CircPRELID2 functions as a promoter of renal cell carcinoma through the miR-22-3p/ETV1 cascade.

BACKGROUND: Emerging evidence has indicated that a number of circular RNAs (circRNAs) participate in renal cell carcinoma (RCC) carcinogenesis. Nevertheless, the activity and molecular process of circPRELID2 (hsa_circ_0006528) in RCC progression remain unknown. METHODS: CircPRELID2, miR-22-3p and ETS variant 1 (ETV1) levels were gauged by qRT-PCR. Effect of the circPRELID2/miR-22-3p/ETV1 axis was evaluated by detecting cell growth, motility, and invasion. Immunoblotting assessed related protein levels. The relationships of circPRELID2/miR-22-3p and miR-22-3p/ETV1 were confirmed by RNA immunoprecipitation (RIP), luciferase reporter or RNA pull-down assay. RESULTS: CircPRELID2 was up-regulated in RCC. CircPRELID2 silencing suppressed RCC cell growth, motility and invasion. Moreover, circPRELID2 silencing weakened M2-type macrophage polarization in THP1-induced macrophage cells. CircPRELID2 sequestered miR-22-3p, and circPRELID2 increased ETV1 expression through miR-22-3p. Moreover, the inhibitory impact of circPRELID2 silencing on RCC cell malignant behaviors was mediated by the miR-22-3p/ETV1 axis. Furthermore, circPRELID2 knockdown in vivo hampered growth of xenograft tumors. CONCLUSION: Our study demonstrates that circPRELID2 silencing can mitigate RCC malignant development through the circPRELID2/miR-22-3p/ETV1 axis, highlighting new therapeutic targets for RCC treatment.

A rare case of TFEB/6p21/VEGFA-amplified renal cell carcinoma diagnosed by whole-exome sequencing: clinicopathological and genetic feature report and literature review.

BACKGROUND: TFEB/6p21/VEGFA-amplified renal cell carcinoma (RCC) is rare and difficult to diagnose, with diverse histological patterns and immunohistochemical and poorly defined molecular genetic characteristics. CASE PRESENTATION: We report a case of a 63-year-old male admitted in 2017 with complex histomorphology, three morphological features of clear cell, eosinophilic and papillary RCC and resembling areas of glomerular and tubular formation. The immunophenotype also showed a mixture of CD10 and P504s. RCC with a high suspicion of collision tumors was indicated according to the 2014 WHO classification system; no precise diagnosis was possible. The patient was diagnosed at a different hospital with poorly differentiated lung squamous cell carcinoma one year after RCC surgery. We exploited molecular technology advances to retrospectively investigate the patient's molecular genetic alterations by whole-exome sequencing. The results revealed a 6p21 amplification in VEGFA and TFEB gene acquisition absent in other RCC subtypes. Clear cell, papillary, chromophobe, TFE3-translocation, eosinophilic solid and cystic RCC were excluded. Strong TFEB and Melan-A protein positivity prompted rediagnosis as TFEB/6p21/VEGFA-amplified RCC as per 2022 WHO classification. TMB-L (low tumor mutational load), CCND3 gene acquisition and MRE11A and ATM gene deletion mutations indicated sensitivity to PD-1/PD-L1 inhibitor combinations and the FDA-approved targeted agents Niraparib (Grade C), Olaparib (Grade C), Rucaparib (Grade C) and Talazoparib (Class C). GO (Gene Ontology) and KEGG enrichment analyses revealed major mutations and abnormal CNVs in genes involved in biological processes such as the TGF-ß, Hippo, E-cadherin, lysosomal biogenesis and autophagy signaling pathways, biofilm synthesis cell adhesion substance metabolism regulation and others. We compared TFEB/6p21/VEGFA-amplified with TFEB-translocated RCC; significant differences in disease onset age, histological patterns, pathological stages, clinical prognoses, and genetic characteristics were revealed. CONCLUSION: We clarified the patient's challenging diagnosis and discussed the clinicopathology, immunophenotype, differential diagnosis, and molecular genetic information regarding TFEB/6p21/VEGFA-amplified RCC via exome analysis and a literature review.

