Survival In Renal Cell Carcinoma Patients Research Articles

Abstract 3457: Distinct signatures of tumor-associated macrophage subpopulations predict survival in renal cell carcinoma

Abstract Background: Comprising 90% of renal cancer cases in adults, renal cell carcinoma (RCC) is marked by significant heterogeneity in its tumor microenvironment. This study aims to test the hypothesis that tumor-associated macrophages (TAMs) play a role in modulating RCC progression and patient response to treatment. We explored the prognostic implications of TAM signatures on RCC survival, leveraging immunomics to decipher TAM-related alterations in the tumor microenvironment. Methods: Utilizing independent single-cell RNA-seq data from human RCC samples, we crafted 8 distinct RCC TAM signatures reflective of TAM presence. A LASSO Cox regression model was developed to prognosticate survival, tested against the TCGA dataset and independently validated across multiple RCC cohorts. Model performance was corroborated through Kaplan-Meier survival plots, receiver operating characteristic (ROC) curves, principal component analysis, and t-SNE analyses. Results: We identified two TAM signatures that correlate positively with patient survival, indicative of the abundance of specific subsets of TAMs in RCC. These signatures showed a strong association of specific TAM markers and macrophage infiltration. Survival analysis demonstrated that specific TAM signature gene expressions are significant prognostic markers. Forest plots underscored their prognostic relevance. A 32-gene risk score model was established, successfully stratifying patients into distinct risk categories, with low-risk patients exhibiting markedly improved overall survival. Conclusions: The study underscores the positive association between abundance of specific TAM subsets of and RCC patient survival. The precision of our LASSO Cox regression model, informed by novel abundance markers of specific TAM subsets, advances our understanding of TAM roles in TIME and RCC progression. These TAM signatures could potentially provide additional insights and targets to enhance the efficacy of RCC treatments. Keywords: Tumor associated macrophage, renal cell carcinoma, prognosis, tumor microenvironment, immunomics. Citation Format: Youngsoo Han, Aidan Shen, Zhaohui Wang, Aliesha Garrett, Chongming Jiang. Distinct signatures of tumor-associated macrophage subpopulations predict survival in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3457.

Real world evidence comparison of first-line (1L) immune-oncology(IO)/tyrosine kinase inhibitor (TKI) vs. IO/IO combination therapy in renal cell carcinoma (RCC).

402 Background: IO/IO and IO/TKI are the preferred first-line combinations for treatment of RCC. While these combinations have been superior to sunitinib, no head-to-head clinical trials have been completed, which leaves uncertainty about the preferred combination. Here, we have leveraged ASCO Cancerlinq data to compare overall survival for RCC patients (pts) receiving first line IO/IO vs. IO/TKI combinations. We hypothesized that IO/IO and IO/TKI would have similar survival. Methods: We performed a retrospective cohort study comparing IO/IO vs IO/TKI therapy for pts with metastatic RCC. We used the Atropos health platform, which is a commercial platform and queried ASCO CancerLinq data for this study. We identified pts with kidney cancer who received IO/IO or IO/TKI combinations between 2019 and 2023. For our primary analysis, we included only pts with ICD10 code consistent with clear cell [cc]RCC, but also did a secondary analysis including all pts with kidney cancer. The IO/TKI pts received either avelumab/axitinib, pembrolizumab/axitinib, nivolumab/cabozantinib, pembrolizumab/lenvatinib, or atezolizumab/cabozantinib within two weeks of each other. The IO/IO pts were identified as pts receiving ipilimumab and nivolumab within 2 weeks of each other without interceding TKI. We conducted a survival analysis of time to death using Cox proportional hazards regression to compare the two groups. The analysis was performed under three different confounder adjustment scenarios: without adjustment, with basic matching on sex and age, and with high dimensional propensity score (hdPS) using inverse probability of treatment weighting. Results: A total of 584 pts (286 IO/IO and 296 IO/TKI) with kidney cancer and 146 with ccRCC (75 IO/IO and 71 IO/TKI) were included. Mean age was 63-65 years and 30-35% female sex across groups. Table shows the restricted mean survival time (RMST) and HR for the Cox models. In the ccRCC cohort, 20 pts with IO/IO and 7 with IO/TKI died with RMST of 947 and 1071 days, respectively (hdPS HR 0.35, p=0.03). In the RCC cohort, 76 pts with IO/IO vs 49 with IO/TKI died with RMST 1126 vs 1017 (hdPS HR 0.61, p=0.04). Conclusions: In this exploratory, hypothesis-generating analysis of CancerLinq data, pts treated with IO/TKI had longer OS vs those treated with IO/IO. Limitations include the retrospective nature of the study, low power, lack of randomization, and potential unmeasured confounding factors (e.g., confounding by indication). Further investigation and prospective validation are needed to confirm these findings. [Table: see text]

