Network pharmacology and molecular docking analysis reveal insights into the molecular mechanism of Gualou Qumai Wan in clear cell renal cell carcinoma

Background:To initially clarify the potential therapeutic targets and pharmacological mechanism regarding Gualou Qumai Wan(GQW),a kind of traditional Chinese medicine(TCM),in clear cell renal cell carcinoma(ccRCC)by virtue of the network pharmacology analysis and molecular docking analysis.Methods:The screening of bioactive components and targets of GQW was based on the Traditional Chinese Medicine System Pharmacology(TCMSP)and the UniProt platform served for standardizing their targets.Online Mendelian Inheritance in Man(OMIM),PharmGkb,TTD,DrugBank and GeneCards databases were searched to collect the disease targets of ccRCC.Cytoscape assisted in constructing herb-compound-target(H-C-T)networks.The STRING database was searched for constructing the target protein-protein interaction(PPI)networks,while the R programming language served for analyzing GO functional terms and the KEGG pathways related to potential targets.Analyses of core genes related to survival and tumor microenvironment(TME)were conducted respectively based on the GEPIA2 database and TIMER 2.0 database.Human Protein Atlas(HPA)and The Cancer Genome Atlas(TCGA)helped to obtain core genes’protein expression as well as transcriptome expression level.Autodock Vina software validated the molecular docking regarding GQW components and pivotal targets.Results:The constructed H-C-T networks mainly had 33 compounds and 65 targets.A topological analysis of the PPI network identified that ESR1,AKT1,HIF1A,PTGS2,TP53 and VEGFA serve as core targets in the way GQW affects ccRCC.According to the GO and KEGG pathway enrichment analyses,the effects of GQW are mediated by genes related to hypoxia and oxidative stress as well as the Chemical carcinogenesis-receptor activation and PI3K-Akt signaling pathways.AKT1 shows a close relation to the recruitment of various immune cells and can remarkably affect disease prognosis according to reports.Molecular docking and molecular dynamics simulations showed that diosgenin has higher affinity with core targets.Conclusion:The study makes a comprehensive explanation of the biological activity,potential targets,as well as molecular mechanism regarding GQW against ccRCC,which promisingly assists in revealing the action mechanism of TCM formulae in disease treatment and the respective and scientific basis.

Solute carrier-related signature for assessing prognosis and immunity in patients with clear-cell renal cell carcinoma

Background:Clear-cell renal cell carcinoma(ccRCC)is the most common malignant kidney cancer.However,the tumor microenvironment and crosstalk involved in metabolic reprogramming in ccRCC are not well-understood.Methods:We used The Cancer Genome Atlas to obtain ccRCC transcriptome data and clinical information.The EMTAB-1980 cohort was used for external validation.The GENECARDS database contains the first 100 solute carrier(SLC)-related genes.The predictive value of SLC-related genes for ccRCC prognosis and treatment was assessed using univariate Cox regression analysis.An SLC-related predictive signature was developed through Lasso regression analysis and used to determine the risk profiles of patients with ccRCC.Patients in each cohort were separated into high-and low-risk groups based on their risk scores.The clinical importance of the signature was assessed through survival,immune microenvironment,drug sensitivity,and nomogram analyses using R software.Results:SLC25A23,SLC25A42,SLC5A1,SLC3A1,SLC25A37,SLC5A6,SLCO5A1,and SCP2 comprised the signatures of the eight SLCrelated genes.Patients with ccRCC were separated into high-and low-risk groups based on the risk value in the training and validation cohorts;the high-risk group had a significantly worse prognosis(p<0.001).The risk score was an independent predictive indicator of ccRCC in the two cohorts according to univariate and multivariate Cox regression(p<0.05).Analysis of the immune microenvironment showed that immune cell infiltration and immune checkpoint gene expression differed between the two groups(p<0.05).Drug sensitivity analysis showed that compared to the low-risk group,the high-risk group was more sensitive to sunitinib,nilotinib,JNK-inhibitor-VIII,dasatinib,bosutinib,and bortezomib(p<0.001).Survival analysis and receiver operating characteristic curves were validated using the E-MTAB-1980 cohort.Conclusions:SLC-related genes have predictive relevance in ccRCC and play roles in the immunological milieu.Our results provide insight into metabolic reprogramming in ccRCC and identify promising treatment targets for ccRCC.

