Primary Renal Cell Carcinoma Research Articles

Metastatic Renal Cell Carcinoma to the Brain: A Contemporary Clinicopathologic Analysis With Comparison of Immunohistochemical Profiles to Selected Primary Brain Tumors With Clear Cell Features.

Brain metastases from renal cell carcinoma (RCC) are associated with significant morbidity and mortality. However, there are only few large series in the pathology literature specifically analyzing the clinicopathologic and immunohistochemical features in comparison with primary brain tumors with clear cell features. We identified 34 cases of metastatic RCC to the brain from the Urologic Pathology and Neuropathology files of 2 institutions between 2000 and 2018. Mean patient age at diagnosis of primary RCC was 59 years (range: 37 to 82 y). The mean size of 34 primary RCC was 7.9 cm (range: 2.5 to 19.5 cm). Twenty of 34 (59%) cases of brain metastases had primary RCC categorized as pT3. Brain imaging showed a solitary, well circumscribed, enhancing lesion in 18 of 34 (53%) patients and multifocal lesions in 16 of 34 (47%) patients. The mean size of metastatic RCC to the brain was 2.3 cm (range: 0.3 to 5.5 cm). Fifteen of 34 (44%) cases had isolated brain metastases and 19 of 34 (56%) cases had concomitant extracerebral metastases. The histologic subtypes were clear cell RCC 29 of 34 (85%) cases, RCC unclassified 4 of 34 (12%) cases, and papillary RCC 1 of 34 (3%) cases. We also included primary brain tumors with clear cell features including hemangioblastoma (30 cases), microcystic meningioma (11 cases), and clear cell meningioma (3 cases). The utility of an immunohistochemical panel that includes PAX8, carbonic anhydrase IX, SST2Ra, and inhibin is very useful in the distinction of these entities in a subset of patients.

The prognostic value of ephrin type-A2 receptor and Ki-67 in renal cell carcinoma patients: An Immunohistochemical and Bioinformatical Approach; A STROBE - compliant article.

Patients with renal cell carcinoma (RCC), the most common malignant renal epithelial tumor, usually present with advanced disease and unpredicted clinical behavior. The receptor tyrosine kinase, ephrin type-A receptor 2 (EphA2) was found to be overexpressed in several malignancies and its expression was found to be associated with poor prognostic features.Our study is an observational study with the aim of investigating the prognostic value of EphA2 in RCC patients and its association with clinicopathological parameters as well as Ki-67 expression, which is a well-known proliferative and prognostic marker in RCC.EphA2 and Ki-67 immunohistochemical staining was performed on whole sections representative of 50 patients diagnosed with primary RCC from 2013 to 2018. In addition, the association between EphA2 mRNA expression and clinicopathological parameters as well as the patients’ outcome was also evaluated using two large publicly available databases.Our results showed a significant association between EphA2 immunohistochemical expression and tumor size, nuclear grade, tumor stage, patients’ outcome and Ki-67 expression (P < .05 for all). The same trend was also observed with EphA2 mRNA expression using larger patients’ cohorts in 2 publicly available databases. Notably, EphA2 protein expression showed higher levels of co-expression with the proliferative marker Ki-67.Our results suggested that higher expression of EphA2 and Ki-67 in tumor tissues predicts a locally aggressive behaviour and poor outcome of patients with RCC. Moreover, our results give a rationale for the potential benefits of using novel therapeutic strategies with the aim of targeting EphA2 receptor in RCC patients that might help in improving their outcome.

The therapeutic value of SC66 in human renal cell carcinoma cells

The PI3K-AKT-mTOR cascade is required for renal cell carcinoma (RCC) progression. SC66 is novel AKT inhibitor. We found that SC66 inhibited viability, proliferation, migration and invasion of RCC cell lines (786-O and A498) and patient-derived primary RCC cells. Although SC66blocked AKT-mTORC1/2 activation in RCC cells, it remained cytotoxic in AKT-inhibited/-silenced RCC cells. In RCC cells, SC66 cytotoxicity appears to occur via reactive oxygen species (ROS) production, sphingosine kinase 1inhibition, ceramide accumulation and JNK activation, independent of AKT inhibition. The ROS scavenger N-acetylcysteine, the JNK inhibitor (JNKi) and the anti-ceramide sphingolipid sphingosine-1-phosphate all attenuated SC66-induced cytotoxicity in 786-O cells. In vivo, oral administration of SC66 potently inhibited subcutaneous 786-O xenograft growth in SCID mice. AKT-mTOR inhibition, SphK1 inhibition, ceramide accumulation and JNK activation were detected in SC66-treated 786-O xenograft tumors, indicating that SC66 inhibits RCC cell progression through AKT-dependent and AKT-independent mechanisms.

