Survival In Renal Cell Carcinoma Research Articles

Nomogram for predicting survival of renal cell carcinoma with tumor thrombus based on perioperative clinicopathological factors from a Chinese high-volume center.

To investigate perioperative clinicopathological predictors and establish a predictive nomogram for survival in patients with renal cell carcinoma and venous tumor thrombus undergoing nephrectomy and thrombectomy. Patients with renal cell carcinoma and venous tumor thrombus undergoing nephrectomy and thrombectomy were included in the study between January 2014 and June 2020. Cox regression analysis was used for univariate and multivariate survival analyses. A predictive nomogram for survival was established and internally validated using bootstrap resampling method. A total of 228 patients were enrolled in this study. The median age was 60 years (interquartile range 53-66 years), consisting of 174 (76.3%) males and 54 (23.7%) females. The median follow-up time was 17.5 months (range 1-74 months), 26.8% (61 of 228) patients died of all causes. In multivariable analysis, hemoglobin less than the lower limit of normal (hazard ratio 1.73; 95% confidence interval 1.01-2.96; P = 0.045), sarcomatoid feature (hazard ratio 3.67; 95% confidence interval 1.97-6.82; P < 0.001), perirenal fat invasion (hazard ratio 1.80; 95% confidence interval 1.05-3.09; P = 0.033), histological subtype (hazard ratio 2.74; 95% confidence interval 1.39-5.41; P = 0.004), and metastasis at surgery (hazard ratio 1.71; 95% confidence interval 1.01-2.90; P = 0.047) were independently associated with overall survival. The result of internal validation presented that the predictive performance of the nomogram for survival measured by C-index was 0.77. We developed a predictive nomogram with well-internal validation for survival in patients with renal cell carcinoma and venous tumor thrombus, which can greatly promote risk stratification and treatment planning.

Carbonic anhydrase 10 functions as a tumor suppressor in renal cell carcinoma and its methylation is a risk factor for survival outcome.

Carbonic anhydrase 10 (CA10), one of the carbonic anhydrase isozymes, is explored to be downregulated in several tumor types, which indicates its critical role in tumorigenesis. However, its biologic and pathological function remains elusive in the pathogenesis of renal cell carcinoma (RCC). We examined expressions and functions of CA10 in RCC primary tumors and cell lines, assessed its tumor suppressive functions and further explored its impact on survival outcome of RCC patients. We found that CA10 was down-expressed in RCC primary tumors compared with adjacent non-malignant renal tissues. Promoter CpG methylation seemed to directly suppress the transcription of CA10 in RCC cells, which could be reversed by demethylation treatment. Restoration of CA10 in 786-O and Caki-2 cell lines inhibited their cell proliferation and promoted their apoptosis by regulating relevant apoptosis factors. Kaplan-Meier curve identified that CA10 methylation status was associated with progression-free survival in RCC (P = 0.021). Multivariate Cox regression analyses indicated the CA10 methylation status [HR, 4.724; 95% CI, 1.056-21.136; P = 0.042] was an independent predictor of disease progression. Collectively, our study demonstrates that CA10 as a tumor suppressor is frequently inactivated by promoter CpG methylation in RCC and its methylation is a risk factor for the prognosis of RCC.

Development and Validation of a CT-Based Radiomics Nomogram for Predicting Postoperative Progression-Free Survival in Stage I-III Renal Cell Carcinoma.

BackgroundMany patients experience recurrence of renal cell carcinoma (RCC) after radical and partial nephrectomy. Radiomics nomogram is a newly used noninvasive tool that could predict tumor phenotypes.ObjectiveTo investigate Radiomics Features (RFs) associated with progression-free survival (PFS) of RCC, assessing its incremental value over clinical factors, and to develop a visual nomogram in order to provide reference for individualized treatment.MethodsThe RFs and clinicopathological data of 175 patients (125 in the training set and 50 in the validation set) with clear cell RCC (ccRCC) were retrospectively analyzed. In the training set, RFs were extracted from multiphase enhanced CT tumor volume and selected using the stability LASSO feature selection algorithm. A radiomics nomogram final model was developed that incorporated the RFs weighted sum and selected clinical predictors based on the multivariate Cox proportional hazard regression. The performances of a clinical variables-only model, RFs-only model, and the final model were compared by receiver operator characteristic (ROC) analysis and DeLong test. Nomogram performance was determined and validated with respect to its discrimination, calibration, reclassification, and clinical usefulness.ResultsThe radiomics nomogram included age, clinical stage, KPS score, and RFs weighted sum, which consisted of 6 selected RFs. The final model showed good discrimination, with a C-index of 0.836 and 0.706 in training and validation, and good calibration. In the training set, the C-index of the final model was significantly larger than the clinical-only model (DeLong test, p = 0.008). From the clinical variables-only model to the final model, the reclassification of net reclassification improvement was 18.03%, and the integrated discrimination improvement was 19.08%. Decision curve analysis demonstrated the clinical usefulness of the radiomics nomogram.ConclusionThe CT-based RF is an improvement factor for clinical variables-only model. The radiomics nomogram provides individualized risk assessment of postoperative PFS for patients with RCC.