Aryl hydrocarbon receptor nuclear translocator 2 as a prognostic biomarker and immunotherapeutic indicator for clear cell renal cell carcinoma

Background:In many cancer types,aryl hydrocarbon receptor nuclear translocator 2(ARNT2)has been found to be associated with tumor cell proliferation and prognosis.However,the role of ARNT2 in clear cell renal cell carcinoma(ccRCC)has not been completely elucidated.In this study,the potential role of ARNT2 in ccRCC development was characterized.Methods:A pan-cancer dataset(TCGA-TARGET-GTEx)was accessed from UCSC Xena Data Browser.ARNT2 expression in normal and tumor samples was compared.Univariate Cox regression was performed to evaluate the prognostic value of ARNT2.Single sample gene set enrichment analysis(ssGSEA)was used to estimate the enrichment of functional pathways and gene signatures.CIBERSORT and ESTIMATE methods evaluated the immune infiltration.The ARNT2 expression was determined in ccRCC tissue and cell lines using RT-qPCR and Western blot.Results:ARNT2 expression was significantly dysregulated in 23 out of 30 cancer types.Pan-cancer data revealed a strong correlation between ARNT2 expression and immune modulators,immune cell infiltration,and genomic alternations.In ccRCC patients,the low-ARNT2 expression group had higher immune infiltration,CD8 T cells,and programmed cell death ligand 1 expression,as well as higher enrichment score of immunotherapeutic predictors than those in the high-ARNT2 expression group.Low-ARNT2 expression group was more responsive to immunotherapy.Moreover,low ARNT2 expression was observed in ccRCC tissue and cell lines.Conclusions:Dysregulated ARNT2 expression is involved in cancer development and the modulation of the immune microenvironment.ARNT2 can be potentially used as a prognostic indicator and an immunotherapeutic indicator for ccRCC.

Iris metastasis from clear cell renal cell carcinoma: A case report

BACKGROUND Clear cell renal cell carcinoma(ccRCC)is a common type of tumor that can metastasize to any organs and sites.However,it is extremely rare for ccRCC to metastasize to the iris.Here,we describe a rare case of iris metastasis from ccRCC with a history of left nephrectomy in 2010.CASE SUMMARY A 62-year-old male was admitted to the hospital due to blurred vision and red eyes,and a mass was found on the iris in the right eye.B-scan ultrasonography revealed a well-bounded high-density lesion at the corner of the anterior chamber at the 3-4 o’clock position.Phacoemulsification with simultaneous intraocular lens implantation and iridocyclectomy was performed in the right eye.The lesion was confirmed to be metastatic ccRCC by histological and immunohistochemical analyses.The patient was still alive at 9 mo after surgical treatment.Ocular metastasis can be an initial sign with a poor prognosis.Timely detection and treatment may improve survival.Clinicians should pay attention to similar metastatic diseases to prevent misdiagnosis leading to missed treatment oppor-tunities.CONCLUSION This report of the characteristics and successful management of a rare case of iris metastasis from ccRCC highlights the importance of a comprehensive medical history,histopathology,immunohistochemistry,and clinical manifestation for successful disease diagnosis.

Warthin-like papillary renal cell carcinoma: A case report

BACKGROUND Warthin-like papillary renal cell carcinoma(WPRCC)has been described as a rare pathological subtype of papillary renal cell carcinoma in the 2022 World Health Organization Classification of the Urinary and Male Reproductive System.Herein we report a case of WPRCC in the left kidney.CASE SUMMARY Physical examination of a previously healthy 47-year-old woman revealed a lump in her left kidney,4.5 cm×3.5 cm×3.5 cm in size.Based on the clinical information,imaging data,histmorphological features,and immunohistochemistry results,the pathological diagnosis was WPRCC in left kidney.CONCLUSION Resection of the mass in the left kidney was performed and her postoperative course was uneventful.

