Frequency Of Renal Cell Carcinoma Research Articles

Does sunitinib still have a place in the current recommendations for the systemic treatment of advanced renal cell carcinoma?

Renal cancer is a common malignancy. The frequency of renal cell carcinoma (RCC) in the structure of oncological diseases is steadily increasing. Despite the migration of the stage towards an increase in the frequency of primary detection of localized forms of the disease, renal cancer belongs to the aggressive and unpredictable malignant neoplasms. One third of patients already have distant metastases at the time of diagnosis. Surgery is the only radical method of treatment of renal cancer. However, despite the successes of surgery in the treatment of RCC, according to various data, more than 30% of radically operated patients show dissemination of the tumor process during follow-up. Radiation therapy and chemotherapy are ineffective in treating metastatic RCC (mRCC). The results of nonspecific immunotherapy in the treatment of metastatic renal cancer were also unsatisfactory. Progress in the study of molecular biology has led to the discovery of a new group of anti-tumor drugs related to angiogenesis inhibitors. The use of targeted therapies has increased the efficacy of drug therapy in the treatment of mRCC several times over the use of cytokine immunotherapy. One of the first such drugs registered in 2007 for the treatment of mRCC was sunitinib, which in a number of clinical trials has demonstrated the greatest efficacy and acceptable toxicity. Along with new drug regimens, the multikinase inhibitor sunitinib remains the drug of choice for first-line therapy of inoperable locally advanced and disseminated clear cell and non-small cell RCC in patients with favorable prognosis. The literature review presents a critical analysis of the data related to sunitinib research in kidney cancer and changes in the position of monotherapy with this drug in advanced forms of the disease.

PAX8 EXPRESSION AND ITS ASSOCIATIONS IN PRIMARY RENAL CELL CARCINOMA: A CROSS SECTIONAL STUDY

Objective: To determine the frequency of PAX8 expression in cases of primary renal cell carcinoma (RCC) and its association with patient demographics and tumor type.
 Study Design: Cross sectional study.
 Place and Duration of Study: Department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi, from Jun 2016 to Jun 2017.
 Methodology: After ethics approval, 57 cases were selected by non probability consecutive sampling. Inclusion criteria was diagnosis of primary renal cell carcinoma of all histological types, in both genders, among adults aged >18 years. Exclusion criteria were poorly fixed specimens and metastatic renal cell carcinoma. The main outcome measure was PAX8 frequency in renal cell carcinoma. The secondary outcome measure was correlation of PAX8 expression with age, gender, tumor type and grade. Data was entered and analyzed on Statistical Package for the Social Sciences.
 Results: Out of 57 cases, majority were males 37, (64.9%). The mean age was 55.35 ± 12.60 years. Clear cell carcinoma was the most frequent histopathologic variant in 47 (81%) cases followed by papillary carcinoma in 6 (10.2%), chromophobe cell carcinoma 2 (3.5%), sarcomatoid renal carcinoma 1 (1.75%) and mucinous tubular and spindle cell carcinoma 1 (1.75%). PAX8 expression was positive in 52 (91.2%). No significant difference was found in the frequency of PAX8 expression across age (p=0.321), gender (p=1.00) and tumor type (p=1.00). There was significant difference seen across tumor grade p=0.03.
 Conclusion: PAX8 is an important additional diagnostic marker for renal cell carcinoma. It can be recommended for inclusion in immunohistochemical panel for diagnosis..............

Survival and causes of death in patients with von Hippel-Lindau disease

BackgroundHistorically, the survival of patients with von Hippel-Lindau disease (vHL) has been poorer than that of the general population. We aimed to determine whether the survival of VHL mutation carriers...

Abstract 3159: Identification of circulating tumor cells from renal cell carcinoma patients by a multi-parameter flow cytometry assay