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation.

Background: Renal cell carcinoma (RCC) displays a glycolytic phenotype (Warburg effect). Increased lactate production, impacting on tumor biology and microenvironment modulation, has been implicated in epigenetic mechanisms’ regulation, leading to histone deacetylases inhibition. Thus, in-depth knowledge of lactate’s impact on epigenome regulation of highly glycolytic tumors might allow for new therapeutic strategies. Herein, we investigated how extracellular lactate affected sirtuin 1 activity, a class III histone deacetylase (sirtuins, SIRTs) in RCC. Methods: In vitro and in vivo interactions between lactate and SIRT1 in RCC were investigated in normal kidney and RCC cell lines. Finally, SIRT1 and N-cadherin immunoexpression was assessed in human RCC and normal renal tissues. Results: Lactate inhibited SIRT1 expression in normal kidney and RCC cells, increasing global H3 and H3K9 acetylation. Cells exposed to lactate showed increased cell migration and invasion entailing a mesenchymal phenotype. Treatment with a SIRT1 inhibitor, nicotinamide (NAM), paralleled lactate effects, promoting cell aggressiveness. In contrast, alpha-cyano-4-hydroxycinnamate (CHC), a lactate transporter inhibitor, reversed them by blocking lactate transport. In vivo (chick chorioallantoic membrane (CAM) assay), lactate and NAM exposure were associated with increased tumor size and blood vessel recruitment, whereas CHC displayed the opposite effect. Moreover, primary RCC revealed N-cadherin upregulation whereas SIRT1 expression levels were downregulated compared to normal tissues. Conclusions: In RCC, lactate enhanced aggressiveness and modulated normal kidney cell phenotype, in part through downregulation of SIRT1, unveiling tumor metabolism as a promising therapeutic target.

VHL-HIF-2α axis-induced SMYD3 upregulation drives renal cell carcinoma progression via direct trans-activation of EGFR.

It has been well established that the von Hippel-Lindau/hypoxia-inducible factor α (VHL-HIFα) axis and epidermal growth factor receptor (EGFR) signaling pathway play a critical role in the pathogenesis and progression of renal cell carcinoma (RCC). However, few studies have addressed the relationship between the two oncogenic drivers in RCC. SET and MYND domain-containing protein 3 (SMYD3) is a histone methyltransferase involved in gene transcription and oncogenesis, but its expression and function in RCC remain unclear. In the present study, we found that SMYD3 expression was significantly elevated in RCC tumors and correlated with advanced tumor stage, histological and nuclear grade, and shorter survival. Depletion of SMYD3 inhibited RCC cell proliferation, colony numbers, and xenograft tumor formation, while promoted apoptosis. Mechanistically, SMYD3 cooperates with SP1 to transcriptionally promote EGFR expression, amplifying its downstream signaling activity. TCGA data analyses revealed a significantly increased SMYD3 expression in primary RCC tumors carrying the loss-of-function VHL mutations. We further showed that HIF-2α can directly bind to the SMYD3 promoter and subsequently induced SMYD3 transcription and expression. Taken together, we identify the VHL/HIF-2α/SMYD3 signaling cascade-mediated EGFR hyperactivity through which SMYD3 promotes RCC progression. Our study suggests that SMYD3 is a potential therapeutic target and prognostic factor in RCC.

MP08-11 RENAL VEIN OSTIUM WALL INVASION OF RENAL CELL CARCINOMA WITH AN INFERIOR VENA CAVA TUMOR THROMBUS: COMPREHENSIVE MOLECULAR CHARACTERIZATION AND ITS IMPLICATIONS FOR CLINICAL PRACTICE

