Clinical Renal Cell Carcinoma Research Articles

Expression of HIF‑α and their association with clinicopathological parameters in clinical renal cell carcinoma.

This study aimed to assess the cellular localization and expression levels of hypoxia-inducible factor (HIF) -α proteins (specifically HIF-1α, HIF-2α, and HIF-3α) that play a role in the hypoxia pathway and to determine their correlation with clinicopathological parameters and patient survival in renal cell carcinoma (RCC). Tissue microarray (TMA) with cores from 150 clear cell RCCs and 31 non-ccRCC samples. HIF-1α, HIF-2α, and HIF-3α antibodies were used for immunohistochemistry (IHC) of TMA to evaluate the cellular localization and expression levels of HIF-α proteins, specifically in relation to the hypoxia pathway. The expression levels of the HIF-α proteins were higher in the nucleus than in the cytoplasm. Furthermore, the nuclear expression levels of all HIF-α proteins were significantly higher in clear cell RCC (ccRCC) than in non-ccRCC. Cytoplasmic HIF-3α expression was also higher in ccRCC than in non-ccRCC, whereas cytoplasmic HIF-1α and HIF-2α expression levels were similar between the different RCC types. In ccRCC, nuclear HIF-1α expression levels correlated with both nuclear HIF-2α and HIF-3α levels, whereas cytoplasmic HIF-3α expression levels were associated with HIF-1α only.In non-ccRCC, there was a positive correlation observed between nuclear HIF-1α and HIF-3α expression, but no correlation was found with HIF-2α. In patients with ccRCC, the nuclear expressions of HIF-1α and HIF-3α was significantly associated with cancer-specific survival (CSS) in univariate analysis. This association was no longer evident in multivariate analysis. Notably, there was no correlation observed between nuclear HIF-2α expression and CSS in these patients. In contrast, cytoplasmic expression levels showed no association with CSS. The expression levels of the three primary HIF-α proteins were found to be higher in the nucleus than in the cytoplasm. Furthermore, the results indicated that HIF-3α and HIF-1α expression levels were significant univariate factors associated with CSS in patients with clear cell RCC. These results highlight the critical role that HIF-3α and HIF-1α play in the hypoxia pathway.

Enhanced Artificial Intelligence Strategies in Renal Oncology: Iterative Optimization and Comparative Analysis of GPT 3.5 Versus 4.0.

The rise of artificial intelligence (AI) in medicine has revealed the potential of ChatGPT as a pivotal tool in medical diagnosis and treatment. This study assesses the efficacy of ChatGPT versions 3.5 and 4.0 in addressing renal cell carcinoma (RCC) clinical inquiries. Notably, fine-tuning and iterative optimization of the model corrected ChatGPT's limitations in this area. In our study, 80 RCC-related clinical questions from urology experts were posed three times to both ChatGPT 3.5 and ChatGPT 4.0, seeking binary (yes/no) responses. We then statistically analyzed the answers. Finally, we fine-tuned the GPT-3.5 Turbo model using these questions, and assessed its training outcomes. We found that the average accuracy rates of answers provided by ChatGPT versions 3.5 and 4.0 were 67.08% and 77.50%, respectively. ChatGPT 4.0 outperformed ChatGPT 3.5, with a higher accuracy rate in responses (p<0.05). By counting the number of correct responses to the 80 questions, we then found that although ChatGPT 4.0 performed better (p<0.05), both versions were subject to instability in answering. Finally, by fine-tuning the GPT-3.5 Turbo model, we found that the correct rate of responses to these questions could be stabilized at 93.75%. Iterative optimization of the model can result in 100% response accuracy. We compared ChatGPT versions 3.5 and 4.0 in addressing clinical RCC questions, identifying their limitations. By applying the GPT-3.5Turbo fine-tuned model iterative training method, we enhanced AI strategies in renal oncology. This approach is set to enhance ChatGPT's database and clinical guidance capabilities, optimizing AI in this field.

PLCL1 suppresses tumour progression by regulating AMPK/mTOR-mediated autophagy in renal cell carcinoma.

Autophagy has been increasingly recognized as a critical regulatory mechanism in the maintenance of cellular homeostasis. A previous study showed that phospholipase C-like protein 1 (PLCL1) is associated with lipid metabolism in renal cell carcinoma (RCC). However, it is unclear whether PLCL1 regulates autophagy, thereby influencing the progression of RCC. Bioinformatics analysis of five microarray datasets revealed that expression of PLCL1 is decreased in tumours and is positively correlated with prognosis in RCC patients. Three independent public datasets, clinical RCC tissues and RCC cell lines, were validated using real-time qPCR, western blotting and immunohistochemistry. Using wound healing and transwell assays, we observed that elevated PLCL1 levels decreased the migratory distance and the invasive number of 786-O and ACHN cells, but PLCL1 knockdown reversed these changes in 769P cell lines compared to those in controls. The results of flow cytometry analysis indicated that PLCL1 promotes apoptosis. Moreover, transcriptional analysis based on stable overexpression of PLCL1 in 786-O cells revealed that PLCL1 is related to autophagy, and western blotting and autophagic experimental results further verified these findings. Mechanistic investigations confirmed that PLCL1 activates the AMPK/mTOR pathway and interacts with decidual protein induced by progesterone (DEPP). Collectively, our data suggest that PLCL1 functions as a suppressor of RCC progression by activating the AMPK/mTOR pathway, interacting with DEPP, initiating autophagy and inducing apoptosis. PLCL1 may be a promising therapeutic target for the diagnosis and treatment of ccRCC patients.

SHMT as a Potential Therapeutic Target for Renal Cell Carcinoma.