Clinical utility of keratin 14 expression measurement in reflecting the tumor properties and prognosis in patients with renal cell carcinoma: a study with long-term follow-up.

Keratin 14 (KRT14) is hypothesized to be involved in the pathogenesis of renal cell carcinoma (RCC) based on its tumorigenic role in various cancers and its relationship with the prognosis of other urinary system malignancies. This study aimed to evaluate the correlation of KRT14 with tumor properties and prognosis in RCC patients. Data from 180 RCC patients who received tumor resection were retrospectively reviewed. The KRT14 was assessed by immunohistochemistry (IHC) staining in tumor tissues and non-tumor tissues. KRT14 was insufficiently expressed in both tumor and non-tumor tissues, with median (interquartile range) IHC score of 2.0 (0.0-3.4) and 1.0 (0.0-2.0), respectively. While it was relatively higher in tumor versus non-tumor tissues (P < 0.001). Besides, tumor KRT14 was positively correlated with the pathological grade (P = 0.038), tumor size (P = 0.012), T stage (P = 0.006), and TNM stage (P = 0.018). Interestingly, tumor KRT14 high predicted shorter accumulating recurrence-free survival (RFS) (P = 0.003) and accumulating overall survival (OS) (P = 0.001), which was further verified by the multivariate Cox's regression analysis (both P < 0.05). Furthermore, tumor KRT14 high estimated shorter RFS and OS from the Gene Expression Profiling Interactive Analysis and Human Protein ATLAS databases (all P < 0.05). Subgroup analyses indicated that the correlation of tumor KRT14 with accumulating RFS and accumulating OS was more pronounced in RCC patients with better physical status (such as age < 65years and better eastern cooperative oncology group performance status) and higher tumor stages (such as higher pathological grade). High KRT14 in tumor tissue could reflect an advanced tumor features and unsatisfying survival in RCC patients.

The Role of Anticoagulation in Tumor Thrombus Associated with Renal Cell Carcinoma: A Literature Review.

Tumor thrombus (TT) is a complication of renal cell carcinoma (RCC) for which favorable medical management remains undefined. While radical nephrectomy has been shown to increase overall survival in RCC patients, surgical interventions such as cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) utilized to perform TT resection carry high mortality rates. While it has been documented that RCC with TT is associated with venous thromboembolism (VTE) development, anticoagulation use in these patients remains controversial in clinical practice. Whether anticoagulation is associated with improved survival outcomes remains unclear. Furthermore, if anticoagulation is initiated, there is limited evidence for whether direct oral anticoagulants (DOACs), heparin, or warfarin serve as the most advantageous choice. While the combination of immunotherapy and tyrosine kinase inhibitors (TKIs) has been shown to improve the outcomes of RCC, the clinical benefits of this combination are not well studied prospectively in cases with TT. In this literature review, we explore the challenges of treating RCC-associated TT with special attention to anticoagulation. We provide a comprehensive overview of current surgical and medical approaches and summarize recent studies investigating anticoagulation in RCC patients undergoing surgery, targeted therapy, and/or immunotherapy. Our goal is to provide clinicians with updated clinical insight into anticoagulation for RCC-associated TT patients.

