Expression of endogenous retroviruses and response to immune checkpoint therapy in renal cell cancer.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 104-104 ◽  
Author(s):  
Anshuman Panda ◽  
Aguirre De Cubas ◽  
Katy Beckermann ◽  
Gregory Riedlinger ◽  
Mark N. Stein ◽  
...  
Keyword(s):  
Immune Activation ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Cancer ◽  
Endogenous Retroviruses ◽  
Multiple Cancer ◽  
Checkpoint Activation ◽  
Cancer Types ◽  
Cell Renal Cancer

104 Background: In certain cancers, including renal cell carcinoma (RCC), no clear correlation exists between mutation burden and response to immune checkpoint therapy. To look for other markers of immune activation, we investigated the correlation between expression of endogenous retroviruses (ERV) and evidence of immune checkpoint activation in multiple cancer types. Methods: RNA-seq data of 4,910 tumors of 21 cancers from TCGA was analyzed to identify cancers in which there was correlation between ERV expression and evidence of immune checkpoint activation as shown by increased expression of immune checkpoint genes and evidence of CD8+ T-cell infiltration. Expression of candidate ERVs was measured by quantitative RT-PCR in a set of 20 RCC specimens. Results: In the TCGA clear-cell renal cancer, ER+HER2- breast cancer, and colon cancer datasets showed correlation between expression of a subset of ERVs and markers of local immune checkpoint activation. Using hierarchical clustering, tumors could be classified into 3 groups (high/intermediate/low) based on expression of these ERVs. In all these cancer types, the high ERV expressing group showed evidence of immune activation (robust immune infiltration with high CD8+ T cell fraction) and checkpoint (PD-1, CTLA-4) pathway over-expression. Expression of gene pathways associated with histone modification was significantly correlated with overall ERV expression, suggesting underlying dysregulation of chromatin silencing. Of ERVs analyzed ERV3.2 and ERVK-2 were most consistently associated with markers of immune checkpoint activation in multiple cancer types. For validation, expression of ERVs were measured in tumor sepcimens 20 clear cell renal cancer patients treated with immune checkpoint blockade. Expression of ERV3-2 and ERVK-2, was significantly increased in patients with clinical response to immune checkpoint therapy in this cohort. Conclusions: These data suggest that expression of ERV may be associated with activation of immune checkpoint pathways in renal cell cancer and may predict response to immune checkpoint therapy. Similar associations may also exist in some other solid tumors.

scholarly journals Tumor cell PD-L1 expression is a strong predictor of unfavorable prognosis in immune checkpoint therapy-naive clear cell renal cell cancer

2021 ◽  
Author(s):  
Katharina Möller ◽  
Christoph Fraune ◽  
Niclas C. Blessin ◽  
Maximilian Lennartz ◽  
Martina Kluth ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Strong Predictor ◽  
Cell Cancer ◽  
Tumor Type ◽  
Cancer Aggressiveness ◽  
Papillary Rcc

Abstract Background PD-L1 expression predicts response to immune checkpoint inhibitors in renal cell carcinomas (RCC), but has also been suggested to be linked to poor patient outcome. Methods We analyzed PD-L1 in > 1400 RCC in a tissue microarray format by immunohistochemistry. Results were compared with histological tumor type, parameters of cancer aggressiveness, and intratumoral CD8+ cytotoxic cells. Result At a cut-off level of 5% PD-L1 positive tumor cells, PD-L1 positivity was seen in 6.3% of 633 clear cell RCC (ccRCC), 18.2% of 165 papillary RCC, 18.8% of 64 chromophobe RCC, and 41.7% of 103 oncocytomas. In ccRCC, PD-L1 positivity was significantly linked to high ISUP (p < 0.0001), Fuhrman (p < 0.0001), Thoenes grade (p < 0.0001), distant metastasis (p = 0.0042), short recurrence-free (p < 0.0001), and overall survival (p = 0.0002). Intratumoral CD8+ lymphocytes were more frequent in PD-L1 positive (1055 ± 109) than in PD-L1 negative ccRCC (407 ± 28; p < 0.0001). PD-L positive immune cells were seen in 8.2% of all RCC and 13.9% of papillary RCC. In ccRCC, PD-L1 positive immune cells were linked to high numbers of tumor-infiltrating CD8+ cells (p < 0.0001), high ISUP (p < 0.0001), Fuhrman (p = 0.0027), and Thoenes grade (p < 0.0001), and poor tumor-specific survival (p = 0.0280). Conclusions These data suggest that PD-L1 expression in highly immunogenic RCCs facilitates immune evasion and contributes to cancer aggressiveness.