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I (MP08)1 Apr 2020MP08-11 RENAL VEIN OSTIUM WALL INVASION OF RENAL CELL CARCINOMA WITH AN INFERIOR VENA CAVA TUMOR THROMBUS: COMPREHENSIVE MOLECULAR CHARACTERIZATION AND ITS IMPLICATIONS FOR CLINICAL PRACTICE Cheng Liu*, Jianjun Yu, Mengyao Tan, Shidong Jia, and Lulin Ma Cheng Liu*Cheng Liu* More articles by this author , Jianjun YuJianjun Yu More articles by this author , Mengyao TanMengyao Tan More articles by this author , Shidong JiaShidong Jia More articles by this author , and Lulin MaLulin Ma More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000828.011AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Renal cell carcinoma (RCC) is a common cancer worldwide with up to 10% of patients accompanying intravascular tumor thrombus (TT). Patients with RCC may develop phenotypically distinct TT, some of which adhere densely to the venous wall (DATT, densely adherent TT) while some others do not adhere to the endothelium (NATT, non-adherent/minimal adherence TT). To explore whether patients with NATT or DATT can benefit more from the surgical resection and characterize molecular difference between the two groups for patient stratification and prognosis. METHODS: Clinical information and overall survival of 77 non-metastatic patients who went caval thrombectomy was retrospectively analyzed. Whole exome sequencing (WES) and whole transcriptome sequencing (WTS) were performed to profile genomic and transcriptomic landscape of matched primary and TT samples. Genomic alterations and transcriptomic profiling data were processed using public and in-house bioinformatics tools and analyzed for enriched mutations and pathways. Differentially mutated and expressed genes between DATT and NATT groups were assessed by Fisher exact test and DESeq2 respectively. TGCA expression dataset was analyzed through unsupervised hierarchical clustering. RESULTS: Patients with DATT showed worse survival after the surgical operation (Hazard Ratio: 5.1, P = 0.03). WES of tumor samples from prospectively enrolled patients revealed that VHL, PBRM1, BAP1, ARID1A and SETD2 are the most frequent mutated genes, consistent with public TCGA RCC data. Notably, SETD2, PTEN and TP53 mutations are significantly enriched in NATT patients relative to DATT. Analogously, transcriptomic profiling revealed P53 signaling pathway, DNA damage repair pathways and genes involved in tumor metastasis are upregulated in NATT. By contrast, genes related to cell-cell adhesion, blood coagulation, hypoxia, and VEGF signaling pathway are enriched in DATT samples. Interestingly, expression data from public primary RCC samples uncovered a subgroup of samples that are NATT-like harbor enriched TP53, PTEN and SETD2 mutations and have poorer progression-free survival and overall survival, suggesting that NATT may intrinsically represent a more aggressive subgroup of patients. CONCLUSIONS: Patients with non-adherent/minimal adherence TT (NATT) benefit more from surgery than that with densely adherent TT. Interestingly, molecular characterization by whole-exome and whole-transcriptomic sequencing delineated that patients with NATT harbor significantly enriched mutations in SETD2, PTEN and TP53 and may represent a more aggressive subtype. Such genes may serve as predictive biomarkers to stratify patients who can benefit most from the intervention of surgery. Source of Funding: The study was funded by Peking University Medicine Fund of Fostering Young Scholars’ Scientific & Technological Innovation BMU2018PY003; the National Natural Science Foundation of China (Nos.: 81711530048, 81572515, 81672522); Peking University Third Hospital Clinical Research Fund BYSY2018062, BYSY2018012. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e110-e110 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Cheng Liu* More articles by this author Jianjun Yu More articles by this author Mengyao Tan More articles by this author Shidong Jia More articles by this author Lulin Ma More articles by this author Expand All Advertisement PDF downloadLoading ...

Expression of RSK4, CD44 and MMP-9 is upregulated and positively correlated in metastatic ccRCC

BackgroundTo investigate the expression and function of RSK4, MMP-9 and CD44 in primary clear cell renal cell carcinoma (primary ccRCC) and metastatic clear cell renal cell carcinoma (metastatic ccRCC), as well as the correlation with clinicopathological features of patients.MethodThe expression levels of RSK4, CD44 and MMP-9 in 52 primary ccRCC samples and 48 metastatic ccRCC samples were detected by immunohistochemistry, and the relationship between RSK4, CD44 and MMP-9 expression and clinicopathological features as well as prognosis of metastatic ccRCC patients was statistically analysed. Ectopic RSK4 expression in ccRCC cell lines was performed to determine its effect on cell cycle regulation, tumour invasiveness, and metastatic capability.ResultsThe positive rates of RSK4, MMP-9 and CD44 expression in metastatic ccRCC tissues were 75, 68.75 and 91.7%, respectively, while the rates in primary ccRCC tissues were 44.2, 34.6 and 69.2%, respectively. Thus, the positive rates in metastatic ccRCC were higher than those in primary ccRCC (PRSK4 = 0. 002; PMMP-9 = 0. 002; PCD44 = 0. 001). However, the expression of RSK4, CD44 and MMP-9 was unrelated to age, gender, or metastatic sites (P > 0.05) but was related to WHO/ISUP nucleolar grade (PRSK4 = 0.019; PCD44 = 0.026; PMMP-9 = 0.049). In metastatic ccRCC, expression among the three proteins showed a positive correlation (P = 0.008). Moreover, expression between RSK4 and CD44 (P = 0.019) and MMP-9 and CD44 (P = 0.05) also showed positive correlations, whereas RSK4 and MMP-9 showed no significant correlation (P = 1.00). Molecular studies showed that overexpression of RSK4 could enhance the invasive and migratory abilities of ccRCC cell lines through the regulation of CD44 and MMP-9 expression and vice versa.ConclusionsThe overexpression of RSK4, MMP-9 and CD44 is associated with the invasion and metastasis of ccRCC, indicating that they could be potential prognostic factors and serve as new potential therapeutic targets for ccRCC.