Prognostic Significance of Modified Advanced Lung Cancer Inflammation Index in Patients With Renal Cell Carcinoma Undergoing Laparoscopic Nephrectomy: A Multi-Institutional, Propensity Score Matching Cohort Study.

BackgroundWe conducted a multi-institutional clinical study to assess the prognostic value of the advanced lung cancer inflammatory index (ALI) and modified ALI (mALI) in patients with renal cell carcinoma (RCC).MethodsWe collected 440 patients who underwent laparoscopic nephrectomy at three centers from 2014 to 2019. ALI was defined as body mass index (BMI) × serum albumin (ALB)/neutrophil-to-lymphocyte ratio (NLR) and mALI as L3 muscle index × ALB/NLR. Kaplan-Meier curves, receiver operating characteristic (ROC) curves and Cox survival analysis were used to assess the effect of ALI and mALI on overall survival (OS). In addition, we performed 1:1 propensity score matching (PSM) for the high mALI and low mALI groups to further explore the impact of mALI on survival in RCC patients.ResultsThe optimal cut-off values for ALI and mALI were 40.6 and 83.0, respectively. Based on the cut-off values, we divided the patients into high ALI and low ALI groups, high mALI and low mALI groups. ALI and mALI were significantly associated with the AJCC stage, Fuhrman grade, T stage, and M stage. Low ALI (p = 0.002) or low mALI (p < 0.001) was associated with poorer prognosis. ROC curves showed that mALI was a better predictor of OS than ALI. Multivariate Cox regression analysis showed that low mALI (aHR = 2.22; 95% CI 1.19–4.13, p = 0.012) was an independent risk factor for OS in RCC patients who underwent nephrectomy, while ALI (aHR = 1.40; 95% CI 0.73–2.66, p = 0.309) was not significantly associated. Furthermore, after PSM analysis, we found that mALI remained an independent risk factor for OS (aHR = 2.88; 95% CI 1.33–6.26, p = 0.007) in patients with RCC.ConclusionsFor RCC patients undergoing laparoscopic nephrectomy, low ALI and low mALI were associated with poor prognosis, and preoperative mALI can be used as a potential independent prognostic indicator for RCC patients.

Sohlh2 Inhibits the Malignant Progression of Renal Cell Carcinoma by Upregulating Klotho via DNMT3a.

BackgroundRenal cell carcinoma is the most common malignant tumor of the kidney. The 5-year survival of renal cell carcinoma with distant metastasis is very low. Sohlh2 is a newly discovered tumor suppressor gene playing inhibitory roles in a variety of tumors, but its role in renal cell carcinoma has not been reported.MethodsTo clarify the role of Sohlh2 in the occurrence and development of renal cell carcinoma, we constructed stably transfected human renal cell carcinoma cell lines with Sohlh2 overexpression and Sohlh2 knockdown, separately. First, we studied the effects of Sohlh2 on proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of renal cell carcinoma cells in vitro and in vivo. Then, we detected whether Sohlh2 functions through DNMT3a/Klotho using Western blotting, qPCR, and Cell Counting Kit-8 (CCK-8) assay. Finally, we collected 40 resected renal cell carcinoma samples to study the relevance between Sohlh2, DNMT3a, and Klotho by immunohistochemistry.ResultsOur results showed that Sohlh2 was downregulated in renal cell carcinoma, and its expression level was negatively correlated with tumor staging. Both in vitro and in vivo experiments confirmed that Sohlh2 overexpression inhibited the proliferation, migration, invasion, metastasis, and EMT of renal cell carcinoma. Sohlh2 functions through demethylation of Klotho by downregulating the expression of DNA methyltransferase of DNMT3a. In renal cell carcinoma, Sohlh2 was positively correlated with Klotho and negatively correlated with DNMT3a.ConclusionSohlh2 functions as a tumor suppressor gene in renal cell carcinoma by demethylation of Klotho via DNMT3a. Sohlh2 correlated with Klotho positively and with DNMT3a negatively in renal cell carcinoma. Our study suggests that Sohlh2 and DNMT3a/Klotho can be used as potential targets for the clinical treatment of renal cell carcinoma.

Predicting Clear Cell Renal Cell Carcinoma Survival Using Kurtosis of Cytoplasm in the Hematoxylin Channel from Histology Slides.