Delphi consensus on stereotactic ablative radiotherapy for oligometastatic and oligoprogressive renal cell carcinoma-a European Society for Radiotherapy and Oncology study endorsed by the European Association of Urology.

The purpose of this European Society for Radiotherapy and Oncology (ESTRO) project, endorsed by the European Association of Urology, is to explore expert opinion on the management of patients with oligometastatic and oligoprogressive renal cell carcinoma by means of stereotactic ablative radiotherapy (SABR) on extracranial metastases, with the aim of developing consensus recommendations for patient selection, treatment doses, and concurrent systemic therapy. A questionnaire on SABR in oligometastatic renal cell carcinoma was prepared by a core group and reviewed by a panel of ten prominent experts in the field. The Delphi consensus methodology was applied, sending three rounds of questionnaires to clinicians identified as key opinion leaders in the field. At the end of the third round, participants were able to find consensus on eight of the 37 questions. Specifically, panellists agreed to apply no restrictions regarding age (25 [100%) of 25) and primary renal cell carcinoma histology (23 [92%] of 25) for SABR candidates, on the upper threshold of three lesions to offer ablative treatment in patients with oligoprogression, and on the concomitant administration of immune checkpoint inhibitor. SABR was indicated as the treatment modality of choice for renal cell carcinoma bone oligometatasis (20 [80%] of 25) and for adrenal oligometastases 22 (88%). No consensus or major agreement was reached regarding the appropriate schedule, but the majority of the poll (54%-58%) retained the every-other-day schedule as the optimal choice for all the investigated sites. The current ESTRO Delphi consensus might provide useful direction for the application of SABR in oligometastatic renal cell carcinoma and highlight the key areas of ongoing debate, perhaps directing future research efforts to close knowledge gaps.

Molecular and functional characterization of reversible-sunitinib-tolerance state in human renal cell carcinoma.

Therapy failure with the tyrosine kinase inhibitor (TKI) sunitinib remains a great challenge in metastatic renal cell carcinoma (mRCC). Growing evidence indicates that the tumour subpopulation can enter a transient, non-mutagenic drug-tolerant state to endure the treatment underlying the minimal residual disease and tumour relapse. Drug tolerance to sunitinib remains largely unexplored in RCC. Here, we show that sunitinib-tolerant 786-O/S and Caki-2/S cells are induced by prolonged drug treatment showing reduced drug sensitivity, enhanced clonogenicity, and DNA synthesis. Sunitinib-tolerance developed via dynamic processes, including (i) engagement of c-MET and AXL pathways, (ii) alteration of stress-induced p38 kinase and pro-survival BCL-2 signalling, (iii) extensive actin remodelling, which was correlated with activation of focal adhesion proteins. Remarkably, the acute drug response in both sensitive and sunitinib-tolerant cell lines led to dramatic fine-tuning of the actin-cytoskeleton and boosted cellular migration and invasion, indicating that the drug-response might depend on cell state transition rather than pre-existing mutations. The drug-tolerant state was transiently acquired, as the cells resumed initial drug sensitivity after >10 passages under drug withdrawal, reinforcing the concept of dynamic regulation and phenotypic heterogeneity. Our study described molecular events contributing to the reversible switch into sunitinib-tolerance, providing possible novel therapeutic opportunities in RCC.

A Cerebellar Tumor-to-Tumor Metastasis in a Patient With Von Hippel-Lindau Disease.

Tumor-to-tumor metastasis in the central nerve system is uncommon in our routine practice. Most reports include metastatic breast cancer into meningioma. Here we report a metastatic clear cell renal cell carcinoma (ccRCC) into a cerebellar hemangioblastoma in a patient with von Hippel-Lindau (VHL) disease. Imaging cannot distinguish metastatic ccRCC from primary cerebellar hemangioblastoma. Immuno-molecular studies are proven to be diagnostic. We also reviewed previously documented tumor-to-tumor metastasis of ccRCC to cerebellar hemangioblastoma in VHL disease. Lastly, we discussed potential mechanisms involved in the metastasis of ccRCC to hemangioblastoma in the cerebellum in patients with VHL.