Prognostic Role of Matrix Metalloproteinases 2, 7, 8, 9 and Their Type 1 Tissue Inhibitor in Blood Serum of Patients with Kidney Cancer.

The study compared the levels of MMP-2,7,8,9, and TIMP-1 in blood serum of healthy people (N=97) and patients with primary renal cell carcinoma (N=93) to assess relevance of these markers to prognosis of overall survival of these patients, which were followed-up over 1 to 45 months (median 26 months). To evaluate the survival with the Kaplan-Meier estimator, the median values of examined markers in the total group of patients were taken as the threshold levels. This estimator showed that the high levels of serum MMP-7 and MMP-8 were indicative for unfavorable prognosis in the total group of patients with renal cell cancer. Of them, the most significant marker was the level of MMP-7: at its low level (<6.3 ng/ml), a 3-year survival was 93%, whereas survival dropped down to 51% at a higher value of this marker (p<0.001). For MMP-8, the threshold level was 51 ng/ml, and the corresponding survivals were 78 and 58% (p<0.01). The level of MMP-7 was also prognostically significant for the patients with stage I kidney cancer: during a 3-year follow-up, all the patients with low MMP-7 were alive, while the 3-year survival of the patients with a high level of MMP-7 was only 72% (p=0.02). There were the declining trends for survival at high TIMP-1 and low MMP-2. In contrast, the level of MMP-9 virtually did not correlate with survival of the patients with renal cell cancer.

Prevalence of pathogenic germline risk variants (PVs) in 1,829 renal cell carcinoma (RCC) patients (pts).

659 Background: Hereditary RCCs account for 3-5% of all RCC cases. The prevalence and significance of germline PVs of RCC have not been fully characterized. Methods: We evaluated the frequency of pathogenic and likely pathogenic variants, referred to as PVs, in 1829 high-risk RCC pts who underwent targeted clinical germline testing (1-134 genes) at a commercial laboratory. PVs, including single nucleotide variants/indels/ copy number variants, were confirmed using orthogonal technology in accordance with Invitae’s standard operating practices. Actionable genes were defined as established cancer-predisposition genes that confer a higher risk for any cancer phenotype and for which enhanced screening and family genetic testing are recommended by the National Comprehensive Cancer Network. We focused our analysis on genes tested in more than 100 pts (n=93). Results: Among 1892 pts, 54.9% were male, and 68.9% were Caucasians, with median age 50 (range:1-87) years at RCC diagnosis. 11.8% (n=215) of pts had at least 2 primary RCCs, and 30.7% (n= 561) had a personal history of another cancer. The cumulative frequency of pts with PVs was 17.7%. PVs in known RCC susceptibility genes such as FH, FLCN, and SDHB were detected in 1.8% (29/1622), 1.22% (120/1634) and 0.64% (11/1727) of pts respectively. PVs in other cancer-associated genes were most frequently reported in CHEK2 (loss-of-function variants, 30/1276, 2.4%), MUTYH (19/1124, 1.7%), and BRCA2 (17/1276, 1.33%). PVs in DNA-damage repair genes (DRG) accounted for 71.8% of PVs and, overall, were detected in 12.7% of pts. Among the DRG, PVs in the homologous recombination pathway (ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, NBN, PALB2, RECQL4, WRN) were the most prevalent (7.8%) whereas the mismatch repair pathway (MLH1, MSH2, MSH6, PMS2) was altered in only 0.7% of pts. Of the examined cohort, 9.7% of pts had ≥1 actionable PV. In non-Caucasians, BRCA2 PVs were the most common (6/273, 2.20%). Conclusions: PVs were identified in 17.7% of RCC subjects, most of which (71.8%) were in DRG, with »10% of pts having actionable variants. Our work is concordant with known RCC susceptibility genes and potentially highlights novel risk genes that should be validated in future studies.

