shrinkage and selection operator (LASSO) algorithm was utilized, together with univariate and multivariate Cox regression models. Further validation was performed in the testing and whole cohorts. External datasets were utilized to verify the prognostic value of CRLs as well. The CRLs prognostic features in pRCC were established based on the five CRLs (AC244033.2, LINC00886, AP000866.1, MRPS9-AS1 and CKMT2-AS1). The utility of CRLs was evaluated and validated in training, testing and all sets on the basis of the Kaplan-Meier (KM) survival analysis. The risk score could be a robust prognostic factor to forecast clinical outcomes for pRCC patients by the LASSO algorithm and univariate and multivariate Cox regression. Analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) data demonstrated that differentially expressed genes (DEGs) are primarily important for immune responses and the PI3K-Akt pathway. Arachidonic acid metabolism was enriched in the high-risk set by Gene Set Enrichment Analysis (GSEA). In addition, Tumor Immune Dysfunction and Exclusion (TIDE) analysis suggested that there was a high risk of immune escape in the high-risk cohort. The immune functions of the low- and high-risk sets differed significantly based on immune microenvironment analysis. Finally, four drugs were screened with a higher sensitivity to the high-risk set. Taken together, a novel model according to five CRLs was set up to forecast the prognosis of pRCC patients, which provides a potential strategy to treat pRCC by a combination of cuproptosis and immunotherapy.

Current clinical perspective of urological oncology in the adolescent and young adult generation.

Among adolescents and young adults, hematological tumors are the most common malignancies in younger patients; however, solid tumors also increase with advancing age. The pathogenesis of some of these tumors differs from that of tumors which develop in children, or middle-aged and older adults, and special care should be taken in their treatment and management. A treatment plan that takes into consideration future fertility is necessary for testicular tumors, and an educational campaign to encourage early detection is also essential. The treatment of adolescents with advanced testicular tumors should resemble therapeutic approaches for young adults and not a pediatric regimen. Adrenal tumors often develop as part of familiar hereditary syndrome. Therefore, taking the personal and family history is very important, and genetic counseling should be also recommended. In renal tumors, the incidence of translocation renal cell carcinomas is higher. Complete resection is the only promising method for long-term prognosis because of no established treatment for translocation renal cell carcinomas with distant metastasis. Bladder tumors are often detected by symptoms of gross hematuria and are found at a relatively early stage. Along with renal tumors, oncological evaluation including cystoscopy is also considered essential for gross hematuria. Wilms tumors and rhabdomyosarcomas could be managed in accordance with pediatric protocols to improve the treatment outcomes. The dedicated cancer survivorship care for adolescents and young adults could be also indispensable to conquer cancer and maintain a better quality of life.

Pediatric renal tumor epidemiology: Global perspectives, progress, and challenges.

Pediatric renal tumors account for 3%-11% of childhood cancers, the most common of which is Wilms tumor or nephroblastoma. Epidemiology plays a key role in cancer prevention and control by describing the distribution of cancer and discovering risk factors for cancer. Large pediatric research consortium trials have led to a clearer understanding of pediatric renal tumors, identification of risk factors, and development of more risk-adapted therapies. These therapies have improved event-free and overall survival for children. However, several challenges remain and not all children have benefited from the improved outcomes. In this article, we review the global epidemiology of pediatric renal tumors, including key consortium and global studies. We identify current knowledge gaps and challenges facing both high and low middle-incomes countries.

Evaluating the impact of early identification of asymptomatic brain metastases in metastatic renal cell carcinoma.

