Boosting Clear Cell Renal Carcinoma-Specific Drug Discovery Using a Deep Learning Algorithm and Single-Cell Analysis.

Clear cell renal carcinoma (ccRCC), the most common subtype of renal cell carcinoma, has the high heterogeneity of a highly complex tumor microenvironment. Existing clinical intervention strategies, such as target therapy and immunotherapy, have failed to achieve good therapeutic effects. In this article, single-cell transcriptome sequencing (scRNA-seq) data from six patients downloaded from the GEO database were adopted to describe the tumor microenvironment (TME) of ccRCC, including its T cells, tumor-associated macrophages (TAMs), endothelial cells (ECs), and cancer-associated fibroblasts (CAFs). Based on the differential typing of the TME, we identified tumor cell-specific regulatory programs that are mediated by three key transcription factors (TFs), whilst the TF EPAS1/HIF-2α was identified via drug virtual screening through our analysis of ccRCC's protein structure. Then, a combined deep graph neural network and machine learning algorithm were used to select anti-ccRCC compounds from bioactive compound libraries, including the FDA-approved drug library, natural product library, and human endogenous metabolite compound library. Finally, five compounds were obtained, including two FDA-approved drugs (flufenamic acid and fludarabine), one endogenous metabolite, one immunology/inflammation-related compound, and one inhibitor of DNA methyltransferase (N4-methylcytidine, a cytosine nucleoside analogue that, like zebularine, has the mechanism of inhibiting DNA methyltransferase). Based on the tumor microenvironment characteristics of ccRCC, five ccRCC-specific compounds were identified, which would give direction of the clinical treatment for ccRCC patients.

Pazopanib stimulates senescence of renal carcinoma cells through targeting nuclear factor E2-related factor 2 (Nrf2).

Renal cell carcinoma (RCC) is the most common kidney cancer with high mortality rate. Pazopanib has been approved for the treatment of RCC. However, the underlying mechanism is not clear. Here, we report a novel finding by showing that treatment with Pazopanib could promote cellular senescence of the human RCC cell line ACHN. Cells were stimulated with 5, 10, and 20 µM Pazopanib, respectively. Cellular senescence was measured using senescence-associated ß-galactosidase (SA-ß-Gal) staining. Western blot analysis and real-time polymerase chain reaction were used to measure the mRNA and protein expression of nuclear factor E2-related factor 2 (Nrf2), γH2AX, human telomerase reverse transcriptase (hTERT), telomeric repeat binding factor 2 (TERF2), p53 and plasminogen activator inhibitor (PAI). First, we found that exposure to Pazopanib reduced the cell viability of ACHN cells. Additionally, Pazopanib induced oxidative stress  by increasing the production of reactive oxygen species, reducing the levels of glutathione peroxidase, and promoting nuclear translocation of Nrf2. Interestingly, Pazopanib exposure resulted in DNA damage by increasing the expression of γH2AX. Importantly, Pazopanib increased cellular senescence and reduced telomerase activity. Pazopanib also reduced the gene expression of hTERT but increased the gene expression of TERF2. Correspondingly, we found that Pazopanib increased the expression of p53 and PAI at both the mRNA and protein levels. To elucidate the underlying mechanism, the expression of Nrf2 was knocked down by transduction with Ad- Nrf2 shRNA. Results indicate that silencing of Nrf2 in ACHN cells abolished the effects of Pazopanib in stimulating cellular senescence and reducing telomerase activity. Consistently, knockdown of Nrf2 restored the expression of p53 and PAI in ACHN cells. Based on these results, we explored a novel mechanism whereby which Pazopanib displays a cytotoxicity effect in RCC cells through promoting cellular senescence mediated by Nrf2.

Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A).

