Real-world study on the characteristics, post-nephrectomy journey, and outcomes of patients with early-stage renal cell carcinoma based on risk groups.

OBJECTIVES: To examine real-world characteristics, journey, and outcomes among patients with locoregional, nonmetastatic renal cell carcinoma (RCC). METHODS: A retrospective analysis of medical records from the ConcertAI Oncology Dataset was performed on adults in the United States with newly diagnosed nonmetastatic RCC between January 2012-December 2017 who received surgical treatment, and were followed until August 2021. Patients were stratified based on the risk of recurrence after nephrectomy. Recurrence rate and survival outcomes were assessed. RESULTS: The cohort (n = 439) had a median age of 64 years, 66.1% were male, and 76.5% had clear-cell histology. The median follow-up time from nephrectomy was 39.3 months overall, 41.0 months for intermediate-high-risk patients (n = 377; 85.9%) and 24.1 months for high-risk patients (n = 62; 14.1%). For intermediate-high- and high-risk patients, respectively, 68.4% and 56.5% had ≥1 medical oncologist visit after nephrectomy. Of 260 patients with documentation of postoperative imaging assessments, 72% were ordered by medical oncologists, and the median time from initial nephrectomy to the first scan was 110 days (intermediate-high-risk) and 51 days (high-risk). Provider-documented recurrence occurred in 223 (50.8%) patients, of whom 41.7% had ≥1 medical oncologist visit before the recurrence. Three-year disease-free survival (DFS), and overall survival rates were 49.4% and 80.8% (all patients): 27.7% and 64.7% (high-risk); and 52.9% and 83.3% (intermediate-high-risk). CONCLUSIONS: Our study reports low DFS after nephrectomy for patients with intermediate-high- and high-risk RCC. Subsequent approval and use of new and newly approved adjuvant therapeutic options could potentially delay or prevent recurrence.

Sex and survival outcomes in patients with renal cell carcinoma receiving first-line immune-based combinations.

BACKGROUND: There is an ongoing debate as to whether sex could be associated with immune checkpoint inhibitor (ICI) benefit. Existing literature data reveal contradictory results, and data on first-line immune combinations are lacking. METHOD: This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with immuno-oncology combinations as first-line therapy. RESULTS: A total of 1827 mRCC patients from 71 cancer centers in 21 countries were included. The median OS was 38.7 months (95% CI 32.7-44.2) in the overall study population: 40.0 months (95% CI 32.7-51.6) in males and 38.7 months (95% CI 26.4-41.0) in females (p = 0.202). The median OS was higher in males vs. females in patients aged 18-49y (36.9 months, 95% CI 29.0-51.6, vs. 24.8 months, 95% CI 16.8-40.4, p = 0.426, with + 19% of 2y-OS rate, 72% vs. 53%, p = 0.006), in the clear cell histology subgroup (44.2 months, 95% CI 35.8-55.7, vs. 38.7 months, 95% CI 26.0-41.0, p = 0.047), and in patients with sarcomatoid differentiation (34.4 months, 95% CI 26.4-59.0, vs. 15.3 months, 95% CI 8.9-41.0, p < 0.001). Sex female was an independent negative prognostic factor in the sarcomatoid population (HR 1.72, 95% CI 1.15 - 2.57, p = 0.008). CONCLUSIONS: Although the female's innate and adaptive immunity has been observed to be more active than the male's, women in the subgroup of clear cell histology, sarcomatoid differentiation, and those under 50 years of age showed shorter OS than males.

Clinical and pathological characteristics of renal cell carcinomas with MiTF translocation.