scholarly journals Mini-Review: Sarcomatoid Non-Clear Cell Renal Cancer

2017 ◽  
Vol 6 (2) ◽  
pp. 1
Author(s):  
Saikrishna Gadde ◽  
Benjamin Jones ◽  
Christopher Old
Keyword(s):  
Renal Cell Cancer ◽  
Renal Cell ◽  
Renal Carcinoma ◽  
Clear Cell ◽  
Cell Cancer ◽  
Clear Cell Renal Carcinoma ◽  
Cell Renal Carcinoma ◽  
Difficult Cases ◽  
Cell Renal Cancer ◽  
Sarcomatoid Differentiation

Sarcomatoid differentiation can occur within any subdivision of renal cell carcinoma. Although the prevalence of sarcomatoid renal cell cancer has been reported to be anywhere from 1-15% of renal cancers, sarcomatoid non-clear cell renal carcinoma is actually very rare. Studies on these cancers are generally limited to tens of patients. One reason for the paucity of patients with non-clear cell sarcomatoid renal cell cancer is the aggressive nature of this disease. We present a case of sarcomatoid non-clear cell renal carcinoma and review of the treatment for these difficult cases based on the available literature.

Tamoxifen Treatment for Advanced Renal Cell Cancer

1980 ◽  
Vol 66 (5) ◽  
pp. 601-605 ◽  
Author(s):  
Eros Ferrazzi ◽  
Luigi Salvagno ◽  
Adriano Fornasiero ◽  
Giuseppe Cartei ◽  
Mario Fiorentino
Keyword(s):  
Renal Cell Carcinoma ◽  
Stable Disease ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Cancer ◽  
Tamoxifen Treatment ◽  
Mixed Response ◽  
Short Time ◽  
Cell Renal Cancer ◽  
Advanced Renal Cell Cancer

Twelve patients with metastatic clear cell renal cancer received a course of tamoxifen. Three showed stable disease for a period from 2 to 12 months and 1 a mixed response for a short time. It does not appear that tamoxifen may be a useful agent in the treatment of metastatic renal cell carcinoma.

223 Racial differences in outcomes for metastatic renal cell carcinoma (mRCC) patients managed on immune-checkpoint inhibitor (ICI) therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A242-A242
Author(s):  
T Anders Olsen ◽  
Dylan Martini ◽  
Subir Goyal ◽  
Yuan Liu ◽  
Sean Evans ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
African American ◽  
Retrospective Study ◽  
Cell Carcinoma ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Clear Cell ◽  
Emory University ◽  
Caucasian Patients

BackgroundImmune checkpoint inhibitors (ICIs) have increased in prevalence for the treatment of metastatic clear-cell renal cell carcinoma (mccRCC) in recent years given their efficacy and favorable toxicity profile. However, there has been insufficient investigation in the literature of how clinical outcomes differ on the basis of race. In this paper, we investigated differences in clinical outcomes between African American (AA) and Caucasian mRCC patients treated with ICI therapy.MethodsWe performed a retrospective study of 198 patients with mRCC who received ICI at the Emory Winship Cancer Institute from 2015–2020. Clinical outcomes were measured by overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). OS and PFS were calculated from ICI-initiation to date of death and radiographic or clinical progression, respectively. CB was defined as a best radiographic response of complete response, partial response, or stable disease maintained for at least 6 months per response evaluation criteria in solid tumors version 1.1. The association of self-identified race with OS and PFS was generally modeled by Cox proportional hazards model. Univariable and multivariable logistic regression models were used for binary outcomes of CB. The univariate association of immune-related adverse events (irAEs) and non-clear-cell RCC (nccRCC) with race was assessed using Chi-square test.ResultsOur cohort was made up of 38 AA (19%) and 160 Caucasian (81%) patients. Most of the patients were diagnosed with ccRCC (78%) and more than half received PD-1 monotherapy (57%). Most patients were international mRCC database consortium (IMDC) intermediate (57%) or poor-risk (25%) groups. AA patients displayed significantly shorter PFS (HR=1.52, 95% CI: 1.01–2.3, p=0.045) and trended towards decreased CB (OR=0.51, 95% CI: 0.22–1.17, p=0.111) in MVA (table 1). There was no difference in OS (HR=1.09, 95% CI: 0.61–1.95, p=0.778) between the two racial groups in MVA (table 1). On Kaplan-Meier method, AA patients had shorter median OS (17 vs 25 months, p=0.3676) and median PFS (3.1 vs 4.4 months, p=0.0676) relative to Caucasian patients (figure 1). Additionally, AA patients more commonly had nccRCC compared to Caucasian patients (41.7% vs 17.5% nccRCC, p-0.002). AA patients also trended towards a lower incidence of irAEs compared to Caucasian patients in UVA (23.7% vs 35.8%, p=0.153).Abstract 223 Table 1*MVA controlled for age, race, gender, IMDC risk group, number of prior lines of therapy, PD-1 monotherapy, and ccRCC**statistical significance at alpha < 0.05Abstract 223 Figure 1African-American (black) and Caucasian (white) for OS (left panel) and PFS (right panel)ConclusionsIn this group of mRCC patients treated with ICI, African American patients had significantly shorter PFS compared to Caucasian patients. These findings suggest race could play a role in the management of late-stage mRCC. Larger, prospective studies are needed to validate these findings.AcknowledgementsResearch reported in this publication was supported in part by the Breen Foundation and the Biostatistics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Trial RegistrationNot applicable.Ethics ApprovalThis retrospective study was approved by the Emory University Institutional Review Board.ConsentNot applicable.ReferencesNot applicable

