Imaging Tool for Predicting Renal Clear Cell Carcinoma Fuhrman Grade: Comparing R.E.N.A.L. Nephrometry Score and CT Texture Analysis

Background. Clear cell renal cell carcinoma (ccRCC) is the most common renal malignant tumor. Preoperative imaging boasts advantages in diagnosing and choosing treatment methods for ccRCC. Purpose. This study is aimed at building models based on R.E.N.A.L. nephrometry score (RNS) and CT texture analysis (CTTA) to estimate the Fuhrman grade of ccRCC and comparing the advantages and disadvantages of the two models. Materials and Methods. 143 patients with pathologically confirmed ccRCC were enrolled. All patients were stratified into Fuhrman low-grade and high-grade groups with complete CT data and R.E.N.A.L. nephrometry scores. CTTA features were extracted from the ROI delineated at the largest tumor level, and RNS and CTTA features were included in the logistic regression model, respectively. Results. RNS model constructed based on multivariate logistic regression analysis showed that 3 pts for R -scores, 2 pts for E -scores, and 3 pts for L -scores were significant indicators to predict high-grade ccRCC, the AUC of RNS model was 0.911, and the sensitivity and specificity were 71.11% and 83.67%, respectively. The CTTA-model confirmed energy, kurtosis, and entropy as independent predictive factors, and the AUC of CTTA model was 0.941, with an optimal sensitivity and specificity of 84.44% and 93.88%. Conclusions. R.E.N.A.L. nephrometry score has a certain provocative effect on the Fuhrman pathological grading of ccRCC. As a potential emerging technology, CTTA is expected to replace R.E.N.A.L. nephrometry score in evaluating patients’ Fuhrman classification, and this approach might become an available method for assisting clinicians in choosing appropriate operation.

Comparison of Survival Between Unilocular Cystic and Purely Solid Renal Cell Carcinoma

Purpose To evaluate clinicopathologic features and survival outcomes of unilocular cystic renal cell carcinoma (cRCC) compared with purely solid renal cell carcinoma (RCC), and to evaluate the oncologic aggressiveness of unilocular cRCC. Methods The relevant data of 957 patients with sporadic unilateral RCCs underwent surgical treatment in 2 institutions from Jan 2014 to Oct 2018 were obtained. We excluded multilocular cystic renal neoplasm of low malignant potential (MCRNLMP), RCCs with multilocular cysts and necrotic RCCs. 74 unilocular cRCCs were identified by pathology reports. We performed propensity score matching (PSM) and randomly selected 148 purely solid RCCs. The clinicopathologic features and survival outcomes were compared properly. Results After PSM, age, BMI, Charlson Comorbidity Index, and postoperative Chronic Kidney Disease grade were not significantly different. Both overall survival and cancer-specific survival of unilocular cRCCs were significantly better than the purely solid RCCs by the log-rank test. Twenty-five cases of solid RCCs were in the pT3 or pT4 stage, while no pT3 or pT4 tumors were found in unilocular cRCCs. Fuhrman grade, pT stage, lymphatic metastasis and tumor diameter were found to be independent prognostic factors. Conclusion Unilocular cRCCs have a lower Fuhrman grade and pathological stage and a better prognosis compared with solid RCC. Unilocular cRCCs still probably have lymphatic metastasis at diagnosis and may have postoperative metastasis, which is different from MCRNLMP. We recommend that the diagnosis of unilocular cRCC should be reflected in pathology reports. Different subtypes of cRCC should be taken into consideration in counseling and management.