BACKGROUND: Brain metastases (BM) in metastatic renal cell carcinoma (mRCC) have been reported to be present in up to 25% of patients diagnosed with mRCC. There is limited published literature evaluating the role of routine intra-cranial imaging for the screening of asymptomatic BM in mRCC. AIMS: To evaluate the potential utility of routine intra-cranial imaging, a retrospective cohort study was conducted to characterize the outcomes of mRCC patients who presented with asymptomatic BM, as compared to symptomatic BM. METHODS AND RESULTS: The Canadian Kidney Cancer Information System (CKCis) database was used to identify mRCC patients diagnosed with BM. This cohort was divided into two groups based on the presence or absence of BM symptoms. Details regarding patient demographics, disease characteristics, systemic treatments, BM characteristics and survival outcomes were extracted. Statistical analysis was through chi-square tests, analysis of variance, and Kaplan-Meier method to characterize survival outcomes. A p-value of <0.05 was considered statistically significant for all analyses. A total of 267 mRCC patients with BM were identified of which 106 (40%) presented with asymptomatic disease. The majority of patients presented with multiple (i.e., >1) BM (75%) with no significant differences noted in number of BM or BM-directed therapy received in symptomatic, as compared to asymptomatic BM patients. Median [95% confidence interval (CI)] overall survival (OS) from mRCC diagnosis was 42 months (95% CI: 32-62) for patients with asymptomatic BM, and 39 months (95% CI: 29-48) with symptomatic BM (p = 0.10). OS from time of BM diagnosis was 28 months (95% CI: 18-42) for the asymptomatic BM group, as compared to 13 months (95% CI: 10-21) in the symptomatic BM group (p = 0.04). CONCLUSIONS: Given a substantial proportion of patients may present with asymptomatic BM, limiting intra-cranial imaging to patients with symptomatic BM, may be associated with a missed opportunity for timely diagnosis and treatment. The utility of routine intra-cranial imaging in patients with renal cell carcinoma, warrants further prospective evaluation.

Identification and Validation of Cuproptosis-Related LncRNA Signatures in the Prognosis and Immunotherapy of Clear Cell Renal Cell Carcinoma Using Machine Learning.

(1) Objective: We aimed to mine cuproptosis-related LncRNAs with prognostic value and construct a corresponding prognostic model using machine learning. External validation of the model was performed in the ICGC database and in multiple renal cancer cell lines via qPCR. (2) Methods: TCGA and ICGC cohorts related to renal clear cell carcinoma were included. GO and KEGG analyses were conducted to determine the biological significance of differentially expressed cuproptosis-related LncRNAs (CRLRs). Machine learning (LASSO), Kaplan-Meier, and Cox analyses were conducted to determine the prognostic genes. The tumor microenvironment and tumor mutation load were further studied. TIDE and IC50 were used to evaluate the response to immunotherapy, a risk model of LncRNAs related to the cuproptosis genes was established, and the ability of this model was verified in an external independent ICGC cohort. LncRNAs were identified in normal HK-2 cells and verified in four renal cell lines via qPCR. (3) Results: We obtained 280 CRLRs and identified 66 LncRNAs included in the TCGA-KIRC cohort. Then, three hub LncRNAs (AC026401.3, FOXD2-AS1, and LASTR), which were over-expressed in the four ccRCC cell lines compared with the human renal cortex proximal tubule epithelial cell line HK-2, were identified. In the ICGC database, the expression of FOXD2-AS1 and LASTR was consistent with the qPCR and TCGA-KIRC. The results also indicated that patients with low-risk ccRCC-stratified by tumor-node metastasis stage, sex, and tumor grade-had significantly better overall survival than those with high-risk ccRCC. The predictive algorithm showed that, according to the three CRLR models, the low-risk group was more sensitive to nine target drugs (A.443654, A.770041, ABT.888, AG.014699, AMG.706, ATRA, AP.24534, axitinib, and AZ628), based on the estimated half-maximal inhibitory concentrations. In contrast, the high-risk group was more sensitive to ABT.263 and AKT inhibitors VIII and AS601245. Using the CRLR models, the correlation between the tumor immune microenvironment and cancer immunotherapy response revealed that high-risk patients are more likely to respond to immunotherapy than low-risk patients. In terms of immune marker levels, there were significant differences between the high- and low-risk groups. A high TMB score in the high-risk CRLR group was associated with worse survival, which could be a prognostic factor for KIRC. (4) Conclusions: This study elucidates the core cuproptosis-related LncRNAs, FOXD2-AS1, AC026401.3, and LASTR, in terms of potential predictive value, immunotherapeutic strategy, and outcome of ccRCC.

Identification of a claudin-low subtype in clear cell renal cell carcinoma with implications for the evaluation of clinical outcomes and treatment efficacy.