Purpose Grade-dependent decrease of lipid storage in clear cell renal cell carcinoma (ccRCC) leads to morphology changes in HE sections. This study investigated the role of cytoplasmic features in frozen sections of ccRCC on prognosis using the digital pathology approach. Methods We established an automatic pipeline that performed tumor region selection, stain vector normalization, nuclei segmentation, and feature extraction based on the pathologic data from Shanghai General Hospital and The Cancer Genome Atlas database. Extracted features were subjected to survival analysis. Results Kurtosis of the cytoplasm in the hematoxylin channel was correlated with progression-free survival (HR 0.10, 95% CI: 0.04–0.24, p=6.52∗10−7) and overall survival (HR 0.11, 95% CI: 0.05–0.31, p=1.72∗10−5) in ccRCC, which outperformed other texture features in this analysis. Multivariate Cox regression analysis revealed that low kurtosis of cytoplasm in the hematoxylin channel was an independent predictor for a shorter progression-free survival time (p=0.044) and overall survival time (p = 0.01). Kaplan–Meier survival analysis of progression-free survival and overall survival also showed a significantly worse prognosis in patients with low kurtosis of the cytoplasm in the hematoxylin channel (both p < 0.0001). Lower kurtosis of cytoplasm in the hematoxylin channel was associated with higher pathologic grade, less cholesterol ester, and more mitochondrial DNA content. Conclusion Kurtosis of the cytoplasm in the hematoxylin channel predicts survival in clear cell renal cell carcinoma.

Disparities in Cancer Specific and Overall Survival Outcomes in African Americans With Renal Cell Carcinoma: Analysis From the International Marker Consortium for Renal Cancer (INMARC)

ObjectiveTo investigate association of African-American race and survival in Renal Cell Carcinoma (RCC). Patients and MethodsWe queried the International Marker Consortium for Renal Cancer database for patients who underwent partial or radical (RN) nephrectomy. The cohort was divided into African American (AA) and non-African American (NAA) patients. Primary outcome was all-cause mortality. Secondary outcome was cancer-specific mortality. Multivariable Analysis and Kaplan-Meier Analysis were used to elucidate predictive factors and survival outcomes. ResultsThree thousand eight hundred and ninety-three patients were analyzed (AA, n = 564/NAA, n = 3329). AA had greater Stage I (73.8% vs 63.9%, P <.001) and papillary RCC (29.8% vs 8.5%, P <.001). Multivariable Analysis revealed increasing age (HR = 1.03, P <.001), AA (HR = 1.24, P = .027), higher stage (HR = 1.30-3.19, P <.001), RN (HR = 2.45, P <.001), clear cell (HR = 1.23, P <.001), positive margin (HR = 1.34, P .004), and high-grade (HR = 1.58, P <.001) to be associated with worsened all-cause mortality. Increasing age (HR = 1.02, P <.001), AA (HR = 1.48, P = .025), RN (HR = 2.98, P <.001), high-grade (HR = 3.11, P <.001), and higher stage (HR = 3.03-13.2, P <.001) were predictive for cancer-specific mortality. Kaplan-Meier Analysis revealed worsened 5-year overall survival for AA in stage I (80% vs 88%, P = .001), stage III (26% vs 70%, P = .001), and stage IV (23% vs 44%, P = .009). Five-year cancer-specific survival was worse for AA in stage III (36% vs 81%, P <.001) and stage IV (30% vs 49%, P = .007). ConclusionDespite presenting with more indolent histology and lower stage, African-Americans were at greater risk for diminished survival, faring worse in overall survival for all stages and cancer-specific survival in for stage III/IV RCC. Further investigation into factors associated with these disparities is warranted.

Inhibition of DCLK1 with DCLK1-IN-1 Suppresses Renal Cell Carcinoma Invasion and Stemness and Promotes Cytotoxic T-Cell-Mediated Anti-Tumor Immunity.

