Prognosis Of Renal Cell Carcinoma Research Articles

Association of pretreatment neutrophil-to-lymphocyte ratio with clinical outcomes in cancer immunotherapy: An evidence synthesis from 30 meta-analyses

BackgroundThe Neutrophil-to-lymphocyte ratio (NLR) holds relevance in cancer immunotherapy outcomes, yet its validation remains limited. Thus, we conducted an umbrella review to comprehensively assess the association between pretreatment NLR and immunotherapy outcomes, along with evaluating their credibility and strength. MethodsElectronic databases, including PubMed, Web of Science, Embase, Scopus, and Cochrane, were systematically searched for eligible systematic reviews and meta-analyses. Quality assessment and evidence grading utilized AMSTAR, GRADE, and additional classification criteria, following PRISMA and PRIOR guidelines. ResultsThirty unique meta-analyses were included, with 24 associations (80%) exhibiting statistical significance. Notably, associations between pretreatment NLR and the prognosis of renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer garnered highly suggestive or convincing evidence grading. ConclusionsElevated pretreatment NLR correlates with poor outcomes in cancer immunotherapy, suggesting its potential as a biomarker for identifying appropriate treatment populations and predicting clinical outcomes. Nevertheless, further validation through prospective cohort studies is warranted.

Sarcoid-like reaction and hypothyroidism induced by PD-1 inhibitor treatment in metastatic renal cell carcinoma: a case report and literature review

BackgroundPembrolizumab is among the approved treatments for a variety of cancer types, including clear cell renal cell carcinoma (ccRCC). It has contributed to enhancing the prognosis of renal cell carcinoma. However, it is essential to be aware of the numerous potential immune-related side effects associated with its use.Case presentationA 69-year-old patient with a history of metastatic renal cell carcinoma has been undergoing treatment with Pembrolizumab, an immune checkpoint inhibitor. The medication has led to the development of a sarcoid-like reaction, initially misinterpreted as cancer recurrence and progression. Additionally, the patient has experienced new-onset hypothyroidism, which has been attributed to the immunotherapy.ConclusionClinicians, including oncologists, endocrinologists, and radiologists, should maintain a high level of suspicions and awareness regarding the potential adverse events associated with newly introduced immunotherapies like pembrolizumab. This knowledge is crucial for the accurate diagnosis and appropriate management of patients receiving these treatments.

Identification of ANKRD13D as a potential target in renal cell carcinomas.

The correlation of the expression of ankyrin repeat domain (ANKRD) family members with renal cell carcinoma prognosis was investigated. The GEPIA2, GEO2R, UALCAN, GDC, OncoLnc, TIMER, PanglaoDB, CancerSEA, and Tabula Muris databases were used. Twelve ANKRD family members were identified as having overexpressed renal cell carcinoma samples. The ANKRD13D was identified as a renal cell carcinoma-specific target by cross-referencing the multiple survival databases. To clarify the role of ANKRD13D, the expression of NAKRD13D was analyzed at the single-cell level. ANKRD13D was mainly expressed in immune cells and positively correlated with Treg cell infiltration. The expression of ANKRD13D was also positively correlated with PDCD1, CTLA4, LAG3, TNFSF14, and ISG20. The overexpression of ANKRD13D in Treg was confirmed using reverse transcription-quantitative polymerase chain reaction. The structure of ANKRD13D was predicted using AlphaFold. In conclusion, we identified ANKRD13D as a key immune regulator, and targeting ANKRD13D with immune checkpoints blockade may be a promoting strategy for renal cell carcinoma immunotherapy.