Abstract BACKGROUND: Renal cell carcinoma (RCC) is one of the top ten causes of cancer death in the United States. The last ten years have shown a dramatic increase in the number of available treatment options, however metastatic RCC remains largely incurable. The classes of drugs that have been developed can be divided into agents that target the Vascular Endothelial Growth Factor (VEGF) pathway (Sunitinib, Sorafenib, Pazopanib, Axitinib, Bevacizumab), those that target the mammalian Target of Rapamycin (mTOR) pathway (Everolimus, Temsirolimus) and immune based therapies (IL-2 and PD-1 inhibition). There are currently limited biomarkers to guide clinical decisions, mainly due to the lack of tumor cells for longitudinal molecular analysis. Circulating tumor cells (CTCs) are potential a source of tumor cells that can be identified from a blood draw for serial analysis. CTCs have not been reliably detected in RCC due to the significant heterogeneity and high rate of false positive events in this disease when EpCAM has been used. We sought to identify RCC CTCs with alternative markers, such as carbonic anhydrase IX (CAIX) which is found in greater than 90% of clear cell RCC tumors. METHODS AND RESULTS: To evaluate for the presence and subtypes of CTCs from patients with RCC, we utilized a multi-parametric flow cytometry assay. We evaluated heterogeneity across subpopulations of putative CTCs with Epithelial Cell Adhesion Molecule (EpCAM), Carbonic Anhydrase IX (CAIX), Carbonic Anhydrase XII (CAXII), PAX8, and Cytokeratin (CK). Negative controls for immune and endothelial events were performed with markers for CD45, CD14, CD34, CD11b and CD61. We tested twenty blood samples from patients with RCC at the Dana Farber Cancer Institute and University of Wisconsin Carbone Cancer Center. CTC frequency in RCC ranges from 0-5410 CAIX+/CK+ events with a median of 24.5 putative CTCs/7.5mL of blood. A subset of patients with radiographic progression had a higher number of CTCs with a median of 295.2 CTCs/7.5 mL. A range of 1-231 EpCAM+/CK+ events were identified with a median of 5.5 CTCs/7.5mL. There was low frequency of events being CAIX+/EpCAM+/CK+, with a median of 1 CTC/7.5mL of blood. Assay specificity was dramatically improved through the combination of multiple positive markers with stains for immune and endothelial cells given frequent non-specific staining for cytokeratin in RCC blood samples. CONCLUSIONS: CTCs can be identified in patients with RCC using non-traditional markers. CAIX is a more sensitive marker than EpCAM to identify putative CTCs from patients with RCC. Specificity in the assay is critical given the high frequency of false positive events identified if only CD45 is used as a marker for immune cells. Our investigation is ongoing for further molecular characterization of orthogonal endpoints in identified CTCs. Future directions include longitudinal monitoring of CTCs during treatment with VEGF inhibitors. Citation Format: Joshua A. Desotelle, Chorom Pak, Erika Heninger, Jennifer L. Schehr, Rana R. McKay, Benjamin K. Gibbs, Craig Norton, Toni K. Choueiri, Joshua M. Lang. Identification of circulating tumor cells from renal cell carcinoma patients by a multi-parameter flow cytometry assay. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3159.

Identification of novel microRNAs regulating HLA-G expression and investigating their clinical relevance in renal cell carcinoma.

The non-classical human leukocyte antigen G (HLA-G) is expressed at a high frequency in renal cell carcinoma (RCC) and is associated with a higher tumor grade and a poor clinical outcome. This might be caused by the HLA-G-mediated inhibition of the cytotoxicity of T and NK cells. Therefore a selective targeting of HLA-G might represent a powerful strategy to enhance the immunogenicity of RCC lesions. Recent studies identified a number of HLA-G-regulating microRNAs (miRs) and demonstrated an inverse expression of some of these miRs with HLA-G in RCC in vitro and in vivo. However, it was postulated that further miRs might exist contributing to the tightly controlled selective HLA-G expression.By application of a miR enrichment assay (miTRAP) in combination with in silico profiling two novel HLA-G-regulatory miRs, miR-548q and miR-628-5p, were identified. Direct interactions of both miRs with the 3′ untranslated region of HLA-G were confirmed with luciferase reporter gene assays. In addition, qPCR analyses and immunohistochemical staining revealed an inverse, expression of miR-628-5p, but not of miR-548q to the HLA-G protein in primary RCC lesions and cell lines. Stable overexpression of miR-548q and miR-628-5p caused a downregulation of HLA-G mRNA and protein. This leads in case of miR-548q to an enhanced NK cell-mediated HLA-G-dependent cytotoxicity, which could be reverted by ILT2 blockade suggesting a control of the immune effector cell activity at least by this miR. The identification of two novel HLA-G-regulatory miRs extends the number of HLA-G-relevant miRs tuning the HLA-G expression and might serve as future therapeutic targets.

Novel role of a tyrosine kinase inhibitor by reversion of immune suppression in renal cell carcinoma.

e15122 Background: Immune suppression occurs at a high frequency in renal cell carcinoma (RCC) and might contribute to tumor progression and its reversal might be important for the success of T cell-based immunotherapies. It has recently be shown that sunitinib, a receptor tyrosine kinase inhibitor, could reverse the myeloid-derived suppressor cell (MDSC)-mediated immune suppression and prevent tumor-specific T cell anergy as well as the development of regulatory T cells (Treg). Methods: Monolayer and sphaeroid cultures of RCC cells were treated with various concentrations and for different length of time with sunitinib and the expression of HLA class I pathway components and of members of the B7-H family was determined by RT-PCR and flow cytometry. Results: We here show that sunitinib treatment not only reduce the frequency of MDSC and Treg, but also resulted in an enhanced expression of various components of the HLA class I antigen processing machinery (APM), such as e.g. the peptide transporter TAP, tapasin and the HLA class I molecules, and costimulatory molecules in RCC cells, whereas coinhibitory molecules were downregulated under these treatment modalities. This effect was even more pronounced in sphaeroid RCC cultures, which were even more sensitive to the growth inhibitory activity of sunitinib than monolayer cultures. Conclusions: These data suggest that sunitinib is a potential drug to reverse immune suppression not only at the level of immune cells, but also at the level of tumor cells thereby inducing their immunogenicity. No significant financial relationships to disclose.