Correlation between Hypovitaminosis D Status and Hyperactivation of IL-6/STAT3 Signaling in Clear Cell Renal Cell Carcinoma

Objective:To analyze serum vitamin D levels in patients with clear cell renal cell carcinoma(ccRCC)by flow cytometry and to investigate the relationship between hypovitaminosis D status and hyperactivation of IL-6/STAT3 signaling in ccRCC.Methods:Eighty patients diagnosed with ccRCC by our oncology department from January 2019 to December 2021 were selected as study subjects,and the control subjects were selected from patients who were receiving health check-up from our hospital(matched according to case group:control group,1:2),with 160 healthy patients.All serum samples collected from the case-control subjects were allowed to stand for 1–2 hours,centrifuged at 3000 rpm for 10 minutes,and stored in a-80°C refrigerator,from which they were removed and thawed to measure 25-hydroxyvitamin D(25(OH)D)and interleukin 6(IL-6)levels.Results:The blood calcium level of patients in the cancer group was significantly lower than that of patients in the non-cancer group,and the difference was statistically significant(P<0.05).The IL-6 level of the cancer group was significantly higher than that of the non-cancer group.In high vitamin D state,the IL-6 level of the non-cancer group was higher than that of the cancer group,and the average concentration of IL-6 in both the cancer group and the non-cancer group was significantly higher in low vitamin D state compared with high vitamin D state(P<0.05);the correlation between hypovitaminosis D status and renal Ki-67 was found to be positive.Conclusion:The results showed that serum IL-6 levels were elevated in the cancer group and circulating serum 25(OH)D levels were negatively correlated with IL-6 levels.In addition,signal transducer and activator of transcription 3(STAT3)signaling in RCC tissues was activated in ccRCC patients and in those with low vitamin D status among the cancer group and was higher than that in those with high vitamin D status.These results suggest that hypovitaminosis D status in ccRCC patients is associated with activated IL-6/STAT3 signaling and the activation of tumor proliferation markers proliferating cell nuclear antigen(PCNA),cyclin D1,and Ki-67.

Synchronous sporadic bilateral multiple chromophobe renal cell carcinoma accompanied by a clear cell carcinoma and a cyst: A case report

BACKGROUND Renal cell carcinomas are usually unilateral.However,they are bilateral in 2%to 4%of sporadic cases and is considerably more common in familial cases.Synchronous sporadic bilateral multiple chromophobe renal cell carcinoma(CHRCC)with different subtypes is rare.CASE SUMMARY In this case report,we describe a case of synchronous bilateral CHRCC with two histological variants,accompanied by a clear cell carcinoma and a cyst in a 50-year-old male.The patient underwent retroperitoneal laparoscopic bilateral nephron-sparing surgery and there was no serious postoperative renal dysfunction.CONCLUSION We report a rare case of synchronous bilateral CHRCC with two histological variants associated with a clear cell carcinoma and a cyst.

Differentiate Xp11.2 Translocation Renal Cell Carcinoma from Computed Tomography Images and Clinical Data with ResNet-18 CNN and XGBoost

This study aims to apply ResNet-18 convolutional neural network(CNN)and XGBoost to preoperative computed tomography(CT)images and clinical data for distinguishing Xp11.2 translocation renal cell carcinoma(Xp11.2 tRCC)from common subtypes of renal cell carcinoma(RCC)in order to provide patients with individualized treatment plans.Data from45 patients with Xp11.2 tRCC fromJanuary 2007 to December 2021 are collected.Clear cell RCC(ccRCC),papillary RCC(pRCC),or chromophobe RCC(chRCC)can be detected from each patient.CT images are acquired in the following three phases:unenhanced,corticomedullary,and nephrographic.A unified framework is proposed for the classification of renal masses.In this framework,ResNet-18 CNN is employed to classify renal cancers with CT images,while XGBoost is adopted with clinical data.Experiments demonstrate that,if applying ResNet-18 CNN or XGBoost singly,the latter outperforms the former,while the framework integrating both technologies performs similarly or better than urologists.Especially,the possibility of misclassifying Xp11.2 tRCC,pRCC,and chRCC as ccRCC by the proposed framework is much lower than urologists.

