Search Results (578)

Background and Objectives: The worldwide incidence of renal cell carcinoma (RCC) rose by 22% between 2012 and 2022. In Australia, RCC accounted for 2.8% of all cancer diagnoses and contributing to 1.8% of cancer-related deaths. Identification of RCC biomarkers may aid in diagnosis and management. Methods: A systematic review of immunohistochemical markers of RCC studies published between 1990 and 2019 was undertaken to select candidate biomarkers of RCC. Immunohistochemical staining of 73 clear cell RCC tumors and paired normal tissue was undertaken using selected markers. Semi-quantitative and quantitative analysis of staining intensity between paired samples was undertaken to evaluate utility as potential biomarkers, using Chi-square tests and paired t-tests for analysis. As an exploratory analysis, staining intensity was also compared on clinical/demographic variables using linear and logistic regression. Results: There were 123 candidate biomarkers identified in 91 studies. Four candidate markers were selected for further investigation: aminopeptidase A (APA)/cluster of differentiation (CD)249, aminopeptidase N (APN)/CD13, gamma-glutamyl transferase (GGT), and neuron-specific enolase (NSE). APA, GGT, and APN all demonstrated reduced staining intensity in the tumor compared with normal tissue (p < 0.001 for all). NSE demonstrated a statistically significant increase in expression in tumor compared with normal tissue (p < 0.001), and this was more pronounced in patients aged >60 years (p = 0.038). Conclusions: The utility of APA, APN, and GGT as diagnostic biomarkers in clear cell RCC is limited. NSE may have some role as a biomarker for clear cell RCC, particularly among older patients; however, further investigation is required. Full article

In today’s oncology, immunotherapy arises as a potent complement for conventional cancer treatment, allowing for obtaining better patient outcomes. B7-H3 (CD276) is a member of the B7 protein family, which emerged as an attractive target for the treatment of various tumors. The molecule modulates anti-cancer immune responses, acting through diverse signaling pathways and cell populations. It has been implicated in the pathogenesis of numerous malignancies, including melanoma, gliomas, lung cancer, gynecological cancers, renal cancer, gastrointestinal tumors, and others, fostering the immunosuppressive environment and marking worse prognosis for the patients. B7-H3 targeting therapies, such as monoclonal antibodies, antibody–drug conjugates, and CAR T-cells, present promising results in preclinical studies and are the subject of ongoing clinical trials. CAR-T therapies against B7-H3 have demonstrated utility in malignancies such as melanoma, glioblastoma, prostate cancer, and RCC. Moreover, ADCs targeting B7-H3 exerted cytotoxic effects on glioblastoma, neuroblastoma cells, prostate cancer, and craniopharyngioma models. B7-H3-targeting also delivers promising results in combined therapies, enhancing the response to other immune checkpoint inhibitors and giving hope for the development of approaches with minimized adverse effects. However, the strategies of B7-H3 blocking deliver substantial challenges, such as poorly understood molecular mechanisms behind B7-H3 protumor properties or therapy toxicity. In this review, we discuss B7-H3’s role in modulating immune responses, its significance for various malignancies, and clinical trials evaluating anti-B7-H3 immunotherapeutic strategies, focusing on the clinical potential of the molecule. Full article

(1) Background: Sertoli–Leydig cell tumors (SLCTs) are rare ovarian neoplasms that account for less than 0.5% of all ovarian tumors. They usually affect young women and often present with androgenic symptoms. We report a unique case of a 40-year-old woman diagnosed with both SLCT and clear cell papillary renal cell carcinoma (CCP-RCC), a rare tumor association with unclear pathogenesis. (2) Methods: Both tumors were treated surgically. The diagnostic workup included hormonal testing, imaging studies, and extensive genetic testing, including DICER1 mutation analysis and multiplex ligation-dependent probe amplification (MLPA), as well as the examination of a next-generation sequencing (NGS) panel covering ~280 cancer-related genes. (3) Results: Histopathologic examination confirmed a well-differentiated SLCT and CCP-RCC. No pathogenic variants in DICER1 were identified by WES or MLPA. No clinically relevant changes were found in the extended NGS panel either, so a known hereditary predisposition could be ruled out. The synchronous occurrence of both tumors without genomic alterations could indicate a sporadic event or as yet unidentified mechanisms. (4) Conclusions: This case highlights the importance of a multidisciplinary approach in the management of rare tumor compounds. The exclusion of DICER1 mutations and the absence of genetic findings adds new evidence to the limited literature and underscores the importance of long-term surveillance and further research into potential shared oncogenic pathways. Full article