DAB2IP stabilizes p27Kip1 via suppressing PI3K/AKT signaling in clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is the most lethal of the urologic malignancies. We previously discovered that DAB2IP, a novel Ras GTPase-activating protein, was frequently epigenetically silenced in RCC, and DAB2IP loss was correlated with the overall survival of RCC patients. In this study, we determined the biological functions of DAB2IP in clear cell RCC (ccRCC) and its potential mechanisms of action. Correlations between DAB2IP expression level and ccRCC tumor size and patient survival were analyzed, and the results showed that ccRCC patients with high DAB2IP mRNA level exhibited smaller tumor size and better survival than the patients with low DAB2IP. Compared to control, DAB2IP knockdown significantly increased cell proliferation, promoted cell cycle progression in G1/S phase, and decreased p27 expression. Mechanism studies demonstrated that loss of DAB2IP promoted p27 protein phosphorylation, cytosolic sequestration, and subsequently ubiquitination-mediated degradation in ccRCC cells. Further studies confirmed that the proline-rich domain in C terminal (CPR) of DAB2IP suppressed AKT phosphorylation and p27 phosphorylation on S10. Hence, DAB2IP is essential for p27 protein stabilization in ccRCC, which is at less partly mediated by PI3K/AKT signaling pathway.

LINC00926 promotes progression of renal cell carcinoma via regulating miR-30a-5p/SOX4 axis and activating IFNγ-JAK2-STAT1 pathway

The role of long non-coding RNA (lncRNA) in the progression of renal cell carcinoma (RCC) remains further study. Whether lncRNA may be used to predict the immunotherapy efficacy of RCC is less studied. In this study, LINC00926 was found to be mainly located in cytoplasm by FISH and RNA nuclear-cytoplasmic fractionation. Downregulation of LINC00926 in RCC cell lines inhibited the progression and metastasis of RCC cells. RNA pull-down assay and dual-luciferase reporter assay demonstrated that LINC00926 functioned as miR-30a-5p sponge to facilitate SOX4 expression. LINC00926 overexpression in BALB/c mice enhanced PD-L1 surface expression and resulted in immune escape. Mechanistic investigations showed that LINC00926 competitively bound to Lyn, leading to the inhibition of CBL-mediated ubiquitination and degradation, and stabilized Lyn, contributing to the activation of IFNγ-JAK2-STAT1 signaling pathway. Moreover, LINC00926, together with PD-L1 or PD-1 expression, may predict the overall survival in RCC patients. Therefore, LINC00926 has the potential to be a novel therapeutic target and a biomarker to predict ICB immunotherapy response in RCC.

HOXD8 suppresses renal cell carcinoma growth by upregulating SHMT1 expression.

Amplification of amino acids synthesis is reported to promote tumorigenesis. The serine/glycine biosynthesis pathway is a reversible conversion of serine and glycine catalyzed by cytoplasmic serine hydroxymethyltransferase (SHMT)1 and mitochondrial SHMT2; however, the role of SHTM1 in renal cell carcinoma (RCC) is still unclear. We found that low SHMT1 expression is correlated with poor survival of RCC patients. The in vitro study showed that overexpression of SHMT1 suppressed RCC proliferation and migration. In the mouse tumor model, SHMT1 significantly retarded RCC tumor growth. Furthermore, by gene network analysis, we found several SHMT1-related genes, among which homeobox D8 (HOXD8) was identified as the SHMT1 regulator. Knockdown of HOXD8 decreased SHMT1 expression, resulting in faster RCC growth, and rescued the SHMT1 overexpression-induced cell migration defects. Additionally, ChIP assay found the binding site of HOXD8 to SHMT1 promoter was at the -456~-254 bp region. Taken together, SHMT1 functions as a tumor suppressor in RCC. The transcription factor HOXD8 can promote SHMT1 expression and suppress RCC cell proliferation and migration, which provides new mechanisms of SHMT1 in RCC tumor growth and might be used as a potential therapeutic target candidate for clinical treatment.

Incidence and clinical relevance of paraneoplastic syndromes in patients with renal cell carcinoma.

