CAIX-targeted PET imaging agents based on acetazolamide small molecule for clear cell renal cell carcinoma.

Focus on kidney cancer

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.

Solid Renal Masses in Transplanted Allograft Kidneys: A Closer Look at the Epidemiology and Management.

Kidney cancer: Identification of novel targets for therapy

Imaging

ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma

5112 Background: CAIX is an important molecular marker of survival and response to immunotherapy in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to prospectively evaluate the performance of CAIX in patients with metastatic RCC. Methods: This study accrued 32 consecutive patients who were treated for metastatic clear cell RCC between January 2004 and May 2006. Immunohistochemical staining of the primary tumor was performed using the mouse monoclonal antibody MN-75. Patients were stratified into two groups: high CAIX expression (>85%) and low CAIX expression (=85%) according to the percentage of cells staining positive for CAIX. Study endpoints included disease-specific survival time (DSS) and response to treatment according to RECIST criteria. Results: Four (12.5%), 21 (65.6%), and 7 patients (21.9%) were classified into low risk, intermediate risk, and high risk groups according to the University of California Integrated Staging System (UISS). Twenty (62.5%) of the 32 patients had high CAIX expression. The median follow-up was 11.4 months. Patients with low CAIX expression had significantly worse prognosis than patients with high CAIX expression (median survival: 15.2 months vs. not reached, p=0.01, 1-year DSS rate: 63% vs. 83%) and a 3.9 fold increased risk of death from RCC (95% CI, 1.2–12.7). All 4 patients in the low risk UISS group had high CAIX expression, and all were alive at 1 year. Nine patients received high dose IL-2 based immunotherapy, including 8 who had high CAIX expression, and a 1-year DSS rate of 87.5%. Of the patients expressing high CAIX, 3 (37.5%) were responders to IL-2 including 1 partial and 2 complete responses, 3 (37.5%) exhibited stable disease and 2 (25.0%) progressed during treatment. Conclusions: The results of this first prospective study of CAIX in metastatic RCC confirm that high CAIX expression is associated with better survival and enhanced response to IL-2 based immunotherapy. Patients with high CAIX expression, specifically those with low risk RCC, should be considered candidates to receive immunotherapy, whereas patients with low CAIX expression or in higher risk groups may be better candidates for targeted or other experimental therapy. No significant financial relationships to disclose.

Renal Cell Carcinoma: Diagnosis Based on Metastatic Manifestations

Purpose: Hypoxia-inducible factor-1α (HIF-1α) plays an important role in tumoral adaptation to hypoxic conditions by serving as a transcription factor for several crucial proteins, including vascular endothelial growth factor and carbonic anhydrase IX (CAIX). Here, we evaluated the significance of HIF-1α in renal cell carcinoma (RCC).Experimental Design: Immunohistochemical analysis was done on a tissue microarray constructed from paraffin-embedded primary tumor specimens from 357 patients treated by nephrectomy for RCC. Nuclear expression was evaluated by a single pathologist who was blinded to outcome. The expression levels were associated with pathologic variables and survival.Results: HIF-1α expression was greater in RCC than in benign tissue. Clear cell RCC showed the highest expression levels. In clear cell RCC, HIF-1α was significantly correlated with markers of apoptosis (p21, p53), the mammalian target of rapamycin pathway (pAkt, p27), CXCR3, and proteins of the vascular endothelial growth factor family. HIF-1α was correlated with CAIX and CAXII in localized, but not in metastatic RCC. HIF-1α expression predicted outcome in metastatic patients: patients with high HIF-1α expression (>35%) had significantly worse survival than patients with low expression (≤35%); median survival, 13.5 versus 24.4 months, respectively (P = 0.005). Multivariate analysis retained HIF-1α and CAIX expression as the strongest independent prognostic factors for patients with metastatic clear cell RCC.Conclusions: HIF-1α is an important independent prognostic factor for patients with metastatic clear cell RCC. Because HIF-1α and CAIX are independently and differentially regulated in metastatic clear cell RCC, both tumor markers can be complementary in predicting prognosis.