Nesprin1 Deficiency Is Associated with Poor Prognosis of Renal Cell Carcinoma and Resistance to Sunitinib Treatment

Introduction: Nuclear envelope spectrin repeat protein (Nesprin) 1 encoded by SYNE1, crucially regulates the morphology and functions of the cell. Mutations in the SYNE1 gene are associated with various diseases; however, their significance in renal cell carcinoma (RCC) remains unknown. In this study, we have investigated the association of SYNE1/Nesprin1 with the progression and prognosis of clear cell RCC (ccRCC). Methods: In silico analyses of publicly available datasets of patients with RCC were performed. Based on the cohort data, Nesprin1 expression in nephrectomized tissue samples acquired from patients with ccRCC was analyzed using immunohistochemical staining. The invasion, migration, and proliferation of the SYNE1-knockdown human RCC cell lines were analyzed in vitro; moreover, RNA sequencing and gene set enrichment analysis were conducted to study the molecular mechanism underlying the association of SYNE1/Nesprin1 with prognosis of RCC. Results: Patients with RCC-associated SYNE1 gene mutations exhibited significantly worse overall and progression-free survivals. Patients with Nesprin1-negative ccRCC tumors exhibit significantly poorer overall, cancer-specific, and recurrence-free survival rates than those recorded in the Nesprin1-positive group. SYNE1 knockdown enhanced the invasion and migration of RCC cells; however, it did not influence the proliferation of cells. RNA sequencing and gene set enrichment analysis revealed that SYNE1 knockdown significantly altered the expression of genes associated with oxidative phosphorylation. Consistently, patients with RCC exhibiting low SYNE1 expression, who were treated with the vascular endothelial growth factor receptor inhibitor sunitinib, had worse progression-free survival. Conclusions: The results indicate that the expression of SYNE1/Nesprin1 and SYNE1 mutations in patients with RCC are closely linked to their prognosis and responsiveness to sunitinib treatment.

The association between the triglyceride-glucose index and prognosis in postoperative renal cell carcinoma patients: a retrospective cohort study.

Insulin resistance has been proven to be associated with renal cell carcinoma (RCC). However, the prognostic value of the triglyceride-glucose (TyG) index, as a marker for insulin resistance (IR), is still unclear. Therefore, we conducted research to explore the prognostic value and the predictive performance of the TyG index in postoperative RCC patients. A total of 651 postoperative RCC patients from January 2016 to June 2018 were enrolled in the final study. Their clinical and laboratory parameters were collected from medical records and through follow-up by phone. The triglyceride-glucose (TyG) index was calculated as follows: TyG = Ln[TG (mg/dl) × FBG (mg/dL)/2]. The overall survival (OS) and disease-free survival (DFS) were identified as the main outcomes. The TyG index is an independent prognostic factor for OS (HR = 2.340, 95% CI = 1.506 to 3.64, P < 0.001) and DFS (HR = 2.027, 95% CI = 1.347 to 3.051, P < 0.001) in postoperative RCC patients. Kaplan-Meier survival curves of the different TyG index levels showed statistically significant differences in terms of OS and DFS (log-rank test, P < 0.0001). Furthermore, the TyG index was significantly associated with RCC risk factors. The TyG index is significantly associated with RCC survival. The mechanisms responsible for these results may contribute toward the improvement of RCC prognosis and immunotherapy efficacy and the development of new immunotherapeutic targets.

Influence of genetic polymorphisms in vascular endothelial-related genes on the clinical outcome of axitinib in patients with metastatic renal cell carcinoma

ABSTRACT Objective Axitinib is an oral multi-target tyrosine kinase inhibitor used for the treatment of renal cell carcinoma (RCC). Because of the severe adverse events (AEs) associated with axitinib, patients often need dose reductions or discontinue its use, highlighting the need for effective biomarkers to assess efficacy and/or AEs. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) in genes involved in the pharmacodynamic action of axitinib and clinical prognosis and AEs in metastatic RCC (mRCC) patients. Methods This study included 80 mRCC patients treated with first-, second-, or third-line axitinib (5 mg orally twice daily). Clinical parameters and genetic polymorphisms were examined in 75 cases (53 males and 22 females). We assessed three SNPs in each of three candidate genes namely, angiotensin-converting enzyme (ACE), nitric oxide synthase 3 (NOS3), and angiotensin II receptor type 1 (AT1R), all of which are involved in axitinib effects on vascular endothelial function. Results Axitinib-treated patients carrying the ACE deletion allele suffered more frequently from hand-foot syndrome and a deterioration in kidney function (p = .045 and p = 0.005, respectively) whereas those carrying the NOS3 G allele suffered more frequently from proteinuria and multiple AEs (p = .025 and p = 0.036, respectively). Conclusions Our study found that the ACE deletion allele and the NOS3 G allele are associated with increased AEs.