A developed ant colony algorithm for cancer molecular subtype classification to reveal the predictive biomarker in the renal cell carcinoma

Background:Recently,researchers have been attracted in identifying the crucial genes related to cancer,which plays important role in cancer diagnosis and treatment.However,in performing the cancer molecular subtype classification task from cancer gene expression data,it is challenging to obtain those significant genes due to the high dimensionality and high noise of data.Moreover,the existing methods always suffer from some issues such as premature convergence.Methods:To address those problems,we propose a new ant colony optimization(ACO)algorithm called DACO to classify the cancer gene expression datasets,identifying the essential genes of different diseases.In DACO,first,we propose the initial pheromone concentration based on the weight ranking vector to accelerate the convergence speed;then,a dynamic pheromone volatility factor is designed to prevent the algorithm from getting stuck in the local optimal solution;finally,the pheromone update rule in the Ant Colony System is employed to update the pheromone globally and locally.To demonstrate the performance of the proposed algorithm in classification,different existing approaches are compared with the proposed algorithm on eight high-dimensional cancer gene expression datasets.Results:The experiment results show that the proposed algorithm performs better than other effective methods in terms of classification accuracy and the number of feature sets.It can be used to address the classification problem effectively.Moreover,a renal cell carcinoma dataset is employed to reveal the biological significance of the proposed algorithm from a number of biological analyses.Conclusion:The results demonstrate that CAPS may play a crucial role in the occurrence and development of renal clear cell carcinoma.

Single omental metastasis of renal cell carcinoma after radical nephrectomy:A case report

BACKGROUND Renal cell carcinoma(RCC)is the third most common malignancy in the genitourinary tract.The lungs,bone,lymph nodes,liver,and brain are common metastatic sites of RCC.However,there is limited literature on single omental metastasis of RCC.CASE SUMMARY We present the case of a 44-year-old man with single omental metastasis of RCC after laparoscopic radical nephrectomy.Pathological diagnosis of the resected left kidney revealed pT3a clear cell RCC(Fuhrman grade III).At 6 mo postoperatively,abdominal computed tomography revealed a 12-mm enhancing nodule in the left lower peritoneum.At 7 mo after initial operation,laparoscopic removal of the left omental nodule was performed.The pathological results indicated metastatic clear cell RCC.Currently,the patient is being treated with adjuvant pembrolizumab.CONCLUSION Omental metastasis of RCC owing to laparoscopic radical nephrectomy is rare.Urologists should be aware of the diverse nature of RCC.

Ipsilateral synchronous papillary and clear renal cell carcinoma:A case report and review of literature

BACKGROUND There is limited information on ipsilateral synchronous papillary renal cell carcinoma(PRCC)and clear cell renal cell carcinoma(CCRCC).Therefore,these rare tumors are often misdiagnosed preoperatively as a single tumor with intrarenal metastasis or some other diseases.Effective management and long-term overall survival might be affected because the prognosis of the two tumors differs.CASE SUMMARY We describe a case of ipsilateral synchronous PRCC and CCRCC with two histological variants in a 72-year-old man,whose mass was found incidentally,with no other chief complaints and vital signs were normal.Initial ultrasound revealed a hypoechoic lobular mass with a volume of 7.8 cm×4.8 cm×2.8 cm in the middle to lower pole of the left kidney.A subsequent contrast-enhanced computed tomography scan showed a single endophytic mass of 7.5 cm in diameter.The patient underwent laparoscopic left radical nephrectomy.A final diagnosis of ipsilateral synchronous PRCC and CCRCC was confirmed by pathological examination.There was no recurrence or metastasis after 25 mo follow-up.CONCLUSION We report a case of ipsilateral synchronous PRCC and CCRCC,and review related literature to estimate the prevalence of similar cases.The above descriptions may be expected to help understand the disease,and improve diagnosis in the future.