Deferred Cytoreductive Nephrectomy Following Presurgical Vascular Endothelial Growth Factor Receptor–targeted Therapy in Patients with Primary Metastatic Clear Cell Renal Cell Carcinoma: A Pooled Analysis of Prospective Trial Data

BackgroundCancer du Rein Métastatique Nephrectomie et Antiangiogéniques (CARMENA) concluded that sunitinib alone is not inferior to cytoreductive nephrectomy (CN) followed by vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. It remains uncertain whether deferred CN is beneficial in this setting. ObjectiveThe aim of this study was to compare outcome in patients treated with presurgical VEGFR-TKI followed by CN (deferred CN) with that in patients receiving CN followed by VEGFR-TKI (upfront CN). Design, setting, and participantsPooled data from prospective trials in which a strategy of deferred CN in the absence of disease progression was investigated were compared with a retrospective dataset of upfront CN. Outcome measurements and statistical analysisOverall survival (OS) in the Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate-risk group. Results and limitationsPatients were treated between 2006 and 2016. In the MSKCC intermediate-risk group, 144 patients with a strategy of deferred CN after systemic therapy were compared with 131 patients treated with upfront CN. OS in the deferred cohort was 33.0 mo (95% confidence interval [CI] 25.0–51.0) compared with 22.8 mo (95% CI 17.9–30.6) after upfront CN (hazard ratio 0.72 [95% CI 0.52–0.996], p = 0.047). This study is limited by retrospective comparison of data, subgroup analysis, and a lack of intention-to-treat data for the upfront CN cohort. ConclusionsIn MSKCC intermediate-risk patients, a strategy of deferred CN in the absence of progression yields OS, which compares favourably with upfront CN and published trial data from CARMENA. This warrants a formal individual patient data analysis of CARMENA, SURTIME, and single-arm prospective studies to define the role and timing of deferred CN in intermediate-risk patients. Patient summaryIn this study, we report outcomes in patients with metastatic renal cell cancer treated with targeted therapy followed by nephrectomy, which compared favourably with nephrectomy followed by targeted therapy and results from published studies.

Expression of growth factors and their receptors in the primary renal cell carcinoma: new data and review.

IntroductionThe aim of our study was to investigate expression levels and the prognostic value of multiple growth factors and their receptors in the primary tumor cells of renal cell carcinoma (RCC).Material and methodsExpression of vascular endothelial growth factor (VEGF)A, fibroblast growth factor (FGF)2, vascular endothelial growth factor receptor (VEGFR)1, VEGFR2, FGFR1, FGFR2, platelet-derived growth factor receptor (PDGFR)α, and PDGFRβ was investigated in 65 primary RCC specimens by immuhistochemical staining using the appropriate antibodies. Expression levels were evaluated by the semi-quantitative method. A search for correlations of expression levels of investigated growth factors and receptors with RCC features and patients outcomes was performed.ResultsExpression of all growth factors and their receptors was detected both on the surface and in the cytoplasm of the primary tumor cells in RCC patients. The expression of all analyzed factors was interconnected. FGFR2 expression correlated with the largest number of other growth factors and receptors. A strong correlation was revealed between high expression of the studied markers, high Fuhrman grade, and advanced RCC stages. In a univariate analysis overexpression of VEGFR2 (p <0.0001) and FGFR2 (p = 0.014) had negative influence on cancer-specific survival.ConclusionsExpression of growth factors and tyrosine kinase receptors in the primary tumor cells is strongly interconnected and associated with unfavorable features of RCC.

Alteration of CYP4A11 expression in renal cell carcinoma: diagnostic and prognostic implications.

Background: Cytochrome P-450 4A11 (CYP4A11) and peroxisome proliferator-activated receptor-α (PPARα) are expressed at high levels in renal proximal tubules, and upregulation of CYP4A11 protein levels is known to be influenced by PPAR agonists. The goal of this study was to evaluate the clinicopathological role of CYP4A11 expression in renal cell carcinoma (RCC).Methods: We performed immunohistochemical analysis of CYP4A11, CYP4A22 and PPARα and correlated the results with the clinicopathological features of RCC (n=139). Reverse transcription digital droplet polymerase chain reaction (RT-ddPCR) against CYP4A11 and CYP4A22 was also performed.Results: CYP4A11 mRNA expression levels were higher in non-neoplastic kidney tissues than in matched tumor tissues in 12 matched pairs of freshly frozen primary clear-cell RCC (ccRCC) and nontumor tissue (p=0.002). Immunohistochemical staining showed that CYP4A11 expression was significantly lower in ccRCC than in non-ccRCCs, including papillary, chromophobe, and unclassified RCCs (p<0.001). CYP4A11 expression was associated with PPARα expression, males and high nuclear histologic grades (p=0.001, p=0.018 and p<0.001). Univariate and multivariate analyses revealed that CYP4A11 expression was correlated with short overall survival (p=0.007 and p=0.010).Conclusion: These findings suggest that CYP4A11 expression is a potential poor prognostic factor of RCC. The considerable decrease in CYP4A11 expression is a predictive diagnostic factor of ccRCC, and CYP4A11 metabolism in ccRCC might be different from that in non-ccRCCs.