A study on sporadic renal cell carcinoma in young adults, our institutional experience

Background: Renal cell carcinoma (RCC) accounts for around 2–3% of all adult malignant neoplasms. Most RCC instances are sporadic, with about 4–6% being familial. Sporadic RCC is uncommon in young patients under 45, accounting for 3–7% of all instances. We report our experience with sporadic RCCs in young adults between the age of 20 and 45 years. Aims and Objectives: The aim is to study clinical presentation, evaluation, management, and prognosis of sporadic RCC in young adults. Materials and Methods: A retrospective review of 22 patients diagnosed with sporadic RCC between ages 20 and 45 years during a period of 7 years from 2016 to 2022 was performed at Government Stanley Medical College. Demographic details such as age, gender, clinical condition, blood investigations, radiological imaging, and histopathological evaluation were conducted. Patients were assessed for long-term outcomes by comparing metastasis and lymph node involvement with survival outcomes. Results: The mean age at diagnosis was 37 years. Most patients belong to lower socioeconomic status (54.5%), Tumors were detected incidentally in 9 patients (41%) and were symptomatic in 13 (59%). Around 87% of patients were not having any associated comorbidities. The average duration of presenting complaints in symptomatic patients was 41 days. About 59% of patients were smokers or chewing tobacco before diagnosis. Renal biopsy was performed in 27% of patients before definitive surgery. The difference in prognosis was found to be insignificant between patients who were asymptomatic at the time of diagnosis compared to patients who were symptomatic. The tumor stage and grade had a significant impact on survival. The mean postoperative follow-up was 38 months. Conclusion: The result of our study shows that sporadic RCC does not behave aggressively in young adults. The most important determinants in prognosis are tumor stage and histological grade. The type of surgical procedure does not affect the overall outcome.

P1117 Molecular and clinical characterization of metabolic associated steatotic liver disease in the setting of immune-mediated inflammatory diseases: a link with cancer risk in IBD?

Abstract Background Growing evidence suggests an increased prevalence of metabolic associated steatotic liver disease (MASLD) in the context of immune-mediated inflammatory diseases (IMIDs). The risk of incident extrahepatic cancers is higher in MASLD. We aimed to clinically and mechanistically characterize IMID-MASLD patients compared to classic-MASLD, and its relation to cancer risk in IBD. Methods Ambidirectional, case‒control study including a prospective cohort of IMID patients (IBD, psoriasis, hidradenitis, and spondyloarthritis). MASLD and advanced-MASLD was established by the controlled attenuation parameter and transient elastography, respectively. Controls from the general population were age-, sex-, type 2 diabetes-, and BMI-matched in a 1:2 ratio. Liver biopsies were collected when significant liver fibrosis was suspected. Total RNA was obtained from freshly frozen cases and analyzed by RNA-seq. Differential gene expression was performed with‘limma-voom’. Gene set enrichment analysis was performed using the fgsea R package with a preranked “limma t-statistic” gene list. Data on global cancer prevalence was retrospectively collected on a multicenter IBD cohort. Results 1435 IMID patients and 2918 controls were initially included. Advanced-MASLD prevalence was significantly higher among IMID patients than controls(p&amp;lt;0.0001). In multivariate analysis, concomitant IMID was an independent and the strongest predictor of advanced-MASLD (adjusted OR 2.587; &amp;lt; 0.001).Transcriptomic data was obtained in 109 patients and showed 87 significant genes differentially expressed between IMID- and classic-MASLD. IMID-MASLD cases displayed an enriched expression of genes implicated in pro-tumoral activities or the control of the cell cycle concomitant with a negative expression of genes related to metabolism (figure 1). A comparable transcriptomic signature was observed in IBD-MASLD, involving genes as IGFBP2, PLEKHA4, or metallothioneins, all of them associated to pour prognosis in renal cell carcinoma (RCC). In the multicentre IBD cohort (n=1905; female 50.5%; mean age 50.7 years, mean follow up: 13.3 years) we observed a global cancer prevalence of 9.0%, with a higher-than-expected RCC prevalence (table 1). Whereas RCC represents 3.2% of all cancers in the general population, it accounts for 8.7% in our IBD cohort, in agreement with our molecular data. Conclusion Advanced MASLD has a disproportionately high prevalence in IMID populations. Both conditions can trigger a protumoral condition that can lead to an accelerated form of MASLD independent of classic metabolic pathways and a higher cancer risk, as is the case of RCC in the IBD population.

