scholarly journals Prognostic Significance of COVID-19 Receptor ACE2 and Recommendation for Antihypertensive Drug in Renal Cell Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Kihun Kim ◽  
Yeji Ko ◽  
Dai Sik Ko ◽  
Yun Hak Kim
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Ace Inhibitor ◽  
Cox Regression ◽  
Statistical Significance ◽  
Prognostic Significance ◽  
World Health ◽  
Rank Test ◽  
Kaplan Meier

Purpose. Owing to its worldwide spread, the coronavirus disease (COVID-19) epidemic was declared a pandemic by the World Health Organization on March 11, 2020. Angiotensin-converting enzyme 2 (ACE2) is the outer surface protein of the cell membrane that is abundantly distributed in the heart, lungs, and kidneys and plays an important role in molecular docking of the severe acute respiratory syndrome coronavirus 2. In this study, we aimed to analyze the difference in the survival rate according to ACE2 expressions in pan-cancer. Materials and Methods. We downloaded clinical and genomic data from The Cancer Genome Atlas. We used Kaplan-Meier with a log-rank test, and the Cox proportional hazards regression to analyze prognostic significance. Results. In the Kaplan-Meier curve, clear cell renal cell carcinoma (ccRCC), uveal melanoma, and prostate adenocarcinoma showed statistical significance. In the Cox regression, thyroid carcinoma and glioblastoma multiforme and ccRCC showed significant results. Only ccRCC had statistical significance, and high ACE2 expression is related to good prognosis. It is known that the ACE inhibitor, a primary antihypertensive agent, increases ACE2 expression. Conclusion. Based on these results, we believe that the ACE inhibitor will be important to increase the lifespan of ccRCC patients. This study is the first research to offer a recommendation on the use of anti-hypertensive drugs to ccRCC patients.

scholarly journals Prognostic Significance of COVID-19 Receptor ACE2 and Recommendation For Anti-Hypertensive Drug in Renal Cell Carcinoma

2020 ◽  
Author(s):  
Kihun Kim ◽  
Yeji Ko ◽  
Dai Sik Ko ◽  
Yun Hak Kim
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Ace Inhibitor ◽  
Cox Regression ◽  
Prognostic Significance ◽  
World Health ◽  
Rank Test ◽  
Kaplan Meier ◽  
Pan Cancer

Abstract Background: Owing to its worldwide spread, the coronavirus disease (COVID-19) epidemic was declared a pandemic by the World Health Organization on March 11, 2020. Angiotensin-converting enzyme 2 (ACE2) is the outer surface protein of the cell membrane that is abundantly distributed in the heart, lungs, and kidneys, and plays an important role in molecular docking of the severe acute respiratory syndrome coronavirus 2. In this study, we aimed to analyze the difference in the survival rate according to ACE2 expressions in pan-cancer. Methods: The clinical and genomic data of pan-cancer patients were accessed from The cancer Genome Atlas. To identify the prognostic significance of ACE2, we used Kaplan-Meier with log-rank test, and the Cox proportional hazards regression to analyze prognostic significance. Results: In the Kaplan-Meier curve, clear cell renal cell carcinoma (ccRCC), uveal melanoma, and prostate adenocarcinoma showed statistically significant. In the Cox regression, thyroid carcinoma and glioblastoma multiforme, and ccRCC showed significant results. Only ccRCC had statistically significant, and high ACE2 expression is related to good prognosis. Conclusions: It is known that ACE inhibitor, a primary antihypertensive agent, increases ACE2 expression. Based on these results, we believe that the ACE inhibitor will be important to increase the lifespan of ccRCC patients. This study is the first research to offer a recommendation on the use of anti-hypertensive drugs to ccRCC patients.