Paraneoplastic syndromes (PNS) are defined as the signs and symptoms attributed to cytokines or hormones released from a tumor or a patient's immune system. PNS have been reported with many cancers for decades and data supporting their relevance in renal cell carcinoma (RCC) are largely historical. The widespread use of electronic medical record (EMR) systems provides a more robust method to capture data. The objective of this study was to establish contemporary data regarding the incidence and relevance of PNS in patients undergoing nephrectomy for suspected RCC. In this retrospective single-institution study, 851 patients undergoing nephrectomy for suspected RCC between 2011 and 2018 were assessed for the presence or absence of PNS as defined by laboratory abnormalities. Factors associated with PNS and with all-cause mortality were examined. The incidence of PNS was 33.1% among 851 patients prior to nephrectomy. The most prevalent PNS were anemia (22.4%), thrombocytosis (7.5%), and elevated C-reactive protein (CRP) (7.4%). PNS were more common in women (39.2% vs. 29.4%, p = 0.0032) and higher stage RCC (31.1% of stage I vs. 54.2% of stage IV, p = 0.0036). Factors associated with the presence of PNS in multivariable analysis included female gender, high comorbidity, and stage IV RCC. Prenephrectomy PNS were associated with poorer survival in multivariable analysis (HR: 2.12, p = 0.0002). Resolution of PNS occurred in 52.1% of patients after nephrectomy, including 55.2% with stage I to III and 38.5% with stage IV RCC (p = 0.10). Using EMR data, laboratory evidence of PNS was present in one-third of a contemporary cohort of patients undergoing nephrectomy, with >50% of PNS resolving after surgery. Consistent with prior reports, PNS are more common in higher-stage RCC and are associated with poorer survival in RCC patients.

Hsa_circ_0057105 modulates a balance of epithelial-mesenchymal transition and ferroptosis vulnerability in renal cell carcinoma.

The incidence of renal cell carcinoma (RCC) has increased in recent years. Metastatic RCC is common and remains a major cause of mortality. A regulatory role for circular RNAs (circRNAs) in the occurrence and progression of RCC has been identified, but their function, molecular mechanisms, and potential clinical applications remain poorly understood. High-throughput RNA sequencing was used to explore the differential expression of circRNAs and their related pathways in RCC patients. Transwell and CCK-8 assays were used to assess the function of hsa_circ_0057105 in RCC cells. The clinical relevance of hsa_circ_0057105 was evaluated in a cohort of RCC patients. The hsa_circ_0057105 regulatory axis was defined using RNA pull-down, luciferase reporter assays, and fluorescence in situ hybridization assays, and the in vivo effect of hsa_circ_0057105 was validated using animal experiments. Single-sample gene set enrichment analysis and correlation analysis of RNA-seq data showed that hsa_circ_0057105 was potentially oncogenic and may serve to regulate epithelial-mesenchymal transition (EMT) activation in RCC. Hsa_circ_0057105 expression was associated with advanced TNM stages and was an independent prognostic factor for poor RCC patient survival. Phenotypic studies show that hsa_circ_0057105 can enhance the migration and invasion abilities of RCC cells. Further, hsa_circ_0057105 was shown to inhibit the expression of miR-577, a miRNA that regulated the expression of both COL1A1, which induced EMT activation, and VDAC2, which modulated ferroptosis sensitivity. The dual regulatory roles of hsa_circ_0057105 on EMT and ferroptosis sensitivity were verified using rescue experiments. Animal studies confirmed that hsa_circ_0057105 increased the metastatic ability and ferroptosis sensitivity of RCC cells in vivo. In RCC, hsa_circ_0057105 regulates COL1A1 and VDAC2 expression through its sponge effect on miR-577, acting like a 'double-edged sword'. These findings provide new insight into the relationship between EMT and ferroptosis in RCC and provide potential biomarkers for RCC surveillance and treatment.

Analysis of clinical characteristics and prognostic factors of elderly patients with renal cell carcinoma based on the SEER database.

To study the difference of clinical characteristics and prognostic factors from elderly patients with renal cell carcinoma (RCC), the statistical analysis was carried out based on the surveillance, epidemiology, and end results database. The relevant clinical information of 19,472 RCC patients from 2010 to 2015 were collected, and the differences of clinicopathological characteristics and survival rate was analyzed by log-rank method and Chi square test, respectively. Multivariate Cox regression model was used to explore the independent risk factors affecting the long-term survival of RCC patients. Results showed that the proportion of elderly RCC patients in the 60-64-year group in 2010 was 15.20%, but the value elevated to 18.51% in 2015, and the Chi-square test revealed the significant correlation between elderly RCC patients with gender, race, American Joint Committee on cancer stage, T stage, N stage, and M stage. The difference of survival time between the 60-69 year, 70-79 year, 80-84 year, and 85+ year group was significant, and Kaplan-Meier analysis showed a negative effects of age on survival rate of RCC patients, indicating a worsening trend with increasing age. Cox proportional hazards model analysis further confirmed that age was the important independent prognostic factor. Our study reveals that the onset age of RCC in elderly population is gradually decreasing, and the malignant degree of elderly RCC patients is increasing with age. The female elderly population could be more susceptible to RCC than male elderly population, and 85+ year population could also be cancer susceptible with a higher lymph node metastasis rate, later tumor stage, and poor prognosis, suggesting that these elderly populations should pay more attention to the RCC screening.