Comprehensive analysis of ETS1 expression and its prognostic value in clear cell renal cell carcinoma.

ETS1, a member of the large ETS domain family of transcription factors, plays a role in the progression of many types of carcinoma. ETS1 expression has been linked to a more favorable prognosis in renal cell carcinoma. The objective of this study was to assess the predictive significance of ETS1 in individuals suffering from clear cell renal cell carcinoma (ccRCC). The correlation between ETS1 expression and ccRCC was analyzed. Data on ETS1 and clinical information for ccRCC patients were obtained from the Cancer Genome Atlas database and analyzed using R software. Then, we presented validation results using RT-qPCR (quantitative reverse transcription PCR). The receiver operator characteristic (ROC) curves were generated using the pROC software package to determine the cutoff values for ETS1. Additionally, the ImmuneScore, StromalScore, and ESTIMATEScore were calculated using the ESTIMATES algorithm. The connection between ccRCC and ETS1 was investigated using enrichment analysis based on Gene Oncology and the Kyoto Encyclopedia of Genes and Genomes. The tumor immunity estimation resource (TIMER) and the integrated repository portal for tumor-immune system interactions (TISIDB) databases were utilized to analyze the association between ETS1 expression and immune cell infiltration in ccRCC. The impact of ETS1 on the survival of ccRCC patients was evaluated using the PrognoScan database. We evaluated the Tumor Mutation Burden (TMB) value between the two sets of samples with high and low ETS1 expression, as well as the differences in gene mutations between the two groups. The mRNA expression of ETS1 in ccRCC was higher compared to normal tissues. Results showed a significant positive correlation between elevated ETS1 expression levels and improved overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS), with a P < 0.05. Furthermore, high ETS1 expression levels were closely linked to early tumor stage and prolonged survival time. TMB in the ETS1-high expression group was significantly less than that in the ETS1-low expression group. Downregulation of ETS1 expression correlated with poor prognosis and immune infiltration in ccRCC, further suggesting that ETS1 may be a biomarker for better prognosis in ccRCC patients.

Microvascular invasion is associated with poor prognosis in renal cell carcinoma: a retrospective cohort study and meta-analysis.

This retrospective cohort study and meta-analysis aims to explore the association between microvascular invasion (MVI) and clinicopathologiccal features, as well as survival outcomes of patients with renal cell carcinoma (RCC). The retrospective cohort study included 30 RCC patients with positive MVI and another 75 patients with negative MVI as controls. Clinicopathological features and follow-up data were compiled. The meta-analysis conducted searches on PubMed, Cochrane Library, Web of Science, Embase, and WanFang Data from the beginning to 30 September 2023, for comparative studies relevant to MVI patients. The Newcastle-Ottawa Scale and Egger Test were used to assess the risk of biases and certainty of evidence in the included studies. The cohort study showed that MVI was associated with advanced primary tumor stage, high pathological grades, high tumor size, high clinical symptoms and lymph node invasion (P <0.05). Kaplan-Meier analyses demonstrated MVI was associated with worse CSS rates when compared to MVI negative group (P <0.05). However, in the multivariate analysis it was not presented as an independent predictor of cancer survival mortality (P >0.05). The meta-analysis part included 11 cohort studies. The results confirmed that patients with MVI positive had worse 12 and 60 mo CSS rates (HR12mo = 0.86, 95%CI 0.80-0.92; HR60mo = 0.63, 95% CI 0.55-0.72; P < 0.00001). Moreover, the meta-analysis also confirmed that MVI group was associated with higher rate of advanced tumor stage, pathological grades, tumor size diameter, higher rate of clinical symptoms and lymph node invasion (P <0.05). The presence of MVI in renal cell carcinoma patients is linked to poorer survival outcomes and worse clinicopathological features. In spite of this, it does not seem to be an independent predictor for cancer survival mortality in renal cell carcinoma. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023470640, identifier CRD42023470640.