INTRODUCTION: Microphthalmia Transfactor Family (MiTF) translocation renal cell carcinomas (RCCs) represent a rare subtype of renal cell cancers. They are diagnosed in young patients and have a poor prognosis. The aim of our study was to analyze the clinical and pathological features of patients with MiTF RCC. MATERIAL AND METHOD: We performed a retrospective, monocentric, descriptive study including all patients operated for RCC between January 2015 and January 2023. The diagnosis of MiTF RCC was suspected by immunohistochemistry (IHC) and confirmed by fluorescent in situ hybridization (FISH). Survival data according to histological subtype (MiTF versus ccRCC) were analyzed using the Kaplan-Meier method and compared using a log-rank test. The primary endpoint was recurrence-free survival (RFS). A descriptive cohort analysis was performed. RESULTS: Of the 960 patients included, 19 (2%) had FISH-confirmed MiTF tumors. The median age at diagnosis was 42 years [18-75], the sex ratio was 1.11 females for 1 male, and 4 (21%) patients were immediately metastatic. Median RFS was 21months for patients in the MiTF group and was significantly lower than that of ccRCC patients, HR=4.33 [CI95% 2.06; 9.10; P<0.001]. Of the 11 patients with cT1-T2 tumors, 9 (81.8%) were treated with nephron sparing-surgery, with 2 (22.2%) harbored local recurrence. CONCLUSION: Our study shows that patients with MiTF translocation RCC have a significantly lower RFS than non-MiTF RCC patients. Nephron sparing surgery must be weighted by the high risk of recurrence in this particularly young population.

Comparison of different 2D muscle indexes measured at the level of the 3rd lumbar vertebra in survival prediction in patients with renal cell carcinoma.

BACKGROUND: Low computed tomography (CT)-determined muscle mass, commonly determined with height-adjusted muscle indexes (MIs), predicts worse survival in several cancers and has been suggested as a prognostic assessment tool. Although several MIs measured at the level of the 3rd lumbar vertebra (L3) are commonly used, it remains unestablished how different L3-determined MIs perform in survival prognostication compared to each other. The objective of this study was to investigate the performance of different MIs for survival prognostication in renal cell carcinoma (RCC). METHODS: We retrospectively enrolled 214 consecutive patients with RCC. We determined three L3-MIs (psoas muscle index (PMI), psoas muscle index and erector spinae index (PMI+ESI), and whole skeletal muscle index (SMI)) from preoperative CT scans. Categorization of those with low and normal muscle mass was based on the Youden Index sex-specific MI cut-offs. We determined sensitivity, specificity, and accuracy metrics for predicting 1-year, 5-year, and overall survival (OS) using Cox regression models. RESULTS: Low PMI, PMI+ESI, and SMI significantly predicted decreased 1-year, 5-year, and OS in uni- and multivariate models. PMI+ESI and SMI were more accurate than PMI in males, and PMI and PMI+ESI were more accurate than SMI in females in the prediction of 1-year survival. However, there were no differences in accuracies between MIs in 5-year and OS prediction. INTERPRETATION: PMI+ESI performed well overall in short-term prognostication, but there were no differences between the MIs in long-term prognostication. We recommend the use of PMI+ESI for muscle evaluation, particularly when SMI cannot be evaluated.

End-stage renal disease after renal cancer surgery: risk factors and overall survival.

OBJECTIVE: Several risk factors for end-stage renal disease (ESRD), in patients undergoing surgical treatment for renal cell carcinoma (RCC), have been suggested by others. This study aimed to investigate such risk factors and disclose the effect of developing ESRD, postoperatively, on overall survival. The risk of developing ESRD after RCC diagnosis was also evaluated. MATERIAL AND METHODS: The data of 16,220 patients with RCC and 162,199 controls were extracted from the Renal Cell Cancer Database Sweden, with linkages across multiple national registers between 2005 and 2020. Cox proportional hazards regression, Kaplan-Meier curves and cumulative incidence were used for statistical analysis. RESULTS: The 5-year cumulative incidence of ESRD following RCC diagnosis was 2.4% (95% confidence interval [CI] 2.1-2.6) and 0.4% (95% CI 0.3-0.4) for the patients with RCC and controls, respectively. Age, chronic kidney disease, higher T-stage and radical nephrectomy (RN) were significant risk factors for ESRD within 1-year of surgery. A total of 104 and 12,152 patients with and without ESRD, respectively, survived 1-year postoperatively. The 5-year overall survival rates of patients with ESRD and those with RCC only were 50% (95% CI 0.40-0.60) and 80% (95% CI 0.80-0.81), respectively. CONCLUSIONS: Patients who developed ESRD following renal cancer surgery had significantly poorer survival outcomes. Advanced age, comorbidities, higher-stage tumours and RN were identified as risk factors for developing ESRD. Surgical decisions are crucial. Efforts to spare renal function, including nephron-sparing surgery and active surveillance in appropriate cases, are highly relevant to reduce the development of severe kidney dysfunction.