Integrated analysis identifies microRNA-188-5p as a suppressor of AKT/mTOR pathway in renal cancer.

Many current microRNA (miRNA) expression datasets for renal cell carcinoma (RCC) often show inconsistent analysis results, so a shift to comprehensive analysis of multiple datasets can effectively accelerate molecular screening for precision medicine and translational medicine research. MicroRNA (miR)-188-5p is a clinically noteworthy miRNA whose aberrant expression was previously observed in a variety of cancers, but its role in RCC is unclear. In this study, we undertook a comprehensive analysis of four RCC miRNA expression datasets and validated the results using The Cancer Genome Atlas (TCGA) dataset and a cohort of collected clinical samples. Fifteen miRNAs were identified as potential diagnostic markers by the analysis of four RCC miRNAs datasets. Analysis of the TCGA kidney renal clear cell carcinoma dataset showed significantly shorter survival in RCC patients with reduced miR-188-5p expression levels, and our collection of RCC clinical samples showed low miR-188-5p expression in the tumors. Overexpression of miR-188-5p in Caki-1 and 786-O cells inhibited cell growth, colony formation, invasion, and migration. In contrast, miR-188-5p inhibitors reversed these cell phenotypes. We identified a binding site for miR-188-5p in the 3'-UTR region of myristoylated alanine-rich C-kinase substrate (MARCKS) mRNA and demonstrated an interaction between these two molecules. Quantitative RT-PCR and western blot analysis revealed that miR-188-5p could regulate the AKT/mTOR signaling pathway through MARCKS. Mouse transplantation tumor assay indicated that miR-188-5p reduced the tumorigenicity of RCC in vivo. MicroRNA-188-5p could be a valuable new molecule for RCC diagnosis and prognosis.

Effect of transfused donor and autoerythrocytes on the oncological outcomes of surgical treatment in patients with renal cell carcinoma with tumor-related venous thrombosis: observational study

Background. The only effective treatment for renal cell carcinoma with tumor inferior vena cava (IVC) thrombosis is surgery. Nephrectomy with thrombectomy (NETE) is usually associated with clinically significant blood loss. The role of blood-sparing methods using autoerythrocyte reinfusion device (ARD) or replacement of blood loss with donor erythrocytes (DE) on the outcomes of NETE has not been well studied.&#x0D; Aim. To study the rate of hemostasis disorders with intraoperative ARD use, as well as the effect of ARD and DE transfusions on specific (SS), relapse-free (RFS), and progression-free (PFS) survival of patients with renal cell carcinoma (RCC) after NETE.&#x0D; Materials and methods. The observational study included medical data of 507 patients with RCC and tumor IVC thrombosis operated after NETE. The median volume of blood loss was 4000 [20006500] mL. In 312 (61.5%) patients, ARD without a leukocyte filter was used to compensate for blood loss (median volume of reinfused autoerythrocytes AE was 1140 [700; 1900] mL). Transfusion of DE was required in 387 (76.3%) cases; the median number of DE transfused doses was 3 [1; 5]; 475 (93.7%) patients were discharged from the hospital. The median follow-up of all surviving patients was 24 (1189) months.&#x0D; Results. Indications for blood transfusions (DE and AE) were directly correlated to the pN (r=0.101; p=0.024) and pT (r=0.091; p=0.040) categories, respectively. The use of AE had no significant effect on the rate of hemostasis disorders and coagulopathic complications compared to other methods of blood loss replacement: 6.8% (21/311) vs 4.7% (9/193), p=0.227; 5.1% (16/311) vs 4.1% (8/193), p=0.394, respectively. ARD had no effect on SS, RFS (after radical surgery), and PFS (after cytoreductive surgery) after NETE. There was a reduction of SS in patients who received DE transfusions compared with those who did not (hazard ratio 0.4; 95% confidence interval 0.10.9; p=0.048). The effects of DE transfusions on RFS and PFS were not identified.&#x0D; Conclusion. Intraoperative ARD use is an effective and safe method of correcting anemia, which does not increase the risk of coagulopathic complications or decrease survival rates. The non-use of the leukocyte filter during AE preparation does not worsen the medium-term oncological results of RCC surgical treatment with tumor IVC thrombosis. The effect of DE transfusion on the survival of RCC patients after NETE requires further research.