Alternative Polyadenylation Regulatory Factors Signature for Survival Prediction in Kidney Renal Cell Carcinoma.

Alternative polyadenylation (APA) plays a vital regulatory role in various diseases. It is widely accepted that APA is regulated by APA regulatory factors. Whether APA regulatory factors affect the prognosis of renal cell carcinoma remains unclear, and this is the main topic of this study. We downloaded the transcriptome and clinical data from The Cancer Genome Atlas (TCGA) database. We used the Lasso regression system to construct an APA model for analyzing the relationship between common APA regulatory factors and renal cell carcinoma. We also validated our APA model using independent GEO datasets (GSE29609, GSE76207). It was found that the expression levels of 5 APA regulatory factors (CPSF1, CPSF2, CSTF2, PABPC1, and PABPC4) were significantly associated with tumor gene mutation burden (TMB) score in renal clear cell carcinoma, and the risk score constructed using the expression level of 5 key APA regulatory factors could be used to predict the outcome of renal clear cell carcinoma. The TMB score is associated with the remodeling of the immune microenvironment. By identifying key APA regulatory factors in renal cell carcinoma and constructing risk scores for key APA regulatory factors, we showed that key APA regulators affect prognosis of renal clear cell carcinoma patients. In addition, the risk score level is associated with TMB, indicating that APA may affect the efficacy of immunotherapy through immune microenvironment-related genes. This helps us better understand the mRNA processing mechanism of renal clear cell carcinoma.

The Predictive Value of Urinary HMGB1 Level in the Diagnosis and Prognosis of Renal Cell Carcinoma

The Predictive Value of Urinary HMGB1 Level in the Diagnosis and Prognosis of Renal Cell Carcinoma

Altered NCR3 Splice Variants May Result in Deficient NK Cell Function in Renal Cell Carcinoma Patients.

The natural killer (NK) cell function of patients with malignant tumours may be suppressed by deficiency, and the poor prognosis of renal cell carcinoma (RCC) patients may be due to escape from NK cell cytotoxicity, especially with respect to natural cytotoxicity receptors (NCRs) on the NK cell surface. However, the specific mechanism remains unclear. Therefore, in this study, we sought to explore the role of NCR, especially NCR3 splice variants, in the process of NK cell deficiency in RCC patients. We used flow cytometry to analyse the phenotype of NK cells from the peripheral blood and kidney tumour tissue of RCC patients. The NKp30-mediated NK cell killing function was measured by antibody-dependent cell-mediated cytotoxicity (ADCC) in NK and RCC cell coincubation. We extracted RNA from the peripheral blood mononuclear cells (PBMCs) of RCC patients and renal carcinoma tissue and carried out real-time quantitative PCR to detect the mRNA levels of NKp30a, NKp30b and NKp30c. mRNA expression levels of cytokines (IL-6, IL-8, IL-10, IL-18 and TGF-β) based on RNA extracted from renal carcinoma tissue and adjacent normal kidney tissues were also measured by real-time quantitative PCR. Regarding the phenotype of NK cells in RCC patients, the proportion of NK cells in tumour tissue was significantly reduced, with changes in the NK cell proportion being most obvious in NKp30+ NK cells. Furthermore, the results of the ADCC function assay showed limited NKp30+ NK cell-mediated cytotoxicity in RCC patients. Through real-time quantitative PCR, we found lower expression of NKp30a and NKp30b, the immunostimulatory splice variants of NCR3 encoding NKp30, in RCC patients. Moreover, expression of activating cytokines (IL-6 and IL-8) in renal cancer tissue was decreased, though inhibitory cytokine (TGF-β) expression remained unchanged, which may result in an immunosuppressive cytokine microenvironment. Decreased expression of immunostimulatory NCR3 splice variants and the inhibitory cytokine microenvironment in RCC patients may contribute to deficient NK cell cytotoxicity and renal carcinoma cell immune escape from NK cell killing, which may provide a theoretical basis for finding new immunotherapeutic targets for RCC.