Belzutifan is a hypoxia-inducible factor-2α (HIF-2α) inhibitor that received FDA approval in 2021 for treating cancers resulting from von Hippel-Lindau (VHL) disease, including clear cell renal cell carcinoma (ccRCC), followed by approval in 2023 for sporadic ccRCC that has progressed through multiple lines of therapy. HIF-2α is a promising drug target, as VHL is commonly inactivated in ccRCC, which results in HIF-2α-mediated signaling that is considered central to tumorigenesis. Belzutifan has demonstrated efficacy in clinical trials in the first-line and subsequent line settings, and in combination with tyrosine kinase inhibitors. Despite being overall well tolerated, belzutifan has a distinct safety profile because of its unique mechanism of action. Anemia was the most common adverse event observed in clinical trials and is considered an on-target effect. Hypoxia is also frequently observed and commonly results in dose reductions, treatment discontinuation, and supplemental oxygen use. This review summarizes the rates of hypoxia seen in clinical trials of belzutifan in ccRCC. As the cause of hypoxia is not well understood, this review also discusses possible mechanisms of hypoxia based on preclinical studies of the HIF pathway and HIF-2α inhibitors. Finally, this review proposes monitoring and management recommendations for clinicians prescribing belzutifan to ccRCC patients. Full article

Advanced renal cell carcinoma (RCC) has a poor prognosis; this drives the exploration of alternative systemic therapies to identify more effective treatment options. Recent research has revealed that crebanine, an alkaloid derivative of the Stephania genus, induces apoptotic effects in various cancers; however, a thorough investigation of the role of crebanine in RCC has not been conducted thus far. For this study, we evaluated tumor cell viability, clonogenicity, cell-cycle distributions, morphological changes, and cell mortality with the aim of exploring the antitumor effects of crebanine in RCC. Furthermore, we compared gene and protein expressions using RNA sequencing analysis and Western blotting. The findings indicated that crebanine significantly inhibited RCC colonies and caused G1-phase cell-cycle arrest with sub-G1-phase accumulation, thus leading to suppressed cell proliferation and cell death. In addition, Hoechst 33342 staining was used to observe apoptotic cells, which revealed chromatin condensation and a reduction in the nuclear volume associated with apoptosis. Further, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated that differentially expressed genes are involved in the initiation of DNA replication, centrosome duplication, chromosome congression, and mitotic processes in the cell cycle along with signaling pathways, such as I-kappaB kinase/NF-kappaB signaling, Hippo signaling, and intrinsic apoptotic pathways. Consistent with GO and KEGG analyses, increased levels of cleaved caspase-3, cleaved caspase-7, and cleaved PARP, and decreased levels of cIAP1, BCL2, survivin, and claspin were observed. Finally, the expressions of G1/S phase transition cyclin D1, cyclin E/CDK2, and cyclin A2/CDK2 complexes were downregulated. Overall, these findings supported the potential of crebanine as an adjuvant therapy in RCC. Full article

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of kidney cancer and is often diagnosed at advanced stages. PIEZO1, a mechanosensitive ion channel, has been implicated in cancer progression, but its prognostic relevance in ccRCC remains unclear. This study aimed to evaluate the expression pattern of PIEZO1 in ccRCC and its association with clinicopathological characteristics and patient survival. Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded tumor tissues from 111 patients with ccRCC, along with 23 matched peritumoral non-cancerous tissues. Protein expression was quantified using the H-score system. Associations with tumor grade, staging, and overall survival (OS) were analyzed. mRNA expression data were retrieved from The Cancer Genome Atlas (TCGA) to validate the protein-level findings. Functional enrichment and pathway analyses were conducted to explore the biological context of PIEZO1-related gene expression. PIEZO1 showed predominantly cytoplasmic localization, with significantly lower expression in tumor tissues compared to adjacent non-malignant tissue (p < 0.0001). High PIEZO1 expression was correlated with higher tumor grade (p = 0.0147) and shorter OS (p = 0.0047). These findings were confirmed at the mRNA level in the TCGA cohort. Multivariate Cox regression analysis identified PIEZO1 as an independent prognostic factor for OS. In conclusion, PIEZO1 may serve as a clinically relevant biomarker in ccRCC. Its overexpression is associated with more aggressive tumor characteristics and poor prognosis, underscoring the need for further investigation into its functional role and potential as a therapeutic target. Full article