Simple SummaryIn this study, we found that the novel small molecule kinase inhibitor DCLK1-IN-1 not only inhibited DCLK1 phosphorylation, stemness, and EMT-related properties of RCC cells but also revealed its potential as an immunotherapy agent and potential combination therapy with anti-PD1 against RCC in immune co-culture experiments.The approval of immune checkpoint inhibitors has expanded treatment options for renal cell carcinoma (RCC), but new therapies that target RCC stemness and promote anti-tumor immunity are needed. Previous findings demonstrate that doublecortin-like kinase 1 (DCLK1) regulates stemness and is associated with RCC disease progression. Herein, we demonstrate that small-molecule kinase inhibitor DCLK1-IN-1 strongly inhibits DCLK1 phosphorylation and downregulates pluripotency factors and cancer stem cell (CSC) or epithelial-mesenchymal transition (EMT)-associated markers including c-MET, c-MYC, and N-Cadherin in RCC cell lines. Functionally, DCLK1-IN-1 treatment resulted in significantly reduced colony formation, migration, and invasion. Additionally, assays using floating or Matrigel spheroid protocols demonstrated potent inhibition of stemness. An analysis of clinical populations showed that DCLK1 predicts RCC survival and that its expression is correlated with reduced CD8+ cytotoxic T-cell infiltration and increases in M2 immunosuppressive macrophage populations. The treatment of RCC cells with DCLK1-IN-1 significantly reduced the expression of immune checkpoint ligand PD-L1, and co-culture assays using peripheral blood monocytes (PBMCs) or T-cell expanded PBMCs demonstrated a significant increase in immune-mediated cytotoxicity alone or in combination with anti-PD1 therapy. Together, these findings demonstrate broad susceptibility to DCLK1 kinase inhibition in RCC using DCLK1-IN-1 and provide the first direct evidence for DCLK1-IN-1 as an immuno-oncology agent.

Morphomics Can Predict Oncological Features and Survival of Metastatic Renal Cell Carcinoma After Cytoreductive Nephrectomy

This study analyzed the ability of body composition to predict the outcome of patients with metastatic renal cell carcinoma (RCC) who received cytoreductive nephrectomy followed by systemic therapy. A retrospective study was conducted from December 2010 to November 2017 in a single tertiary medical center. The medical charts and computed tomography images were reviewed. Statistical analysis included oncological features, their correlation with body composition factors, and overall survival. Skeletal muscle volume was significantly higher in patients with Fuhrman grade 2 RCC than those with grade≥3. Patients with intermediate International Metastatic RCC Database Consortium risk had significantly higher BMI and skeletal muscle compared to those with poor risk. Multivariate analysis showed that increased skeletal muscle and decreased visceral adipose tissue were significant predictors of a better overall survival. Body composition highly correlated with the oncological features of metastatic RCC and impacted survival.

Inflammatory response markers and survival prediction in patients with renal cell carcinoma

Introduction Many factors influence the clinical course of patients with renal cell carcinoma (RCC). The most commonly used prognostic indicators are TNM stage, tumor size and RCC type. In this study we evaluated the prognostic relevance of albumin and C-reactive protein (CRP), and Glasgow Prognostic scores (GPS), in patients with primary RCC. Methods We retrospectively reviewed all patients surgically treated for primary RCC between 1982 and 2018 at Umeå University Hospital. There were 872 patients, 527 males and 345 females. Data on albumin, CRP and GPS points before surgery were extracted, as well as TNM stage, RCC type, tumor grade, tumor size, and primary treatment. The patients were followed for recurrence and death for up to 37.2 years. We used Kaplan-Meier estimators, Cox-proportional hazards models, to assess the relation between potentially prognostic indicators and RCC-specific death, and all-cause mortality. Results Of 872 patients, 708 had clear-cell RCC, 114 papillary RCC, 36 chromophobe RCC and 9 undefined RCC type while 5 patients had missing RCC type data. Except that, women had a significantly (p = 0.002) lower proportion of pRCC, no difference in RCC types and levels of albumin and CRP was observed between genders. Albumin, CRP, and GPSs were all univariately associated to RCC survival (p < 0.001). CRP demonstrated the strongest prognostic association (HR 1.67 95% Ci (1.53–1.83, overriding both albumin and GPS in multivariable models. The AUC for CRP was 0.77 (95% CI: 0.74-0.80). Conclusion Elevated CRP, low albumin levels, and elevated GPSs were all associated to poor survival in patients with RCC, Only CRP remained independent in multivariate analysis.