Function of NEK2 in clear cell renal cell carcinoma and its effect on the tumor microenvironment.

BACKGROUND: Previous studies have revealed the critical functions of NEK2 in controlling the cell cycle which is linked to poor prognosis in multiple tumor types, but less research has been devoted to clear cell renal cell carcinoma (ccRCC). METHODS: We downloaded clinical data from the gene expression omnibus (GEO) and TCGA databases together with transcriptional and mutational datasets. Strongly coexpressed genes with NEK2 were extracted from TCGA-KIRC cohort, and were submitted to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for functional analyses. According to NEK2 levels, the survival status, mutational characteristics, response to immunotherapy and sensitivity to drugs of the patients were studied. The potential correlations between NEK2 levels and immune cell state as well as immune cell infiltration were examined using the GEPIA, TIMER and TISIDB databases. Double immunofluorescence (IF) was performed to identify the NEK2 overexpression and relationship with CD8 in ccRCC. RESULTS: The NEK2 gene was overexpressed and would enhance the nuclear division and cell cycle activities in ccRCC. ccRCC patients with high NEK2 expression had worse clinical outcomes, higher mutation burden and better therapeutic response. Moreover, NEK2 gene overexpression was positively related to various immune cell marker sets, which was also proved by validation cohort, and more infiltration of various immune cells. CONCLUSION: ccRCC patients with NEK2 high expression have a poorer prognosis than those with NEK2 low expression, resulting from its function of promoting proliferation, accompanied by increased infiltration of CD8 + T cells and Tregs and T-cell exhaustion and will respond better to proper treatments.

The prognostic impact of peripheral blood eosinophil counts in metastatic renal cell carcinoma patients treated with nivolumab.

Although immune checkpoint inhibitors (ICIs) have gained approval for metastatic renal cell carcinoma (mRCC), the response rate is still limited. Therefore, it is urgent to explore novel markers of responses to ICIs that can help assess clinical benefits. Recently, it has been noted that peripheral blood eosinophil counts are an independent factor correlated with clinical outcome of ICIs in some types of cancer. We investigated peripheral blood absolute eosinophil counts (AECs) at baseline and 4 weeks after the initiation of nivolumab for mRCC patients between February 2016 and May 2022. In addition, we examined clinicopathological features including irAEs and analyzed the correlation between AECs and clinical efficacy of nivolumab. The median progression-free survival (PFS) and overall survival (OS) for all patients were 5.7 and 25.5 months, respectively. The median AECs in patients with irAEs were significantly higher at baseline and 4 weeks after the treatment compared to those without irAEs (p < 0.001 and p = 0.001). With the cutoff value of AECs of 329 cells/µL at 4 weeks after the treatment for prediction of irAEs, high-AECs groups had significantly higher number of responders compared with that in low-AECs group (p < 0.001). Accordingly, the PFS and OS were significantly better in patients with high-AECs group than those in low-AECs group (p = 0.03 and p = 0.009). High-AECs at 4 weeks after the treatment serve as the prominent surrogate marker associated with the incidence of irAEs and better clinical outcome in mRCC patients receiving nivolumab.

Development and validation of prognostic nomograms for adult with papillary renal cell carcinoma: A retrospective study.

OBJECTIVE: The aim of the study was to create two consensus nomograms for predicting Overall Survival (OS) and Cancer-Specific Survival (CSS) in adults with papillary Renal Cell Carcinoma (pRCC). METHODS: Using the Surveillance, Epidemiology, and End Results databases, a retrospective analysis of 1,074 adults with pRCC from 2004 to 2015 was performed. These patients were then randomly divided into two independent cohorts with a ratio of 7:3 (training cohort: 752; validation cohort: 322). In a retrospective analysis of 752 patients from the training cohort, independent prognostic variables affecting OS and CSS were found. R software was used to create prognostic nomograms based on the findings of Cox regression analysis. The performance of the nomograms was assessed using the Concordance Index (C-index), the Area Under Curve (AUC), a calibration curve, and Decision Curve Analysis (DCA). Data from the 107 postoperative pRCC patients at the Affiliated Hospital of Xuzhou Medical University were used for external validation of the nomogram. RESULTS: For OS and CSS, the C-indices and AUCs of the training cohort and the validation cohort indicated that the model had excellent discrimination. The DCA demonstrated that the model was clinically applicable, and the calibration curves in the internal and external validations showed that the model's accuracy was high. CONCLUSION: The authors developed and validated a prognostic nomogram that accurately predicted the 3-, 5-, and 8-year OS and CSS of adults with pRCC. Clinicians can use this knowledge to direct the clinical management and counseling of patients with pRCC.

