肾透明细胞癌联合免疫治疗新策略——有氧糖酵解的研究进展及展望

肾恶性肿瘤的发病率逐年上升,其中肾透明细胞癌约占所有肾恶性肿瘤的80%,肾透明细胞癌独特的遗传背景和突变特征往往涉及以乏氧信号、糖酵解代谢、氨基酸代谢、线粒体氧化磷酸化等通路为代表的肿瘤微环境（tumor microenvironment,TME）内稳态失调。免疫检查点抑制剂（immune checkpoint inhibitor,ICI）联合酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）已经成为晚期肾透明细胞癌患者的一线治疗方案,但是,联合治疗方案的疗效仍有待提高,且缺乏明确诊断、指导用药、评估预后的生物标志物。近年来,多组学研究从不同层次探索肾透明细胞癌分子通路的异常改变。肾透明细胞癌发生代谢重编程,在氧气充足的情况下也以低效能的糖酵解为能量供应来源,促进自身无限生长,并且有氧糖酵解通路展现的显著异常与不良预后相关。肾透明细胞癌异常的糖酵解信号能促进肿瘤生长,并与TME中的免疫细胞相互作用,使促肿瘤免疫和抗肿瘤免疫平衡失调,造成抑制性免疫微环境,介导肿瘤免疫逃逸,从而对免疫治疗产生不利影响。因此,通过阻断异常糖代谢来抑制肿瘤生长,以有氧糖酵解通路和免疫微环境为切入点,可为肾透明细胞癌以及泛肿瘤治疗提供新的研究方向。然而,如何在复杂的肿瘤免疫微环境中最大程度地将肿瘤细胞代谢重编程转化为用药靶点并运用于临床实践仍待探讨。在肾透明细胞癌中,糖酵解抑制剂联合ICI或TKI作为新方案或能协同发挥抗肿瘤效应,逆转治疗抵抗。本文通过对糖酵解代谢途径中的关键限速酶、转运体及其抑制剂与肿瘤免疫微环境之间的关系进行综述,探讨糖酵解抑制剂在肾透明细胞癌中的作用机制和肿瘤免疫微环境的变化,及其与靶向治疗或免疫治疗联合应用的巨大临床转化价值,未来将为肾透明细胞癌的临床诊疗提供新思路,为患者带来临床获益。     

Systemic inflammation score predicts postoperative prognosis of patients with clear-cell renal cell carcinoma

Background:

Growing evidence indicates that inflammation has a crucial role in the development and progression of cancer. We developed a novel systemic inflammation score (SIS) based on preoperative serum albumin and lymphocyte-to-monocyte ratio (LMR), and examined its prognostic value for patients with clear-cell renal cell carcinoma (ccRCC) after surgery.

Methods:

The study comprised 441 ccRCC patients undergoing nephrectomy between 2008 and 2009 in a single centre. The SIS was developed and its associations with clinicopathological features and overall survival (OS) were evaluated.

Results:

The SIS consisted of serum albumin and LMR that were both retained as independent indicators adjusting for other haematological and laboratory markers of systemic inflammation responses and traditional clinicopathological features. A high SIS was significantly associated with aggressive tumour behaviours and served as an independent prognostic factor of reduced OS. Furthermore, the SIS could significantly stratify patient prognosis in different tumour stages and Mayo Clinic stage, size, grade and necrosis scores. Incorporation of the SIS into a prognostic model including TNM stage, Fuhrman grade and lymphovascular invasion generated a nomogram, which predicted accurately 3- and 5-year survival for ccRCC patients.

Conclusions:

The SIS as a potentially powerful prognostic biomarker might improve traditional clinicopathological analysis to refine clinical outcome prediction for ccRCC patients after surgery.     