Primary renal squamous cell carcinoma: A case report and literature review

Squamous cell carcinoma is an aggressive but rarely diagnosed cancer of the kidney. Most cases occur in association with renal calculi and thus require a high index of suspicion for their diagnosis. Though aggressive, it usually presents at a late stage and has an average 5-year survival rate of less than 10%. This is a case report of a 61-year-old male who presented with right flank pain and swelling of 4 years duration and fever and weight loss for 4 months. There was no hematuria and urinalysis and serum chemistry were within normal limits. A tumor in the right kidney was identified clinically and by computerized urography (CTU). At nephrectomy, multiple stones, hydronephrosis and pyonephrosis were found in addition to the tumor in the right kidney. Histological examination revealed squamous cell carcinoma of the kidney.

Proton Therapy for Primary Renal Cell Carcinoma: The First Nationwide Retrospective Study in Japan.

This multi-institutional study aimed to investigate the efficacy and feasibility of proton beam therapy (PBT) for renal cell carcinoma (RCC) in Japan. The survival, local control, and toxicities in 22 RCC patients treated between 2001 and 2016 at 6 Japanese PBT institutes were analyzed. The 22 patients comprised 20 men and had a median age of 67 (range=42-88) years. The total irradiation dose was 60-79.6 Gy (relative biological effectiveness). Over a median follow-up of 37 months, the 3-year overall and disease-specific survival rates were 95% and 100%, respectively, and no recurrence occurred. No patient experienced grade 3 or higher adverse events. The serum blood urea nitrogen (p=0.25) and creatinine levels (p=0.95) were not significantly affected, although the mean estimated glomerular filtration rate was reduced by 7.1±11.2 ml/min/1.73 m2 Conclusion: Despite the small number of patients, high-dose PBT can control RCC while maintaining their renal function with high probability, and could be and alternative curative therapy especially for inoperable patients.

P1342 Secondary cardiac tumour -a metastasis from renal cell carcinoma via transvenous extension

Abstract Secondary cardiac tumour is 20-40 times more common than primary cardiac tumour. Most common tumour that metastasize to the heart are lung cancer, breast cancer and hematologic malignancy. Melanoma and pleural mesothelioma has high inclination to metastasize. Other cancer with high rate of cardiac metastasis include gastric, ovarian, renal and pancreatic cancer. The presentation of cardiac metastasis is usually non-specific and sometimes mimic other cardiac condition. We would like to present one such case where we used multimodality approach for proper evaluation. A 57 year old lady presented with intermittent chest discomfort for one month which worsen on day of admission. Otherwise she had good effort tolerance. Electrocardiogram had no acute ischemic changes and Troponin T was not elevated. Bedside echocardiography revealed a large cardiac mass in right atrium around 66mm x 29mm, protruding to right ventricle. Apart from that noted aneurysm of interatrial septum towards LA. MRI cardiac showed an inhomogenous mass extending from the right renal vein and inferior vena cava(IVC) into the right atrium(RA). The tumour mass in the right atrium a highly mobile and flops across the tricuspid valve into the right ventricle during ventricular diastole causing right ventricular outflow tract obstruction. The mass was hyperintense on T2- and isointense on T1-weighted images. There was vascularity within the mass with inhomogenous gadolinium enhancement. There was also 2 masses in right kidney , a larger inhomogenous encapsulated mass at the right lower pole and smaller at lower pole. The findings were suggestive of a primary renal cell carcinoma with tumour mass extension into right renal vein, inferior vena cava and into the right atrium. A staging CT scan thorax , abdomen and pelvis did not show any other possible primary source of cancer and reconfirm the extracardiac finding of the MRI. No evidence of tumour extension into hepatic veins and left renal vein. There was however small nodular opacities in both right and left lung suggesting lung metastasis. A combined operation was done with our cardiothoracic surgeon and urologist from nearby tertiery hospital. Nephrectomy and removal of tumour thrombus from IVC and RA was done with 18 degree Celcius circulatory arrest with cardiopulmonary bypass. Section of renal mass showed a poorly circumscribed lobulated tumour with areas of hemorrhage and necrosis. The tumour was close to capsule but has not breached it. The tumour was mainly clear cell carcinoma variant, nuclear grade III. Section from IVC that extend to RA appeared elongated sausage-like measuring 150mm in length and 30mm in diameter had tumour embolus. Pulmonary artery and perirenal blood vessel also had tumour emboli. The hilar nodes however were free from tumour. Patient recovered well and was discharged home day 9 post operation. Follow-up echocardiogram 3weeks post-op showed no recurrence of the mass and good LV function. Abstract P1342 Figure. Echo, CTscan, MRI and Pathology images

Sex-specific analysis of renal cell carcinoma histology and survival in Japan: A population-based study 2004 to 2016.