Multicenter Study of Controlling Nutritional Status (CONUT) Score as a Prognostic Factor in Patients With HIV-Related Renal Cell Carcinoma

ObjectiveIn recent years, the controlled nutritional status (CONUT) score has been widely recognized as a new indicator for assessing survival in patients with urological neoplasms, including renal, ureteral, and bladder cancer. However, the CONUT score has not been analyzed in patients with HIV-related urological neoplasms. Therefore, we aimed to evaluate the prognostic significance of the CONUT score in patients with HIV-related renal cell carcinoma (RCC).MethodsA total of 106 patients with HIV-related RCC were recruited from four hospitals between 2012 and 2021, and all included patients received radical nephrectomy or partial nephrectomy. The CONUT score was calculated by serum albumin, total lymphocyte counts, and total cholesterol concentrations. Patients with RCC were divided into two groups according to the optimal cutoff value of the CONUT score. Survival analysis of different CONUT groups was performed by the Kaplan–Meier method and a log rank test. A Cox proportional risk model was used to test for correlations between clinical variables and cancer-specific survival (CSS), overall survival (OS), and disease-free survival (DFS). Clinical variables included age, sex, hypertension, diabetes, tumor grade, Fuhrman grade, histology, surgery, and CD4+ T lymphocyte count.ResultThe median age was 51 years, with 93 males and 13 females. At a median follow-up of 41 months, 25 patients (23.6%) had died or had tumor recurrence and metastasis. The optimal cutoff value for the CONUT score was 3, and a lower CONUT score was associated with the Fuhrman grade (P=0.024). Patients with lower CONUT scores had better CSS (HR 0.197, 95% CI 0.077-0.502, P=0.001), OS (HR 0.177, 95% CI 0.070-0.446, P<0.001) and DFS (HR 0.176, 95% CI 0.070-0.444, P<0.001). Multivariate Cox regression analysis indicated that a low CONUT score was an independent predictor of CSS, OS and DFS (CSS: HR=0.225, 95% CI 0.067-0.749, P=0.015; OS: HR=0.201, 95% CI 0.061-0.661, P=0.008; DFS: HR=0.227, 95% CI 0.078-0.664, P=0.007). In addition, a low Fuhrman grade was an independent predictor of CSS (HR 0.192, 95% CI 0.045-0.810, P=0.025), OS (HR 0.203, 95% CI 0.049-0.842, P=0.028), and DFS (HR 0.180, 95% CI 0.048-0.669, P=0.010), while other factors, such as age, sex, hypertension, diabetes, tumor grade, histology, surgery, and CD4+ T lymphocyte count, were not associated with survival outcome.ConclusionThe CONUT score, an easily measurable immune-nutritional biomarker, may provide useful prognostic information in HIV-related RCC.

Knockdown of ubiquitin-like modifier-activating enzyme 2 promotes apoptosis of clear cell renal cell carcinoma cells

Small ubiquitin-related modifier (SUMO) proteins are involved in the development of tumors. Ubiquitin-like modifier-activating enzyme 2 (UBA2) is an important member of the SUMO modification system; however, its role in clear cell renal cell carcinoma (ccRCC) is unclear. Therefore, we investigated the expression and function of UBA2 in ccRCC. Both mRNA and protein expression levels of UBA2 were found to be higher in ccRCC than in normal renal tissues and significantly related to the tumor size, Fuhrman grade, and tumor stage. UBA2 knockdown inhibited ccRCC cell growth, promoted apoptosis in vitro and in vivo, and decreased the abundance of a p53 mutant, c-Myc, and key enzymes of the SUMO modification system. Meanwhile, overexpression of UBA2 had the opposite effects. Overexpression of the p53 mutant or c-Myc alleviated the effects of UBA2 knockdown on ccRCC cell proliferation and apoptosis. In conclusion, targeting UBA2 may have a therapeutic potential against ccRCC.

Histone demethylase KDM4D inhibition suppresses renal cancer progression and angiogenesis through JAG1 signaling

Kidney cancer, especially clear cell renal cell carcinoma (ccRCC), is one of the representative genitourinary tumors. Investigation of underlying mechanisms of ccRCC development is crucial for patient management. Histone demethylase KDM4D has been reported to be responsible for development of a variety of cancers. However, the role of KDM4D in ccRCC progression is poorly understood. In our study, we performed immunohistochemistry analysis of tissue microarrays first, and results showed that high expression level of KDM4D is connected with advanced Fuhrman grade (p = 0.0118) and lower overall survival (p = 0.0020). Then, we revealed that KDM4D can prompt ccRCC development by interacting with genes related to vessel morphogenesis. Finally, we disclosed that KDM4D directly interacts with JAG1 promoter and advances tumor angiogenesis by upregulating VEGFR-3 and antagonizing notch signaling. The results of our study indicate that KDM4D would be a potential prognostic marker and therapeutic target for ccRCC patients.