Interleukin-4 Promoter Polymorphisms: A Genetic Prognostic Factor for Survival in Metastatic Renal Cell Carcinoma

2007 ◽  
Vol 25 (7) ◽  
pp. 845-851 ◽  
Author(s):  
Thomas Kleinrath ◽  
Christoph Gassner ◽  
Peter Lackner ◽  
Martin Thurnher ◽  
Reinhold Ramoner
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clinical Course ◽  
Prognostic Significance ◽  
Interleukin 4 ◽  
Promoter Polymorphisms ◽  
Cox Regression Analysis ◽  
Metastatic Rcc

Purpose Renal cell carcinoma (RCC) is considered a cytokine-responsive tumor. The clinical course of a patient may thus be influenced by the patient's capacity to produce distinct cytokines. Therefore, cytokine gene polymorphisms in RCC patients were analyzed to determine haplotype combinations with prognostic significance. Patients and Methods A selection of 21 single nucleotide polymorphisms within the promoter regions of 13 cytokine genes were analyzed in a cross-sectional single-center study of 80 metastatic RCC patients. Univariate and multivariate analyses and the Cox forward-stepwise regression model were chosen to assess genetic risk factors. Results Multivariate Cox regression analysis confirmed by a bootstrap technique identified the heterozygous IL4 genotype −589T−33T/−589C−33C as an independent prognostic risk factor (risk ratio, 3.1; P < .01; 95% CI, 1.4 to 6.9; adjusted for age, sex, and nuclear grading) in metastatic RCC patients. IL4 haplotype −589T−33T and −589C−33C were found with a frequency of 0.069 and 0.925, respectively, which represents a two-fold decrease of IL4 haplotype −589T−33T (P < .01) and an increase of IL4 haplotype −589C−33C frequency (P < .05) in metastatic RCC compared with other white reference study populations. The median overall survival was decreased 3.5-fold (P < .05) in heterozygote patients carrying IL4 haplotype −589T−33T and −589C−33C (3.78 months) compared with patients homozygote for IL4 haplotype −589C−33C (13.44 months). In addition, a linkage disequilibrium between the IL4 gene and the KIF3A gene was detected. Conclusion Our findings indicate that IL4 promoter variants influence prognosis in patients with metastatic RCC and suggest that genetically determined interleukin-4 (IL-4) production affects the clinical course of the disease possibly through regulation of immune surveillance.

scholarly journals Age at diagnosis is a determinant factor of renal cell carcinoma– specific survival in patients treated with nephrectomy

2008 ◽  
Vol 2 (6) ◽  
pp. 610 ◽  
Author(s):  
Pierre I. Karakiewicz ◽  
Claudio Jeldres ◽  
Nazareno Suardi ◽  
George C. Hutterer ◽  
Paul Perrotte ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Cubic Spline ◽  
Age At Diagnosis ◽  
Fuhrman Grade ◽  
Effect Of Age

Objective: Based on combined data for 4880 patients, 2 previous studies reported that advanced age is a predictor of increased renal cell carcinoma–specific mortality (RCC-SM). We explored the effect of age in cubic spline analyses to identify the age groups with the most elevated risk for renal cell carcinoma (RCC).Methods: Our study included 3595 patients from 14 European centres who had partial or radical nephrectomies. We used the Kaplan–Meier method to compile life tables, and we performed Cox regression analyses to assess RCC-SM. Covariates included age at diagnosis, sex, TNM (tumour, node, metastasis) stage, tumour size, Fuhrman grade, symptom classification and histological subtype.Results: Age ranged from 10 to 89 (mean 63, median 67) years. The median duration of follow-up was 2.9 years. The median survival for the cohort was 13.4 years. Stage distribution was as follows: 1915 patients (53.3%) had stage I disease, 388 (10.8%) had stage II, 895 (24.9%) had stage III and 397 (11.0%) had stage IV disease. In multivariate analyses, we coded age at diagnosis as a cubic spline, and it achieved independent predictor status (p < 0.001). The risk of RCC-SM was lowest among patients younger than 50 years. We observed an increase in RCC-SM until the age of 50, at which point the level of risk reached a plateau. We observed a second increase among patients aged 75–89 years. We found similar patterns when we stratified patients according to the 2002 American Joint Committee on Cancer (AJCC) stages.Conclusion: The effect of age shows prognostic significance and indicates that follow-up and possibly secondary treatments might need to be adjusted according to the age of the patient.

Can Systemic Immune-Inflammation Index Create a New Perspective for the IMDC Scoring System in Patients with Metastatic Renal Cell Carcinoma?