Serine hydroxymethyltransferase (SHMT) is a serine-glycine-one-carbon metabolic enzyme in which SHMT1 and SHMT2 encode the cytoplasmic and mitochondrial isoenzymes, respectively. SHMT1 and SHMT2 are key players in cancer metabolic reprogramming, and thus are attractive targets for cancer therapy. However, the role of SHMT in patients with renal cell carcinoma (RCC) has not been fully elucidated. We aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of SHMT1 and SHMT2 in patients with kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), and kidney renal papillary cell carcinoma (KIRP); elucidate the association between SHMT expression and RCC; and identify potential new targets for clinical RCC treatment. Several online databases were used for the analysis, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER. SHMT1 and SHMT2 transcript levels were significantly down- and upregulated, respectively, in patients with KICH, KIRC, and KIRP, based on sample type, individual cancer stage, sex, and patient age. Compared to men, women with KIRC and KIRP showed significantly up- and downregulated SHMT1 transcript levels, respectively. However, SHMT2 transcript levels were significantly upregulated in the patients mentioned above. KIRC and KIRP patients with high SHMT1 expression had longer survival periods than those with low SHMT1 expression. In patients with KIRC, the findings were similar to those mentioned above. However, in KICH patients, the findings were the opposite regarding SHMT2 expression. SHMT1 versus SHMT2 were altered by 9% versus 3% (n = 66 KICH patients), 4% versus 4% (n = 446 KIRC patients), and 6% versus 7% (n = 280 KIRP patients). SHMT1 versus SHMT2 promoter methylation levels were significantly up- and downregulated in patients with KIRP versus KIRC and KIRP, respectively. SHMT1, SHMT2, and their neighboring genes (NG) formed a complex network of interactions. The molecular functions of SHMT1 and its NG in patients with KICH, KIRC, and KIRP, included clathrin adaptor, metalloendopeptidase, and GTPase regulator activities; lipid binding, active transmembrane transporter activity, and lipid transporter activity; and type I interferon receptor binding, integrin binding, and protein heterodimerization, respectively. Their respective Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were involved in lysosome activity, human immunodeficiency virus 1 infection, and endocytosis; coronavirus disease 2019 and neurodegeneration pathways (multiple diseases); and RIG-I-like receptor signaling pathway, cell cycle, and actin cytoskeleton regulation. The molecular functions of SHMT2 and its NG in patients with KICH, KIRC, and KIRP included cell adhesion molecule binding and phospholipid binding; protein domain-specific binding, enzyme inhibitor activity, and endopeptidase activity; and hormone activity, integrin binding, and protein kinase regulator activity, respectively. For patients with KIRC versus KIRP, the KEGG pathways were involved in cAMP and calcium signaling pathways versus microRNAs (MiRNAs) in cancer cells and neuroactive ligand-receptor interactions, respectively. We identified the key transcription factors of SHMT1 and its NG. SHMT1 and SHMT2 expression levels were different in patients with RCC. SHMT1 and SHMT2 may be potential therapeutic and prognostic biomarkers in these patients. Transcription factor (MYC, STAT1, PPARG, AR, SREBF2, and SP3) and miRNA (miR-17-5P, miR-422, miR-492, miR-137, miR-30A-3P, and miR-493) regulations may be important strategies for RCC treatment.

Pre-operative Plasma Fibrinogen Level as a Potential Predictor of Pathological T3 Upstaging in Clinically Localized Renal Cell Carcinoma.

We investigated pre-operative factors for predicting pathological T3 (pT3) upstaging in clinical T1 renal cell carcinoma (RCC). We evaluated 181 patients with renal tumors suspected to be clinical T1 RCC. All patients had undergone a partial or radical nephrectomy. Pre-operative parameters, including patient characteristics, RENAL nephrometry score and blood tests were analyzed to determine factors predicting pT3 upstaging. Eight (4.4%) tumors were diagnosed as pT3. Large tumor diameter, less than 4 mm distance between the tumor and the renal collecting system and a high level of preoperative plasma fibrinogen were associated with pT3 stage. Multivariate analysis showed that a preoperative plasma fibrinogen level >330 mg/dl was a significant independent factor predicting upstage (p=0.041). Furthermore, among patients diagnosed with RCC (n=162), a preoperative plasma fibrinogen level >330 mg/dl was related to poor overall survival (p<0.001) and poor recurrence-free survival (p=0.002). A high preoperative plasma fibrinogen level may be a predictor of pT3 upstaging and may suggest the need for radical nephrectomy rather than partial nephrectomy because of the associated poor oncological outcomes.

Computer tomography-based shape of tumor contour and texture of tumor heterogeneity are independent prognostic indicators for clinical T1b-T2 renal cell carcinoma.

To evaluate association between computer tomography (CT)-based features of renal cell carcinoma (RCC) and survival outcomes. Data of 958 patients with clinical T1b-T2 RCC who underwent partial/radical nephrectomy from June 2003 to March 2022 were retrospectively evaluated. CT images of patients were reviewed by two radiologists for texture analysis of tumor heterogeneity and shape analysis of tumor contour. Patients were divided into three groups according to patterns of CT-based features: (1) favorable feature group (n = 117); (2) intermediate feature group (n = 606); and (3) unfavorable feature group (n = 235). Kaplan-Meier survival analysis and multivariate Cox regression analysis were performed to evaluate overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS). RCCs with unfavorable CT-based feature showed larger size on CT, higher nuclear grade, higher rate of histologic necrosis, and higher rate of capsular invasion than those in the other two groups (all p < 0.001). Unfavorable feature was associated with poorer OS (p = 0.001), CSS (p < 0.001), and RFS (p < 0.001) on Kaplan-Meier analysis. In multivariate analysis, intermediate and unfavorable features were independent predictors for recurrence (hazard ratio [HR] 2.51, 95% confidence interval [CI] 1.09-5.79, p = 0.031 and HR 3.71, 95% CI 1.58-8.73, p = 0.003, respectively), but not for overall death or RCC-specific death. A combination of irregular tumor contour feature with heterogeneous tumor texture feature on CT is associated with poor RFS in clinical T1b-T2 RCC preoperatively.