MP39-01 SYSTEM ASC TRANSPORTER 2, A KEY ENZYME FOR GLUTAMINE PATHWAY, IS A POSSIBLE BIOMARKER FOR METASTATIC PROGRESSION AND SURVIVAL IN RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I (MP39)1 Sep 2021MP39-01 SYSTEM ASC TRANSPORTER 2, A KEY ENZYME FOR GLUTAMINE PATHWAY, IS A POSSIBLE BIOMARKER FOR METASTATIC PROGRESSION AND SURVIVAL IN RENAL CELL CARCINOMA Yoshinari Muto, Makoto Sumitomo, Kenji Zennami, Masashi Takenaka, Takuhisa Nukaya, Kosuke Fukaya, Manabu Ichino, Kiyoshi Takahara, Hitomi Sasaki, and Ryoichi Shiroki Yoshinari MutoYoshinari Muto More articles by this author , Makoto SumitomoMakoto Sumitomo More articles by this author , Kenji ZennamiKenji Zennami More articles by this author , Masashi TakenakaMasashi Takenaka More articles by this author , Takuhisa NukayaTakuhisa Nukaya More articles by this author , Kosuke FukayaKosuke Fukaya More articles by this author , Manabu IchinoManabu Ichino More articles by this author , Kiyoshi TakaharaKiyoshi Takahara More articles by this author , Hitomi SasakiHitomi Sasaki More articles by this author , and Ryoichi ShirokiRyoichi Shiroki More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002054.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The glutamine (Gln) pathway has been implicated in tumor progression in various malignancies including renal cell carcinoma (RCC). However, the detail underlying this pathway remains to be elucidated. Since both glutaminase 1 (GLS1) and system ASC transporter 2 (ASCT2) were reported to play a crucial role in this pathway, we investigated whether these enzymes could be associated with cancer development and survival in RCC. METHODS: Tumor (T) and non-tumor (N) tissues were sampled from 66 RCC patients. Metabolome analyses were performed by liquid chromatography mass spectrometry (LC/MS) and important metabolites including Gln and glutamate (Glu) were analyzed. The protein expression of GLS1 and ASCT2 was evaluated by immunohistochemistry (IHC) using formalin-fixed, paraffin-embedded sections of surgical specimen from 80 metastatic RCC (mRCC) patients who received standard treatment using tyrosine-kinase inhibitors (TKIs) with or without immune checkpoint inhibitors (ICIs). The mRCC patients who received treatment with ICIs in the first- or second-line treatment were categorized into the “ICI group”, whereas others were categorized into the “TKI-only group”. In this study, the endpoint was progression-free survival 2 (PFS2) defined as the interval between first-line treatment and the second relapse. RESULTS: LC/MS analyses showed that both Gln T/N ratio and Glu T/N ratio in mRCC patients were significantly increased compared with those in non-mRCC patients (p=0.002 and p=0.048, respectively). On the other hand, the median value of Gln T/N ratios was shown to be over 100-fold higher than that of Glu T/N ratios. IHC analyses using mRCC tumor tissues revealed that ASCT2 was expressed more strongly in tumor cells than in normal cells, while GLS1 was expressed both in normal and tumor cells at the equal level. Kaplan–Meier analysis showed that ICI group had better PFS2 than TKI-only group in patients with ASCT2 high expression levels (p=0.009), while there was no significant difference on PFS2 between two groups in patients with ASCT2 low expression levels. CONCLUSIONS: Our results suggest that ASCT2 rather than GLS1 may be a key enzyme for Gln pathway in RCC. Our results also suggest that ASCT2 is associated with metastatic progression and survival, confirming its role as a possible biomarker to determine the appropriate treatment for mRCC patients. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e704-e704 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yoshinari Muto More articles by this author Makoto Sumitomo More articles by this author Kenji Zennami More articles by this author Masashi Takenaka More articles by this author Takuhisa Nukaya More articles by this author Kosuke Fukaya More articles by this author Manabu Ichino More articles by this author Kiyoshi Takahara More articles by this author Hitomi Sasaki More articles by this author Ryoichi Shiroki More articles by this author Expand All Advertisement Loading ...

675P Changes in treatment patterns and survival in renal cell carcinoma (RCC) patients in Norway: A nationwide registry study for 1995-2018

In Norway cancer treatment is publicly funded, providing equal care to all patients. Nationwide population registries capture data on diagnoses, treatment and comorbidities. This enabled us to collect data for this longitudinal retrospective study and describe clinical and demographic characteristics, treatment patterns and survival of patients with RCC.