Comparisons of different lymph node staging systems for predicting overall survival of node-positive patients with renal cell carcinoma: a retrospective cohort study using the Surveillance, Epidemiology and End Results database

ObjectivesTo compare the prognostic values of three lymph node staging systems in renal cell carcinoma (RCC), including the number of positive lymph nodes (NPLN), lymph node ratio (LNR) and log...

Nomograms for predicting overall survival and cancer-specific survival of patients with stage IV renal cell carcinoma: A SEER population-based study

<sec><strong>Background</strong> The purpose of this study was to explore independent favorable prognostic factors for predicting 1-, 3-, and 5-year overall survival (OS) and cancer-specific survival (CSS) in patients with stage Ⅳ cell renal cell carcinoma (RCC) by constructing nomograms. </sec><sec><strong>Methods</strong> A total of 2636 patients diagnosed with stage Ⅳ RCC from 2010 to 2015 were enrolled in the surveillance, epidemiology, and end results database. Multivariate Cox hazard regression and competing risk analysis were used for searching prognosis factors in the cohort. The nomograms were constructed for predicting 1-, 3-, and 5-year of OS and CSS. Concordance index (C-index) and the calibration curves were used to evaluate the discrimination and accuracy of the nomograms. </sec><sec><strong>Results</strong> Age, nephrectomy, histology, N stage, and brain/liver/lung metastasis were identified as independent favorable prognostic factors in OS and CSS via univariate and multivariate analyses. Other variables were further selected by clinical practice and net reclassification improvement (NRI). Finally, age, nephrectomy, histology, grade, tumor size, T stage, N stage, and bone/brain/liver/lung metastasis were chosen to construct nomograms. The C-index of the OS and CSS in nomograms were 0.697 (95% confidence interval (CI), 0.683–0.711) and 0.655 (95% CI, 0.639–0.671), respectively. The calibration curves revealed high consistency between the nomograms prediction and actual observation. </sec><sec><strong>Conclusions</strong> The nomograms may help clinicians to conveniently predict the survival of RCC patients with stage Ⅳ and provide guidance in choosing the suitable management. </sec>

Preoperative serum low-density lipoprotein cholesterol is an independent prognostic factor in patients with renal cell carcinoma after nephrectomy

BackgroundLittle is known about the association between the preoperative low-density lipoprotein cholesterol (LDL-C) level and prognosis in patients with renal cell carcinoma (RCC) after nephrectomy, and its prognostic value needs to be elucidated.MethodsThe clinical and follow-up data of 737 RCC patients who underwent nephrectomy were retrospectively analyzed. The optimal cut-off LDL-C level was determined using X-tile, and then patients were divided into low and high LDL-C groups. The association between LDL-C levels and survival of RCC patients was assessed using the Kaplan-Meier method and Cox regression analysis.ResultsThe optimal cut-off LDL-C level was 1.93 mmol/L, and patients were divided into the low (≤ 1.93 mmol/L) and high LDL-C (> 1.93 mmol/L) groups. The Kaplan-Meier analysis showed that patients in the low LDL-C group had significantly shorter overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) than those in the high LDL-C group (P = 0.001, P = 0.001, and P = 0.003, respectively). The COX univariate analysis showed that the preoperative LDL-C level was closely associated with OS, CSS, and RFS in RCC patients (P = 0.002, P = 0.003, and P = 0.005, respectively). The multivariate analysis showed that the preoperative LDL-C level was an independent factor for predicting survival (OS, CSS and RFS) in RCC patients after nephrectomy. The low preoperative LDL-C levels predicted worse OS (hazard ratio [HR]: 2.337; 95% confidence interval [CI]: 1.192–4.581; P = 0.013), CSS (HR: 3.347; 95% CI: 1.515–7.392; P = 0.003), and RFS (HR: 2.207; 95% CI: 1.178–4.132; P = 0.013).ConclusionsThe preoperative LDL-C level is an independent factor for the prognosis of RCC patients after nephrectomy, and low preoperative LDL-C levels predict worse survival (OS, CSS, and RFS).