Targeting Alpha-Ketoglutarate Disruption Overcomes Immunoevasion and Improves PD-1 Blockade Immunotherapy in Renal Cell Carcinoma.

The Warburg effect-related metabolic dysfunction of the tricarboxylic acid (TCA) cycle has emerged as a hallmark of various solid tumors, particularly renal cell carcinoma (RCC). RCC is characterized by high immune infiltration and thus recommended for immunotherapeutic interventions at an advanced stage in clinical guidelines. Nevertheless, limited benefits of immunotherapy have prompted investigations into underlying mechanisms, leading to the proposal of metabolic dysregulation-induced immunoevasion as a crucial contributor. In this study, a significant decrease is found in the abundance of alpha-ketoglutarate (αKG), a crucial intermediate metabolite in the TCA cycle, which is correlated with higher grades and a worse prognosis in clinical RCC samples. Elevated levels of αKG promote major histocompatibility complex-I (MHC-I) antigen processing and presentation, as well as the expression of β2-microglobulin (B2M). While αKG modulates broad-spectrum demethylation activities of histone, the transcriptional upregulation of B2M is dependent on the demethylation of H3K4me1 in its promoter region. Furthermore, the combination of αKG supplementation and PD-1 blockade leads to improved therapeutic efficacy and prolongs survival in murine models when compared to monotherapy. Overall, the findings elucidate the mechanisms of immune evasion in anti-tumor immunotherapies and suggest a potential combinatorial treatment strategy in RCC.

PD07-09 MANAGEMENT AND OUTCOMES OF MEDICALLY IMMUNOSUPPRESSED PATIENTS WITH CT1 RENAL CELL CARCINOMA

You have accessJournal of UrologyCME1 Apr 2023PD07-09 MANAGEMENT AND OUTCOMES OF MEDICALLY IMMUNOSUPPRESSED PATIENTS WITH CT1 RENAL CELL CARCINOMA Ali Ghasemzadeh, Eric Wendt, Brendan Dolan, Juliana Craig, Kyle Richards, Tudor Borza, Glenn Allen, David Jarrard, E. Jason Abel, and Daniel Shapiro Ali GhasemzadehAli Ghasemzadeh More articles by this author , Eric WendtEric Wendt More articles by this author , Brendan DolanBrendan Dolan More articles by this author , Juliana CraigJuliana Craig More articles by this author , Kyle RichardsKyle Richards More articles by this author , Tudor BorzaTudor Borza More articles by this author , Glenn AllenGlenn Allen More articles by this author , David JarrardDavid Jarrard More articles by this author , E. Jason AbelE. Jason Abel More articles by this author , and Daniel ShapiroDaniel Shapiro More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003231.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although there is a paucity of data, non-metastatic small renal cell carcinoma (RCC) patients who are medically immunosuppressed because of a prior organ transplant or treatment of an underlying disease have a theoretically higher risk of disease progression. This study describes the treatment and outcomes of medically immunosuppressed patients with clinical T1 RCC (cT1). METHODS: An institutional database of patients treated or biopsied for RCC was queried for patients with pathologic diagnosis of cT1 RCC and were on chronic medical immunosuppression, defined as use of a WHO designated immunosuppressant or prednisone ≥5mg for at least 3 months prior to treatment of RCC and continued use during follow up. Outcomes for patients undergoing 1) surgery 2) ablation or 3) active surveillance (AS) are described. Wilcoxon Rank Sum, Fisher’s exact test and Kaplan Meier analysis was performed. RESULTS: Between 2010-2022, 74 medically immunosuppressed patients with RCC were identified who were treated with surgery (n=29), ablation (n=33), or AS (n=12). Median age was 60 years (IQR 51-68), median Charlson comorbidity index was 3 [IQR 2-5] and median follow-up was 48 months (IQR 29-80). Most patients were immunosuppressed due to prior organ transplant (57/74, 77%). Seven (58%) AS patients underwent deferred treatment (6 ablations, 1 nephrectomy) due to progressive tumor growth. Surgical patients were significantly younger than ablation or AS patients and had fewer comorbidities. The surgery and ablation 30-day readmission rate (17% vs 9%, p=0.7) and 90-day complication rate (24% vs 21%, p=0.9) was similar, respectively. No 90-day deaths occurred. One (3%) surgical and 2 (6%) ablation patients recurred locally. One (3%) surgical, 1 (3%) ablation, and no AS patients progressed to metastatic disease. No significant differences were noted for the local recurrence free, metastasis free, and overall survival for the 3 cohorts (P>0.05 for all) (Figure 1). CONCLUSIONS: For medically immunosuppressed patients with cT1 RCC, treatment outcomes are similar to historical series of non-immunosuppressed patients. These data suggest that small RCC tumors are not more aggressive in patients with medical immunosuppression but require careful selection to avoid morbidity and maintain oncologic control. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e165 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ali Ghasemzadeh More articles by this author Eric Wendt More articles by this author Brendan Dolan More articles by this author Juliana Craig More articles by this author Kyle Richards More articles by this author Tudor Borza More articles by this author Glenn Allen More articles by this author David Jarrard More articles by this author E. Jason Abel More articles by this author Daniel Shapiro More articles by this author Expand All Advertisement PDF downloadLoading ...