Thyroid follicular renal cell carcinoma excluding thyroid metastases:A case report

BACKGROUND Thyroid follicular renal cell carcinoma is a special type of renal cell carcinoma newly recognized in recent years.It has attracted attention because of its unique histology,immunophenotype,and clinical characteristics.It has a very low incidence,and the number of case reports available for review is limited.Moreover,a thyroid mass with type of tumour is rare.CASE SUMMARY We report a case of a renal mass with a bilateral thyroid mass that was accidentally discovered in a 60-year-old man during physical examination.B-mode ultrasound showed a hypoechoic mass in the middle and lower parenchyma of the right kidney,and computed tomography showed an iso-density shadow tumour in the right kidney.Contrast agents had a significant continuous enhancement effect on the tumour,and the enhancement was not uniform.After partial nephrectomy,pathological analysis was performed to rule out the possibility that the renal tumour was caused by thyroid tumour metastasis.Needle biopsy of the thyroid tumour confirmed that the renal cell carcinoma was not related to the thyroid tumour.The patient was alive at the last postoperative follow-up.CONCLUSION This is the third published case in which thyroid tumour biopsy was performed to confirm that thyroid follicular renal cell carcinoma is not thyroid related.

Epigenomics of clear cell renal cell carcinoma： mechanisms and potential use in molecular pathology

Clear cell renal cell carcinoma （ccRCC） is one frequent form of urologic malignancy with numerous genetic and epigenetic alterations. This review summarizes the recent major findings of epigenetic alterations including DNA methylation, histone modifications, microRNAs and recently identified long noncoding RNAs in the development and progression of ccRCC. These epigenetic profilings can provide a promising means of prognostication and early diagnosis for patients with ccRCCs. With the developed high- throughput technologies nowadays, the epigenetic analyses will have possible clinical applications in the molecular pathology of ccRCC.

Aberrant DNA methyltransferase 1 expression in clear cell renal cell carcinoma development and progression

Objective： To better understand the contribution of dysregulated DNA methyltransferase 1 （DNMT1） expression to the progression and biology of clear cell renal cell carcinoma （ccRCC）. Methods： We examined the differences in the expression of DNMT1 in 89 ecRCC and 22 normal tissue samples by immunohistochemistry. In addition, changes in cell viability, apoptosis, colony formation and invading ability of ccRCC cell lines （786-0 and Caki-1） were assessed after transfection with DNMT1 siRNA. Results： We found DNMT1 protein was significantly higher expressed in ccRCC than that of in no-tumor tissues （56.2% and 27.3%, respectively, P=0.018）. The expression of DNMT1 was strongly associated with ccRCC tumor size, tumor pathology stage, histological grading, lymph node metastasis, vascular invasion, recurrence and prognosis. Moreover, knockdown of DNMT1 expression significantly inhibited ccRCC cell viability, induced apoptosis, decreased colony formation and invading ability. Conclusions： Expression of DNMTI protein is increased in ccRCC tissues, and DNMT1 expression is associated with poor prognosis of patients. Experiments in vitro further showed DNMT1 played an essential role in proliferation and invasion of renal cancer cells. Moreover, targeting this enzyme could be a promising strategy for treating ccRCC, as evidenced by inhibited cell viability, increased apoptosis, decreased colony formation and invading ability.

Safety of axitinib and sorafenib monotherapy for patients with renal cell carcinoma:a meta-analysis

We sought to investigate safety of axitinib or sorafenib in renal cell carcinoma（RCC） patients and compare toxicity of these two vascular endothelial growth factor receptor inhibitors. Databases of PubMed and Embase were searched.We included phase II and III prospective trials, as well as retrospective studies, in which patients diagnosed with RCC were treated with axitinib or sorafenib monotherapy at a starting dose of 5 mg and 400 mg twice daily, respectively.The overall incidence of high grade hypertension, fatigue, gastrointestinal toxicity and hand-foot syndrome, along with their 95% confidence intervals（CI）, were calculated using fixed-or random-effects model according to heterogeneity test results. A total of 26 trials, including 4790 patients, were included in our meta-analysis. Among them, 6 arms were related to axitinib and 22 were associated with sorafenib. The incidences of hypertension（24.9%vs. 7.9%）, fatigue（8.2% vs. 6.6%）, and gastrointestinal toxicity（17.6% vs. 11.3%） were higher in patients receiving axitinib versus those receiving sorafenib, while the incidence of hand-foot syndrome was lower in patients receiving axitinib versus those receiving sorafenib（9.5% vs. 13.3%）. In conclusion, axitinib showed noticeably higher risks of toxicity versus sorafenib. Close monitoring and effective measures for adverse events are recommended during therapy.