Multimodal deep learning for personalized renal cell carcinoma prognosis: Integrating CT imaging and clinical data

Background and Objective: Renal cell carcinoma represents a significant global health challenge with a low survival rate. The aim of this research was to devise a comprehensive deep-learning model capable of predicting survival probabilities in patients with renal cell carcinoma by integrating CT imaging and clinical data and addressing the limitations observed in prior studies. The aim is to facilitate the identification of patients requiring urgent treatment.Methods: The proposed framework comprises three modules: a 3D image feature extractor, clinical variable selection, and survival prediction. Based on the 3D CNN architecture, the feature extractor module predicts the ISUP grade of renal cell carcinoma tumors linked to mortality rates from CT images. Clinical variables are systematically selected using the Spearman score and random forest importance score as criteria. A deep learning-based network, trained with discrete LogisticHazard-based loss, performs the survival prediction. Nine distinct experiments are performed, with varying numbers of clinical variables determined by different thresholds of the Spearman and importance scores.Results: Our findings demonstrate that the proposed strategy surpasses the current literature on renal cancer prognosis based on CT scans and clinical factors. The best-performing experiment yielded a concordance index of 0.84 and an area under the curve value of 0.8 on the test cohort, which suggests strong predictive power.Conclusions: The multimodal deep-learning approach developed in this study shows promising results in estimating survival probabilities for renal cell carcinoma patients using CT imaging and clinical data. This may have potential implications in identifying patients who require urgent treatment, potentially improving patient outcomes. The code created for this project is available for the public on: GitHub

CircRARS synergises with IGF2BP3 to regulate RNA methylation recognition to promote tumour progression in renal cell carcinoma.

As the most prominent RNA modification, N6-methyladenosine (m6 A) participates in the regulation of tumour initiation and progression. Circular RNAs (circRNAs) also play crucial roles in ubiquitous life processes. Whether circRNAs are required for m6 A regulation in renal cell carcinoma (RCC) remains unclear. Meta-analysis and bioinformatics identified that IGF2BP3 was upregulated in RCC and indicated a worse prognosis. IGF2BP3 significantly promoted RCC progression in vitro and in vivo. Mechanistically, circRARS bound to KH1-KH2 domains of IGF2BP3 to enhance m6 A modification recognition. A 12-nt sequence (GUCUUCCAGCAA) was proven to be the IGF2BP3-binding site of circRARS. Additionally, CAPN15, CD44, HMGA2, TNRC6A and ZMIZ2 were screened to be the target genes regulated by the IGF2BP3/circRARS complex in an m6 A-dependent manner. Stabiliser proteins, including HuR, Matrin3 and pAbPC1, were recruited by circRARS, thereby increasing the mRNA stability of the forementioned five target genes. Consequently, the IGF2BP3/circRARS complex facilitated the lipid accumulation of RCC cells and promoted sunitinib resistance via target genes. circRARS synergised with IGF2BP3 to facilitate m6 A recognition, thereby promoting RCC progression. Thus, IGF2BP3 could be a potential biomarker for RCC diagnosis and prognosis and a therapeutic target.