Differential expression analysis identifies a prognostically significant extracellular matrix-enriched gene signature in hyaluronan-positive clear cell renal cell carcinoma.

Hyaluronan (HA) accumulation in clear cell renal cell carcinoma (ccRCC) is associated with poor prognosis; however, its biology and role in tumorigenesis are unknown. RNA sequencing of 48 HA-positive and 48 HA-negative formalin-fixed paraffin-embedded (FFPE) samples was performed to identify differentially expressed genes (DEG). The DEGs were subjected to pathway and gene enrichment analyses. The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) data and DEGs were used for the cluster analysis. In total, 129 DEGs were identified. HA-positive tumors exhibited enhanced expression of genes related to extracellular matrix (ECM) organization and ECM receptor interaction pathways. Gene set enrichment analysis showed that epithelial-mesenchymal transition-associated genes were highly enriched in the HA-positive phenotype. A protein-protein interaction network was constructed, and 17 hub genes were discovered. Heatmap analysis of TCGA-KIRC data identified two prognostic clusters corresponding to HA-positive and HA-negative phenotypes. These clusters were used to verify the expression levels and conduct survival analysis of the hub genes, 11 of which were linked to poor prognosis. These findings enhance our understanding of hyaluronan in ccRCC.

CXCR2/Snail-1-Induced Epithelial-Mesenchymal Transition in the Formation and Progression of RCC with Inferior Vena Cava Tumour Thrombus.

BACKGROUND: Renal cell carcinoma (RCC), a common and highly invasive malignant tumour, presents clinical challenges due to its propensity for easy metastasis. Inferior vena cava tumour thrombus is a common RCC complication significantly impacting patient prognosis. This study investigates C-X-C chemokine receptor type 2 (CXCR2)/Snail-1-induced epithelial-mesenchymal transition (EMT) in RCC with inferior vena cava tumour thrombus. METHODS: Tissues from 51 RCC patients were analysed for CXCR2 and Snail-1 Messenger Ribonucleic Acid (mRNA) levels using Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Elevated levels of both were observed in tumour and inferior vena cava tumour thrombus tissues. Using Short Hairpin RNA (shRNA) technology, we inhibited CXCR2 and Snail-1 expression to investigate their impact on EMT, invasiveness, and metastatic potential in RCC cells. RESULTS: Compared with that in the Short Hairpin RNA-Negative Control (ShNC) group, inhibition of CXCR2 and Snail-1 suppressed the degree of EMT, invasiveness, and metastatic ability of RCC cells (p < 0.01). Further mechanistic studies showed that CXCR2/Snail-1 participated in the formation and progression of RCC by regulating the extracellular signal-regulated kinase 1/2 (ERK1/2) signalling pathways. Additionally, compared with that in the ShNC group, knockdown of CXCR2 and Snail-1 significantly inhibited the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9; p < 0.01), thereby regulating the metastasis of RCC. CONCLUSIONS: Our findings suggest that CXCR2/Snail-1-induced EMT plays an important role in the formation and progression of RCC with inferior vena cava tumour thrombus. CXCR2/Snail-1 participates in the invasion and metastasis of RCC by regulating the expression of multiple signalling pathways and related genes. These results provide new insights and directions for the treatment of RCC.

Identification of prognostic stemness-related genes in kidney renal papillary cell carcinoma.