MP39-04 LARGEN PLAYS IMPORTANT ROLES IN MALIGNANT AGGRESSIVENESS AND IS A PROGNOSTIC FACTOR IN PATIENTS WITH CLEAR CELL RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I (MP39)1 Sep 2021MP39-04 LARGEN PLAYS IMPORTANT ROLES IN MALIGNANT AGGRESSIVENESS AND IS A PROGNOSTIC FACTOR IN PATIENTS WITH CLEAR CELL RENAL CELL CARCINOMA Yasuyoshi Miyata, Yuta Mukae, Tomohiro Matsuo, Tsuyoshi Matsuda, Junki Harada, Asato Otsubo, Kensuke Mitsunari, Kojiro Ohba, Hideki Sakai, and Kazuo Yamamoto Yasuyoshi MiyataYasuyoshi Miyata More articles by this author , Yuta MukaeYuta Mukae More articles by this author , Tomohiro MatsuoTomohiro Matsuo More articles by this author , Tsuyoshi MatsudaTsuyoshi Matsuda More articles by this author , Junki HaradaJunki Harada More articles by this author , Asato OtsuboAsato Otsubo More articles by this author , Kensuke MitsunariKensuke Mitsunari More articles by this author , Kojiro OhbaKojiro Ohba More articles by this author , Hideki SakaiHideki Sakai More articles by this author , and Kazuo YamamotoKazuo Yamamoto More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002054.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Mitochondria is recognized as a key player in the biosynthetic and energetic capabilities of cells. Largen has been identified as a controller of cell size in mammalian cells via the regulation of mitochondrial function. Therefore, we speculated that Largen played important roles for cancer cell survival of renal cell carcinoma (RCC) via regulation of energy and cancer-related protein synthesis. The aim of this study was to clarify the pathological significance and prognostic roles of Largen in patients with clear cell (cc) RCC. METHODS: The immunoreactivity of Largen was investigated in 192 ccRCC and 60 normal kidney tissues by immunohistochemical technique. In addition, we measured proliferation index (PI) and apoptotic index (AI) using anti-Ki-67 antibody and anti-cleaved caspase-3, respectively. Tumor necrosis was evaluated by receptor-interacting protein kinase (RIP) 3 expression. Moreover, in human RCC cell lines (ACHN and 780-O), Largen expression was knocked down using small interfering RNA and the resulting changes in cell survival, migration, and invasion were investigated. RESULTS: In vitro studies showed that Largen knock-down led to the stimulation of cell death, but not to suppression of cell proliferation, migration, and invasion. In ccRCC patients, Largen expression was significantly higher in cancer tissues than in normal kidney tissues (mean±SD of IRS: 3.2 ± 1.7 vs 1.2±1.1; p<0.001). Largen expression was positively correlated with tumor grade (grade 1=2.3±1.3, grade 2=3.4±1.6, and grade 3/4=4.7±1.4; p<0.001), pT stage (p<0.001), and the presence of metastasis (p<0.001). Kaplan-Meier survival curves showed that a higher Largen IRS was a significant predictor of shorter overall survival time (p<0.001) and multivariate analyses showed that it was an independent predictor (hazard ratio=1.53, 95% confidential interval (CI)=1.24–1.91, p<0.001). Univariate analyses showed that Largen was positively correlated with PI (p<0.001) and it was negatively correlated with AI (p<0.001) and tumor necrosis (p=0.024). However, multi-variate analyses adjusted by pathological features showed Largen was independently associated with tumor necrosis (odds ratio=0.35, 95% CI= 0.17–0.75, p=0.007), but not with PI and AI. CONCLUSIONS: Largen played important roles in malignant aggressiveness and was a prognostic indicator, due to its regulation of tumor necrosis in patients with ccRCC. Finally, we propose that Largen is a novel therapeutic target and useful predictor in these patients. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e705-e705 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yasuyoshi Miyata More articles by this author Yuta Mukae More articles by this author Tomohiro Matsuo More articles by this author Tsuyoshi Matsuda More articles by this author Junki Harada More articles by this author Asato Otsubo More articles by this author Kensuke Mitsunari More articles by this author Kojiro Ohba More articles by this author Hideki Sakai More articles by this author Kazuo Yamamoto More articles by this author Expand All Advertisement Loading ...

1549P Pazopanib exposure in advanced soft tissue and bone sarcoma: A pharmacokinetic/pharmacodynamic analysis

Pazopanib (PAZ) is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma (RCC) and soft tissue sarcoma (STS). A relationship was reported between PAZ trough concentration (Cmin) and progression free survival (PFS) in RCC (Suttle A.B. 2015; Verheijen R.B. 2017). However, information on the exposure-efficacy relationship in sarcoma remains sparse. A PAZ Cmin threshold of 27 mg/L was determined in an exploratory study (Bellesoeur A. 2017).

Shorter Leukocyte Telomere Length Is Associated with Worse Survival of Patients with Bladder Cancer and Renal Cell Carcinoma.

Simple SummaryIntrinsic telomere shortening promotes tumorigenesis in cells with impaired DNA damage repair mechanisms, as dysfunctional telomeres lead to chromosomal instability. More recent data show that the telomere length of peripheral blood leukocyte (PBL) cells can be a prognostic marker for survival of patients with solid tumors. However, reports on bladder cancer (BC) and renal cell carcinoma (RCC) are not consistent and partly contradictory. Our results show, first, that telomere length is shorter in patients with BC or RCC compared to patients without malignant disease. More importantly, the relative telomere length (RTL) of PBL cells is associated with survival of patients with BC and RCC. Thus, telomere length in PBL cells could be an auxiliary prognostic marker in BC and RCC.Background: Telomeres are protein–DNA complexes at the tips of linear chromosomes. They protect the DNA from end-to-end fusion and exonucleolytic degradation. Shortening of telomeric DNA during aging can generate dysfunctional telomeres, promoting tumorigenesis. More recent data indicate that both short and long telomeres of peripheral blood leukocyte (PBL) cells can serve as prognostic biomarkers for cancer risk and may be associated with survival of patients with solid cancers. Telomere length in PBL cells could also be a potential prognostic biomarker for survival in bladder cancer (BC) or renal cell carcinoma (RCC). Methods: The relative telomere length (RTL) of PBL cells was assessed in patients with BC (n = 144) and RCC (n = 144) by using qPCR. A control population of patients without malignant disease (NC, n = 73) was included for comparison. The correlation and association of RTL with histopathological parameters and overall survival (OS) were evaluated. Results: Patients with BC and RCC had significantly shorter telomeres compared to patients without malignant disease. Within the cancer cohorts, multivariate analysis revealed that short RTL is an independent predictor of worse survival in BC (p = 0.039) and RCC (p = 0.041). Conclusion: Patients with BC and RCC had significantly shorter telomeres compared to the normal population. Shorter RTL in BC and RCC was an independent predictor of reduced survival.