Background/Objectives: Clear cell renal cell carcinoma (ccRCC) is a common kidney cancer with limited therapeutic options. This study investigated the expression of HEAT repeat-containing protein 1 (HEATR1) and solute carrier family 27 member 2 (SLC27A2) in ccRCC and their potential as prognostic markers and therapeutic targets. Methods: Analysis of a public proteomic dataset (CPTAC) and immunohistochemistry (IHC) validation in an independent cohort of 52 ccRCC patients was performed. HEATR1 and SLC27A2 expression were correlated with survival outcomes. Reactome pathway analysis was conducted to explore the functional roles of HEATR1 and SLC27A2. Results: The analysis showed that HEATR1 is upregulated and associated with poor prognosis, while SLC27A2 is downregulated and similarly linked to shorter progression-free survival. High HEATR1 expression and low SLC27A2 expression correlated with shorter progression-free survival (PFS) and overall survival (OS) in patients with high-grade ccRCC. Reactome analysis indicated HEATR1’s involvement in RNA metabolism and SLC27A2’s role in lipid metabolism, particularly peroxisomal lipid metabolism and fatty acyl-CoA biosynthesis. HEATR1 exhibited a dual localization in both the cytoplasm and nucleus, while SLC27A2 was primarily observed at the cell membrane and the nucleus. This different subcellular distribution suggests multifaceted roles for both proteins in ccRCC pathogenesis. Conclusions: HEATR1 and SLC27A2 are potential prognostic markers in ccRCC. Further research is needed to validate these findings in larger, more diverse cohorts and elucidate their roles in ccRCC progression. Full article

Background/Objectives: Alterations in long non-protein-coding RNAs (lncRNAs) are known to influence cellular proliferation, apoptosis, and metastasis in human cancers, including renal cell carcinoma (RCC). Methods: Using pyrosequencing, we analyzed DNA methylation (DNAm) at 23 loci within the LINC00404 CpG island across 28 human cancer cell line models, 181 RCC tumor tissues, 154 paired tumor-adjacent normal tissues (adNs), and 194 metastatic tissue samples. Results: Our analysis revealed that all CpG sites exhibited tumor-specific hypermethylation (all p ≤ 1.4 × 10⁻⁵). Moreover, primary RCC tissues with distant metastases (M1) and metastatic tissue samples (Mtx) showed significant hypermethylation compared to RCC without distant metastases (M0). Notably, DNAm in Mtx displayed a significant increase in 22 CpG sites, compared to 12 CpG sites in the M1/M0 comparison, suggesting that DNAm in Mtx differs both qualitatively and quantitatively. Conclusions: Given that elevated levels of DNAm were also observed in the majority of cell line models, our findings suggest that LINC00404 may play a pivotal role in the malignant development and progression of RCC metastasis, as well as in other human cancers. Full article

Clear cell renal cell carcinoma (ccRCC) is a significant global cancer, particularly impacting individuals in Western countries. Despite that, the molecular mechanisms driving renal cell carcinoma progression remain poorly understood, highlighting the need to investigate these mechanisms and identify novel therapeutic targets. Literature evidence suggests that elongation factor Tu GTP binding domain containing 2 (EFTUD2) and prominin (PROM1) gene expression have significant diagnostic potential in early tumor detection, potentially reflecting the trends in progression, and may become a novel therapeutic target. Therefore, this study aimed to evaluate EFTUD2 and PROM1 protein expression on clinical characteristics of ccRCC patients, especially overall and progression-free survival. To achieve that goal, we have combined publicly available liquid chromatography–mass spectrometry (LC-MS/MS) protein expression data with a comprehensive literature review to identify key protein markers for further study and immunohistochemical (IHC) analysis. Our findings highlight the importance of considering protein expression heterogeneity within tumors. The significant variation in EFTUD2 expression, its association with PFS, and its intricate connections with the mRNA splicing machinery underscore the need for a more nuanced understanding of its role in ccRCC. Similarly, the downregulation of PROM1 and its potential effects on cell surface interactions warrant further exploration. Future studies should focus on elucidating the mechanisms underlying these observations, exploring their potential as therapeutic targets, and investigating the specific pathways affected by their dysregulation. Full article