Background: In bladder and breast cancer, the claudin-low subtype is widely identified, revealing a distinct tumor microenvironment (TME) and immunological feature. Although we have previously identified individual claudin members as prognostic biomarkers in clear cell renal cell carcinoma (ccRCC), the existence of an intrinsic claudin-low subtype and its interplay with TME and clinical outcomes remains unclear. Methods: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA)- kidney clear cell carcinoma (KIRC) cohort and E-MTAB-1980 were derived as the training and validation cohorts, respectively. In addition, GSE40435, GSE53757, International Cancer Genome Consortium (ICGC) datasets, and RNA-sequencing data from local ccRCC patients were utilized as validation cohorts for claudin clustering based on silhouette scores. Using weighted correlation network analysis (WGCNA) and multiple machine learning algorithms, including least absolute shrinkage and selection operator (LASSO), CoxBoost, and random forest, we constructed a claudin-TME related (CTR) risk signature. Furthermore, the CTR associated genomic characteristics, immunity, and treatment sensitivity were evaluated. Results: A claudin-low phenotype was identified and associated with an inferior survival and distinct TME and cancer immunity characteristics. Based on its interaction with TME, a risk signature was developed with robust prognostic prediction accuracy. Moreover, we found its association with a claudin-low, stem-like phenotype and advanced clinicopathological features. Intriguingly, it was also effective in kidney chromophobe and renal papillary cell carcinoma. The high CTR group exhibited genomic characteristics similar to those of claudin-low phenotype, including increased chromosomal instability (such as deletions at 9p) and risk genomic alterations (especially BAP1 and SETD2). In addition, a higher abundance of CD8 T cells and overexpression of immune checkpoints, such as LAG3, CTLA4 and PDCD1, were identified in the high CTR group. Notably, ccRCC patients with high CTR were potentially more sensitive to immune checkpoint inhibitors; their counterparts could have more clinical benefits when treated with antiangiogenic drugs, mTOR, or HIF inhibitors. Conclusion: We comprehensively evaluated the expression features of claudin genes and identified a claudin-low phenotype in ccRCC. In addition, its related signature could robustly predict the prognosis and provide guide for personalizing management strategies.

Development of a polyamine gene expression score for predicting prognosis and treatment response in clear cell renal cell carcinoma.

Backgrounds: Polyamine metabolism (PM) is closely related to the tumor microenvironment (TME) and is involved in antitumor immunity. Clear cell renal cell carcinoma (ccRCC) not only has high immunogenicity but also has significant metabolic changes. However, the role of PM in the immune microenvironment of ccRCC remains unclear. This study aimed to reveal the prognostic value of PM-related genes (PMRGs) expression in ccRCC and their correlation with the TME. Methods: The expression levels PMRGs in different cells were characterized with single-cell sequencing analysis. The PMRG expression pattern of 777 ccRCC patients was evaluated based on PMRGs. Unsupervised clustering analysis was used in identifying PMRG expression subtypes, and Lasso regression analysis was used in developing polyamine gene expression score (PGES), which was validated in external and internal data sets. The predictive value of PGES for immunotherapy was validated in the IMvigor210 cohort. Multiple algorithms were used in analyzing the correlation between PGES and immune cells. The sensitivity of PGES to chemotherapeutic drugs was analyzed with the "pRRophetic" package. We validated the genes that develop PGES in tissue samples. Finally, weighted gene co-expression network analysis was used in identifying the key PMRGs closely related to ccRCC, and cell function experiments were carried out. Results: PMRGs were abundantly expressed on tumor cells, and PMRG expression was active in CD8+ T cells and fibroblasts. We identified three PMRG expression subtypes. Cancer and immune related pathways were active in PMRG expression cluster A, which had better prognosis. PGES exhibited excellent predictive value. The high-PGES group was characterized by high immune cell infiltration, high expression of T cell depletion markers, high tumor mutation burden and tumor immune dysfunction and exclusion, was insensitive to immunotherapy but sensitive to sunitinib, temsirolimus, and rapamycin, and had poor prognosis. Spermidine synthetase (SRM) has been identified as a key gene and is highly expressed in ccRCC at RNA and protein levels. SRM knockdown can inhibit ccRCC cell proliferation, migration, and invasion. Conclusions: We revealed the biological characteristics of PMRG expression subtypes and developed PGES to accurately predict the prognosis of patients and response to immunotherapy.