Using MsfNet to Predict the ISUP Grade of Renal Clear Cell Carcinoma in Digital Pathology Images

Clear cell renal cell carcinoma(ccRCC)represents the most frequent form of renal cell carcinoma(RCC),and accurate International Society of Urological Pathology(ISUP)grading is crucial for prognosis and treatment selection.This study presents a new deep network called Multi-scale Fusion Network(MsfNet),which aims to enhance the automatic ISUP grade of ccRCC with digital histopathology pathology images.The MsfNet overcomes the limitations of traditional ResNet50 by multi-scale information fusion and dynamic allocation of channel quantity.The model was trained and tested using 90 Hematoxylin and Eosin(H&E)stained whole slide images(WSIs),which were all cropped into 320×320-pixel patches at 40×magnification.MsfNet achieved a micro-averaged area under the curve(AUC)of 0.9807,a macro-averaged AUC of 0.9778 on the test dataset.The Gradient-weighted Class Activation Mapping(Grad-CAM)visually demonstrated MsfNet’s ability to distinguish and highlight abnormal areas more effectively than ResNet50.The t-Distributed Stochastic Neighbor Embedding(t-SNE)plot indicates our model can efficiently extract critical features from images,reducing the impact of noise and redundant information.The results suggest that MsfNet offers an accurate ISUP grade of ccRCC in digital images,emphasizing the potential of AI-assisted histopathological systems in clinical practice.

Novel immunotherapy approaches for metastatic urothelial and renal cell carcinoma

The treatment of metastatic renal cell carcinoma(RCC)and urothelial carcinoma(UC)remains a major challenge.Past research has implicated the immune system in tumor surveillance of both malignancies,leading to the application of immunotherapy agents for both cancers.Among them,the most promising agents are the checkpoint blockade drugs,such as antibodies targeting the cytotoxic T-lymphocyte-associated antigen 4(CTLA-4),programmed death receptor 1(PD-1),and PD-1 ligand(PD-L1).In normal physiology,these immune checkpoints act as inhibitory signals to fine-tune the duration and strength of immune reactions,which is pivotal for maintaining self-tolerance.However,tumor cells also utilize immune checkpoint pathways to evade anti-tumor immune response,leading to disease progression and metastasis.Thus,there has been intense preclinical and clinical effort focused on the application of checkpoint inhibitors in metastatic RCC and UC.To date,nivolumab(anti-PD-1)and atezolizumab(anti-PD-L1)have been approved for the treatment of metastatic RCC and UC,respectively.Despite these successes,challenges remain in how to further improve response rates to immunotherapy and how to select patients that will benefit from this approach.In this report,we review existing data and research on immunotherapy in metastatic RCC and UC.

Low expression of fatty acid oxidation related gene ACADM indicates poor prognosis of renal clear cell carcinoma and is related to tumor immune infltration

This research aims to identify the key fatty acid beta-oxidation(FAO)genes that are altered in kidney renal clear cell carcinoma(KIRC)and to analyze the role of these genes in KIRC The Gene Expression Omnibus(GEO)and FAO datasets were used to identify these key genes.Wilcoxon rank sum test was used to assess the levels of acyl-CoA dehydrogenase medium chain(ACADM)between KIRC and non cancer samples.The logistic regression and Wilcoxon rank sum test were used to explore the association between ACADM and clinical features.The diagnostic performance of ACADM for KIRC was asessed using a diagnostic receiver operating ch aracteristic(ROC)curve.The co-expressed genes of ACADM were identifed in LinkedOmics database,and their function and pathway enrichment were analyzed.The correlation between ACADM expression level and immune infitration was analyzed by Gene Set Variation Analysis(GSVA)method Additionally,the proliferation,migration,and invasion abilities of KIRC cells were assessed after overexpressing ACADM.Following differential analysis and intersection,we identifed six hub genes,induding ACADM.We found that the expression level of ACADM was decreased in KIRC tissues and had a better diagnostic efect(AUC=0.916).Survival analysis suggested that patients with decreased ACADM expression had a worse prognosis.According to correlation analysis,a variety of dinical features were associated with the expression level of ACADML By analyzing the infiltration level of immune cells,we found that ACADM may be related to the enrichment of immune cells.Finally,ACADM overexpression inhibited proliferation,migration,and invasion of KIRC cells.In conclusion,our findings suggest that reduced ACADM expression in KIRC patients is indicative of poor prognosis.These results imply that ACADM may be a diagnostic and prognostic marker for individuals with KIRC,offering a reference for dinicians in diagnosis and treatment.