2021 ◽  
pp. 1-8
Author(s):  
Fatma Bugdayci Basal ◽  
Cengiz Karacin ◽  
Irem Bilgetekin ◽  
Omur Berna Oksuzoglu
Keyword(s):  
Renal Cell Carcinoma ◽  
Prognostic Factor ◽  
Regression Model ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Independent Prognostic Factor ◽  
Cox Regression Model ◽  
Kaplan Meier

Introduction: The aim of the study was to evaluate impact of the systemic immune-inflammation index (SII) on prognosis and survival within the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score groups. Methods: The records of 187 patients with metastatic renal cell carcinoma (RCC) were reviewed retrospectively. The SII was calculated as follows: SII = Neutrophil × Platelet/Lymphocyte. The patients were categorized into 2 groups based on a median SII of 730 (×109 per 1 L) as SII low (<730) and SII high (≥730). The Kaplan-Meier method was used for survival analysis and a Cox regression model was utilized to determine independent predictors of survival. Results: The median age was 61 years (range: 34–86 years). Kaplan-Meier tests revealed significant differences in survival between the SII-low and SII-high levels (27.0 vs. 12.0 months, respectively, p < 0.001). The Cox regression model revealed that SII was an independent prognostic factor. The implementation of the log-rank test in the IMDC groups according to the SII level provided the distinction of survival in the favorable group (SII low 49.0 months vs. SII high 11.0 months, p < 0.001), in the intermediate group (SII low 26.0 vs. SII high 15.0 months, p = 0.007), and in the poor group (SII low 19.0 vs. SII high 6.0 months, p = 0.019). Conclusion: The SII was an independent prognostic factor and provided significant differences in survival for the favorable, intermediate, and poor IMDC groups. Thus, the SII added to the IMDC score may be clinically beneficial in predicting survival.

scholarly journals rs3200401 MALAT1 GENE POLYMORPHISM IS NOT RELATED TO AGE OF KIDNEY CANCER ONSET

2020 ◽  
Vol 20 (2) ◽  
pp. 119-123
Author(s):  
A.D. Volkohon ◽  
V. Yu. Harbuzova ◽  
O.V. Ataman
Keyword(s):  
Renal Cell Carcinoma ◽  
Gene Polymorphism ◽  
Cell Carcinoma ◽  
Kidney Cancer ◽  
Renal Cell ◽  
Cox Regression ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Today, the long non-coding RNA MALAT1 is considered to be one of the major RNAs involved in the emergence and metastasizing of various malignant tumours. Recent experiments have shown that MALAT1 plays an important role in the onset and progression of kidney cancer as well. It was found that cancer patient survival depends on the level of MALAT1 gene expression. The aim of the study was to investigate the possible association between rs3200401 MALAT1 gene polymorphism and age of kidney cancer onset among Ukrainian patients. Materials and methods. The venous blood of 101 patients with clear cell renal cell carcinoma (42 women and 59 men) was used for study. Determination of MALAT1 gene rs320040 polymorphism was performed by the Real-Time polymerase chain reaction method using TaqManSNP Assay C_3246069_10 components. Statistical analysis of the data obtained was performed using SPSS (version 17.0). To test the possible association between rs3200401 genotypes and the age of kidney cancer onset Kaplan-Meier and Cox regression techniques were used. P value < 0.05 was considered as statistically significant. Results. The obtained results of MALAT1 gene rs3200401 polymorphic site genotyping revealed that 71 (70.3%) patients with renal cell carcinoma had CC genotype, 29 (28.7%) – CT, 1 (1%) – TT genotype. Survival analysis by Kaplan-Meier method showed that life expectancy until the tumour occurrence was not related to rs3200401 locus (log rank P = 0.449 – for codominant model; log rank P = 0.847 – for dominant model). The results of Cox regression analysis also showed no link between MALAT gene rs3200401-site and risk of renal cell carcinoma development (P > 0.05). No statistically significant results were found after adjustment for sex, body mass index, metastasis, smoking and drinking habits (P > 0.05). Conclusions. The rs3200401 gene polymorphism of long non-coding RNA MALAT1 is not associated with the age of kidney cancer onset in Ukrainian population.