BACKGROUND: As part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both with and without toxicity. Significant TFS was reported for the nivolumab/ipilimumab arms of the CheckMate 067 and 214 trials for patients with advanced melanoma or renal cell carcinoma (aRCC), respectively, where immunotherapy was often halted for toxicity rather than a predefined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16-260 trial, which was designed to reduce toxicity and cap immunotherapy duration. METHODS: Data were analyzed from 128 patients with clear-cell aRCC treated with first-line nivolumab monotherapy for up to 2 years. Salvage nivolumab/ipilimumab for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (29% of patients). TFS was defined as the area between Kaplan-Meier curves for a time from registration to protocol therapy cessation and for a time from registration to subsequent systemic therapy initiation or death, estimated from 36-month mean times. The time on or off protocol treatment with grade 3+treatment-related adverse events (TRAEs) was also captured. RESULTS: At 36 months from enrollment, 68.3% of patients were alive: 96.8% of International Metastatic RCC Database Consortium (IMDC) favorable-risk patients and 56.6% of those with intermediate/poor-risk, respectively. The 36-month mean time on protocol therapy was 11.5 months including 0.6 months with grade 3+TRAEs (16.0 months for favorable-risk patients and 9.6 months for intermediated/poor-risk patients). The 36-month mean TFS for the whole population was 9.4 months (12.9 months including 1.5 months with grade 3+TRAEs for favorable-risk and 8.0 months including 1.0 months with grade 3+TRAEs for intermediate/poor-risk). At 36 months, 65.6% of favorable-risk patients and 27.1% of intermediate/poor-risk patients were alive and subsequent systemic treatment-free. CONCLUSIONS: Nivolumab monotherapy with salvage nivolumab/ipilimumab in non-responders is an active treatment approach in treatment-naïve patients with aRCC and, similar to nivolumab/ipilimumab in CheckMate 214, results in substantial TFS and toxicity-free TFS. TFS was greatest in patients with favorable-risk disease, supporting the use of an immunotherapy-only regimen in this population.

[Total polyphenols of Cydonia oblonga inhibited proliferation and migration of renal cancer cells by PI3K/Akt/mTOR pathway].

The mechanism of total polyphenols of Cydonia oblonga Miller(TPCOM) against kidney cancer was elucidated through a combination of network pharmacology, bioinformatics, and experimental verification. The active polyphenolic compounds from C. oblonga were screened by network pharmacological techniques and kidney cancer-related targets were collected through the database. The differential gene expression analysis was performed on RNA sequencing data from tumor tissue and normal tissue of kidney cancer patients obtained from the Gene Expression Omnibus(GEO) database. The results of network pharmacology predictions and differential gene expression analysis were used to identify the core genes targeted by TPCOM in kidney cancer. Survival analysis was conducted to identify key targets that could impact patient survival, followed by Kyoto Encyclopedia of Genes and Genomes(KEGG) and Gene Ontology(GO) enrichment analyses. Cell proliferation and activity experiments(cell counting kit-8) were conducted using TPCOM at concentrations ranging from 20 to 640 µg·mL~(-1) on 786-O and Renca cells. Additionally, TPCOM at concentrations of 40, 80, and 160 µg·mL~(-1) was applied to kidney cancer cells to assess its effect on cell migration and its regulation of protein expression levels related to the protein kinase B(Akt), mammalian target of rapamycin(mTOR), and phosphoinositide 3-kinase(PI3K) signaling pathways. Network pharmacology predicted eight active polyphenolic compounds from C. oblonga. Survival analysis revealed 15 significantly differentially expressed genes in kidney cancer that were affected by TPCOM and had a significant impact on patient survival. KEGG and GO analysis results indicated that these 15 targets were primarily associated with the PI3K/Akt signaling pathway, cell migration, and proliferation. The results showed that TPCOM could inhibit the proliferation of 786-O and Renca cells, with IC_(50) values of 121.4 and 137.9 µg·mL~(-1), respectively. TPCOM was also found to inhibit the migration of these cells and suppress the PI3K/Akt/mTOR signaling pathway. TPCOM may exert its anti-kidney cancer effects by inhibiting the activation of the PI3K/Akt/mTOR signaling pathway, thereby restraining the proliferation and migration of kidney cancer cells. This study provides a foundation for the research on the anti-tumor effects of natural product C. oblonga, particularly in Xinjiang, and holds significance for further promoting its development and utilization.

Special populations in metastatic renal cell carcinoma.

PURPOSE OF REVIEW: This review focuses on special populations poorly represented in current evidence-based practice for metastatic renal cell carcinoma (mRCC). This includes the elderly and frail, patients on immunosuppression or with autoimmune diseases, patients with brain, liver, and/or bone metastases, and RCC with sarcomatoid features. RECENT FINDINGS: Certain populations are poorly represented in current trials for mRCC. Patients with central nervous system (CNS) metastases are often excluded from first-line therapy trials. Modern doublet systemic therapy appears to benefit patients with bone or liver metastases, but data supporting this conclusion is not robust. Post-hoc analyses on patients with sarcomatoid differentiation have shown improved response to modern doublet therapy over historical treatments. The elderly are underrepresented in current clinical trials, and most trials exclude all but high-performing (nonfrail) patients, though true frailty is likely poorly captured using the current widely adopted indices. It is difficult to make conclusions about the efficacy of modern therapy in these populations from subgroup analyses. Data from trials on other malignancies in patients with autoimmune diseases or solid organ transplant recipients on immunosuppression suggest that immune checkpoint inhibitors (ICIs) may still have benefit, though at the risk of disease flare or organ rejection. The efficacy of ICIs has not been demonstrated specifically for RCC in this group of patients. SUMMARY: The elderly, frail, and immunosuppressed, those with tumors having aggressive histologic features, and patients with brain, bone, and/or liver metastases represent the populations least understood in the modern era of RCC treatment.