TRIM27 interacts with I\u03bab\u03b1 to promote the growth of human renal cancer cells through regulating the NF-\u03baB pathway

BackgroundThe tripartite motif (TRIM) family proteins exhibit oncogenic roles in various cancers. The roles of TRIM27, a member of the TRIM super family, in renal cell carcinoma (RCC) remained unexplored. In the current study, we aimed to investigate the clinical impact and roles of TRIM27 in the development of RCC.MethodsThe mRNA levels of TRIM27 and Kaplan–Meier survival of RCC were analyzed from The Cancer Genome Atlas database. Real-time PCR and Western blotting were used to measure the mRNA and protein levels of TRIM27 both in vivo and in vitro. siRNA and TRIM27 were exogenously overexpressed in RCC cell lines to manipulate TRIM27 expression.ResultsWe discovered that TRIM27 was elevated in RCC patients, and the expression of TRIM27 was closely correlated with poor prognosis. The loss of function and gain of function results illustrated that TRIM27 promotes cell proliferation and inhibits apoptosis in RCC cell lines. Furthermore, TRIM27 expression was positively associated with NF-κB expression in patients with RCC. Blocking the activity of NF-κB attenuated the TRIM27-mediated enhancement of proliferation and inhibition of apoptosis. TRIM27 directly interacted with Iκbα, an inhibitor of NF-κB, to promote its ubiquitination, and the inhibitory effects of TRIM27 on Iκbα led to NF-κB activation.ConclusionsOur results suggest that TRIM27 exhibits an oncogenic role in RCC by regulating NF-κB signaling. TRIM27 serves as a specific prognostic indicator for RCC, and strategies targeting the suppression of TRIM27 function may shed light on future therapeutic approaches.

Progress in survival in renal cell carcinoma through 50 years evaluated in Finland and Sweden.

Global survival studies have shown favorable development in renal cell carcinoma (RCC) treatment but few studies have considered extended periods or covered populations for which medical care is essentially free of charge. We analyzed RCC survival in Finland and Sweden over a 50-year period (1967-2016) using data from the NORDCAN database provided by the local cancer registries. While the health care systems are largely similar in the two countries, the economic resources have been stronger in Sweden. In addition to the standard 1- and 5-year relative survival rates, we calculated the difference between these as a measure of how well survival was maintained between years 1 and 5. Relative 1- year survival rates increased almost linearly in both countries and reached 90% in Sweden and 80% in Finland. Although 5-year survival also developed favorably the difference between 1- and 5-year survival rates did not improve in Sweden suggesting that the gains in 5-year survival were entirely due to gains in 1-year survival. In Finland there was a gain in survival between years 1 and 5, but the gain in 1-years survival was the main contributor to the favorable 5-year survival. Age group specific analysis showed large survival differences, particularly among women. Towards the end of the follow-up period the differences narrowed but the disadvantage of the old patients remained in 5-year survival. The limitations of the study were lack of information on performed treatment and clinical stage in the NORDCAN database. In conclusion, the available data suggest that earlier diagnosis and surgical treatment of RCC have been the main driver of the favorable change in survival during the past 50 years. The main challenges are to reduce the age-specific survival gaps, particularly among women, and push survival gains past year 1.

Nephrectomy Delay of More than 10 Weeks from Diagnosis Is Associated with Decreased Overall Survival in pT3 RCC.