Benefits of Routine Screening for Renal Cell Carcinoma of Native Kidney in Renal Transplant Recipients

Renal-cell carcinoma (RCC) is the most common solid organ cancer in kidney transplantation recipients (KTRs). Analyze the incidence, prognosis, and evolution of primitive kidney RCC in KTRs at our institution. Observational descriptive retrospective study in which all KTRs from January 2000 to December 2022 were included. We performed an annual abdominal ultrasound in all KTRs. Demographic and clinical data were collected. The surgical approach, location, size, histologic type, and tumor grade were analyzed. We assessed the coexistence of risk factors. We reported the appearance of tumors in other locations, changes in immunosuppressants (IS) after the diagnosis, and survival and recurrence rates observed during follow-up. Eighteen RCCs of native kidneys were diagnosed with an incidence in our population of 1.08%. The majority were men (77.8%), with a mean age of 59.9 years. The pathologic analysis revealed 11 clear cell carcinomas, 6 papillary carcinomas, and 1 chromophobe cell carcinoma. The median tumor size was 2.7 cm. TNM stage was T1aN0M0 in 15 cases. Laparoscopy was performed to remove the tumor in most cases. All our patients underwent changes in IS therapy, with conversion to mammalian target of rapamycin inhibitors when possible and reduction of IS in all of them. After a mean follow-up of 78.6 months, survival was 100% without tumor recurrence. Seven of the patients were diagnosed with a new tumor in another location. In our experience, annual abdominal ultrasound in KTRs may be an option for the early detection of RCC in native kidneys.

Anoikis-related genes signature development for clear cell renal cell carcinoma prognosis and tumor microenvironment

Clear cell renal cell carcinoma (ccRCC) is one of the most common primary malignancies of the urinary tract, highly heterogeneous, and increasing in incidence worldwide. Anoikis is a specific type of programmed cell death in which solid tumor cells or normal epithelial cells that do not have metastatic properties lose adhesion to the extracellular matrix or undergo inappropriate cell adhesion-induced apoptosis. Anoikis is thought to play a critical role in tumorigenesis, maintenance, and treatment, according to an increasing amount of research. However, there is still some uncertainty regarding the general impact of anoikis-related genes (ARGs) on the prognostic importance, tumor microenvironment characteristics, and treatment reaction of ccRCC patients. For this study, we used The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus datasets to access the RNA sequencing results and clinical information from ccRCC patients. 29 ARGs related to survival were found using differential analysis and univariate Cox regression analysis. The samples were then divided into two clusters that had different immune traits via unsupervised cluster analysis using 29 prognosis-associated differently expressed ARGs. Then, to build an ARGs signature, 7 genes (PLAU, EDA2R, AFP, PLG, TUBB3, APOBEC3G, and MALAT1) were found using Least Absolute Shrinkage and Selection Operator regression analysis. The new ARGs signature demonstrated outstanding prognostic capability for ccRCC patients' overall survival. In conclusion, for ccRCC patients, we created an ARGs signature that strongly connects to immunological traits and therapy response. Clinicians may find this ARGs signature helpful in developing more individualized and detailed treatment strategies for ccRCC patients.

Circulating inflammatory cytokines in relation to the risk of renal cell carcinoma: A gender-specific two-sample Mendelian randomization study.

Currently there is no specific molecular biomarker for the diagnosis and treatment of renal cell carcinoma (RCC). Here we performed a gender-specific two-sample Mendelian randomization analysis to systematically assess the effects of circulating cytokines on RCC. We have employed cis-quantitative trait loci as instrumental variables for the protein levels and expression of circulating cytokines. We estimated the causal effects of circulating cytokines on RCC risk in males and females with several Mendelian randomization methods. We observed a significant causal effect of Eotaxin on the increased risk of RCC in males (Odds ratio [OR] = 2.546, 95% confidence interval [CI] = 1.617-4.010, p value = 5.496 × 10-5), but not in females (OR = 1.352, 95% CI = 0.766-2.388, p value = 0.298). Besides, we also identified several cytokines as potentially associated with RCC in males including RANTES, MCP3, PDGFbb, TRAIL, and several other cytokines as potentially associated with RCC in females including sICAM and SCGFb. Our study highlighted that a higher level of circulating Eotaxin is causally associated with an increased risk of RCC in males but not in females. Further studies are needed to elucidate the exact mechanism and its potential application in the prognosis and treatment of RCC.