Incidence of benign lesions according to tumor size in solid renal masses

The incidence of solid renal masses has increased sharply in recent years due to widespread use of abdominal imaging studies. The aim of the present study was to evaluate the incidence of benign lesions in solid renal masses according to tumor size. The authors retrospectively reviewed the records of 305 patients with 328 renal solid masses treated by surgery. Based on a report by one pathologist, the specimen tumor size and the histology of each lesion were tabulated. The frequency of renal cell carcinoma and benign renal lesions was evaluated and a correlation between tumor size and pathological features of the masses was observed. The frequency of malignant lesions in the 328 renal masses was 83.2%. When lesions were stratified into groups with diameters <or= 3 cm or > 3 cm, the incidence of benign histology was 22.9% and 13.3%, respectively (p = 0.026). The odds ratios for finding a benign lesion in masses <or= 3 cm was 1.93 (IC 95%, 1.07 - 3.46) compared to masses > 3 cm. The incidence of benign lesions is significantly higher in renal masses smaller than 3 cm in diameter, which should be taken in account when the treatment of renal solid masses is planned.

Expression and regulation of non‐classical HLA‐G in renal cell carcinoma

Under physiological conditions, the non-classical major histocompatibility complex class Ib molecule human leukocyte antigen G (HLA-G) is selectively expressed in placental trophoblasts, thymus and cornea. In pathological situations, HLA-G expression was frequently found in tumour cells of distinct origin, thereby allowing these tumour cells to escape immune surveillance. Although HLA-G expression occurs at a relatively high frequency in renal cell carcinoma (RCC) of the clear cell subtype, the molecular mechanisms of its aberrant expression in RCC has not yet been determined. Therefore, the constitutive and cytokine-mediated HLA-G expression as well as its mode of regulation was investigated. In addition to HLA-G-specific mRNA expression, membrane-bound and soluble/shed HLA-G protein was determined. Eight of 14 RCC cell lines analysed (57%) exhibited HLA-G-specific transcripts, whereas only 6 of 14 RCC cell lines (43%) expressed HLA-G protein, suggesting a post-transcriptional control of HLA-G in some cases. Treatment of RCC cell lines with either interferon-gamma or interleukin-10, respectively, increased HLA-G-specific mRNA and protein in six of eight HLA-G(+) RCC lines (75%), but not in HLA-G(-) RCC cells. A 5'-aza-2-deoxycytidine (5-Aza-dC)-mediated demethylation of the HLA-G promoter DNA resulted in an enhanced HLA-G expression in four of six RCC cell lines, whereas a de novo induction of HLA-G was only observed in one HLA-G(-) RCC cell line on treatment with 5-Aza-dC. Thus, there exist multiple mechanisms controlling HLA-G expression in RCC, which might also have an impact on the development of RCC-specific immunotherapies.

Association Between Renal Cell Carcinoma and Plasma Cell Dyscrasias: A Case Series of Six Patients

Multiple malignancies in the same patient are unusual. This is particularly true for patients with hematologic malignancies who have a concomitant solid tumor. We report the unexpectedly higher frequency of renal cell carcinoma (RCC) associated with plasma cell dyscrasias. We report 6 cases of RCC in our institutional database of 600 patients with plasma cell dyscrasias over the past 10 years. We discuss the possible mechanisms that predisposed these patients to a secondary malignancy.

CT of renal cell carcinoma in patients on chronic hemodialysis.

The occurrence rate of renal cell carcinoma is significantly higher in the native kidneys of patients undergoing chronic hemodialysis than in kidneys of normal subjects. These carcinomas may be difficult to detect because these kidneys tend to be small and distorted owing to acquired cystic disease. Four cases of renal cell carcinoma detected by CT are presented (three in patients undergoing chronic hemodialysis, and one in a patient with a functioning transplant who had history of dialysis). All kidneys had extensive acquired cystic disease. In two cases, contrast-enhanced scans showed a solid lesion of lower density than the kidney. In another case, in which IV contrast material could not be given, the mass was of higher density than the kidney and retroperitoneal lymphadenopathy was present. In the fourth case, no distinct solid mass could be identified. The only sign of malignancy in this case was extensive lymphadenopathy. Whenever CT examination of the abdomen is performed in a patient undergoing chronic hemodialysis, the kidneys must be evaluated carefully because of the increased frequency of renal cell carcinoma. In a few cases, a distinct solid lesion may not be apparent or may be subtle owing to distortion of renal anatomy by acquired cystic disease.