Active surveillance in asymptomatic or minimally symptomatic renal cell carcinoma: Retrospective analyses of a cohort of three oncological centers from Spain.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 441-441
Author(s):  
Maria Jove ◽  
Olatz Etxaniz ◽  
Nuria Sala ◽  
Albert Font ◽  
Laura Jimenez Colomo ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Active Surveillance ◽  
Renal Cell ◽  
Cox Regression ◽  
Statistical Significance ◽  
Descriptive Analysis ◽  
Sequential Therapy ◽  
Therapy Strategy ◽  
The Impact

441 Background: Some patients (pt) with metastatic renal cell carcinoma (mRCC) have an indolent course. Treatment toxicities can worsen quality of life. Active surveillance (AS) in paucisymptomatic pts is an option often used but few data is available. Our aim is to analyze the impact of initial AS in a sequential therapy strategy in terms of overall survival (OS). Methods: Data frompt diagnosed with mRCC from January 2005 to December 2013 in 3 centres of Spain were retrospectively analyzed. AS subgroup was defined as pt with ≥6 months (m) between diagnosis and first-line (L) treatment (tto) start. A descriptive analysis and median OS (mOS) were performed comparing pt with or without AS (AS vs. tto <6m). OS curve and medians were estimated using Kaplan Meier Method. A multivariate cox regression analyses with different prognostic factors was also realized. Results: From a cohort of 277 pt with mRCC, 69 pt (25%) were on initial AS and 208 pts on tto <6m (75%). Median time on observation until systemic tto was started on pt on AS was 14 m 95%CI (17.6-26.02). Pt characteristics of AS vs tto <6 m were: median age 63/60; males 70/72%; histology: 94/76% clear cell, 3/12% papillar, 0/4% chromophob; M1 at diagnosis: 22/48%; prognosis (Heng risk criteria): 0/17.% poor, 38.5/57% intermediate, 61.5/25% good; prior nephrectomy: 93/73%; number of metastatic locations (loc): 87/68% ≤2 loc, 12.5/32.5% ≥3 loc; lines of treatment: first L 46/53%, second L 38/23%, and third L 16/24%. When comparing exposure in months to each tto L, pt on AS had longer period of tto in second L (10.06/4.14 m, p=0.014). mOS were: 62 m 95%CI (52.97-71.03) vs. 22 m 95% CI (19.87-24.12) for AS/tto <6 m respectively (p<0.001) with statistical significance after multivariate analysis (Cox regression, HR=0.39; 95% CI, 0.25-0.63). Factors that independently influence on OS were: ≥2 M1 sites and papillar histology, negatively, and prior nephrectomy and >1 year from diagnosis to M1, positively. Conclusions: Our results suggest that AS before starting first L of tto is not a detrimental action in a selected population of mRCC pt with good risk characteristics allowing them to remain free of therapy’s toxicity during a long time period.

Multicenter comparison of outcomes for clinical and pathologic T3a renal cell carcinoma.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 758-758
Author(s):  
Aaron Bradshaw ◽  
Fady Ghali ◽  
Nathan Miller ◽  
Cathrine Keiner ◽  
Raksha Dutt ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Primary Outcome ◽  
Cox Regression ◽  
Multivariable Analysis ◽  
Rank Test ◽  
Similar Proportion ◽  
Secondary Outcomes

758 Background: The identification of venous thrombus in patients with renal cell carcinoma (RCC) is particularly challenging, with a substantial number upstaged to pathologic T3a following intervention. We compared survival outcomes between patients with initial cT3a status versus those upstaged to pT3a. Methods: This is a retrospective, multicenter analysis of patients with cT3a or pT3a RCC who underwent operative management. Primary outcome was recurrence-free survival (RFS). Secondary outcomes were overall survival (OS) and cancer-specific survival (CSS). Cox regression multivariable analysis (MVA) was utilized for primary outcome. Kaplan-Meier analyses (KMA) were conducted to describe RFS, OS, and CSS with log-rank test comparing clinical and upstaged pathologic T3a groups. Results: 770 patients were analyzed (cT3a 184, pT3a 586, median follow-up 28 months). Average pathologic tumor size was smaller in pT3a (7.2 cm vs 8.7 cm, p < 0.01), with no significant differences in clinical variables. A similar proportion underwent radical nephrectomy (vs. partial) (89.7% cT3a and 85.0% pT3a, p = 0.11) with no significant different in positive margin rate (3.8% cT3a, 4.8% pT3a, p = 0.23). However, a higher proportion of patients with cT3a disease were pathologically node positive (19.0% vs. 10.8%, p < 0.01) and demonstrated a higher rate of recurrence (cT3a 51.1% vs. pT3a 34.1%, p < 0.01) despite shorter mean follow-up (cT3a 33.0 vs. pT3a 50.7 mo, p < 0.01). MVA for RFS revealed cT3a staging (pT3a referent, HR 1.72, p < 0.01), positive margins (HR 2.85, p < 0.01), and clear cell histology (HR 1.68, p < 0.01) to be independently associated with higher recurrence rate, while partial nephrectomy (radical referent, HR 0.259, p < 0.01) was associated with a decreased rate. KMA revealed 5-year RFS of 34.4% and 60.6% for cT3a and pT3a respectively (p < 0.01). KMA for secondary outcomes revealed 5-year OS rates of 56.7% and 62.0% (p = 0.02) and 5-year CSS of 74.4% and 67.7% for cT3a and pT3a respectively (p = 0.01). Conclusions: Patients with cT3a RCC have poorer oncologic outcomes than those with upstaged pT3a RCC. Suspected venous involvement on pre-operative imaging may indicate more aggressive or advanced disease than that found during surgery.