Advanced renal cell carcinoma management: the Latin American Cooperative Oncology Group (LACOG) and the Latin American Renal Cancer Group (LARCG) consensus update.

PURPOSE: Renal cell carcinoma is an aggressive disease with a high mortality rate. Management has drastically changed with the new era of immunotherapy, and novel strategies are being developed; however, identifying systemic treatments is still challenging. This paper presents an update of the expert panel consensus from the Latin American Cooperative Oncology Group and the Latin American Renal Cancer Group on advanced renal cell carcinoma management in Brazil. METHODS: A panel of 34 oncologists and experts in renal cell carcinoma discussed and voted on the best options for managing advanced disease in Brazil, including systemic treatment of early and metastatic renal cell carcinoma as well as nonclear cell tumours. The results were compared with the literature and graded according to the level of evidence. RESULTS: Adjuvant treatments benefit patients with a high risk of recurrence after surgery, and the agents used are pembrolizumab and sunitinib, with a preference for pembrolizumab. Neoadjuvant treatment is exceptional, even in initially unresectable cases. First-line treatment is mainly based on tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs); the choice of treatment is based on the International Metastatic Database Consortium (IMCD) risk score. Patients at favourable risk receive ICIs in combination with TKIs. Patients classified as intermediate or poor risk receive ICIs, without preference for ICI + ICIs or ICI + TKIs. Data on nonclear cell renal cancer treatment are limited. Active surveillance has a place in treating favourable-risk patients. Either denosumab or zoledronic acid can be used for treating metastatic bone disease. CONCLUSION: Immunotherapy and targeted therapy are the standards of care for advanced disease. The utilization and sequencing of these therapeutic agents hinge upon individual risk scores and responses to previous treatments. This consensus reflects a commitment to informed decision-making, drawn from professional expertise and evidence in the medical literature.

GHITM regulates malignant phenotype and sensitivity to PD-1 blockade of renal cancer cells via Notch signalling.

Growth hormone inducible transmembrane protein (GHITM), one member of Bax inhibitory protein-like family, has been rarely studied, and the clinical importance and biological functions of GHITM in kidney renal clear cell carcinoma (KIRC) still remain unknown. In the present study, we found that GHITM was downregulated in KIRC. Aberrant GHITM downregulation related to clinicopathological feature and unfavourable prognosis of KIRC patients. GHITM overexpression inhibited KIRC cell proliferation, migration and invasion in vitro and in vivo. Mechanistically, GHITM overexpression could induce the downregulation of Notch1, which acts as an oncogene in KIRC. Overexpression of Notch1 effectively rescued the inhibitory effect induced by GHITM upregulation. More importantly, GHITM could regulate PD-L1 protein abundance and ectopic overexpression of GHITM enhanced the antitumour efficiency of PD-1 blockade in KIRC, which provided new insights into antitumour therapy. Furthermore, we also showed that YY1 could decrease GHITM level via binding to its promoter. Taken together, our study revealed that GHITM was a promising therapeutic target for KIRC, which could modulate malignant phenotype and sensitivity to PD-1 blockade of renal cancer cells via Notch signalling pathway.

Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.

BACKGROUND: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy. CONCLUSIONS: Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).

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.

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.

Ginsenoside Rh4 Facilitates the Sensitivity of Renal Cell Carcinoma to Ferroptosis via the NRF2 Pathway.