Dishevelled2基因及其蛋白在透明细胞性肾细胞癌组织中的表达及其临床意义

目的探讨透明细胞性肾细胞癌（CCRCC）组织及其癌旁组织中Dishevelled2（DVL2）基因及其蛋白的表达情况及其临床意义。方法用半定量反转录一聚合酶链反应（RT—PCR）和荧光实时定量PCR方法检测22例CCRCC患者的原位肾癌组织及其配对癌旁组织DVL2基因表达情况,并检测了32例总样本中Ⅲ＋Ⅳ期与I＋Ⅱ期肾癌组织中DVL2基因的表达差异;应用免疫组织化学法回顾性研究22例CCRCC患者的原位肾癌组织及其配对癌旁组织中DVL2蛋白的表达情况,同时检测了10例无正常肾组织配对的CCRCC患者肿瘤组织。结果半定量RT—PCR结果表明,在22例CCRCC样本中,DVL2mRNA在17例（77．2％）CCRCC原发灶中的表达较其配对癌旁组织上调,其结果与实时荧光定量PCR结果基本一致（仁2．535,P=0．0197）,实时荧光定量PCR结果显示,13例Ⅲ＋Ⅳ期CCRCC中8例（61．5％）肾癌组织DVL2mRNA表达高于I＋Ⅱ期。肾癌组织;免疫组织化学分析表明,DVL2蛋白定位于CCRCC细胞的胞膜及胞质,22例CCRCC中有18例（81．8％）癌组织表达强度高于癌旁组织,但32例CCRCC的DVL2蛋白表达在不同年龄、性别、肿瘤分期间差异均无统计学意义（Fisher精确概率法,均P〉0．05）。结论在mRNA及蛋白水平上,CCRCC中DVL2表达水平显著高于癌旁组织,并且Ⅲ＋Ⅳ期肿瘤患者原位癌组织中DVL2的表达量高于I＋Ⅱ期,提示DVL2可能是一个潜在的与CCRCC发生及转移相关的分子标志物。     

Podoplanin associates with adverse postoperative prognosis of patients with clear cell renal cell carcinoma

Podoplanin, a transmembrane sialomucin‐like glycoprotein, was recently shown to be involved in tumor progression and metastasis, and its potential role in facilitating platelet‐based tumor embolization and promigratory phenotype of cancer cells was also demonstrated. In this study, we assessed the clinical significance of tumoral podoplanin expression in 295 patients with clear cell renal cell carcinoma (ccRCC) through immunohistochemistry on tissue microarrays and analyzing the staining intensity. Univariate analysis suggested an adverse prognostic effect of high tumoral podoplanin expression on patients' overall survival (OS) and recurrence‐free survival (RFS) (P < 0.001 for both). In the multivariate analysis, high tumoral podoplanin expression (using staining intensity as either a continuous or dichotomous variable) was still an independent adverse prognostic factor for patient survival (OS, P < 0.001, RFS, P < 0.001 for continuous; OS, P < 0.001, RFS, P = 0.002 for dichotomous). Moreover, stratified analysis identified a higher prognostic power in the intermediate/high risk patient groups. After utilizing those parameters in the validated multivariate analysis, two nomograms were constructed to predict ccRCC patients' OS and RFS (c‐index 0.815 and 0.805, respectively), and performed better than existing integrated models (P < 0.001 for all comparisons). In conclusion, high tumoral podoplanin expression could independently predict an adverse clinical outcome for ccRCC patients, and it might be useful in future for clinical decision‐making and therapeutic developments.     

趋化因子CCL5表达与肾透明细胞癌病理特征及预后的相关性研究

目的:明确趋化因子CCL5表达水平与肾透明细胞癌患者病理特征及患者预后的相关性。方法:收集本院2006年1月至2014年1月行手术治疗并术后病理证实为肾透明细胞癌患者肿瘤及对应癌旁组织标本（90例）,术后随访时间为18~90个月,应用免疫组织化学、蛋白印迹法、ELISA方法分别检测趋化因子CCL5表达、血清浓度状况,分析CCL5表达与肾脏透明细胞癌临床病理特征及预后的关系。结果:肾透明细胞癌患者血清中趋化因子CCL5浓度显著高于正常非肿瘤患者（P=0.015 2）;趋化因子CCL5在肾透明细胞癌组织内蛋白表达水平显著高于癌旁组织（P<0.01）;CCL5表达强度与肿瘤大小（P<0.01）、病理分级（P<0.01）、临床分期（P<0.05）呈正相关性,而与性别与年龄关系不密切（P>0.05）;CCL5表达强度与患者总生存时间（OR）呈负相关性且具有显著性差异（P<0.001）。结论:趋化因子CCL5表达水平与透明细胞癌患者病理特征及预后关系密切,其异常高表达可能是促进透明细胞癌发生发展的重要原因,并有可能作为肾透明细胞癌早期监测指标及潜在治疗靶点。     