Renal cell carcinoma (RCC) is a renal cortical tumor with high clinical incidence. The effect of glutathione peroxidases (GPXs) on RCC and the possible mechanism are still unclear. This study aims to explore the expression level of GPXs gene in RCC and its effect on the clinical prognosis of patients with RCC via bioinformatics analysis. The mRNA expressions of GPXs family genes were obtained from the public data of The Cancer Genome Atlas (TCGA) database. The Kruskal-Wails test was used to analyze the differences in mRNA expression of GPXs family genes between samples from patients with RCC and the normal population. UALAN databases were used to analyze the differences in protein expression of GPXs family genes between samples from patients with renal clear cell carcinoma and the normal population, and to evaluate the role of GPXs family genes in RCC. The Kaplan-Meier Plotter was used to analyze the correlation between different types of RCC and overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and progression-free survival (PFS). Kaplan-Meier survival curve was drawn based on the GPX8 gene expression to study the relationship between GPX8 gene expression and prognosis of RCC patients. Based on the results of multivariate Cox regression analysis, a Nomogram scoring model for RCC prediction was established by introducing GPX8 gene. The mRNA expressions of GPX1 and GPX4 were higher in the sample of renal chromophobe cell carcinoma, renal clear cell carcinoma, and renal papillary cell carcinoma than those in the normal population (all P<0.01), and GPX7 and GPX8 were significantly over-expressed in patients with renal papillary cell carcinoma and renal clear cell carcinoma (all P<0.01). Compared with the normal group, the protein expressions of GPX1, GPX2, GPX7, and GPX8 were increased significantly in renal clear cell carcinoma (all P<0.01), while GPX3 and GPX4 expressions were decreased significantly (both P<0.01). The protein expressions of GPX1, GPX2, GPX7, and GPX8 were increased significantly in patients with renal clear cell carcinoma at different tumor grades (all P<0.01), while GPX3 and GPX4 expressions were decreased significantly (both P<0.01). Survival analysis showed that OS, DFS, DSS, and PFS were all decreased in patients with clear cell carcinoma compared with patients with papillary cell carcinoma and chromophobe cell carcinoma. According to the GPX8 level, patients were assigned into the low, medium, and high expression groups. Compared with the low GPX8 level group, the OS (P<0.01), DFS (P=0.03), DSS (P<0.01), and PFS (P=3.18×10-7) were significantly decreased in the high level group. Univariate Cox proportional regression analysis showed that the high level of GPX8 was associated with poor OS of 3 different types of renal cancer. Multifactorial analysis showed that GPX8 was an independent factor affecting the OS of patients with renal papillary cell carcinoma. Race and post tumor node metastasis (pTNM) typing were independent factors influencing the OS of patients with renal clear cell carcinoma. GPX8 and pTMN were independent factors influencing the OS of patients with renal chromophobe cell carcinoma. Based on these variables, the Nomogram risk models of 3 types of cell carcinoma were established, and the discrimination and calibration of the models were evaluated using the Consistency index (C-index) and calibration curves. The C-index of the risk model of renal papillary cell carcinoma was 0.62 (95% CI 0.51 to 1.00, P=0.03). The results of receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) was 0.88. The C-index of the risk model of renal clear cell carcinoma was 0.72 (95% CI 0.52 to 1.00, P=0.03). The results of ROC curve showed that the AUC was 0.90. The C-index of the risk model of chromophobe cell carcinoma of kidney was 0.90 (95% CI 0.85 to 1.00, P<0.01). The results of ROC curve showed that the AUC was 0.59. GPXs family genes, especially GPX8, are potential markers for poor prognosis of RCC, and the occurrence and development of RCC can be predicted in clinical practice based on the expressions of GPXs family genes.

Characterization of Patients With Metastatic Renal Cell Carcinoma Experiencing Complete Response to First-line Therapies: Results From the International Metastatic Renal Cell Carcinoma Database Consortium.

Purpose: Circulating biomarkers are an emerging tool to monitor treatment response and the emergence of resistant phenotypes. However, studies of circulating biomarkers, including circulating tumor cells (CTCs), in patients with clear cell renal cell carcinoma (ccRCC) have been limited due to difficulty in biomarker identification. Platforms relying on EpCAM and cytokeratin to identify CTCs have been limited due to significant phenotypic and intrapatient heterogeneity in renal cancer. Carbonic anhydrase IX (CAIX) and XII (CAXII) are more broadly expressed in ccRCC and recently been shown to capture CTCs from patients with ccRCC. However, downregulation of these targets can also occur; EpCAM is also expressed on a subset of cells that could go undetected if only CAIX was used to capture these cells. The aim of this study is to optimize multi-marker capture and analysis of ccRCC CTCs using EpCAM, CAIX and CAXII for further molecular analysis. Methods: We utilized the VERSA platform, an integrated CTC capture and analysis technology, to optimize capture of multiple ccRCC cell lines using antibodies to CAIX and/or EpCAM. To maximize the capture efficiency of ccRCC CTCs, we altered the magnetic particle type, antibody concentration, and tested both direct and indirect capture methods. Once an optimal method of capture was determined, we captured CTCs in an initial cohort of ten patients with ccRCC. CTCs were identified as cells that were captured by either CAIX or EpCAM, had an intact nucleus, were negative for CD45/CD34/CD66b, and positive for cytokeratin. Results: Capture of cell lines show that a combined CAIX + EpCAM capture was more efficient than single antibody capture using either EpCAM or CAIX alone. The type of magnetic particle used in the assay also affected capture efficiency. Sera-Mag beads (GE Healthcare) captured significantly more cells than FlowComp Dynabeads (Life Technologies) (94% vs 76%). Further increases in efficiency were made by incubating with antibody prior to bead conjugation (indirect binding, 94%) when compared to incubating the cells with antibody-conjugated beads (direct binding, 98%). This may result from increased accessibility of free antibody to partially obstructed antigens that is unique to renal cell carcinoma. This optimized assay has now been applied to ccRCC patients and has identified CTCs in up to 90% of patients with metastatic disease. Conclusions: We have increased the capture efficiency and identification of ccRCC cells by capturing with a combination of CAIX and EpCAM antibodies and optimizing bead and binding conditions. In doing so, we are able to identify and interrogate populations of CTCs that would be lost in capture methods that rely on EpCAM alone. These assays are now being utilized in multiple biomarker and therapeutic trials for patients with clear cell renal cell carcinoma. Citation Format: Rory M. Bade, Benjamin K. Gibbs, Jamie M. Sperger, Christos Kyriakopolous, Hamid Emamekhoo, Rana R. McKay, Toni K. Choueiri, Joshua M. Lang. Development of multi-marker capture and analysis of circulating tumor cells in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4585.

Immunochemotherapy for Metastatic Renal Cell Carcinoma Using a Regimen of Interleukin-2, Interferon-alpha and 5-fluorouracil

miRNA Profiling for Clear Cell Renal Cell Carcinoma: Biomarker Discovery and Identification of Potential Controls and Consequences of miRNA Dysregulation

ASSESSMENT OF TUMOR INVASION OF THE VENA CAVAL WALL IN RENAL CELL CARCINOMA CASES BY MAGNETIC RESONANCE IMAGING