BACKGROUND: Renal cell carcinoma (RCC) is one of the most common malignancies of the urinary system and ferroptosis is considered as a promising therapeutic approach for treating RCC. Ginsenoside Rh4 (Rh4) was proved to have anticancer properties and play roles in ferroptosis. This study aimed to investigate the potential of ginsenoside Rh4 (Rh4) in enhancing the sensitivity of renal cell carcinoma (RCC) cells to ferroptosis and to elucidate the underlying mechanisms. METHODS: RCC cell lines of 786-O and ACHN were treated with RAS-selective lethal 3 (RSL3) and/or Rh4. Cell-viability assays were used to determine how Rh4 affected the sensitivity of RCC cells to RSL3-induced ferroptosis. Quantitative real-time polymerase chain reaction was conducted to examine the levels of ferroptosis-related genes. Additionally, the knockdown of nuclear factor E2-related factor 2 (NRF2) was performed to investigate the role of NRF2 in mediating the effects of Rh4. RESULTS: RSL3 suppressed the progression of RCC cells by inducing ferroptosis. Furthermore, Rh4 led to more RCC sensitivity to ferroptosis induced by RSL3. Rh4 downregulated the ferroptosis-related gene expression including superoxide dismutase 1 (p < 0.01), glutathione peroxidase 4 (p < 0.01), and catalase (p < 0.01), which was attenuated by NRF2 knockdown. This finding suggested that Rh4 exerted its sensitising effect on ferroptosis through the NRF2 pathway. CONCLUSIONS: Rh4 made RCC cells more sensitive to ferroptosis by inhibiting the NRF2 signaling and suppressing the expression of antioxidant enzymes. Therefore, combining Rh4 with ferroptosis-inducing reagents to treat RCC had potential therapeutic application.

FDG PET/CT in the Diagnosis and After Sunitinib Follow-up of Synchronous Base of Tongue and Thyroid Metastases From Renal Cell Carcinoma.

ABSTRACT: Renal cell carcinoma (RCC) is a leading cause of mortality among genitourinary malignancies with limited therapeutic options. The hematogenous route, lymphatic spread, and direct invasion have been documented in RCC. Usually, metastases are regional lymph nodes, lungs, bone, liver, adrenal glands, contralateral kidney, and brain. Metastases to the rare sites such as skin, breast, head and neck were documented in the literature. In the present case, we describe the synchronous metastases to the base of the tongue and thyroid gland in RCC and the response to sunitinib therapy on 18F-FDG PET/CT.

The vasculogenic mimicry related signature predicts the prognosis and immunotherapy response in renal clear cell carcinoma.

BACKGROUND: Clear cell carcinoma of the kidney is a common urological malignancy characterized by poor patient prognosis and treatment outcomes. Modulation of vasculogenic mimicry in tumor cells alters the tumor microenvironment and the influx of tumor-infiltrating lymphocytes, and the combination of its inducers and immune checkpoint inhibitors plays a synergistic role in enhancing antitumor effects. METHODS: We downloaded the data from renal clear cell carcinoma samples and vasculogenic mimicry-related genes to establish a new vasculogenic mimicry-related index (VMRI) using a machine learning approach. Based on VMRI, patients with renal clear cell carcinoma were divided into high VMRI and low VMRI groups, and patients' prognosis, clinical features, tumor immune microenvironment, chemotherapeutic response, and immunotherapeutic response were systematically analyzed. Finally, the function of CDH5 was explored in renal clear cell carcinoma cells. RESULTS: VMRI can be used for prognostic and immunotherapy efficacy prediction in a variety of cancers, which consists of four vasculogenic mimicry-related genes (CDH5, MMP9, MAPK1, and MMP13), is a reliable predictor of survival and grade in patients with clear cell carcinoma of the kidney and has been validated in multiple external datasets. We found that the high VMRI group presented higher levels of immune cell infiltration, which was validated by pathological sections. We performed molecular docking prediction of vasculogenic mimicry core target proteins and identified natural small molecule drugs with the highest affinity for the target protein. Knockdown of CDH5 inhibited the proliferation and migration of renal clear cell carcinoma. CONCLUSIONS: The VMRI identified in this study allows for accurate prognosis assessment of patients with renal clear cell carcinoma and identification of patient populations that will benefit from immunotherapy, providing valuable insights for future precision treatment of patients with renal clear cell carcinoma.

Effect of galectin-1 on prognosis and responsiveness of immune checkpoint plus tyrosine kinase inhibition in renal cell carcinoma.