Update on the treatment of metastatic renal cell carcinoma

Metastatic renal cell cancer(mRCC)management has undergone a paradigm shift in recent decades.The first revolution came with the emergence of vascular endothelial growth factor inhibitors;there was a second wave with the unprecedented success of checkpoint inhibitors,and then the latest approach,which is becoming the new care standard in mRCC,of combining these two strategies in different ways.Updated results of Checkmate-214 after 42 mo of follow-up were consistent with previously published results showing the superiority of nivolumab/ipilimumab over sunitinib in progression free survival(PFS),overall survival(OS),and objective response rate(ORR)in intermediate and high-risk patients.However,several studies presented at the American Society of Clinical Oncology 2020 suggested that the best place,and so far,the only one for nivolumab/ipilimumab is the frontline setting.The update on Keynote-426 after 23 mo of follow-up showed no superiority of pembrolizumab/axitinib over sunitinib in favorable-risk mRCC,suggesting that it should no longer be the first line of choice in low-risk patients.Finally,the phase III Checkmate 9ER trial results revealed the superiority of nivolumab/cabozantinib vs sunitinib in PFS,OS,and ORR,providing a new first-line option among all International Metastatic RCC Database Consortium risk patients.Some phase II clinical trials also presented this year showed promising results with new combination therapies such as nivolumab/sitravatinib,cabozantinib/atezolizumab,and lenvatinib/pembrolizumab,providing promising grounds upon which to start phase III studies.In addition,other works are using novel therapeutic agents with different mechanisms of action,including telaglenastat(a glutaminase inhibitor),entinostat[an inhibitor of histone deacetylases(HDACs)],and olaparib and talazoparib,poly(ADP-ribose)polymerase inhibitors widely used in other tumors.However,some questions regarding mRCC management still need to be addressed,such as head-to-head comparisons between the current options,treatment sequencing,non-clear cell mRCC,and the role of biomarkers to ascertain the best treatment choice.

Pomegranate extract inhibits EMT in clear cell renal cell carcinoma in a NF-κB and JNK dependent manner

Objective:Clear cell renal cell carcinoma(ccRCC)is the most common subtype of renal cell carcinoma(RCC)and is characterized by biallelic inactivation of the von Hippel-Lindau(VHL)tumor suppressor gene.One effect of VHL inactivation is hypoxia inducible factor alpha(HIFa)-independent constitutive activation of nuclear factor kappa B(NF-κB)and c-jun N-terminal kinase(JNK).Both NF-κB and JNK drive ccRCC growth and epithelial to mesenchymal transition(EMT).The purpose of this study was to determine the biochemical effects of pomegranate juice extracts(PE)on RCC cell lines.Methods:The pre-clinical effects of PE on NF-κB,JNK,and the EMT phenotype were assayed,including its effect on proliferation,anchorage-independent growth,and invasion of pVHLdeficient RCCs.Results:PE inhibits the NF-κB and JNK pathways and consequently inhibits the EMT phenotype of pVHL-deficient ccRCCs.The effects of PE are concentration-dependent and affect not only biochemical markers of EMT(i.e.,cadherin expression)but also functional manifestations of EMT,such as invasion.These effects are manifested within days of exposure to PE when diluted 2000-fold.Highly dilute concentrations of PE(106 dilution),which do not impact these pathways in the short term,were found to have NF-κB and JNK inhibitory effects and ability to reverse the EMT phenotype following prolonged exposure.Conclusion:These findings suggest that PE may mediate inhibition growth of pVHL-deficient ccRCCs and raises the possibility of its use as a dietary adjunct to managing patients with active surveillance for small,localized,incidentally identified renal tumors so as to avoid more invasive procedures such as nephrectomy.