Banana-shaped survival curves of metastatic renal cell carcinoma treated with first-line immune-combinations, not just a matter of "palateau".

The first-line therapy of metastatic renal cell carcinoma (mRCC) has revolutionized with the approval of immune checkpoint inhibitors (ICIs) in combination with or without tyrosine kinase inhibitors (TKIs). The choice among the many different immuno-combinations (ICI-ICI or ICI-TKI) is challenging due to the lack of predictive factors. The different shapes of the Kaplan-Meier survival curves (e.g. "banana-shaped curves") have raised many questions on the long-term survival benefit. Here, we analyzed the factors that could have impacted the different long-term survival, including the prognostic factors distribution (IMDC score), histological factors (sarcomatoid features, PD-L1 expression), and treatment characteristics (mechanism of action, duration, discontinuation rate). This overview highlights the factors that should be considered in the first-line setting for the patients' therapeutic choice and prognostic assessment. They are also fundamental parameters to examined for head-to-head studies and real-life, large-scale studies.

An epidemiological and clinicopathological study of type 1 vs. type 2 morphological subtypes of papillary renal cell carcinoma- results from a nation-wide study covering 50 years in Iceland.

INTRODUCTION: Papillary renal cell carcinoma (pRCC) is the second most common histology of renal cell carcinoma (RCC), accounting for 10-15% of cases. Traditionally, pRCC is divided into type 1 and type 2, although this division is currently debated as a prognostic factor of survival. Our aim was to investigate the epidemiology and survival of the pRCC subtypes in a whole nation cohort of patients during a 50-year period. MATERIALS AND METHODS: A Population based retrospective study including consecutive cases of RCC in Iceland from 1971-2020. Comparisons were made between histological classifications of RCC, with emphasis on pRCC subtypes (type 1 vs. 2) for outcome estimation. Changes in RCC incidence were analyzed in 5-year intervals after age standardization. The Kaplan-Meier method and Cox regression were used for outcome analysis. RESULTS: A total of 1.725 cases were identified, with 74.4%, 2.1% and 9.2% having clear cell (ccRCC), chromophobe (chRCC), and pRCC, respectively. The age standardized incidence (ASI) of pRCC was 1.97/100.000 for males and 0.5/100.000 for females, and the proportion of pRCC increased from 3.7% to 11.5% between the first and last intervals of the study (p < 0.001). Age standardized cancer specific mortality (ASCSM) of pRCC was 0.6/100.000 and 0.19/100.000 for males and females, respectively. The annual average increase in ASI was 3.6% for type 1 pRCC, but the ASI for type 2 pRCC and ASCSM for both subtypes did not change significantly. Male to female ratio was 4.4 for type 1 pRCC and 2.3 for type 2. The average tumor size for type 1 and 2 was 58.8 and 73.7 mm, respectively. Metastasis at diagnosis was found in 8.7% in the type 1 pRCC, compared to 30.0% of patients with type 2 pRCC (p < 0.001). Estimated 5-year cancer-specific survival (CSS) were 94.4%, 80.7%, and 69.3% for chRCC, pRCC and ccRCC, respectively (p < 0.001). For the pRCC subtypes, type 1 was associated with better 5-year CSS than type 2 (86.3% vs. 66.0%, p < 0.001), although this difference was not significant after adjusting for cancer stage and grading. CONCLUSIONS: pRCC histology was slightly less common in Iceland than in other countries. Males are more than three times more likely to be diagnosed with pRCC, compared to other RCC histologies. The subtype of pRCC was not found to be an independent risk factor for worse survival, and as suggested by the most recent WHO Classification of Urinary Tumors, grade and TNM-stage seem to be the most important factors for estimation of survival for pRCC patients.

Prognostic impact of FAN score in patients receiving nivolumab plus ipilimumab for metastatic renal cell carcinoma.