scholarly journals Identification of DNA methylation signatures associated with poor outcome in lower-risk Stage, Size, Grade and Necrosis (SSIGN) score clear cell renal cell cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Louis Y. El Khoury ◽  
Shuang Fu ◽  
Ryan A. Hlady ◽  
Ryan T. Wagner ◽  
Liguo Wang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Renal Cell ◽  
Lower Risk ◽  
Clear Cell ◽  
Cell Cancer ◽  
Low Risk ◽  
Cell Renal Cell Carcinoma ◽  
A Genome ◽  
Size Grade ◽  
Prognostic Power

Abstract Background Despite using prognostic algorithms and standard surveillance guidelines, 17% of patients initially diagnosed with low risk clear cell renal cell carcinoma (ccRCC) ultimately relapse and die of recurrent disease, indicating additional molecular parameters are needed for improved prognosis. Results To address the gap in ccRCC prognostication in the lower risk population, we performed a genome-wide analysis for methylation signatures capable of distinguishing recurrent and non-recurrent ccRCCs within the subgroup classified as ‘low risk’ by the Mayo Clinic Stage, Size, Grade, and Necrosis score (SSIGN 0–3). This approach revealed that recurrent patients have globally hypermethylated tumors and differ in methylation significantly at 5929 CpGs. Differentially methylated CpGs (DMCpGs) were enriched in regulatory regions and genes modulating cell growth and invasion. A subset of DMCpGs stratified low SSIGN groups into high and low risk of recurrence in independent data sets, indicating that DNA methylation enhances the prognostic power of the SSIGN score. Conclusions This study reports a global DNA hypermethylation in tumors of recurrent ccRCC patients. Furthermore, DMCpGs were capable of discriminating between aggressive and less aggressive tumors, in addition to SSIGN score. Therefore, DNA methylation presents itself as a potentially strong biomarker to further improve prognostic power in patients with low risk SSIGN score (0–3).

C07 Polymorphisms of RAGE and glyoxalase I genes in patients with clear cell renal cell cancer

2013 ◽  
Vol 12 (4) ◽  
pp. e1115, C07
Author(s):  
M. Chocholatý ◽  
K. Havlová ◽  
M. Schmidt ◽  
M. Kalousová ◽  
M. Jáchymová ◽  
...  
Keyword(s):  
Renal Cell Cancer ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Cancer ◽  
Glyoxalase I

NAXIVA: A phase II neoadjuvant study of axitinib for reducing extent of venous tumor thrombus in clear cell renal cell cancer (RCC) with venous invasion.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 275-275
Author(s):  
Grant D. Stewart ◽  
Sarah J. Welsh ◽  
Stephan Ursprung ◽  
Ferdia Gallagher ◽  
Iosif Mendichovszky ◽  
...  
Keyword(s):  
Renal Cell Cancer ◽  
Surgical Approach ◽  
Renal Cell ◽  
Tumor Thrombus ◽  
Response Rate ◽  
Clear Cell ◽  
Cell Cancer ◽  
Surgical Morbidity ◽  
Venous Tumor Thrombus ◽  
Extent Of Surgery