A Listeria-based vaccine targeting ISG15 exerts anti-tumor efficacy in renal cell carcinoma.

Renal cell carcinoma (RCC) is the deadliest form of urological cancer and is projected to be the fourth most common neoplasm in the USA in males by 2040. In addition to the current poor prognosis with 5-year survival rates hardly reaching 15%, the prevalence of resistance to currently available systemic therapies has also established an urgent need to develop new treatment regimen(s) for advanced RCC. Interferon-stimulated gene 15 (ISG15) is the first identified ubiquitin-like modifier and has been intensively studied for its central role in innate immunity against intracellular pathogens. However, in this study, we identified ISG15 as a novel tumor-associated antigen and prognostic marker in RCC. Further, we therapeutically targeted elevated ISG15 expression by means of a Listeria monocytogenes (Lm)-based vaccine, designated Lm-LLO-ISG15, in both subcutaneous and orthotopic RCC mouse models. Treatment with Lm-LLO-ISG15 resulted in an influx of tumor-infiltrating effector T cells and significant anti-tumor efficacy in both subcutaneous and orthotopic RCC tumor models. Treatment with Lm-LLO-ISG15 also generated a robust interferon-gamma response and attracted a larger pool of polyfunctional T cells into the tumor microenvironment. Importantly, the therapeutic efficacy of Lm-LLO-ISG15 in RCC is comparable to that of anti-PD-1 and sunitinib, the current frontline therapies for RCC patients. Collectively, our work illustrates that targeting ISG15 in RCC with a CTL-based immunotherapy such as Lm-LLO-ISG15 is a promising and potentially translatable therapeutic strategy to enhance survival in RCC patients.

Effects of Contrast Enhancement Phase on the Reproducibility and Predictivity of CT-Based Renal Lesions Radiomic Features

The extraction of quantitative medical imaging features, or radiomics, has been an exponentially growing research field in recent decades. Nonetheless, more studies are investigating the limitations of the quantitative imaging features, especially the reproducibility of RFs across different scanning settings. In this experiment, we investigate the reproducibility of renal cell carcinoma (RCC) RFs between the non-contrast, arterial, and late phases contrast-enhanced computed tomography (CE-CT) scans; and the ability of ComBat technique to harmonize these RFs. In addition, we assessed the predictive performance of the RFs extracted from the different phases. A total of 69 CECT scans with the three different phases were analyzed. Original RFs were extracted from the segmented lesions on each phase using Pyradiomics toolbox. The agreement in RF values before and after harmonization was evaluated with the concordance correlation coefficient (CCC). Our results show that most RFs are not reproducible across different imaging phases. In addition, ComBat harmonization did not significantly increase the number of reproducible RFs in any of the three scenarios. Furthermore, RFs extracted from the arterial phase were, on average, the most predictive of overall survival in RCC patients. The findings can guide the analysis of retrospective RCC heterogeneous data acquired in different phases and add to the call for radiomics-specific harmonization techniques.