FAN score is reportedly associated with prognostic outcomes in patients with urothelial carcinoma being treated with immune check point inhibitors. However, the prognostic impact of pre-treatment FAN score in patients with metastatic renal cell carcinoma (RCC) treated with nivolumab plus ipilimumab remains unclear. We retrospectively evaluated the association between pre-treatment FAN score and prognostic outcomes in 154 patients with metastatic RCC treated with nivolumab plus ipilimumab. The pre-treatment FAN score was '0' in 56 patients (36%), '1' in 60 patients (40%), '2' in 37 patients (24%) and '3' in one patient (1%). Progression-free survival was not significantly different between patients with different FAN scores, but second progression-free survival (PFS2), cancer-specific survival (CSS) and overall survival (OS) were significantly different. In multivariable Cox proportional hazard analyses, FAN score ≥ 2 was a significant predictor of poor PFS2 (vs. FAN score 0, HR: 2.43, 95% CI 1.21-4.87, P = 0.01), poor CSS (vs. FAN score 0, HR: 2.71, 95% CI 1.13-6.47, P = 0.02) and poor OS (vs. FAN score 0, HR: 2.42, 95% CI 1.11-5.25, P = 0.02). High pre-treatment FAN score could be a significant independent predictor of poor prognosis in patients receiving nivolumab plus ipilimumab for metastatic RCC.

Development and validation of a multicenter Cox regression model to predict all-cause mortality in patients with renal masses suspicious for renal cancer.

OBJECTIVE: Life expectancy models are useful tools to support clinical decision-making. Prior models have not been used widely in clinical practice for patients with renal masses. We sought to develop and validate a model to predict life expectancy following the detection of a localized renal mass suspicious for renal cell carcinoma. MATERIALS AND METHODS: Using retrospective data from 2 large centers, we identified patients diagnosed with clinically localized renal parenchymal masses from 1998 to 2018. After 2:1 random sampling into a derivation and validation cohort stratified by site, we used age, sex, log-transformed tumor size, simplified cardiovascular index and planned treatment to fit a Cox regression model to predict all-cause mortality from the time of diagnosis. The model's discrimination was evaluated using a C-statistic, and calibration was evaluated visually at 1, 5, and 10 years. RESULTS: We identified 2,667 patients (1,386 at Corewell Health and 1,281 at Johns Hopkins) with renal masses. Of these, 420 (16%) died with a median follow-up of 5.2 years (interquartile range 2.2-8.3). Statistically significant predictors in the multivariable Cox regression model were age (hazard ratio [HR] 1.04; 95% confidence interval [CI] 1.03-1.05); male sex (HR 1.40; 95% CI 1.08-1.81); log-transformed tumor size (HR 1.71; 95% CI 1.30-2.24); cardiovascular index (HR 1.48; 95% CI 1.32-1.67), and planned treatment (HR: 0.10, 95% CI: 0.06-0.18 for kidney-sparing intervention and HR: 0.20, 95% CI: 0.11-0.35 for radical nephrectomy vs. no intervention). The model achieved a C-statistic of 0.74 in the derivation cohort and 0.73 in the validation cohort. The model was well-calibrated at 1, 5, and 10 years of follow-up. CONCLUSIONS: For patients with localized renal masses, accurate determination of life expectancy is essential for decision-making regarding intervention vs. active surveillance as a primary treatment modality. We have made available a simple tool for this purpose.

Discovery and Validation of a 15-Gene Prognostic Signature for Clear Cell Renal Cell Carcinoma.