Improving CNNs classification with pathologist-based expertise: the renal cell carcinoma case study

The prognosis of renal cell carcinoma (RCC) malignant neoplasms deeply relies on an accurate determination of the histological subtype, which currently involves the light microscopy visual analysis of histological slides, considering notably tumor architecture and cytology. RCC subtyping is therefore a time-consuming and tedious process, sometimes requiring expert review, with great impact on diagnosis, prognosis and treatment of RCC neoplasms. In this study, we investigate the automatic RCC subtyping classification of 91 patients, diagnosed with clear cell RCC, papillary RCC, chromophobe RCC, or renal oncocytoma, through deep learning based methodologies. We show how the classification performance of several state-of-the-art Convolutional Neural Networks (CNNs) are perfectible among the different RCC subtypes. Thus, we introduce a new classification model leveraging a combination of supervised deep learning models (specifically CNNs) and pathologist’s expertise, giving birth to a hybrid approach that we termed ExpertDeepTree (ExpertDT). Our findings prove ExpertDT’s superior capability in the RCC subtyping task, with respect to traditional CNNs, and suggest that introducing some expert-based knowledge into deep learning models may be a valuable solution for complex classification cases.

Construction of the metabolic reprogramming-associated gene signature for clear cell renal cell carcinoma prognosis prediction

BackgroundMetabolism reprogramming is a hallmark that associates tumor growth, metastasis, progressive, and poor prognosis. However, the metabolism-related molecular patterns and mechanism in clear cell renal cell carcinoma (ccRCC) remain unclear. Herein, the purpose of this study was to identify metabolism-related molecular pattern and to investigate the characteristics and prognostic values of the metabolism-related clustering.MethodsWe comprehensively analyzed the differentially expressed genes (DEGs), and metabolism-related genes (MAGs) in ccRCC based on the TCGA database. Consensus clustering was used to construct a metabolism-related molecular pattern. Then, the biological function, molecular characteristics, Estimate/immune/stomal scores, immune cell infiltration, response to immunotherapy, and chemotherapy were analyzed. We also identified the DEGs between subclusters and constructed a poor signature and risk model based on LASSO regression cox analysis and univariable and multivariable cox regression analyses. Then, a predictive nomogram was constructed and validated by calibration curves.ResultsA total of 1942 DEGs (1004 upregulated and 838 downregulated) between ccRCC tumor and normal samples were identified, and 254 MRGs were screened out from those DEGs. Then, 526 ccRCC patients were divided into two subclusters. The 7 metabolism-related pathways enriched in cluster 2. And cluster 2 with high Estimate/immune/stomal scores and poor survival. While, cluster 1 with higher immune cell infiltrating, expression of the immune checkpoint, IFN, HLA, immune activation-related genes, response to anti-CTLA4 treatment, and chemotherapy. Moreover, we identified 295 DEGs between two metabolism-related subclusters and constructed a 15-gene signature and 9 risk factors. Then, a risk score was calculated and the patients into high- and low-risk groups in TCGA-KIRC and E-MTAB-1980 datasets. And the prediction viability of the risk score was validated by ROC curves. Finally, the clinicopathological characteristics (age and stage), risk score, and molecular clustering, were identified as independent prognostic variables, and were used to construct a nomogram for 1-, 3-, 5-year overall survival predicting. The calibration curves were used to verify the performance of the predicted ability of the nomogram.ConclusionOur finding identified two metabolism-related molecular subclusters for ccRCC, which facilitates the estimation of response to immunotherapy and chemotherapy, and prognosis after treatment.