53例国人肾透明细胞癌中PBRM 1基因的突变分析

目的 分析Polybromo 1（PBRM 1）基因在国人肾透明细胞癌中的突变特点,探讨基因突变与临床病理特征和预后的关系。方法 选取53例肾透明细胞癌患者,利用PCR结合直接测序的方法检测PBRM 1基因2～5号外显子、15～17号外显子的突变情况。分析PBRM 1基因突变与临床病理特征和预后的相关性。结果 53例样本中检测出PBRM 1基因突变14例,突变率为26％。突变较集中分布在第15、17外显子,第15外显子5例,第17外显子6例。PBRM 1基因突变组和无突变组的中位无进展生存期分别为5个月（95％CI：1.6～8.4个月）和14个月（95％CI：9.7～18.3个月）,中位生存期分别为7个月（95％CI：2.6～11.4个月）和18个月（95％CI：5.6～30.4个月）,差异均有统计学意义（P＜0.05）。 PBRM 1基因突变与性别、年龄、发病部位、分期及疾病控制率等无关（P＞0.05）。结论 中国人肾透明细胞癌中PBRM 1基因突变率较高,突变主要位于第15、17外显子。PBRM 1基因突变可能是肾透明细胞癌患者预后不良的危险因素。     

Adjuvant therapy in renal cell carcinoma

Several drugs have demonstrated clinical activity in metastatic renal cell carcinoma (mRCC). The identification of key metabolic pathways has led to the development of novel targeted therapies which have drastically changed the treatment paradigm of mRCC. Moreover, immune-checkpoint inhibitors have recently shown significant activity in advanced disease. Despite these advancements, the role of adjuvant therapy in localized, non-metastatic RCC remains unclear. The utility of many of these agents in the adjuvant setting is currently being actively explored. In this review, we will summarize the main clinical trials investigating adjuvant therapy in renal cell carcinoma, focusing primarily on immunotherapy and targeted agents.     

Identification of international metastatic renal cell carcinoma database consortium (IMDC) intermediate-risk subgroups in patients with metastatic clear-cell renal cell carcinoma

Majority of patients with clear-cell renal cell carcinoma (ccRCC) at first line (1L) treatment are classified in the intermediate-risk (IR) subgroup according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score. As these patients have different prognosis, the aim of this study is to better characterize IR patients in order to better tailor the treatment. Retrospective analysis was performed from IGReCC (Institut Gustave Roussy Renal Cell Carcinoma) database. Overall survival (OS) was defined from start of 1L therapy to death or last follow-up. A multivariable Cox model with backward selection procedure (α = 0.01) and a Classification and Regression Tree (CART) analysis were performed to identify which prognostic factors were associated to OS in IR patients.From 2005 to 2017, 777 patients with ccRCC were treated with an anti-VEGF 1L therapy. Among 571 evaluable patients for IMDC score, 290 (51%) were classified as IR. With median follow-up 5.8 years (min: 0, max: 12.4) 212 deaths (73%) were observed and median OS was 25 months. Only platelet count was significantly associated to OS (hazard ratio 1.88 [95% CI 1.27–2.88] p = 0.0017). Median OS for patients with PLT > UNL was 18 months [95% CI 12–23] versus 29 months [95% CI 21.4–35.7] for patients with normal PLT count. The selection of PLT count was confirmed on bootstrap samples and was also selected for the first split of the CART-tree analysis.Patients in the IR group have a heterogeneous prognosis. Elevated PLT count seems identifies a subgroup of patients with poor outcome in the IMDC intermediate-risk population with ccRCC.     

MYC pathway is activated in clear cell renal cell carcinoma and essential for proliferation of clear cell renal cell carcinoma cells