BACKGROUND: In renal cell carcinoma (RCC), no clinically available biomarker has been utilized for checkpoint inhibitor immunotherapy (IO) + tyrosine kinase inhibitor (TKI) combinations. Galectin-1 overexpression is found in tumors, with potential immune-regulating roles. METHODS: RNA-sequencing was performed in two cohorts of RCC treated with IO/TKI combination therapy (ZS-MRCC, JAVELIN-101). Immunohistochemistry and flow cytometry were performed to investigate immune cell infiltration and function in the tumor microenvironment of RCC. The RECIST criteria were used to define response and progression-free survival (PFS). RESULTS: Galectin-1 expression was elevated in RCC with higher stage (p < 0.001) and grade (p < 0.001). Galectin-1 expression was also elevated in non-responders of IO/TKI therapy (p = 0.047). High galectin-1 was related with shorter PFS in both ZS-MRCC cohort (p = 0.036) and JAVELIN-101 cohort (p = 0.005). Multivariate Cox analysis defined galectin-1 as an independent factor for PFS (HR 2.505; 95% CI 1.116-5.622; p = 0.026). In the tumor microenvironment, high galectin-1 was related with decreased GZMB+CD8+ T cells (Speraman's ρ = -0.31, p = 0.05), and increased PD1 + CD8+ T cells (Speraman's ρ = 0.40, p = 0.01). Besides, elevated number of regulatory T cells (p = 0.039) and fibroblasts (p = 0.011) was also found in high galectin-1 tumors. Finally, a random-forest score (RFscore) was built for predicting IO/TKI benefit. IO/TKI therapy showed benefit only in low-RFscore patients (HR 0.489, 95% CI 0.358-0.669, p < 0.001), rather than high-RFscore patients (HR 0.875, 95% CI 0.658-1.163, p = 0.357). CONCLUSIONS: High galectin-1 indicated therapeutic resistance and shorter PFS of IO/TKI therapy. High galectin-1 also indicated CD8+ T cell dysfunction. High galectin-1 could be applied for patient selection of IO/TKI therapy in RCC.

Bioinformatics analysis highlights CCNB1 as a potential prognostic biomarker and an anti-kidney renal papillary cell carcinoma drug target.

Kidney renal papillary cell carcinoma (KIRP) is a common urinary tumor that causes lymph node invasion. Once metastatic, the prognosis is poor and there is a lack of effective early diagnostic markers for this tumor. The expression of CCNB1 in KIRP tumor tissues was significantly higher than that in normal tissues in The Cancer Genome Atlas database with or without the genotype-tissue expression database, and a consistent result was obtained in 32 paired tissues. In addition, CCNB1 expression increased remarkably with the progression of the T and M stages. Moreover, using the online HPA database, we verified that the immunohistochemical scores of CCNB1 in KIRP were higher than those in the normal kidney tissues. The higher expression group of CCNB1 showed a worse prognosis in KIRP. Moreover, the receiver operating characteristic curve, univariate and multivariate analyses, and construction of the column diagram further illustrated that CCNB1 was an independent prognostic factor for KIRP. Meanwhile, CCNB1 could better predict the 1- and 3-year survival rates of KIRP. Six genes were significantly and positively co-expressed with CCNB1. We also found that the CCNB1 high-expression group was enriched in the ECM_RECEPTOR_INTERACTION and FOCAL_ADHESION pathways. Finally, drug sensitivity analysis combined with molecular docking identified 5 targeting drugs with the strongest binding activity to CCNB1. CCNB1 is a potential and reliable biomarker for KIRP diagnosis and can be used to predict the survival of patients with KIRP. The 5 selected drugs targeting CCNB1 may provide new hopes for patients with KIRP metastasis.

Analysis of Factors Contributing to Adverse Events and Evaluation of Their Impact on Prognosis in Metastatic Renal Cell Carcinoma Patients-Real-World Experience in a Single-Center Retrospective Study and Narrative Review.

Background and Objectives: More than 430,000 new cases of renal cell carcinoma (RCC) were reported in 2020. Clear cell RCC, which occurs in 80% of cases, is often associated with mutations in the VHL gene, leading to dysregulation of hypoxia-induced transcription factors pathways and carcinogenesis. The purpose of this study is to examine the adverse events (AEs) of cabozantinib treatment and the relationship between individual patient factors and the frequency of their occurrence in detail. Materials and Methods: Seventy-one patients with metastatic RCC were treated with second or further lines of cabozantinib at the Department of Genitourinary Oncology, Maria Sklodowska-Curie National Research Institute of Oncology. Comprehensive data, including demographics, clinicopathological factors, and AEs, were collected from January 2017 to June 2021. This study evaluated the impact of various patient-related factors on the rate of adverse events and treatment tolerance using a Cox proportional hazards model. Results: Cabozantinib-induced AEs were significantly associated with body mass index (BMI), body surface area (BSA), IMDC prognostic score, and treatment line. Notably, patients receiving cabozantinib post-tyrosine kinase inhibitors reported fewer AEs. Dose reduction was unrelated to adverse event frequency, but patients requiring dose reduction were characterized with lower body mass and BSA but not BMI. Conclusions: The factors described make it possible to predict the incidence of AEs, which allows for faster detection and easier management, especially in the high-risk group. AEs should be reported in detail in real-world studies, as their occurrence has a significant impact on prognosis.