PURPOSE: Develop and validate gene expression-based biomarker associated with recurrent disease to facilitate risk stratification of clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: We retrospectively identified 110 patients who underwent radical nephrectomy for ccRCC (discovery cohort). Patients who recurred were matched on the basis of grade/stage to patients without recurrence. Capture whole-transcriptome sequencing was performed on RNA isolated from archival tissue using the Illumina platform. We developed a gene-expression signature to predict recurrence-free survival/disease-free survival (DFS) using a 15-fold lasso and elastic-net regularized linear Cox model. We derived the 31-gene cell cycle progression (mxCCP) score using RNA-seq data for each patient. Kaplan-Meier (KM) curves and multivariable Cox proportional hazard testing were used to validate the independent prognostic impact of the gene-expression signature on DFS, disease-specific survival (DSS), and overall survival (OS) in two validation data sets (combined n = 761). RESULTS: After quality control, the discovery cohort comprised 50 patients with recurrence and 41 patients without, with a median follow-up of 26 and 36 months, respectively. We developed a 15-gene (15G) signature, which was independently associated with worse DFS and DSS (DFS: hazard ratio [HR], 11.08 [95% CI, 4.9 to 25.1]; DSS: HR, 9.67 [95% CI, 3.4 to 27.7]) in a multivariable model adjusting for clinicopathologic parameters (including stage, size, grade, and necrosis [SSIGN] score and Memorial Sloan Kettering Cancer Center nomogram) and mxCCP score. The 15G signature was also independently associated with worse DFS and DSS in both validation data sets (Validation A [n = 382], DFS: HR, 2.6 [95% CI, 1.6 to 4.3]; DSS: HR, 3 [95% CI, 1.4 to 6.1] and Validation B (n = 379), DFS: HR, 2.1 [95% CI, 1.2 to 3.6]; OS: HR, 3 [95% CI, 1.6 to 5.7]) adjusting for clinicopathologic variables and mxCCP score. CONCLUSION: We developed and validated a novel 15G prognostic signature to improve risk stratification of patients with ccRCC. Pending further validation, this signature has the potential to facilitate optimal treatment allocation.

Clear cell and non-clear cell renal cell carcinoma in young adults: clinicopathological features, survival outcomes and prognostic factors.

OBJECTIVES: Renal cell carcinoma (RCC) is infrequent among young adults. Few studies reported the outcome of RCC in young adults by pathological subtypes. The purpose of this study was to explore the clinicopathological features, survival outcomes and prognostic factors of young adult patients with clear cell (CCRCC) and non-clear cell renal cell carcinoma (NCCRCC). METHODS: This study included young adult patients aged 18-40 years who were diagnosed as renal cell carcinoma (RCC) between 2012 and 2022 at Peking University Third Hospital. All patients underwent either partial nephrectomy or radical nephrectomy, and some received adjuvant therapy. A comparative analysis was performed to investigate the differences in clinicopathological characteristics between the cohort of CCRCC and NCCRCC. Kaplan-Meier survival analysis was utilized to plot survival curves for young adults with RCC. The univariate and multifactorial prognostic analyses were conducted using the log-rank test and COX proportional hazards model. RESULTS: A total of 300 RCC patients aged 18-40 years were performed, of which 201 were diagnosed with CCRCC (67%) and 99 were diagnosed with NCCRCC(33%). The NCCRCC included 29 cases (9.7%) of chromophobe RCC, 28 cases (9.3%) of MiT family translocation RCC, 22 cases (7.3%) of papillary RCC, 11 cases (3.7%) of low malignant potential multifocal cystic RCC, and 6 cases of unclassified RCC (2.0%), 2 cases of mucinous tubule and spindle cell carcinoma (0.7%), and 1 case of FH-deficient RCC (0.3%).The mean age was 33.4 ± 6.1 years old. The overall and progression free 5-year survival rate was 99.1 and 95.3%, respectively. The NCCRCC cohort demonstrated a statistically significant decrease in progression-free survival (PFS) rate when compared to the CCRCC cohort (p < 0.001). There was no statistically significant difference observed in overall survival (OS) (p = 0.069). Pathological stage was a significant independent predictor for OS (p = 0.045). Pathological stage and nuclear grade were both independent predictors for PFS (p = 0.020; p = 0.005). CONCLUSIONS: The clinical and pathological features of young adults diagnosed with CCRCC exhibit notable distinctions from those of NCCRCC patients. The survival outcome was significantly influenced by the pathological stage, while both the nuclear grade and pathological stage had a significant impact on tumor progression. This study offered significant contributions to the understanding of the clinicopathological characteristics and prognostic determinants of renal cell carcinoma (RCC) in young adults.

CD44 Expression in Clear Cell Renal Cell Carcinoma (ccRCC) Correlates with Tumor Grade and Patient Survival and Is Affected by Gene Methylation.