BACKGROUND: Kidney renal papillary cell carcinoma (KIRP) is the second most prevalent malignant cancer originating from the renal epithelium. Nowadays, cancer stem cells and stemness-related genes (SRGs) are revealed to play important roles in the carcinogenesis and metastasis of various tumors. Consequently, we aim to investigate the underlying mechanisms of SRGs in KIRP. METHODS: RNA-seq profiles of 141 KIRP samples were downloaded from the TCGA database, based on which we calculated the mRNA expression-based stemness index (mRNAsi). Next, we selected the differentially expressed genes (DEGs) between low- and high-mRNAsi groups. Then, we utilized weighted gene correlation network analysis (WGCNA) and univariate Cox analysis to identify prognostic SRGs. Afterwards, SRGs were included in the multivariate Cox regression analysis to establish a prognostic model. In addition, a regulatory network was constructed by Pearson correlation analysis, incorporating key genes, upstream transcription factors (TFs), and downstream signaling pathways. Finally, we used Connectivity map analysis to identify the potential inhibitors. RESULTS: In total, 1124 genes were characterized as DEGs between low- and high-RNAsi groups. Based on six prognostic SRGs (CCKBR, GPR50, GDNF, SPOCK3, KC877982.1, and MYO15A), a prediction model was established with an area under curve of 0.861. Furthermore, among the TFs, genes, and signaling pathways that had significant correlations, the CBX2-ASPH-Notch signaling pathway was the most significantly correlated. Finally, resveratrol might be a potential inhibitor for KIRP. CONCLUSIONS: We suggested that CBX2 could regulate ASPH through activation of the Notch signaling pathway, which might be correlated with the carcinogenesis, development, and unfavorable prognosis of KIRP.

Clinical and pathological characteristics of renal cell carcinomas with MiTF translocation.

INTRODUCTION: Microphthalmia Transfactor Family (MiTF) translocation renal cell carcinomas (RCCs) represent a rare subtype of renal cell cancers. They are diagnosed in young patients and have a poor prognosis. The aim of our study was to analyze the clinical and pathological features of patients with MiTF RCC. MATERIAL AND METHOD: We performed a retrospective, monocentric, descriptive study including all patients operated for RCC between January 2015 and January 2023. The diagnosis of MiTF RCC was suspected by immunohistochemistry (IHC) and confirmed by fluorescent in situ hybridization (FISH). Survival data according to histological subtype (MiTF versus ccRCC) were analyzed using the Kaplan-Meier method and compared using a log-rank test. The primary endpoint was recurrence-free survival (RFS). A descriptive cohort analysis was performed. RESULTS: Of the 960 patients included, 19 (2%) had FISH-confirmed MiTF tumors. The median age at diagnosis was 42 years [18-75], the sex ratio was 1.11 females for 1 male, and 4 (21%) patients were immediately metastatic. Median RFS was 21months for patients in the MiTF group and was significantly lower than that of ccRCC patients, HR=4.33 [CI95% 2.06; 9.10; P<0.001]. Of the 11 patients with cT1-T2 tumors, 9 (81.8%) were treated with nephron sparing-surgery, with 2 (22.2%) harbored local recurrence. CONCLUSION: Our study shows that patients with MiTF translocation RCC have a significantly lower RFS than non-MiTF RCC patients. Nephron sparing surgery must be weighted by the high risk of recurrence in this particularly young population.

Expression of HIF­α and their association with clinicopathological parameters in clinical renal cell carcinoma.

Objectives: This study aimed to assess the cellular localization and expression levels of hypoxia-inducible factor (HIF) -α proteins (specifically HIF-1α, HIF-2α, and HIF-3α) that play a role in the hypoxia pathway and to determine their correlation with clinicopathological parameters and patient survival in renal cell carcinoma (RCC). Materials and methods: Tissue microarray (TMA) with cores from 150 clear cell RCCs and 31 non-ccRCC samples. HIF-1α, HIF-2α, and HIF-3α antibodies were used for immunohistochemistry (IHC) of TMA to evaluate the cellular localization and expression levels of HIF-α proteins, specifically in relation to the hypoxia pathway. Results: The expression levels of the HIF-α proteins were higher in the nucleus than in the cytoplasm. Furthermore, the nuclear expression levels of all HIF-α proteins were significantly higher in clear cell RCC (ccRCC) than in non-ccRCC. Cytoplasmic HIF-3α expression was also higher in ccRCC than in non-ccRCC, whereas cytoplasmic HIF-1α and HIF-2α expression levels were similar between the different RCC types. In ccRCC, nuclear HIF-1α expression levels correlated with both nuclear HIF-2α and HIF-3α levels, whereas cytoplasmic HIF-3α expression levels were associated with HIF-1α only.In non-ccRCC, there was a positive correlation observed between nuclear HIF-1α and HIF-3α expression, but no correlation was found with HIF-2α. In patients with ccRCC, the nuclear expressions of HIF-1α and HIF-3α was significantly associated with cancer-specific survival (CSS) in univariate analysis. This association was no longer evident in multivariate analysis. Notably, there was no correlation observed between nuclear HIF-2α expression and CSS in these patients. In contrast, cytoplasmic expression levels showed no association with CSS. Conclusion: The expression levels of the three primary HIF-α proteins were found to be higher in the nucleus than in the cytoplasm. Furthermore, the results indicated that HIF-3α and HIF-1α expression levels were significant univariate factors associated with CSS in patients with clear cell RCC. These results highlight the critical role that HIF-3α and HIF-1α play in the hypoxia pathway.