scholarly journals Prognostic significance of pathologic nodal positivity in non-metastatic patients with renal cell carcinoma who underwent radical or partial nephrectomy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sung Han Kim ◽  
Boram Park ◽  
Eu Chang Hwang ◽  
Sung-Hoo Hong ◽  
Chang Wook Jeong ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Partial Nephrectomy ◽  
Renal Cell ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Survival Outcomes ◽  
Prognostic Impact ◽  
Cox Regression Analysis

AbstractThis retrospective, five-multicenter study was aimed to evaluate the prognostic impact of pathologic nodal positivity on recurrence-free (RFS), metastasis-free (MFS), overall (OS), and cancer-specific (CSS) survivals in patients with non-metastatic renal cell carcinoma (nmRCC) who underwent either radical or partial nephrectomy with/without LN dissection. A total of 4236 nmRCC patients was enrolled between 2000 and 2012, and followed up through the end of 2017. Survival measures were compared between 52 (1.2%) stage pT1-4N1 (LN+) patients and 4184 (98.8%) stage pT1-4N0 (LN−) patients using Kaplan–Meier analysis with the log-rank test and Cox regression analysis to determine the prognostic risk factors for each survival measure. During the median 43.8-month follow-up, 410 (9.7%) recurrences, 141 (3.3%) metastases, and 351 (8.3%) deaths, including 212 (5.0%) cancer-specific deaths, were reported. The risk factor analyses showed that predictive factors for RFS, CSS, and OS were similar, whereas those of MFS were not. After adjusting for significant clinical factors affecting survival outcomes considering the hazard ratios (HR) of each group, the LN+ group, even those with low pT stage, had similar to or worse survival outcomes than the pT3N0 (LN−) group in multivariable analysis and had significantly more relationship with RFS than MFS. All survival measures were significantly worse in pT1-2N1 patients (MFS/RFS/OS/CSS; HR 4.12/HR 3.19/HR 4.41/HR 7.22) than in pT3-4N0 patients (HR 3.08/HR 2.92/HR 2.09/HR 3.73). Therefore, LN+ had an impact on survival outcomes worse than pT3-4N0 and significantly affected local recurrence rather than distant metastasis compared to LN− in nmRCC after radical or partial nephrectomy.

scholarly journals The Immunoexpression of YAP1 and LATS1 Proteins in Clear Cell Renal Cell Carcinoma: Impact on Patients’ Survival

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
J. Godlewski ◽  
J. Kiezun ◽  
B. E. Krazinski ◽  
Z. Kozielec ◽  
P. M. Wierzbicki ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Prognostic Factors ◽  
Cell Carcinoma ◽  
Tumor Cells ◽  
Renal Cell ◽  
Cellular Localization ◽  
Cox Regression ◽  
Clear Cell ◽  
Rank Test ◽  
Cell Renal Cell Carcinoma