Background/Objectives: An accurate evaluation of variant actionability is essential in cancer management. In Von Hippel–Lindau Syndrome (VHL), the interpretation of the germline variants is confounded by the presence of non-syndromic component tumors, such as clear cell renal cell carcinoma (ccRCC), hemangioblastoma, pheochromocytoma, and neuroendocrine tumors. These tumors frequently occur sporadically, without any association with VHL syndrome. The presence of these tumors in a patient with a germline VHL variant could lead to inaccurate attribution of these tumors to the germline variant and VHL syndrome. In our previous INT²GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) programs, we demonstrated that integrating tumor-derived and germline evidence offers a comprehensive approach for the accurate assessment of the germline variants in cancer syndromes. Methods/Results: Here, we present a novel INT²GRATE variant evidence framework (VEF) for evaluating the clinical actionability of the germline variants in VHL syndrome, offering an integrated approach that incorporates both constitutional and tumor data. We analyzed 2672 variants in the VHL gene and their associated tumors and clinical evidence to effectively distinguish between constitutional, sporadic, VHL differentials, and VHL allelic genetic conditions. The germline INT²GRATE variants, along with their comprehensive associated evidence, were made accessible in the first open-access INT²GRATE Variant data Portal. Conclusions: This novel and integrated approach to variant assessment and data sharing in hereditary cancer syndromes is essential in the clinical evaluation of genomic variants, advancing precision oncology, and improving patient care. Full article

Background: Tankyrase (TNKS1) regulates the WNT/β-catenin pathway, while CDK8 is a transcriptional regulator overexpressed in renal cell carcinoma (RCC). This study aims to identify novel dual inhibitors of tankyrase and Cyclin-dependent kinase 8 (CDK8), utilizing bioinformatics and in vitro methods and to assess their efficiency in renal cancer cells. Methods: To identify leads, the ChemBridge library was screening using high-throughput virtual screening (HTVS), which was followed by protein–ligand interaction analysis, Molecular Dynamics (MD) simulation, and Gibbs binding free energy estimation. A-498, Caki-1, and HK-2 cells were employed to validate in vitro efficacy. Results: TCS9725 was discovered by HTVS with binding affinities of −8.1 kcal/mol and −8.2 kcal/mol for TNKS1 and CDK8, respectively. TCS9725 had robust binding interactions with root mean square deviation values of 0.00 nm. The ΔG binding estimate was −27.45 for TNKS1 and −27.88 for CDK8, respectively. ADME predictions favored specific small-molecule inhibition profiles. TCS9725 reduced TNKS1 and CDK8 activities with IC50s of 243 nM and 403.6 nM, respectively. The compound efficiently inhibited the growth of A-498 and Caki-1 cells with GI50 values of 385.9 nM and 243.6 nM, respectively, with high selectivity compared to the non-cancerous kidney cells. TCS9725 decreased STAT1 and β-catenin positivity in A-498 and Caki-1 cells. The compound induced apoptosis and reduced TGFβ-stimulated trans-endothelial migration and p-smad2/3 signaling in both RCC cells. Conclusions: This work provides valuable insights into the therapeutic potential of TCS9725, a dual inhibitor of TNKS1 and CDK8. Further developments of this molecule could lead to new and effective treatments for this devastating disease. Full article

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer. Extensive efforts have been made to utilize radiomics from computed tomography (CT) imaging to predict tumor immune microenvironment (TIME) measurements. This study proposes a Green Learning (GL) framework for approximating tissue-based biomarkers from CT scans, focusing on the PD-L1 expression and CD68 tumor-associated macrophages (TAMs) in ccRCC. Our approach includes radiomic feature extraction, redundancy removal, and supervised feature selection through a discriminant feature test (DFT), a relevant feature test (RFT), and least-squares normal transform (LNT) for robust feature generation. For the PD-L1 expression in 52 ccRCC patients, treated as a regression problem, our GL model achieved a 5-fold cross-validated mean squared error (MSE) of 0.0041 and a Mean Absolute Error (MAE) of 0.0346. For the TAM population (CD68+/PanCK+), analyzed in 78 ccRCC patients as a binary classification task (at a 0.4 threshold), the model reached a 10-fold cross-validated Area Under the Receiver Operating Characteristic (AUROC) of 0.85 (95% CI [0.76, 0.93]) using 10 LNT-derived features, improving upon the previous benchmark of 0.81. This study demonstrates the potential of GL in radiomic analyses, offering a scalable, efficient, and interpretable framework for the non-invasive approximation of key biomarkers. Full article