Exosomal microRNA-1 and MYO15A as a target for therapy and diagnosis in renal cell carcinoma

Exosomes are 40–100 nm nano-sized extracellular vesicles and are receiving increasing attention as novel structures that participate in intracellular communication. We previously found that miRNA-1 (miR-1) functions as a tumor suppressor in renal cell carcinoma (RCC). In this study, we investigated the function of exosomal miR-1 and the possibility that the exosome constitutes a tumor maker in RCC. First, we established the method to collect exosomes from cell lysates and human serum by a spin column-based method. Next, we assessed exosomes using Nanosight nanoparticle tracking analysis and Western blot analysis with exosome marker CD63. We confirmed that exosomes labeled with PKH26 fused with recipient cells. Moreover, miR-1 expression was elevated in RCC cells treated with exosomes derived from miR-1-transfected cells. Functional analyses showed that exosomal miR-1 significantly inhibited cell proliferation, migration and invasion compared to control treatment. Our analyses with TCGA database of RCCs showed that miR-1 expression was significantly downregulated in clinical RCC samples compared to that in normal kidney samples, and patients with low miR-1 expression had poorer overall survival in comparison to patients with high expression. Furthermore, RNA sequence analyses showed that expression levels of several genes were altered by exposure to exosomal miR-1. The analyses with TCGA database indicated that high expression of MYO15A was associated with a poorer outcome in RCC. In addition, RT-qPCR analysis of exosomes from clinical patients’ sera showed that MYO15A was significantly upregulated in RCC patients compared to that in healthy controls. This study showed that treatment with exosomal miR-1 might be an effective approach to treating RCCs. In addition, exosomal MYO15A could be a diagnostic tumor marker in RCCs.

Circ_000829 Plays an Anticancer Role in Renal Cell Carcinoma by Suppressing SRSF1-Mediated Alternative Splicing of SLC39A14.

Background Covalently closed circular RNAs (circRNAs) play critical oncogenic or anticancer roles in various cancers including renal cell carcinoma (RCC), pointing to their regulation as a promising strategy against development of RCC. We, thus, studied the tumor-suppressive role of circ_000829 in RCC through in vitro and in vivo experiments. Methods The expression of circ_000829 was validated in clinical RCC tissues and RCC cell lines. Based on ectopic expression and knockdown experiments, we examined the interactions among circ_000829, serine and arginine rich splicing factor 1 (SRSF1), and solute carrier family 39 member 14 (SLC39A14, zinc transporter). Then, the effects of circ_000829, SRSF1, and SLC39A14 on cell cycle distribution and proliferation in vitro and on tumor growth in vivo were evaluated in RCC cells. Results Circ_000829 was poorly expressed in RCC tissues and cells, while SRSF1 was highly expressed. Restoration of circ_000829 reduced the levels of SRSF1 and SLC39A14B, thereby repressing the RCC cell proliferation in vitro and tumor growth in vivo. Meanwhile, overexpression of SRSF1 and SLC39A14B promoted the proliferation and cell cycle entry of RCC cells. Mechanistically, circ_000829 directly bound to SRSF1, and SRSF1 enhanced the expression of SLC39A14B by mediating the alternative splicing of SLC39A14. SLC39A14B upregulation negated the effect of SLC39A14 knockdown on RCC cell proliferation. Conclusion Hence, this study suggests the antiproliferative role of circ_000829 in RCC growth and further elucidates the underlying mechanism involving the inhibited SRSF1-mediated alternative splicing of SLC39A14 mRNA.

Plasma and Urine Free Glycosaminoglycans as Monitoring Biomarkers in Nonmetastatic Renal Cell Carcinoma—A Prospective Cohort Study

BackgroundNo liquid biomarkers are approved in renal cell carcinoma (RCC), making early detection of recurrence in surgically treated nonmetastatic (M0) patients dependent on radiological imaging. Urine- and plasma free glycosaminoglycan profiles—or free GAGomes—are promising biomarkers reflective of RCC metabolism. ObjectiveTo explore whether free GAGomes could detect M0 RCC recurrence noninvasively. Design, setting, and participantsBetween June 2016 and February 2021, we enrolled a prospective consecutive series of patients elected for (1) partial or radical nephrectomy for clinical M0 RCC (cohort 1) or (2) first-line therapy following RCC metachronous metastatic recurrence (cohort 2) at Sahlgrenska University Hospital, Gothenburg, Sweden. The study population included M0 RCC patients with recurrent disease (RD) versus no evidence of disease (NED) in at least one follow-up visit. Plasma and urine free GAGomes—consisting of 40 chondroitin sulfate (CS), heparan sulfate, and hyaluronic acid (HA) features—were measured in a blinded central laboratory preoperatively and at each postoperative follow-up visit until recurrence or end of follow-up in cohort 1, or before treatment start in cohort 2. Outcome measurements and statistical analysisWe used Bayesian logistic regression to correlate GAGome features with RD versus NED and with various histopathological variables. We developed three recurrence scores (plasma, urine, and combined) proportional to the predicted probability of RD. We internally validated the area under the curve (AUC) using bootstrap resampling. We performed a decision curve analysis to select a cutoff and report the corresponding net benefit, sensitivity, and specificity of each score. We used univariable analyses to correlate each preoperative score with recurrence-free survival (RFS). Results and limitationsOf 127 enrolled patients in total, 62 M0 RCC patients were in the study population (median age: 63 year, 35% female, and 82% clear cell). The median follow-up time was 3 months, totaling 72 postoperative visits —17 RD and 55 NED cases. RD was compatible with alterations in 14 (52%) of the detectable GAGome features, mostly free CS. Eleven (79%) of these correlated with at least one histopathological variable. We developed a plasma, a urine, and a combined free CS RCC recurrence score to diagnose RD versus NED with AUCs 0.91, 0.93, and 0.94, respectively. At a cutoff equivalent to ≥30% predicted probability of RD, the sensitivity and specificity were, respectively, 69% and 84% in plasma, 81% and 80% in urine, and 80% and 82% when combined, and the net benefit was equivalent to finding an extra ten, 13, and 12 cases of RD per hundred patients without any unnecessary imaging for plasma, urine, and combined, respectively. The combined score was prognostic of RFS in univariable analysis (hazard ratio = 1.90, p = 0.02). Limitations include a lack of external validation. ConclusionsFree CS scores detected postsurgical recurrence noninvasively in M0 RCC with substantial net benefit. External validity is required before wider clinical implementation. Patient summaryIn this study, we examined a new noninvasive blood and urine test to detect whether renal cell carcinoma recurred after surgery.