In this study, we aimed to evaluate the impact of surgical wait time (SWT) on outcomes of patients with renal cell carcinoma (RCC), and to investigate risk factors associated with prolonged SWT. Using the National Cancer Database, we retrospectively reviewed the records of patients with pT3 RCC treated with radical or partial nephrectomy between 2004 and 2014. The cohort was divided based on SWT. The primary outcome was 5-year overall survival (OS). Logistic regression analysis was used to investigate the risk factors associated with delayed surgery. Cox proportional hazards models were fitted to assess relations between SWT and 5-year OS after adjusting for confounding factors. A total of 22,653 patients were included in the analysis. Patients with SWT > 10 weeks had higher occurrence of upstaging. Using logistic regression, we found that female patients, African-American or Spanish origin patients, treatment in academic or integrated network cancer center, lack of insurance, median household income of <$38,000, and the Charlson–Deyo score of ≥1 were more likely to have prolonged SWT. SWT > 10 weeks was associated with decreased 5-year OS (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.15–1.33). This risk was not markedly attenuated after adjusting for confounding variables, including age, gender, race, insurance status, Charlson–Deyo score, tumor size, and surgical margin status (adjusted HR, 1.13; 95% CI, 1.04–1.24). In conclusion, the vast majority of patients underwent surgery within 10 weeks. There is a statistically significant trend of increasing SWT over the study period. SWT > 10 weeks is associated with decreased 5-year OS.

Delayed surgery for localised and metastatic renal cell carcinoma: a systematic review and meta-analysis for the COVID-19 pandemic.

PurposeThe COVID-19 pandemic has led to the cancellation or deferment of many elective cancer surgeries. We performed a systematic review on the oncological effects of delayed surgery for patients with localised or metastatic renal cell carcinoma (RCC) in the targeted therapy (TT) era.MethodThe protocol of this review is registered on PROSPERO(CRD42020190882). A comprehensive literature search was performed on Medline, Embase and Cochrane CENTRAL using MeSH terms and keywords for randomised controlled trials and observational studies on the topic. Risks of biases were assessed using the Cochrane RoB tool and the Newcastle–Ottawa Scale. For localised RCC, immediate surgery [including partial nephrectomy (PN) and radical nephrectomy (RN)] and delayed surgery [including active surveillance (AS) and delayed intervention (DI)] were compared. For metastatic RCC, upfront versus deferred cytoreductive nephrectomy (CN) were compared.ResultsEleven studies were included for quantitative analysis. Delayed surgery was significantly associated with worse cancer-specific survival (HR 1.67, 95% CI 1.23–2.27, p < 0.01) in T1a RCC, but no significant difference was noted for overall survival. For localised ≥ T1b RCC, there were insufficient data for meta-analysis and the results from the individual reports were contradictory. For metastatic RCC, upfront TT followed by deferred CN was associated with better overall survival when compared to upfront CN followed by deferred TT (HR 0.61, 95% CI 0.43–0.86, p < 0.001).ConclusionNoting potential selection bias, there is insufficient evidence to support the notion that delayed surgery is safe in localised RCC. For metastatic RCC, upfront TT followed by deferred CN should be considered.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00345-021-03734-1.

FDG-PET avidity as a prognostic biomarker for overall survival in renal cell carcinoma.

e16564 Background: Positron emission tomography with (18F)-fluorodeoxyglucose (FDG-PET) is not considered a standard of care (SOC) in renal cell carcinoma (RCC) because of its variability in metabolic activity. We investigated the rate of PET-positivity in our institutional cohort and tested whether PET-positivity had prognostic value in metastatic (m)RCC. Methods: Patients with FDG-PET imaging at any time during the course of disease were identified from medical records. PET-positivity was defined according to PERCIST criteria and a five-point rating scale analogue to Deauville Scoring was used to stratify PET-avidity. Tracer uptake of the hottest lesion was measured as SUVmax. Clinical parameters and PET-positivitywere correlated with overall survival (OS). Kaplan-Meier plots, log-rank analyses, kendall rank correlation, univariate and multivariable cox regression models were employed, where appropriate. Results: A totalof 90 patients was analyzed. The median age was 64.0 (34.0-83.0) and 56 (62.2%) patients had clear cell RCC. Metastatic disease was present in 64 (71.1%) and 22 (24.4%) patients received ongoing medical treatment. 72 (80.0%) patients had prior nephrectomy. PET-positivity occurred in 57 (63.3%) patients, with similar rates among metastatic (41/64; 64%) and non-metastatic patients (16/26; 62%). PET-positive patients had shorter median OS compared to PET-negative patients (38.5 months (CI95:24.5-NR) vs. not reached (CI95: 69.6-NR), P= 0.0013). A weak correlation was found between PET-Uptake and histologic grade (Kendall’s tau 0.22; P= 0.03). Prior nephrectomy, presence of primary lesions, presence of distant metastases, histologic grade and PET-positivity were significant predictors of OS in univariate regression. In multivariable analysis, only PET-positivity remained significant (HR 4.1 (CI95: 1.1-15.4), P= 0.04). Conclusions: RCC is a metabolically active cancer, which in the majority of patients is suitable for FDG-PET diagnostic procedures. PET-positivity was an independent prognostic factor for OS in RCC, indicating its putative clinical use. Further studies to define the role of FDG-PET imaging in RCC are ongoing.