DDX39B Predicts Poor Survival and Associated with Clinical Benefit of Anti-PD-L1 Therapy in ccRCC

Background: Immune checkpoint inhibitors (ICI) have been shown to improve overall survival (OS) in clear cell renal cell carcinoma (ccRCC) patients. However, less than half of the ccRCC patients have objective response to ICI. Objective: We aim to assess the role of DDX39B in predicting ccRCC patients' OS and ICI therapy response. Methods: DDX39B was detected by immunohistochemistry in a tissue microarray of 305 ccRCC patients. DDX39B and its relationship with the prognosis of ccRCC were also evaluated in TCGA set and a RECA-EU set. The expression of DDX39B and patients survival was also analysed in two datasets of ccRCC patients treated with ICI. Results: Overexpression of DDX39B predicted poor OS of ccRCC patients in SYSU set, TCGA set, and a RECA-EU set. DDX39B expression was significantly positive with the expression of PD-L1 and other immunomodulators., DDX39B negatively correlated with cytotoxic T-lymphocyte and HDAC10 exon 3 inclusion in ccRCC. DDX39B knockdown decreased the expression of PD-L1 and increased the expression of HDAC10 exon 3 in renal cancer ACHN cells. Patients of ccRCC with lower levels of HDAC10 exon 3 inclusion have higher TNM stage, higher Fuhrman grade and poor OS. There was a tendency that patients with DDX39B high expression had longer OS and PFS than patients with DDX39B low expression in ccRCC patients treated with ICI. Conclusion: DDX39B gene is highly expressed in ccRCC and is closely related to patients’ OS. DDX39B might increase PD-L1 expression via the enhancement of HDAC10 exon 3 skipping, thereby promoting the ICI therapy response.

Impact of Metabolic Syndrome And Metabolic Syndrome Components on Tumor Aggresiveness of Renal Cell Carcinoma

Objective: The objective of this study was to evaluate the effects of Metabolic Syndrome (MetS) and MetS components on tumor size, Fuhrman grade and pathological T stage in renal cell carcinoma (RCC). Materials and Methods: The data of 151 patients who were operated for RCC between January 2010 and April 2018 were retrospectively reviewed according to the he National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), and the effects of MetS and its components on tumor size, Fuhrman grade and pathological T stage were comparatively investigated. Results: Of the 151 patients operated for RCC in our clinic, 27.2% had MS, 29.1% had diabetes mellitus (DM), 41% had hypertension (HT), 68.3% had low high-density lipoprotein (HDL), 41% had elevated triglyceride (TGL) elevation, and 27.2% had obesity. It was found that the size of the tumor was statistically significantly increased in the presence of the metabolic criteria examined. There was a statistically significant increase in the Fuhrman grade of the patients with MetS, DM, low HDL, high TGL and obesity. In the presence of clinical conditions such as HT, low HDL and high TGL, there was a statistically significant increase in the pathological T stage. Conclusion: In patients undergoing surgery for RCC, MetS and its components had a statistically significant correlation with tumor size, Fuhrman grade, and pathological stage. If our results are supported by further studies, the correlation between MetS and RCC could be revealed more clearly.

Oncological Outcomes of Patients With Different Pathological Features of pT3a Renal Tumor: A Systematic Review and Quantitative Synthesis