Predictive value of renal tumor contour irregularity score in pathological T3a upstaging of clinical T1 renal cell carcinoma: A multi-institutional study.

To explore the predictive value of renal tumor contour irregular degree (CID) in pathological T3a upstaging of clinical T1 renal cell carcinoma (RCC). We performed a retrospective multi-institutional review of 1,487 patients with clinical T1N0M0 RCC between January 2009 and June 2019. Kaplan-Meier survival curve and Cox regressions were used to analyze the prognostic factors of disease-free survival (DFS). Logistic regressions were performed to determine predictors of pathological T3a upstaging in clinical T1 RCC. Among 1,487 patients with cT1 RCC, 96 (6.5%) were pathological T3a upstaging. Multivariable logistic regression analysis showed that age (odds ratio [OR] = 1.022, 95% confidence interval [CI] = 1.001-1.042, P = 0.036), tumor maximum diameter(OR = 1.242, 95% CI = 1.042--1.480, P = 0.015) and CID (OR = 1.067, 95% CI = 1.051-1.083, P < 0.001) were independent predictors of pathological T3a upstaging. The area under the curve (AUC) of the prediction model that included the CID was 0.846, while the AUC of the prediction model that did not include CID was only 0.741, the difference was statistically significant (P < 0.001). Kaplan-Meier survival curve showed that patients with pathological T3a upstaging had significantly worse DFS than patients without pathological T3a upstaging (P < 0.001). Multivariable Cox analysis showed that pathological T3a upstaging (HR = 1.836, 95% CI = 1.013-3.329, P = 0.002) is an independent prognostic factor for DFS in patients with cT1N0M0 RCC. The predictive model of CID combined with tumor maximum diameter and age significantly improved the ability to predict pathological T3a upstaging in clinical T1 RCC, compared with the prediction model of tumor maximum diameter combined with age. The predictive model of CID combined with tumor maximum diameter and age may be applicable to patients considering partial vs. radical nephrectomy.

MP24-11 IS PATHOLOGICAL UPSTAGING TO T3 RENAL CELL CARCINOMA ASSOCIATED WITH A SIMILAR PROGNOSIS TO NON-UPSTAGED PATHOLOGIC T3 DISEASE? A MULTICENTER ANALYSIS

You have accessJournal of UrologyCME1 May 2022MP24-11 IS PATHOLOGICAL UPSTAGING TO T3 RENAL CELL CARCINOMA ASSOCIATED WITH A SIMILAR PROGNOSIS TO NON-UPSTAGED PATHOLOGIC T3 DISEASE? A MULTICENTER ANALYSIS Ryan Nasseri, Kevin Hakimi, Ava Saidian, Riccardo Autorino, Brian Lane, Yasuha Fujii, Michele Marchioni, Hajime Tanaka, Dattatraya Patil, Francesco Porpiglia, Sabrina Noyes, Chandru Sundaram, James Porter, Andrea Minervini, Umberto Capitianio, Francesco Montorsi, Viraj Master, and Ithaar Derweesh Ryan NasseriRyan Nasseri More articles by this author , Kevin HakimiKevin Hakimi More articles by this author , Ava SaidianAva Saidian More articles by this author , Riccardo AutorinoRiccardo Autorino More articles by this author , Brian LaneBrian Lane More articles by this author , Yasuha FujiiYasuha Fujii More articles by this author , Michele MarchioniMichele Marchioni More articles by this author , Hajime TanakaHajime Tanaka More articles by this author , Dattatraya PatilDattatraya Patil More articles by this author , Francesco PorpigliaFrancesco Porpiglia More articles by this author , Sabrina NoyesSabrina Noyes More articles by this author , Chandru SundaramChandru Sundaram More articles by this author , James PorterJames Porter More articles by this author , Andrea MinerviniAndrea Minervini More articles by this author , Umberto CapitianioUmberto Capitianio More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Viraj MasterViraj Master More articles by this author , and Ithaar DerweeshIthaar Derweesh More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002563.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Pathological upstaging to T3a disease may occur following radical (RN) or partial nephrectomy (PN) for patients with T1/T2 renal cell carcinoma (RCC). Follow up and perceived prognosis for these patients is similar to those who initially presented with clinical T3 RCC. We sought to compare survival outcomes in patients who underwent surgical therapy for upstaged versus non-upstaged pT3 RCC. METHODS: We conducted a retrospective analysis of a multi-institutional dataset of patients who underwent radical (RN) or partial nephrectomy (PN) with final pathologic stage of pT3. Patients were classified as being upstaged (US) from cT1 or cT2 or non-upstaged (NUS) with cT3 disease. Primary outcome was cancer specific survival (CSS)/cancer specific mortality (CSM), with secondary outcomes being Overall Survival (OS)/all-cause mortality (ACM) and Progression/progression-free survival (PFS). Multivariable Cox regression analysis (MVA) was conducted for predictors of mortality outcomes and Kaplan Meier Analyses (KMA) were conducted for survival outcomes comparing US and NUS groups. RESULTS: 1232 patients were analyzed (853 US/379 NUS; median follow up 46.2 months). MVA for CSM found that clear cell RCC (HR 2.1, p <0.001), positive surgical margin (HR 1.7, p=0.047), and NUS (HR 1.5, p=0.003) were independently associated with worsened CSM. MVA for ACM revealed age (HR 1.01, p=0.002), RN (HR 2.5, p <0.001), preoperative GFR <60 (HR 1.4, p=0.007), clear-cell RCC (HR 1.4, p=0.007), positive surgical margin (HR 2.2, p <0.001), and NUS (1.27, p=0.023) were independently associated with worsened ACM. MVA for Progression revealed Age (HR 1.01, p=0.022), positive margin (HR 1.9, p=0.016), and NUS (HR 1.67, p <0.001) to be predictive. Comparing NUS and US groups, KMA revealed worsened 5 year CSS (56% vs. 75%, p <0.001; Figure), 5 year OS (42% vs. 58%, p <0.001) and 5 year PFS (33% vs. 58%, p <0.001). CONCLUSIONS: Pathologic upstaging of clinical T1/T2 to T3 RCC was associated with improved survival outcomes when compared to non-upstaged pathologic T3 RCC. Such differences need to be taken into account when designing follow up protocols and for refinement of risk stratification in the T3 RCC stage group. Further investigation is requisite. Source of Funding: Stephen Weissman Kidney Cancer Research Fund © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e396 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ryan Nasseri More articles by this author Kevin Hakimi More articles by this author Ava Saidian More articles by this author Riccardo Autorino More articles by this author Brian Lane More articles by this author Yasuha Fujii More articles by this author Michele Marchioni More articles by this author Hajime Tanaka More articles by this author Dattatraya Patil More articles by this author Francesco Porpiglia More articles by this author Sabrina Noyes More articles by this author Chandru Sundaram More articles by this author James Porter More articles by this author Andrea Minervini More articles by this author Umberto Capitianio More articles by this author Francesco Montorsi More articles by this author Viraj Master More articles by this author Ithaar Derweesh More articles by this author Expand All Advertisement PDF DownloadLoading ...