Background and aimsIn Western countries, sex differences in renal cell carcinoma (RCC) histology and survival have been previously described: compared with men, clear cell subtype is more common but overall prognosis is better among women. The goal of the present study was to examine sex differences in RCC histology and survival in Japan, using a large‐scale population‐based data set.MethodsWith the use of a population‐based cancer registry in Japan (2004‐2016), patients with primary RCC were followed for 5 years (median follow‐up time 2.1 years). We distinguished histological subtypes of clear cell, papillary, and chromophobe from “others” subtype. Sex‐specific prevalence ratio (PR) for each histological subtype was estimated by Poisson regression with robust variance, adjusted for age and year of diagnosis. Sex‐specific survival rates were estimated by Cox proportional hazard regression, adjusted for age, year of diagnosis, histological subtypes, and other prognostic variables, with multiple imputation.ResultsThe prevalence of clear cell and “others” subtypes was similar between men and women among all the 5265 study subjects during the 12 years of study (clear cell, male 88.6% vs female 87.1%; “others“, male 5.3% vs female 5.3%). However, papillary subtype was less common among women than men (male 4.6% vs female 2.8%; PR = 0.63; 95% CI, 0.45‐0.88), while chromophobe subtype was more common among women (male 1.6% vs female 4.8%; PR = 3.18; 95% CI, 2.26‐4.47). Although “others” subtype (but not papillary/chromophobe subtypes) independently predicted prognosis (HR = 1.74; 95% CI, 1.32‐2.30), no sex differences were observed in RCC survival.ConclusionWe did not observe a statistically significant difference in the prevalence of clear cell subtype between men and women in Japan, which differs from the pattern previously described in Western countries. Sex differences in RCC histology may not affect RCC survival in this population.

Concordance of PD-1 and PD-L1 (B7-H1) in paired primary and metastatic clear cell renal cell carcinoma.

ObjectivesPrevious studies noted discordance of programmed death‐1 (PD‐1) and one of its ligands (PD‐L1) across patient‐matched primary and metastatic clear cell renal cell carcinoma (ccRCC). There are inconsistencies if the primary or metastatic tumor has higher expression, and whether metastatic tumor expression is associated with patient outcome. Thus, we examined PD‐1 and PD‐L1 in patient‐matched tumors using a large number of ccRCC patients with long follow‐up.Materials and MethodsWe analyzed PD‐1 and PD‐L1 using immunohistochemistry in patient‐matched primary and metastatic tumors from 110 ccRCC patients. Concordance was assessed among longitudinal metastatic tumors, as well as across patient‐matched primary and metastatic tumors. Cox proportional hazards regression was used to evaluate the associations of metastatic tumor expression with cancer‐specific survival.ResultsWe observed inter‐metastatic tumor heterogeneity of PD‐1 in 25 (69%) of the 36 patients and of PD‐L1 in seven (19%) patients. Concordance between patient‐matched primary and metastatic tumors was 73% (Kappa = 0.16, 95% CI: −0.003‐0.32). Similarly, concordance of PD‐L1 between metastatic and patient‐matched primary tumors was 78% (Kappa = 0.27, 95% CI: 0.09‐0.46). Both markers demonstrated higher expression in primary vs metastatic tumors. Metastatic tumor expression of PD‐1 was significantly associated with metastatic location (P < .0001) and ccRCC‐specific survival (HR = 2.15, 95% CI: 1.06‐4.36, P = .035).ConclusionsThe expression of PD‐1 and PD‐L1 is discordant across patient‐matched ccRCC tumors, with higher expression in primary tumors. Higher PD‐1 expression was associated with metastatic location and lower cancer‐specific survival. If validated, these results highlight the importance of evaluating these biomarkers in metastatic tissue specifically.

Tumour immune microenvironment in primary and metastatic papillary renal cell carcinoma.