Identifying and validating MMP family members (MMP2, MMP9, MMP12, and MMP16) as therapeutic targets and biomarkers in kidney renal clear cell carcinoma (KIRC).

Kidney Renal Clear Cell Carcinoma (KIRC) is a malignant tumor that carries a substantial risk of morbidity and mortality. The MMP family assumes a crucial role in tumor invasion and metastasis. This study aimed to uncover the mechanistic relevance of the MMP gene family as a therapeutic target and diagnostic biomarker in Kidney Renal Clear Cell Carcinoma (KIRC) through a comprehensive approach encompassing both computational and molecular analyses. STRING, Cytoscape, UALCAN, GEPIA, OncoDB, HPA, cBioPortal, GSEA, TIMER, ENCORI, DrugBank, targeted bisulfite sequencing (bisulfite-seq), conventional PCR, Sanger sequencing, and RT-qPCR based analyses were used in the present study to analyze MMP gene family members to accurately determine a few hub genes that can be utilized as both therapeutic targets and diagnostic biomarkers for KIRC. By performing STRING and Cytohubba analyses of the 24 MMP gene family members, MMP2 (matrix metallopeptidase 2), MMP9 (matrix metallopeptidase 9), MMP12 (matrix metallopeptidase 12), and MMP16 (matrix metallopeptidase 16) genes were denoted as hub genes having highest degree scores. After analyzing MMP2, MMP9, MMP12, and MMP16 via various TCGA databases and RT-qPCR technique across clinical samples and KIRC cell lines, interestingly, all these hub genes were found significantly overexpressed at mRNA and protein levels in KIRC samples relative to controls. The notable effect of the up-regulated MMP2, MMP9, MMP12, and MMP16 was also documented on the overall survival (OS) of the KIRC patients. Moreover, targeted bisulfite-sequencing (bisulfite-seq) analysis revealed that promoter hypomethylation pattern was associated with up-regulation of hub genes (MMP2, MMP9, MMP12, and MMP16). In addition to this, hub genes were involved in various diverse oncogenic pathways. The MMP gene family members (MMP2, MMP9, MMP12, and MMP16) may serve as therapeutic targets and prognostic biomarkers in KIRC.

[Modern view on the problem of diagnostics of renal angiomioadenomatous tumor].

INTRODUCTION: Angiomyoadenomatous tumor as a nosological entity is not included in the latest version of the International Histological Classification of Kidney Tumors (WHO, 2022) and is related to provisional entity. Currently, there is no consensus among researchers about the nosological affiliation of an angiomyoadenomatous tumor. AIM: To comparatively analyze the histological, immunophenotypic, ultrastructural and molecular parameters of renal angiomyoadenomatous tumor and clear cell papillary renal cell tumor. MATERIALS AND METHODS: The study was performed on surgical specimen from 5 and 10 patients with renal angiomyoadenomatous tumor and with clear cell papillary renal cell tumor, respectively. Immunohistochemical study was carried out on paraffin sections according to the standard protocol. Antibodies HMWCK, AE1/AE3, 7, E-Cadherin, EMA, PAX8 and 9 were chosen. To study tumor tissues on semi-thin and ultra-thin sections, an electron microscope Philips TECNAI 12 BioTwinD-265 was used. For in situ fluorescent diagnostic detection, defined centromere probes, LSI 13/21, LSI N25 /LSI ARSA, TelVysion telomeric probe and a two-color VHL/CEP3 probe were used. RESULTS: Angiomyoadenomatous tumor is characterized by a three-phase structure. In contrast to clear cell papillary renal cell tumor, angiomyoadenomatous tumors show complete membranous expression of CA9. CONCLUSION: Our results allow to state that angiomyoadenomatous tumor and clear cell papillary renal cell tumor are different neoplasms.