MP47-08 SURGICAL DELAY AFTER BIOPSY AND RISK OF UPSTAGING FOR CLINICAL T1A RENAL CELL CARCINOMA

You have accessJournal of UrologyCME1 May 2022MP47-08 SURGICAL DELAY AFTER BIOPSY AND RISK OF UPSTAGING FOR CLINICAL T1A RENAL CELL CARCINOMA Leilei Xia, Ruchika Talwar, Raju Chelluri, Daniel Lee, and Thomas Guzzo Leilei XiaLeilei Xia More articles by this author , Ruchika TalwarRuchika Talwar More articles by this author , Raju ChelluriRaju Chelluri More articles by this author , Daniel LeeDaniel Lee More articles by this author , and Thomas GuzzoThomas Guzzo More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002618.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Renal mass biopsy (RMB) has been increasingly used as the initial management of small renal masses. However, little is known about whether surgical delay after the positive biopsy results increases the risk of upstaging for small renal cell carcinomas (RCCs). METHODS: Patients with clinical T1aN0M0 RCCs (≤4cm) diagnosed between 2010 and 2016 who underwent RMB and then partial nephrectomy (PN) or radical nephrectomy (RN) were identified from the National Cancer Database (NCDB). Surgical delay time (SDT) was defined as days between RMB and definitive surgical resection (PN or RN). SDT was categorized into five groups: 1-30 days, 31-60 days, 61-90 days, 91-120 days, and 121-180 days. Upstaging to pT3a was used as the primary outcome of interest. Positive surgical margin (PSM) was used as a secondary outcome and analyses were restricted to PN cohort only. RESULTS: A total of 4,340 patients were included and 237 (5.5%) patients had pT3a upstaging. Of the 2,874 patients who had PN, PSM rate was 8.2%. pT3a upstaging and PSM rates stratified by SDT is shown in the Figure. Multivariable logistic regression showed that compared with SDT of 1-30 days, SDT of 31-60 days (odds ratio [OR]=1.04, P= 0.833), 61-90 days (OR=1.17, P= 0.481), and 91-120 days (OR=1.14, P= 0.631) were not associated with increased odds of pT3a upstaging. Patients with SDT of 121-180 days had a higher risk of pT3a upstaging (OR= 1.93, P=0.016). When STD was ≤ 120 days, multivariable logistic regression with SDT considered as a continuous variable showed increased SDT was also not associated with higher odds of pT3a upstaging (OR=1.002, P=0.461). In the PN cohort, multivariable logistic regressions showed no significant associations between SDT and PSM with SDT either considered as a categorical or continuous variable. CONCLUSIONS: In this NCDB study, increased SDT from RMB to definitive surgical resection of cT1aN0M0 RCCs was not associated with worse oncologic outcomes within 120 days after the RMB but patients with SDT > 120 days might have increased risk of upstaging. These findings have significant implications for patient counseling regarding active surveillance, RMB, and definitive surgical resection for small renal masses. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e812 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Leilei Xia More articles by this author Ruchika Talwar More articles by this author Raju Chelluri More articles by this author Daniel Lee More articles by this author Thomas Guzzo More articles by this author Expand All Advertisement PDF DownloadLoading ...

LncRNA SNHG1 promotes renal cell carcinoma progression through regulation of HMGA2 via sponging miR-103a.

BackgroundLong noncoding RNAs (LncRNAs) plays a vital role in tumorigenesis and development. The molecular mechanism of SNHG1 in renal cell carcinoma (RCC) has not been illustrated. The aim of this research was to explore the expression and function of LncRNA SNHG1 in RCC.Material and MethodsThe expression of SNHG1 in clinical tissues and RCC cell lines was detected. Luciferase reporter assay was performed to verify the correlation between SNHG1, miR‐103a, and HMGA2. CCK‐8 assay was performed to examine cell viability. Cell apoptosis was analyzed using flow cytometry. Cell invasion capacity was determined by Transwell assays. The protein level of HMGA2 was analyzed by Western blotting.ResultsThe expression of SNHG1 markedly increased in RCC tissues and cell lines. Subsequent studies identified SNHG1 as a miRNA sponge for miR‐103a. In addition, SNHG1 knockdown and miR‐103a overexpression significantly inhibited progression of RCC. miR‐103a also regulated HMGA2 levels.ConclusionOur findings showed that SNHG1 was upregulated in RCC cells and tissues. SNHG1 promoted the malignant characteristics of RCC cells. Its regulatory effect may be regulation of HMGA2 by sponging miR‐103a. Therefore, Our study facilitates the understanding of SNHG1 function in RCC.