Outcome benefits of upfront cytoreductive nephrectomy for patients with metastatic renal cell carcinoma: An analysis of the TriNetX database.

BACKGROUND: The role of upfront cytoreductive nephrectomy remains debatable in the present era of tyrosine kinase inhibitors and immune checkpoint inhibitors. Here, we aimed to evaluate the outcomes of metastatic renal cell carcinoma patients treated with upfront CN and modern systemic therapies. METHODS: Using the TriNetX network database, we identified patients, in the period from 2008 to 2022, who were diagnosed with metastatic renal cell carcinoma, receiving first-line systemic therapies with tyrosine kinase inhibitors or immune checkpoint inhibitors. Their overall survivals were evaluated using the Kaplan-Meier method as well as multivariable regressions. RESULTS: We identified 11,094 patients with metastatic renal cell carcinoma. Of them, 2,914 (43%) patients in the tyrosine kinase inhibitor cohort (n = 6,779), and 1,884 (43.7%) in the immune checkpoint inhibitors cohort (n = 4315) underwent upfront cytoreductive nephrectomy. Those receiving upfront cytoreductive nephrectomy showed survival advantages with either tyrosine kinase inhibitor (Hazard ratio 0.722, 95% Confidence interval 0.67-0.73, p<0.001) or immune checkpoint inhibitors (Hazard ratio 65.1, 95% Confidence interval 0.59-0.71, p<0.001). In multivariable analysis, upfront cytoreductive nephrectomy was a factor for improved OS in both cohorts: tyrosine kinase inhibitors (Hazard ratio 0.623, 95% Confidence interval 0.56-0.694, p<0.001) and immune checkpoint inhibitors cohort (Hazard ratio 0.688, 95% Confidence interval 0.607-0.779, p<0.001). CONCLUSIONS: Upfront cytoreductive nephrectomy was associated with an improved overall survival for patients with metastatic renal cell carcinoma receiving either first-line tyrosine kinase inhibitors or immune checkpoint inhibitors. Our results support a clinical role of upfront cytoreductive nephrectomy in the modern era.

Electrolyte disorders induced by six multikinase inhibitors therapy for renal cell carcinoma: a large-scale pharmacovigilance analysis.

To provide evidence for optimization of multi-kinase inhibitors (MKIs) use in the clinic, we use the public database to describe and evaluate electrolyte disorders (EDs) related to various MKIs treated for renal cell carcinoma. We analyzed spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS) in an observational and retrospective manner. Selecting electrolyte disorders' adverse events to multikinase inhibitors (axitinib, cabozantinib, lenvatinib, pazopanib, sunitinib, and sorafenib). We used Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms to analyze suspected adverse reactions of electrolyte disorders induced by MKIs (which were treated for renal cell carcinoma) between January 2004 and December 2022. As of December 2022, 2772 MKIs (which were treated for renal cell carcinoma) ICSRs were related to electrolyte disorders AEs. In general, there were more AEs cases in males, except lenvatinib and 71.8% of the cases were submitted from North America. ICSRs in this study, the age group most frequently affected by electrolyte disorders AEs was individuals aged 45-64 years for axitinib, cabozantinib, pazopanib, and sunitinib, whereas electrolyte disorders AEs were more common in older patients (65-74 years) for sorafenib and lenvatinib. For all EDs documented in ICSRs (excluding missing data), the most common adverse outcome was hospitalization(1429/2674, 53.4%), and the most serious outcome was death/life-threat(281/2674, 10.5%). The prevalence of mortality was highest for sunitinib-related EDs (145/616, 23.5%), excluding missing data (n = 68), followed by cabozantinib-related EDs (20/237, 8.4%), excluding missing data (n = 1). The distribution of time-to-onset of Each drug-related ICSRs was not all the same, and the difference was statistically significant (P = 0.001). With the criteria of ROR, the six MKIs were all significantly associated with electrolyte disorders AEs, the strongest association was the association between cabozantinib and hypermagnesaemia. MKIs have been reported to have significant electrolyte disorders AEs. Patients and physicians need to recognize and monitor these potentially fatal adverse events.