[Oncological results of repeat partial nephrectomy in patients with recurrence after nephron-sparing procedures].

AIM: To carried out a comparative analysis of the risk of complications and oncological results of repeat partial nephrectomy and radical nephrectomy in patients with local recurrence after previous organ-sparing procedures. MATERIALS AND METHODS: Retrospective and prospective data of 64 patients with local recurrence of kidney cancer after nephron-sparing procedures. who underwent surgical treatment in the department of oncourology of the National Medical Research Center of Oncology named after N.N. Blokhin in the period from 2000 to 2022. A total of 37 (57.8%) patients of the main group underwent repeat partial nephrectomy, while in 27 (42.2%) patients in the control group a radical nephrectomy was done. Median follow-up was 35 (3-131; Q1-Q3: 13-57) months. Both groups were comparable in terms of demographic and clinical characteristics (p>0.05). The median time to detect relapse after previous partial nephrectomy was 24 (2-172) months. RESULTS: Complications were noted in 8 (21.6%) patients after repeat partial nephrectomy, compared to 29.6% in the control group (n=8) (p=0.563). A comparative analysis revealed a significant advantage in overall survival in patients of the main group (p=0.042). There were no significant differences between groups in cancer-specific and disease-free survival (p=0.369 and p=0.537, respectively). CONCLUSION: Repeat partial nephrectomy for local recurrence of kidney cancer leads to an increase in overall survival compared to radical nephrectomy, in the absence of significant differences in cancer-specific and relapse-free survival.

Integrating tumor and healthy epithelium in a micro-physiology multi-compartment approach to study renal cell carcinoma pathophysiology.

The advent of micro-physiological systems (MPS) in biomedical research has enabled the introduction of more complex and relevant physiological into in vitro models. The recreation of complex morphological features in three-dimensional environments can recapitulate otherwise absent dynamic interactions in conventional models. In this study we developed an advanced in vitro Renal Cell Carcinoma (RCC) that mimics the interplay between healthy and malignant renal tissue. Based on the TissUse Humimic platform our model combines healthy renal proximal tubule epithelial cells (RPTEC) and RCC. Co-culturing reconstructed RPTEC tubules with RCC spheroids in a closed micro-perfused circuit resulted in significant phenotypical changes to the tubules. Expression of immune factors revealed that interleukin-8 (IL-8) and tumor necrosis factor-alfa (TNF-α) were upregulated in the non-malignant cells while neutrophil gelatinase-associated lipocalin (NGAL) was downregulated in both RCC and RPTEC. Metabolic analysis showed that RCC prompted a shift in the energy production of RPTEC tubules, inducing glycolysis, in a metabolic adaptation that likely supports RCC growth and immunogenicity. In contrast, RCC maintained stable metabolic activity, emphasizing their resilience to external factors. RNA-seq and biological process analysis of primary RTPTEC tubules demonstrated that the 3D tubular architecture and MPS conditions reverted cells to a predominant oxidative phosphorylate state, a departure from the glycolytic metabolism observed in 2D culture. This dynamic RCC co-culture model, approximates the physiology of healthy renal tubules to that of RCC, providing new insights into tumor-host interactions. Our approach can show that an RCC-MPS can expand the complexity and scope of pathophysiology and biomarker studies in kidney cancer research.

Multi-omics and immunogenomics analysis revealed PFKFB3 as a targetable hallmark and mediates sunitinib resistance in papillary renal cell carcinoma: in silico study with laboratory verification.