Clinical T1a Renal Cell Carcinoma, Not Always a Harmless Disease—A National Register Study

BackgroundT1a renal cell carcinoma (RCC) is typically considered a curable disease, irrespective of the choice of local treatment modality. ObjectiveTo identify factors associated with the risk of local and distant recurrence, and overall survival (OS) in patients with primary nonmetastatic clinical T1a RCC. Design, setting, and participantsA population-based nationwide register study of all 1935 patients with cT1a RCC, diagnosed during 2005–2012, identified through The National Swedish Kidney Cancer Register, was conducted. Outcome measurements and statistical analysisOutcome variables were recurrence (local or distant) and OS. Possible explanatory variables included tumor size, RCC type, T stage, surgical technique, age, and gender. Associations with disease recurrence and OS were evaluated by multivariable regression and Cox multivariate analyses, respectively. Results and limitationsAmong 1935 patients, 938 were treated with radical nephrectomy, 738 with partial nephrectomy, and 169 with ablative treatments, while 90 patients had no surgery. Seventy-eight (4%) patients were upstaged to pT3. Local or metastatic recurrences occurred in 145 (7.5%) patients, significantly more often after ablation (17.8%). The risk of recurrence was associated with tumor size, upstaging, and ablation. Larger tumor size, disease recurrence, and older age adversely affected OS, whereas partial nephrectomy and chromophobe RCC (chRCC) were associated with improved survival. Limitations include register design and a lack of comorbidity or performance status data. ConclusionsUpstaging and recurrence occurred, respectively, in 4.0% and 7.5% of patients with nonmetastatic RCCs ≤4 cm. Tumor size upstaging and ablation were associated with the risk for recurrence, while tumor size and recurrence were associated with decreased OS. Patients with chRCC and partial nephrectomy had prolonged OS in a real-world setting. Patient summaryWe studied factors that may influence the risk of disease recurrence and overall survival, in a large nationwide patient cohort having nonmetastatic renal cell carcinoma ≤4 cm. Tumor size, tumor type, and treatment were associated with the risk of recurrence and overall death. Partial nephrectomy prolonged overall survival.

Comparison of prognosis between patients undergoing radical nephrectomy versus partial nephrectomy for renal cell carcinoma ≤7cm T3aN0/xM0: Survival benefit is biased toward partial nephrectomy.

BackgroundThere is limited and controversial evidence on the prognosis of partial nephrectomy (PN) versus radical nephrectomy (RN) in patients with T3aN0/xM0 renal cell carcinoma (RCC) upstaged from clinical T1 RCC. In this study, we aimed to assess the prognosis difference following PN versus RN in patients with ≤7 cm T3aN0/xM0 RCC.MethodsFrom the Surveillance, Epidemiology, and End Results database, a total of 3196 patients receiving treatment of PN/RN for ≤7 cm T3aN0/xM0 RCC with only extrarenal fat extension in 2010–2017 were identified. An inverse probability of treatment weighting (IPTW)‐adjusted cause‐specific Cox model with hazard ratio (HR) and 95% confidence interval (CI) was used for overall survival (OS) and cancer‐specific survival (CSS) analyses. Sensitivity analysis was based on the propensity score matching of PN and RN groups and from the dataset of 2010–2013.ResultsA total of 872 patients underwent PN, compared with 2324 undergoing RN. After IPTW adjustment, there was no significant difference in preoperative baseline characteristics between the PN and RN cohorts. Patients who underwent RN had worse OS (HRIPTW‐adjusted, 1.46; 95% CI, 1.16–1.84; p = 0.001) and comparable CSS (HRIPTW‐adjusted, 1.03; 95% CI, 0.64–1.66; p = 0.890) than those receiving PN in all cohorts and subgroups with T3a RCC of ≤4 cm and perinephric fat extension. Further, in patients with 4–7 cm T3a RCC with perinephric‐fat invasion and all sizes of T3a RCC with sinus/perisinus fat extension, PN led to comparable OS and CSS. Sensitivity analyses validated these results.ConclusionPN provides comparable CSS and OS or even better OS than RN for patients with RCC ≤7 cm T3aN0/xM0. Although our study has some limitations, our results indicated that PN might oncologically safe for clinical T1 RCC, even confirmed a pathologically T3a upstaging post‐PN.

Clinicopathological and Preclinical Patient-Derived Model Studies Define High Expression of NRN1 as a Diagnostic and Therapeutic Target for Clear Cell Renal Cell Carcinoma

BackgroundAcquired therapeutic resistance and metastasis/recurrence remain significant challenge in advance renal cell carcinoma (RCC), thus the establishment of patient-derived cancer models may provide a clue to assess the problem. We recently characterized that neuritogenesis-related protein neuritin 1 (NRN1) functions as an oncogene in testicular germ cell tumor. This study aims to elucidate the role of NRN1 in RCC.MethodsNRN1 expression in clinical RCC specimens was analyzed based on immunohistochemistry. NRN1-associated genes in RCC were screened by the RNA-sequencing dataset from The Cancer Genome Atlas (TCGA). RCC patient-derived cancer cell (RCC-PDC) spheroid cultures were established and their viabilities were evaluated under the condition of gene silencing/overexpression. The therapeutic effect of NRN1-specific siRNA was evaluated in RCC-PDC xenograft models.ResultsNRN1 immunoreactivity was positively associated with shorter overall survival in RCC patients. In TCGA RCC RNA-sequencing dataset, C-X-C chemokine receptor type 4 (CXCR4), a prognostic and stemness-related factor in RCC, is a gene whose expression is substantially correlated with NRN1 expression. Gain- and loss-of-function studies in RCC-PDC spheroid cultures revealed that NRN1 significantly promotes cell viability along with the upregulation of CXCR4. The NRN1-specific siRNA injection significantly suppressed the proliferation of RCC-PDC-derived xenograft tumors, in which CXCR4 expression is significantly repressed.ConclusionNRN1 can be a potential diagnostic and therapeutic target in RCC as analyzed by preclinical patient-derived cancer models and clinicopathological studies.