Among renal cell carcinoma (RCC) the tumour immune microenvironment has been best characterised in clear cell RCC. In this study we investigated the expression of several immune markers, including PD-L1, FoxP3 and CD8 in primary and metastatic papillary RCC. Three tissue microarrays were constructed from 78 cases with primary papillary RCC and paired metastatic tumour (24 cases) from 78 patients treated between 1982 and 2014. Immunohistochemistry analysis was performed using commercially available antibodies for PD-L1 (clone E1L3N), FoxP3, CD8 and Ki-67. Markers expression level in tumour and/or associated immune cells was analysed by tissue type (non-tumour versus primary tumour versus metastatic tumour) and correlated to clinicopathological features and outcome. We found PD-L1 expression in up to one-quarter of primary and metastatic papillary RCC. On univariate analysis, CD8/FoxP3 ratio >1 was associated with favourable outcome, whereas papillary RCCs with high numbers of dual CD8/Ki-67-positive lymphocytes showed an increased likelihood for tumour progression and overall and cancer-related mortality. The association of CD8/FoxP3 ratio >1 and high count of CD8/Ki-67 with outcome remained significant on multivariate analysis when adjusting for stage, grade and patient's age.

Immunohistological Diagnosis of Primary and Metastatic Renal Cell Carcinoma Using Panel of Immunohistochemical Markers

Background: Tumour heterogeneity and lack of markers with high specificity makes diagnosis of renal cell carcinoma (RCC) challenging. The study was undertaken to evaluate panel of IHC markers to enable diagnosis and reproducible classification in primary and metastatic renal tumors. Methods: Descriptive Study wherein 100 cases of RCC and 25 trucut biopsies (20 metastatic and 5 primary renal tumors) were evaluated for morphology and immunostained by panel of immunohistochemical (IHC) markers consisting of CA-9, CD10, CK-7, AMACAR and TFE-3 with additional markers as required. Result: Morphologically tumors were grouped as clear cell and nonclear cell (eosinophilic and poorly differentiated). Clear cell RCCs (CCRCC), clear cell papillary RCC (CCPRCC) and multilocular cystic RCC (MCRNLMP) displayed strong statistical association of CA-9 immunostaining (p=50.00, x2-0.000). Inverse correlation was found between the intensity of the staining of CA-9 and tumor grade. (p=32.97, x2=0.000). CA-9 and CK-7 co-expression was evident in all cases of CCPRCC and MCRNLMP. Papillary RCC exhibited positive statistical correlation with CK-7 and AMACAR. E-cadherin and CD117 were required additionally to differentiate between oncocytoma and chromophobe RCC. CD10 and Pax 8 were most helpful in diagnosing metastatic RCCs Conclusion: IHC panel consisting of CA-9, CD10, CK7, AMACR and TFE3 helps triage RCCs with clear cell/eosinophilic cell / papillary/poorly differentiated pattern. In a setting of metastatic RCC, use of CD10 and Pax 8 together facilitate primary diagnosis of RCC when tissue available is limited.

TFEB Mediates Immune Evasion and Resistance to mTOR Inhibition of Renal Cell Carcinoma via Induction of PD-L1.

Despite the FDA approval of mTOR inhibitors (mTORi) for the treatment of renal cell carcinoma (RCC), the benefits are relatively modest and the few responders usually develop resistance. We investigated whether the resistance to mTORi is due to upregulation of PD-L1 and the underlying molecular mechanism. The effects of transcription factor EB (TFEB) on RCC proliferation, apoptosis, and migration were evaluated. Correlation of TFEB with PD-L1 expression, as well as effects of mTOR inhibition on TFEB and PD-L1 expression, was assessed in human primary clear cell RCCs. The regulation of TFEB on PD-L1 was assessed by chromatin immunoprecipitation and luciferase reporter assay. The therapeutic efficacies of mTORi plus PD-L1 blockade were evaluated in a mouse model. The function of tumor-infiltrating CD8+ T cells was analyzed by flow cytometry. TFEB did not affect tumor cell proliferation, apoptosis, and migration. We found a positive correlation between TFEB and PD-L1 expression in RCC tumor tissues, primary tumor cells, and RCC cells. TFEB bound to PD-L1 promoter in RCCs and inhibition of mTOR led to enhanced TFEB nuclear translocation and PD-L1 expression. Simultaneous inhibition of mTOR and blockade of PD-L1 enhanced CD8+ cytolytic function and tumor suppression in a xenografted mouse model of RCC. These data revealed that TFEB mediates resistance to mTOR inhibition via induction of PD-L1 in human primary RCC tumors, RCC cells, and murine xenograft model. Our data provide a strong rationale to target mTOR and PD-L1 jointly as a novel immunotherapeutic approach for RCC treatment.