Glycolysis-related metabolic reprogramming is a central hallmark of human cancers, especially in renal cell carcinoma. However, the regulatory function of glycolytic signature in papillary RCC has not been well elucidated. In the present study, the glycolysis-immune predictive signature was constructed and validated using WGCNA, glycolysis-immune clustering analysis. PPI network of DEGs was constructed and visualized. Functional enrichments and patients' overall survival were analyzed. QRT-PCR experiments were performed to detect hub genes' expression and distribution, siRNA technology was used to silence targeted genes; cell proliferation and migration assays were applied to evaluate the biological function. Glucose concentration, lactate secretion, and ATP production were measured. Glycolysis-Immune Related Prognostic Index (GIRPI) was constructed and combined analyzed with single-cell RNA-seq. High-GIRPI signature predicted significantly poorer outcomes and relevant clinical features of pRCC patients. Moreover, GIRPI also participated in several pathways, which affected tumor immune microenvironment and provided potential therapeutic strategy. As a key glycolysis regulator, PFKFB3 could promote renal cancer cell proliferation and migration in vitro. Blocking of PFKFB3 by selective inhibitor PFK-015 or glycolytic inhibitor 2-DG significantly restrained renal cancer cells' neoplastic potential. PFK-015 and sunitinib could synergistically inhibit pRCC cells proliferation. Glycolysis-Immune Risk Signature is closely associated with pRCC prognosis, progression, immune infiltration, and therapeutic response. PFKFB3 may serve as a pivotal glycolysis regulator and mediates Sunitinib resistance in pRCC patients.

Clinical safety and efficacy of microwave ablation for small renal masses.

PURPOSE: CT-guided MWA is a safe and effective tool that should be utilized in the treatment of small renal masses (SRMs). We aim to clarify the utility of CT-guided MWA by examining patient outcomes such as recurrence, treatment success, changes in renal function, and complications. METHODS: A retrospective review of consecutive patients with SRMs who underwent same day renal mass biopsy (RMB) and CT-guided MWA between 2015 and 2022 was performed. Treatment safety was assessed by 30-day complications according to the Clavien-Dindo system and change in eGFR >30 days post-procedure. Treatment efficacy was defined by local recurrence and incomplete treatment rates and calculated using the Kaplan-Meier method. RESULTS: A total of 108 renal masses were found in 104 patients. The overall complication rate was 7.4% (8/108), of which 4 were major complications (3.7%). For those with renal function available >30 days post ablation, the median eGFR was 47.2 (IQR: 36.0, 57), compared to 52.3 (IQR: 43.7, 61.5) pre-ablation, p<0.0001. 5-year local recurrence free survival was 86%. Among those with biopsy proven malignancy (n= 66), there were five local recurrences (7.54%) occurring at a median of 25.1 months (IQR 19.9, 36.2) and one case (1.5%) of incomplete treatment. CONCLUSIONS: As the medical field continues to evolve towards less invasive interventions, MWA offers a valuable tool in the management of renal masses. With low major complication and recurrence rates, our findings support the utility of CT-guided MWA as a tool for treatment of SRMs.

Robotic salvage partial nephrectomy following surgical and ablative therapies.

PURPOSE: Partial nephrectomies in the salvage setting after ablative or surgical therapy remain challenging cases that are underreported in the literature (1-5). The aim of this video is to demonstrate techniques for robotic salvage partial nephrectomy to manage recurrent renal cell carcinoma (RCC) after failed prior partial nephrectomy and primary cryotherapy. MATERIALS AND METHODS: A 55-year-old man after previous robotic-assisted right partial nephrectomy presented with a 2.5 cm locally recurrent renal mass abutting the collecting system. A 59-year-old man with right renal cell carcinoma initially treated with cryoablation presented local recurrence. CT imaging demonstrated 2.6 cm right renal mass consistent with tumor recurrence at previous treatment site. RESULTS: Both procedures were completed in under 180 minutes. Clamp time was 22 minutes after the previous partial nephrectomy and 25 minutes after previous cryotherapy. There were no perioperative complications. Pathology in both cases demonstrated pT1a clear cell RCC with negative margins. Both patients have since no evidence of recurrent disease on follow-up imaging at 1 and 2 years, respectively. CONCLUSIONS: Salvage robotic partial nephrectomy should be considered as a feasible treatment option after failure of initial therapy-surgical or ablative. A salvage procedure is often more challenging than its standard therapy-naïve counterpart due to development of dense inflammation after previous interventions. Despite this, robotic partial nephrectomies in the salvage setting can be safely carried out with good surgical outcomes, particularly when utilizing intraoperative ultrasound to identify tumor margins and key anatomy.