Objectives: To evaluate the prognostic impact of positive surgical margins (PSMs) after partial or radical nephrectomy for clear cell renal cell carcinoma (ccRCC) across AJCC stages and assess its relevance to adjuvant therapy eligibility, given that landmark trials excluded patients with PSMs. Methods: We conducted a retrospective study using the National Cancer Database, including 171,151 ccRCC patients treated with partial or radical nephrectomy (2004–2020). Patients receiving systemic therapy or with missing key data were excluded. OS was analyzed using Kaplan–Meier curves, log-rank tests, and multivariable Cox regression. Subgroup analyses compared T2 G2/G3 PSM vs. T2 G4 negative surgical margin (NSM) (N0/Nx M0) and assessed PSM impact within KEYNOTE-564 risk groups. Results: PSMs were present in 5.9% of patients and independently predicted worse OS (HR 1.43; p < 0.001). No OS difference was observed in AJCC stage I (p = 0.54), while stages II (p = 0.001), III, and IV (p < 0.001) showed poorer survival with PSMs. OS in patients with T2 G2/G3 tumors and PSMs was comparable to those with T2 G4 and NSMs (p = 0.69). Within the KEYNOTE-564 risk population, PSMs were associated with a 62% increased risk of death (HR 1.62; p < 0.001). Conclusions: PSMs are independently associated with worse OS in ccRCC. Their prognostic impact varies across AJCC stages, supporting the use of margin status to refine risk models, guide surveillance, and consider PSM patients for adjuvant trials. Full article

Background: This study aimed to evaluate the expression and clinical relevance of three mature miRNAs (miR-21-5p, miR-30c-5p, and miR-182-5p) in patients with clear cell renal cell carcinoma (ccRCC) from southeast Romania, and to explore their potential as non-invasive diagnostic and prognostic biomarkers. Methods: miRNA expression levels were measured using TaqMan^® MGB and qRT-PCR in paired tumor and adjacent non-cancerous tissues, as well as in serum-derived exosomes, from 26 ccRCC patients. Statistical analysis included the Wilcoxon test for group comparisons and non-parametric tests for correlations with clinicopathological features. Receiver operating characteristic (ROC) curves were used to assess diagnostic performance, and miRNA panels were constructed for improved accuracy. Results: Significant dysregulation of the investigated miRNAs was observed. miR-21-5p was markedly overexpressed in both tumor tissues (3.46-fold, p < 0.001) and serum exosomes (3.26-fold, p < 0.001). miR-182-5p showed modest overexpression in tissues (0.56-fold, p < 0.001) and serum (0.85-fold, p < 0.001), whereas miR-30c-5p was significantly downregulated in both tissues (2.48-fold decrease, p < 0.001) and serum exosomes (2.29-fold decrease, p = 0.0003). Elevated miR-182-5p expression correlated with tumor localization in the right kidney (p = 0.02) and lymph node involvement (p = 0.04). Similarly, higher miR-21-5p levels in serum exosomes were associated with right-sided tumors (p = 0.01). ROC analysis revealed distinct expression profiles for all three miRNAs between ccRCC and normal tissue, both in tissue and exosomal samples (all p < 0.05). Combined biomarker panels yielded high diagnostic performance (AUC = 0.94 for tissue, AUC = 0.93 for exosomes). Conclusions: This study underscores the potential of miR-21-5p, miR-30c-5p, and miR-182-5p as non-invasive biomarkers for ccRCC diagnosis and prognosis. The use of serum exosomal miRNA panels offers a promising alternative to tissue-based diagnostics in Romanian ccRCC patients. Full article

Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer, and its prognosis is closely linked to the International Society of Urological Pathology (ISUP) grade. While histopathological evaluation remains the gold standard for grading, non-invasive methods, such as radiomics, offer potential for automated classification. This study aims to develop a radiomics-based machine learning model for the ISUP grade classification of ccRCC using nephrographic-phase CT images, with an emphasis on model interpretability through SHAP (SHapley Additive exPlanations) values. Objective: To develop and interpret a radiomics-based machine learning model for classifying ISUP grade in clear cell renal cell carcinoma (ccRCC) using nephrographic-phase CT images. Materials and Methods: This retrospective study included 109 patients with histopathologically confirmed ccRCC. Radiomic features were extracted from the nephrographic-phase CT scans. Feature robustness was evaluated via intraclass correlation coefficient (ICC), followed by redundancy reduction using Pearson correlation and minimum Redundancy Maximum Relevance (mRMR). Logistic regression, support vector machine, and random forest classifiers were trained using 8-fold cross-validation. SHAP values were computed to assess feature contribution. Results: The logistic regression model achieved the highest classification performance, with an accuracy of 82% and an AUC of 0.86. SHAP analysis identified major axis length, busyness, and large area emphasis as the most influential features. These variables represented shape and texture information, critical for distinguishing between high and low ISUP grades. Conclusions: A radiomics-based logistic regression model using nephrographic-phase CT enables accurate, non-invasive classification of ccRCC according to ISUP grade. The use of SHAP values enhances model transparency, supporting clinical interpretability and potential adoption in precision oncology. Full article