Limited Association Between Ascorbate Concentrations and Vitamin C Transporters in Renal Cell Carcinoma Cells and Clinical Samples

Maintenance of whole-body ascorbate levels and distribution is mediated via sodium-dependent vitamin C transporters (SVCTs). The kidney is one of a few organs that express both SVCT1 and SVCT2. Recent evidence suggests that accumulation of ascorbate may be different in tumour compared to normal tissue, but data on SVCT levels in tumours is sparse. The role of the two SVCT isoforms in ascorbate uptake in renal cell carcinoma (RCC) was investigated in vitro and in clinical samples. In three human RCC cell lines, we investigated SVCT protein levels and cellular location in response to ascorbate supplementation and withdrawal. In clinical RCC samples (n=114), SVCT patterns of staining and protein levels were analysed and compared to ascorbate levels. In cell culture, transporter levels and cellular location were not modified by ascorbate availability at any time up to 8h, although basal SVCT2 levels governed maximal ascorbate accumulation. In clinical samples, SVCT1 protein levels in papillary RCC (pRCC) were similar to matched normal renal cortex, but were increased in clear-cell RCC (ccRCC). Native SVCT2 (72 kDa) was significantly decreased in both pRCC and ccRCC tissues compared to cortex (p<0.01), whereas a modified form of SVCT2 (100 kDa) was significantly increased (p<0.001). There was no association between the transporters (SVCT1, native or modified SVCT2) and ascorbate concentrations in either normal or tumour tissues. SVCT1 and SVCT2 displayed diffuse cytoplasmic staining in both pRCC and ccRCC tumour cells, with cortex showing distinct membrane staining for SVCT1. We observed a re-distribution of ascorbate transporters in tumour tissue compared to normal cortex and a shift from native to modified SVCT2 in cell culture and clinical samples. Data presented here show that SVCT protein levels do not appear to predict intracellular ascorbate accumulation in RCC.

MP39-18 AN AUTOCHTHONOUS MOUSE MODEL OF KIDNEY CANCER WITH T CELL INFILTRATION

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I (MP39)1 Sep 2021MP39-18 AN AUTOCHTHONOUS MOUSE MODEL OF KIDNEY CANCER WITH T CELL INFILTRATION Nitika Sharma, Bo Xu, Jacky Chow, Jason Muhitch, and Eric Kauffman Nitika SharmaNitika Sharma More articles by this author , Bo XuBo Xu More articles by this author , Jacky ChowJacky Chow More articles by this author , Jason MuhitchJason Muhitch More articles by this author , and Eric KauffmanEric Kauffman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002054.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Immunocompetent animal models that recapitulate human renal cell carcinoma (RCC) and its tumor-immune microenvironment are critical for the preclinical study of novel immunotherapeutic strategies. Abundant CD8+ T cell lymphocyte infiltration is a defining feature of human clear cell RCC but is lacking from many mouse models. Iron is a known carcinogen with increased cellular levels in human RCC. In the FeNTA mouse model, chronic systemic administration of iron (Fe) with a chelator (nitrilotriacetic acid, NTA) induces renal carcinogenesis, however the tumor biology is largely uncharacterized. We studied whether FeNTA mouse model cancers have similar biology as human RCC, including an abundance of tumor-infiltrating lymphocytes. METHODS: 60 male mice (AJ strain) were treated for 12 weeks (5X/week) with intraperitoneal FeNTA injection to induce renal tumorigenesis. Renal tumors were harvested at 12-15 months post-treatment and underwent H&E histologic evaluation by a clinical genitourinary pathologist. Tumor lysates were analyzed for PAX8 and HIF2-alpha protein levels by Western Blot, while tumor single-cell suspensions were analyzed for immune cell antigens (CD45, CD3, CD4, CD8) by imaging flow cytometry to quantify tumor-infiltrating T cell lymphocyte populations. RESULTS: Of 60 FeNTA-treated mice, 14 (23.3%) developed renal tumors as confirmed by magnetic resonance imaging and histology. Mean tumor size was 1.5 cm (interquartile range 1.1-1.8 cm). Tumor histology was most similar to clinical clear cell RCC with eosinophilic cytoplasm. The clinical RCC biomarker, PAX8, was expressed in murine tumors, as was the HIF2-alpha protein that typifies human clear cell RCC. Infiltrating immune cells (CD45+) comprised on average 33.2% (+/- standard error, 4.6%) of all tumor cells, including 11.9% (+/- 3.9%) of tumor cells that were specifically T cell lymphocytes (CD45+/CD3+). Most tumor-infiltrating T cells were CD8+/CD4- (74.3+/- 3.7%), while the remainder were CD4+/CD8- (25.7+/- 3.7%). CONCLUSIONS: The FeNTA autochthonous immunocompetent mouse model recapitulates key clinical RCC biology, including a tumor-infiltrating T cell profile similar to that of the human disease. This model may provide a valuable resource for preclinical evaluation of novel immunotherapeutic strategies for RCC. Source of Funding: American Cancer Society © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e711-e712 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nitika Sharma More articles by this author Bo Xu More articles by this author Jacky Chow More articles by this author Jason Muhitch More articles by this author Eric Kauffman More articles by this author Expand All Advertisement Loading ...