The aim of the study was to determine by immunohistochemistry cellular localization and immunoreactivity levels of YAP1 and LATS1 proteins in paired sections of tumor and unchanged renal tissues of 54 clear cell renal cell carcinoma (ccRCC) patients. Associations between clinical-pathological and overall survival (OS; median follow-up was 40.6 months) data of patients and YAP1 and LATS1 immunoreactivity were analyzed by uni- and multivariate Cox regression model and log-rank test. YAP1 immunoreactivity was found in the nuclei of tumor cells in 64.8% of ccRCC patients, whereas only 24.1% of tumors revealed cytoplasmic YAP1 expression. LATS1 immunoexpression was observed only in the cytoplasm of tumor cells in 59.3% of patients. LATS1 immunoreactivity in cancer cells negatively correlated with the size of primary tumor. The overall YAP1 immunoreactivity did not correlate with clinical-pathological data of patients. However, the subgroup of ccRCC patients who presented with cytoplasmic YAP1 immunoexpression had significantly shorter OS (median = 26.8 months) than patients without cytoplasmic YAP1 expression (median undefined). Multivariate Cox analysis revealed that increased cytoplasmic YAP1 (HR = 4.53) and decreased LATS1 immunoreactivity levels (HR = 0.90) were associated with worse prognosis, being independent prognostic factors. These results suggest that YAP1 and LATS1 can be considered as new prognostic factors in ccRCC.

Therapy-relevant gene signatures in the high risk localized renal cell carcinoma setting: Transcriptomic data from patients receiving placebo on a randomized phase III trial (PROTECT).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 353-353
Author(s):  
Phillip M. Rappold ◽  
Andrew W. Silagy ◽  
Fengshen Kuo ◽  
Mahtab Marker ◽  
Albert Reising ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Reference Group ◽  
Expression Profiles ◽  
Prognostic Significance ◽  
Phase Iii ◽  
Gene Signatures ◽  
Metastatic Setting

353 Background: Transcriptomic profiling of the renal cell carcinoma (RCC) tumor microenvironment (TME) has revealed gene signatures predictive of response to therapies in the metastatic setting. High expression of angiogenesis genes correlate with responses to tyrosine kinase inhibitors. Adenosine in the TME exerts immunosuppressive effects that can facilitate tumor growth. Adenosinergic agonism has revealed gene signatures, comprised of inflammatory myeloid mediators, that correlated with response to adenosine pathway inhibition on a previously reported cohort of patients. Given these promising data from the metastatic space, we sought to interrogate prognostic gene expression in the TME from patients with localized disease. Methods: Clinicopathologic and whole-gene microarray data were acquired from 202 patients in the placebo arm of the PROTECT trial (NCT01235962). Transcriptomic scores assessing angiogenesis and adenosine signaling with individual annotations above/below median categorized patients into four groups (angiogenesis high vs. low; adenosine high vs. low). Categorical association with disease free (DFS) and overall survival (OS) was tested with logrank testing and assessed interdependence with the UCLA Integrated Staging System (UISS) in a cox regression model. Results: Overall, 37% of the cohort developed recurrence and 81% were alive at last follow up. Kaplan-Meier analysis showed Adenohi and Angiolo signatures were individually associated with decreased DFS and OS, compared to Adenolo and Angiohi, respectively. Upon integrating these signatures, we found the AdenohiAngiolo group exhibited the worst and the AdenoloAngiohi group had the best DFS and OS. These associations were validated in the TCGA cohort. Multivariate Cox regression models showed AdenohiAngiohi (HR 3.75; 95% CI, 1.72-8.21; p = 0.0009) and AdenohiAngiolo (HR 6.44; 95% CI, 3.06-13.54; p < 0.0001) groups (AdenoloAngiohi as reference group) and pathologic T4 (HR 8.69; 95% CI, 2.66-28.36; p = 0.0003) were significantly associated with worse DFS, but not UISS score (HR 0.56; 95% CI, 0.24-1.31; p = 0.18) and T3 tumors (HR 1.54; 95% CI, 0.8-2.94; p = 0.2; T2 as reference group). Conclusions: RCC TME subgroups stratified into adenosinergic and angiogenic expression profiles carry independent prognostic significance in patients with localized RCC. On multivariate analysis, these gene signatures enhanced conventional clinicopathologic risk stratification variables in predicting DFS after nephrectomy. Given the early data fueling interest in developing the prognostic capacity of these gene signatures in the metastatic space, and their ability to predict outcomes in the post-nephrectomy setting, these biologically relevant subgroups should be explored as a guide for future biomarker-driven adjuvant therapy trials.

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