275 Background: Venous tumor thrombus (VTT) extension occurs in 4-15% cases of renal cell cancer (RCC). The Mayo classification distinguishes 4 levels of VTT extension between the renal vein and supradiaphragmatic inferior vena cava (IVC). Although surgery is performed with curative intent, mortality is high (5-15%) with complications increasing with the level of the VTT. 5-year survival rates are poor; ~40-65% in non-metastatic RCC. It is hypothesised that neoadjuvant targeted therapy could downstage the VTT reducing the extent of surgery, leading to reduced surgical morbidity and mortality, and increased survival. However, level I or II evidence is lacking. NAXIVA provides the first level II evidence in this patient group, assessing the response of VTT to axitinib. Extensive translational sampling will provide in depth interrogation of VTT (using genomics, proteomics, immunophenotyping and metabolomics) to examine the role of the tumor microenvironment of VTT and response to axitinib. Methods: NAXIVA was a single arm, single agent, multi-center phase 2 feasibility study of axitinib in patients with both metastatic and non-metastatic clear cell RCC prior to nephrectomy and thrombectomy. A Simon two stage minimax design was adopted and the trial designed for adequate power to distinguish a <5% from a >25% improvement in the Mayo VTT level. 21 patients were recruited over a 24 month period between 15/Dec/2017 and 06/Jan/2020 at 5 sites across the UK. Patients were treated with 8 weeks of axitinib (starting dose 5mg bd, increasing to 10mg bd as tolerated) prior to planned surgery. The primary endpoint was the percentage of evaluable patients with an improvement in VTT according to the Mayo classification (assessed using MRI abdomen scans at screening and week 9, prior to surgery. Secondary endpoints were percentage change in surgical approach, percentage change in VTT height, response rate (by RECIST) and evaluation of surgical morbidity assessed by Clavien-Dindo classification. Results: The percentage of evaluable patients with an improvement in VTT according to the Mayo classification was 26.58% [80% CI: 15.76%, 39.74%] (6 of 21 evaluable patients). 35.29% (6 of 17 patients who progressed to surgery) had a change in surgical approach to a less invasive option. There was a median percentage reduction in VTT height of 21.49% (SD=27.60%). The response rate (by RECIST) in the evaluable population was 61.90% SD, 14.29% PR, 9.52% PD. In terms of surgical morbidity 11.76% (2 of 17 patients who progressed to surgery) experienced a Clavien-Dindo 3 or greater complication (0 CD3, 1 CD4, 1 CD5). Conclusions: NAXIVA provides unique prospective data on the feasibility of neoadjuvant axitinib administration to down stage IVC VTT and reduce the extent of surgery. Work is ongoing to establish predictors of response. Clinical trial information: NCT03494816 .

scholarly journals Metastatic renal cell carcinoma of unknown primary site. Clinical follow-up

2020 ◽  
Vol 22 (3) ◽  
pp. 149-153
Author(s):  
N. A. Ognerubov ◽  
T. S. Antipova ◽  
G. E. Gumareva
Keyword(s):  
Computed Tomography ◽  
Renal Cell Carcinoma ◽  
Adrenal Gland ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Cancer ◽  
Primary Site ◽  
The Right

Renal cell cancer metastases without evidence of a primary tumor are extremely rare. These variants are usually showed as a spontaneous description of single clinical cases. Aim.This contribution is a clinical follow-up of synchronous renal cell cancer metastases of unknown primary site. Results.A 52-year-old patient U. with a history of increased blood pressure, up to 170/100 mmHg for the last 5 years, who had undergone many instrumental examinations, including ultrasound examination, because of this disease. The computed tomography of the abdomen showed a 4975 mm heterogeneous tumor in the right adrenal gland in October 2017. The combined positron emission and X-ray computed tomography showed a 795441 mm mass in the right adrenal gland, associated with elevated fluorodeoxyglucose metabolic activity SUVmax 7.25. Focal accumulation of the radiopharmaceutical SUVmax 4.31 in a 171124 mm mass was detected in the space of bifurcation in the mediastinum. The lytic lesion (1015 mm) was found in right superior L3 articular process. The patient underwent retroperitoneoscopic adrenalectomy and thoracoscopic removal of mediastinal tumor in November 2017 because of the oligometastatic nature of the process. The histological study identified clear-cell carcinoma with areas of papillary structure in the right adrenal gland. The immunohistochemical study showed carcinoma cells intensively expressing CD10, and some other cells RCC. The immune phenotype of the tumor was identified as clear-cell renal cell carcinoma. The immunohistological and immunohistochemical analysis reviled the metastases of the same variant of renal cell carcinoma in one of 9 lymph nodes. The patient was treated with pazopanib. The primary renal tumor was not detected during the dynamic observation, including the application of annual combined positron emission and X-ray computed tomography. The patient is alive without disease progression with a follow-up of 32 months. Conclusion.Metastases of clear-cell renal cell carcinoma, including adrenal gland, without evidence of a primary site are extremely rare. The main method of treatment is a combination of surgery and targeted therapy, providing long-term local control of the course of the disease.

scholarly journals SYNE1 mutation may enhance the response to immune checkpoint blockade therapy in clear cell renal cell carcinoma patients

Aging ◽  
2020 ◽  
Vol 12 (19) ◽  
pp. 19316-19324
Author(s):  
Pengju Li ◽  
Jeifei Xiao ◽  
Bangfen Zhou ◽  
Jinhuan Wei ◽  
Junhang Luo ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Clear Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cell Renal Cell Carcinoma
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