PurposeTo identify the differences in oncological outcomes for patients with different pT3a renal tumor invasion patterns and pathological features.MethodsThe protocol of this study was registered on PROSPERO (CRD42021234475). Relevant studies were identified by searching the PubMed, Cochrane library, Embase, and Web of Science databases. Cancer-specific survival (CSS) was selected as the endpoint. Pooled hazard ratio (HR) and 95% confidence interval (CI) extracted from multivariate Cox models were evaluated to identify the hazard association.ResultsA total of 22 studies, which enrolled 12384 patients were included for quantitative synthesis. Sinus fat invasion (SFI) + perinephric fat invasion (PFI) was associated with inferior CSS compared to SFI only (p = 0.02). Comparable CSS was observed between SFI and PFI (p = 0.57). SFI ± PFI showed inferior CSS compared to PFI only (p = 0.0002). The presence of pelvicalyceal system invasion significantly increased the risk of cancer-specific mortality (p = 0.0005). Renal vein invasion (RVI) indicated poor oncological outcomes in terms of CSS (p = 0.002). The concomitant RVI and fat invasion (FI) significantly increased the risk of deterioration of CSS compared to RVI or FI (p < 0.0001). Multiple invasion patterns translated into a significantly decreased CSS (p < 0.0001). Aggressive tumor behavior, including lymph node involvement (p = 0.006), distant metastases (p < 0.00001), sarcomatoid differentiation (p < 0.0001), necrosis (p < 0.0001), Fuhrman grade III or IV (p < 0.0001), positive margin (p < 0.0001), and tumor size >7cm (p < 0.0001) were the predictors of inferior CSS. The lymphovascular invasion (p = 0.67) was indolent in terms of CSS.ConclusionThis study confirmed the heterogenicity of pT3a renal tumors. Multiple invasion patterns could translate into a significantly decreased CSS, and SFI should not be merged in the SFI + PFI group. The presence of PSI or RVI could significantly increase the risk of cancer-specific mortality. Lymph node involvement, distant metastases, sarcomatoid differentiation, necrosis, high Fuhrman grade, positive margin, and size >7cm were the predictors of inferior CSS. A precise-risk grade of CSS for different invasion patterns including comprehensive combinations may be useful for the further refinements of the TNM system.Systematic Review RegistrationThe current study was registered on PROSPERO, and the registration numbers is CRD42021234475.

Plasma exosome microRNA-155 expression in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors: A potential biomarker of response to systemic therapy.

4570 Background: The search for a reliable predictive biomarker of response to immune checkpoint-based therapy (ICBT) remains a critically unmet need in the management of metastatic renal cell carcinoma (mRCC). We sought to evaluate the biomarker potential of plasma exosome microRNAs (miRNAs) implicated in RCC and in augmentation of the tumour microenvironment (TME) for such a role. Methods: Eleven miRNAs that are over-expressed in RCC and/or immune-associated were evaluated in 40 patients with mRCC (prior to initiating ICBT) and in 30 healthy volunteers. Exosomes were extracted from 500 uL of plasma and were used for miRNAs extraction. MiRNAs expression was evaluated by RT-PCR. Cycle threshold values were normalized to miR-30-3b, and the relative quantity of the expression (RQ) was compared to those of healthy volunteers and calculated using the 2ΔΔCt method. Mann-Whitney U test was used to evaluate the expression of miRNAs between mRCC pts and healthy volunteers according to best response to first line ICBT between responders (n = 27) v non-responders (n = 13). The cut-off value of significant expression was established by Youden’s index. Responders were defined as those patients experiencing complete response, partial response or stable disease and non-responders were those who experienced progressive disease. Results: The most common first line ICBT was nivolumab + ipilimumab (n = 32), followed by pembrolizumab + axitinib (n = 5), and avelumab + axitinib (n = 3). A significantly higher expression of miRNA-1233 (median 1.85 v 0.81 p = 0.008) and miRNA-155 [miR-155] (3.69 v 0.21 p = 0.006) were found in patients compared to healthy volunteers. Higher miR-155 expression was associated with higher Fuhrman grade (p = 0.002). There was no association with other clinical prognostic factors. MiR-155 was expressed at a significantly lower level in responders than in non-responders (median 0.61 v 35.29, p = 0.042). Response rate amongst patients with low and high expression of miR-155 (RQ ≤ 2.5) was statistically different (p = 0.042) and 84.2% of the pts with low miR-155 expression responded to the treatment. Conclusions: Lower expression of miR-155 was associated with response to ICBT in patients with mRCC. Functionally, miR-155 is involved in regulation and modulation of the TME. These results underscore the need for further work in this area to elucidate the role of this and other miRNAs as biomarkers of response in mRCC.