Clear cell RCC (ccRCC) represents the most common type of kidney cancer, with surgery being the only potential curative treatment. Almost one-third of ccRCC patients relapse either locally or as cases of distant metastases. Several biomarkers have been employed in order to separate ccRCC patients with better prognosis or to predict treatment outcomes, with limited results. CD44 is a membrane glycoprotein with multiple roles in normal development but also cancer. Recently, the CD44 standard isoform has been implicated in tumor progression and the metastasis cascade through microenvironment interactions. Here, through CD44 immunohistochemical staining of ccRCC patient samples and TCGA data analysis, we sought to elucidate the expression patterns (mRNA and protein) of CD44 in clear cell RCC and correlate its expression with clinicopathological parameters. We were able to show that CD44 expression presents a positive association with tumor grade and overall survival, predicting a worse patient outcome in ccRCC. In addition, our data indicate that the CD44 mRNA upregulation can be attributed to reduced gene methylation, implicating epigenetic gene regulation in ccRCC development and progression.

Differential expression analysis identifies a prognostically significant extracellular matrix-enriched gene signature in hyaluronan-positive clear cell renal cell carcinoma.

Hyaluronan (HA) accumulation in clear cell renal cell carcinoma (ccRCC) is associated with poor prognosis; however, its biology and role in tumorigenesis are unknown. RNA sequencing of 48 HA-positive and 48 HA-negative formalin-fixed paraffin-embedded (FFPE) samples was performed to identify differentially expressed genes (DEG). The DEGs were subjected to pathway and gene enrichment analyses. The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) data and DEGs were used for the cluster analysis. In total, 129 DEGs were identified. HA-positive tumors exhibited enhanced expression of genes related to extracellular matrix (ECM) organization and ECM receptor interaction pathways. Gene set enrichment analysis showed that epithelial-mesenchymal transition-associated genes were highly enriched in the HA-positive phenotype. A protein-protein interaction network was constructed, and 17 hub genes were discovered. Heatmap analysis of TCGA-KIRC data identified two prognostic clusters corresponding to HA-positive and HA-negative phenotypes. These clusters were used to verify the expression levels and conduct survival analysis of the hub genes, 11 of which were linked to poor prognosis. These findings enhance our understanding of hyaluronan in ccRCC.

Exosome-related lncRNA score: A value-based individual treatment strategy for predicting the response to immunotherapy in clear cell renal cell carcinoma.

BACKGROUND: Exosomes play a crucial role in intercellular communication in clear cell renal cell carcinoma (ccRCC), while the long non-coding RNAs (lncRNAs) are implicated in tumorigenesis and progression. AIMS: The purpose of this study is to construction a exosomes-related lncRNA score and a ceRNA network to predict the response to immunotherapy and potential targeted drug in ccRCC. METHODS: Data of ccRCC patients were obtained from the TCGA database. Pearson correlation analysis was used to identify eExosomes-related lncRNAs (ERLRs) from Top10 exosomes-related genes that have been screened. The entire cohort was randomly divided into a training cohort and a validation cohort in equal scale. LASSO regression and multivariate cox regression was used to construct the ERLRs-based score. Differences in clinicopathological characteristics, immune microenvironment, immune checkpoints, and drug susceptibility between the high- and low-risk groups were also investigated. Finally, the relevant ceRNA network was constructed by machine learning to analyze their potential targets in immunotherapy and drug use of ccRCC patients. RESULTS: A score consisting of 4ERLRs was identified, and patients with higher ERLRs-based score tended to have a worse prognosis than those with lower ERLRs-based score. ROC curves and multivariate Cox regression analysis demonstrated that the score could be considered as a risk factor for prognosis in both training and validation cohorts. Moreover, patients with high scores are predisposed to experience poor overall survival, a larger prevalence of advanced stage (III-IV), a greater tumor mutational burden, a higher infiltration of immunosuppressive cells, and a greater likelihood of responding favorably to immunotherapy. The importance of EMX2OS was determined by mechanical learning, and the ceRNA network was constructed, and EMX2OS may be a potential therapeutic target, possibly exerting its function through the EMX2OS/hsa-miR-31-5p/TLN2 axis. CONCLUSIONS: Based on machine learning, a novel ERLRs-based score was constructed for predicting the survival of ccRCC patients. The ERLRs-based score is a promising potential independent prognostic factor that is closely correlated with the immune microenvironment and clinicopathological characteristics. Meanwhile, we screened out key lncRNAEMX2OS and identified the EMX2OS/hsa-miR-31-5p/TLN2 axis, which may provide new clues for the targeted therapy of ccRCC.

Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.

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