Preliminary Investigation of a Rapid and Feasible Therapeutic Drug Monitoring Method for the Real-Time Estimation of Blood Pazopanib Concentrations.

Pazopanib is a multi-kinase inhibitor used to treat advanced/metastatic renal cell carcinoma and advanced soft tissue tumors; however, side effects such as diarrhea and hypertension have been reported, and dosage adjustment based on drug concentration in the blood is necessary. However, measuring pazopanib concentrations in blood using the existing methods is time-consuming; and current dosage adjustments are made using the results of blood samples taken at the patient's previous hospital visit (approximately a month prior). If the concentration of pazopanib could be measured during the waiting period for a doctor's examination at the hospital (in approximately 30 min), the dosage could be adjusted according to the patient's condition on that day. Therefore, we aimed to develop a method for rapidly measuring blood pazopanib concentrations (in approximately 25 min) using common analytical devices (a tabletop centrifuge and a spectrometer). This method allowed for pazopanib quantification in the therapeutic concentration range (25-50 µg/mL). Additionally, eight popular concomitant medications taken simultaneously with pazopanib did not interfere with the measurements. We used the developed method to measure blood concentration in two patients and obtained similar results to those measured using the previously reported HPLC method. By integrating it with the point of care and sample collection by finger pick, this method can be used for measurements in pharmacies and patients' homes. This method can maximize the therapeutic effects of pazopanib by dose adjustment to control adverse events.

Deciphering the molecular landscape: integrating single-cell transcriptomics to unravel myofibroblast dynamics and therapeutic targets in clear cell renal cell carcinomas.

Background: Clear cell renal cell carcinomas (ccRCCs) epitomize the most formidable clinical subtype among renal neoplasms. While the impact of tumor-associated fibroblasts on ccRCC progression is duly acknowledged, a paucity of literature exists elucidating the intricate mechanisms and signaling pathways operative at the individual cellular level. Methods: Employing single-cell transcriptomic analysis, we meticulously curated UMAP profiles spanning substantial ccRCC populations, delving into the composition and intrinsic signaling pathways of these cohorts. Additionally, Myofibroblasts were fastidiously categorized into discrete subpopulations, with a thorough elucidation of the temporal trajectory relationships between these subpopulations. We further probed the cellular interaction pathways connecting pivotal subpopulations with tumors. Our endeavor also encompassed the identification of prognostic genes associated with these subpopulations through Bulk RNA-seq, subsequently validated through empirical experimentation. Results: A notable escalation in the nFeature and nCount of Myofibroblasts and EPCs within ccRCCs was observed, notably enriched in oxidation-related pathways. This phenomenon is postulated to be closely associated with the heightened metabolic activities of Myofibroblasts and EPCs. The Myofibroblasts subpopulation, denoted as C3 HMGA1+ Myofibroblasts, emerges as a pivotal subset, displaying low differentiation and positioning itself at the terminal point of the temporal trajectory. Intriguingly, these cells exhibit a high degree of interaction with tumor cells through the MPZ signaling pathway network, suggesting that Myofibroblasts may facilitate tumor progression via this pathway. Prognostic genes associated with C3 were identified, among which TUBB3 is implicated in potential resistance to tumor recurrence. Finally, experimental validation revealed that the knockout of the key gene within the MPZ pathway, MPZL1, can inhibit tumor activity, proliferation, invasion, and migration capabilities. Conclusion: This investigation delves into the intricate mechanisms and interaction pathways between Myofibroblasts and ccRCCs at the single-cell level. We propose that targeting MPZL1 and the oxidative phosphorylation pathway could serve as potential key targets for treating the progression and recurrence of ccRCC. This discovery paves the way for new directions in the treatment and prognosis diagnosis of ccRCC in the future.