Sex Differences in Renal Cell Carcinoma: The Importance of Body Composition

PurposeTo examine sex-specific differences in renal cell carcinoma (RCC) in relation to abdominal fat accumulation, psoas muscle density, tumor size, pathology, and survival, and to evaluate possible associations with RCC characteristics and outcome.MethodsA total of 470 patients with RCC who underwent nephrectomy between 2006 and 2019 were included in this retrospective study. Specific characteristics of RCC patients were collected, including sex, height, tumor size, grade, and data on patient survival, if available. Abdominal fat measurements and psoas muscle area were determined at the level of L3 (cm2).ResultsWomen had a higher subcutaneous (p < 0.001) and men had a higher visceral fat area, relative proportion of visceral fat area (p < 0.001), and psoas muscle index (p < 0.001). Logistic regression analysis showed an association between higher psoas muscle index and lower grade tumors [women: odds ratio (OR) 0.94, 95% confidence interval (CI) 0.89–0.99, p = 0.011; men: OR 0.97 (95% CI, 0.95–0.99, p = 0.012]. Univariate regression analysis demonstrated an association between psoas muscle index and overall survival (women: OR 1.41, 95% CI 1.03–1.93, p = 0.033; men: OR 1.62 (95% CI, 1.33–1.97, p < 0.001). In contrast, there were no associations between abdominal fat measurements and tumor size, grade, or survival. Also, there were no sex-specific differences in tumor size or tumor grades.ConclusionsA higher preoperative psoas muscle index was independently associated with overall survival in RCC patients, with a stronger association in men compared with women. In addition, the psoas muscle index showed an inverse association with tumor grade, whereby this association was slightly more pronounced in women than in men.

The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology

ABSTRACT NKG2D is a major natural killer (NK) cell-activating receptor that recognizes eight ligands (NKG2DLs), including MICA, and whose engagement triggers NK cell effector functions. As NKG2DLs are upregulated on tumor cells but tumors can subvert the NKG2D-NKG2DL axis, NKG2DLs constitute attractive targets for antibody (Ab)-based immuno-oncology therapies. However, such approaches require a deep characterization of NKG2DLs and NKG2D cell surface expression on primary tumor and immune cells. Here, using a bioinformatic analysis, we observed that MICA is overexpressed in renal cell carcinoma (RCC), and we also detected an association between the NKG2D-MICA axis and a diminished overall survival of RCC patients. Also, by flow cytometry (FC), we observed that MICA was the only NKG2DL over-expressed on clear cell renal cell carcinoma (ccRCC) tumor cells, including cancer stem cells (CSC) that also coexpressed NKG2D. Moreover, tumor-infiltrating leukocytes (TIL), but not peripheral blood lymphoid cells (PBL) from ccRCC patients, over-expressed MICA, ULBP3 and ULBP4. In addition, NKG2D was downregulated on peripheral blood NK cells (PBNK) from ccRCC patients but upregulated on tumor-infiltrating NK cells (TINK). These TINK exhibited impaired degranulation that negatively correlated with NKG2D expression, diminished IFN-γ production, upregulation of TIM-3, and an impaired glucose intake upon stimulation with cytokines, indicating that they are dysfunctional, display features of exhaustion and an altered metabolic fitness. We conclude that ccRCC patients exhibit a distorted MICA-NKG2D axis, and MICA emerges as the forefront NKG2DL for the development of targeted therapies in ccRCC.

Analysis of Renal Cell Carcinoma Cell Response to the Enhancement of 5-aminolevulinic Acid-mediated Protoporphyrin IX Fluorescence by Iron Chelator Deferoxamine†.

As a tumor photodiagnostic agent, 5-aminolevulinic acid (ALA) is metabolized in the heme biosynthesis pathway to produce protoporphyrin IX (PpIX) with fluorescence. ALA-PpIX fluorescence was evaluated in human renal cell carcinoma (RCC) cell lines and non-tumor HK-2 cell lines. We found that extracellular PpIX level was correlated with ABCG2 activity, illustrating its importance as a PpIX efflux transporter. Extracellular PpIX was also related to the Km of ferrochelatase (FECH) that chelates PpIX with ferrous iron to form heme. The Vmax of FECH was higher in all RCC cell lines tested than in the HK-2 cell line. TCGA dataset analysis indicates a positive correlation between FECH expression and RCC patient survival. These findings suggest FECH as an important biomarker in RCC. Effects of iron chelator deferoxamine (DFO) on the enhancement of PpIX fluorescence were assessed. DFO increased intracellular PpIX in both tumor and non-tumor cells, resulting in no gain in tumor/non-tumor fluorescence ratios. DFO appeared to increase ALA-PpIX more at 1-h than at 4-h treatment. There was an inverse correlation between ALA-PpIX fluorescence and the enhancement effect of DFO. These results suggest that enhancement of ALA-PpIX by DFO may be limited by the availability of ferrous iron in mitochondria following ALA administration.