Clear cell renal cell carcinoma (ccRCC) is the major and aggressive subtype of RCC. Previously, we identified 383 differentially expressed genes by analyzing full-length cDNA libraries of ccRCC and normal kidney tissues. In this study, we applied functional network analysis to the differentially expressed genes for identifying deregulated molecular pathways in ccRCC, and the results indicated that MYC showed a prominent role in the highest scoring network. The upregulation of MYC expression was validated in ccRCC tissues and cell lines. Furthermore, Knockdown of MYC expression by MYC-specific siRNA significantly inhibited the abilities of uncontrolled proliferation, anchorage-independent growth and arrested cell cycle in the G0/G1 phase in ccRCC cells. Moreover, we found that 37 differentially expressed genes were shown to be MYC-target genes, and the upregulation of the MYC-target genes BCL2, CCND1, PCNA, PGK1, and VEGFA were demonstrated. The expression of these MYC-target genes was significantly correlated with the expression of MYC in ccRCC tissues, and knockdown of MYC also suppressed the expression of these MYC-target genes in ccRCC cells. The recruitment of MYC to the promoter regions of BCL2, CCND1, PCNA, PGK1, and VEGFA was shown by Chromatin immunoprecipitation assay. These results suggest that MYC pathway is activated and plays an essential role in the proliferation of ccRCC cells.     

A novel inflammation-associated prognostic signature for clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) are typically situated in a complex inflammatory and immune microenvironment, which has been reported to contribute to the unfavorable prognosis of patients with ccRCC. There would be beneficial clinical implications for elucidating the roles of its molecular characteristics in the inflammatory microenvironment. This is because it would facilitate the development of reliable biomarkers for pre-stratification prior to the designation of individualized treatment strategies. In the present study, RNA-sequencing data from 607 patients were retrospectively analyzed to elucidate the profile of inflammatory molecules. Based on this, an inflammatory prognostic signature (IPS) was developed and further validated using clinical ccRCC samples. Subsequently, the associated mechanisms in terms of the immune microenvironment and molecular pathways were then investigated. This proposed IPS was found to exhibit superior accuracy compared with the criterion of a good prognostic model for the prediction of patient prognosis from ccRCC [area under the receiver operating characteristic curve (AUC)=0.811] in addition to being an independent factor for prognostic risk stratification [hazard ratio: 11.73 (95% CI, 26.98-5.10); log-rank test, P<0.001]. Pathologically, ccRCC cells identified as high-risk according to their IPS presented with a more malignant tumor structure, including voluminous eosinophilic cytoplasm, acinar/lamellar/tubular growth patterns and atypic nuclei. High-risk ccRCC also exhibited higher infiltration levels by four types of immune cells, including T regulatory cells, but lower infiltration levels by mast cells. Pathways associated with immune-inflammation interaction, including the IL-17 pathway, were found to be upregulated in IPS-identified high-risk ccRCC. Furthermore, by combining the IPS with clinical factors, an integrated prognostic index was developed and validated for increasing the accuracy of patient risk-stratification for ccRCC (AUC=0.911). In conclusion, the complex regulatory mechanisms and molecular characteristics involved in ccRCC-inflammation interaction, coupled with their prognostic potential, were systematically elucidated in the present study. This may have important implications in furthering the understanding into the molecular mechanisms underlying this ccRCC-inflammation interaction, which can in turn be exploited for identifying high-risk patients with ccRCC prior to designing their clinical treatment strategy.     

Safety and tolerability of sorafenib in clear-cell renal cell carcinoma: a Phase III overview

This review summarizes the safety of sorafenib, an oral multikinase inhibitor, focusing on the randomized, placebo-controlled, Phase III Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) in renal cell carcinoma, which formed the basis of the approval of sorafenib. Similar to other targeted agents, sorafenib acts primarily to induce disease stabilization, rather than tumor regression, suggesting that long-term administration is necessary. The tolerability of an agent is important in long-term treatment, and a predictable and manageable side-effect profile is advantageous. Although IL-2 and interferon have been standard care treatments for advanced renal cell carcinoma for over a decade, they are poorly tolerated. Targeted agents offer an alternative for patients with advanced renal cell carcinoma, as initial therapy or after failure of cytokine treatment.     

Chemotherapy for non-clear-cell renal cell carcinoma

Clear-cell carcinoma is the most common histopathologic subtype of kidney tumors. Consequently, clinical trials for advanced-stage kidney cancer have focused on patients with clear-cell carcinoma and not on the less common subtypes, including papillary, chromophobe, collectingduct carcinoma, and sarcomatoid-variant tumors. Whereas immunotherapy has constituted the standard treatment for patients with clear-cell renal cell carcinoma (RCC), it does not appear to have activity in the management of patients with other histologic subtypes. Novel therapies, including those targeting the vascular endothelial growth factor pathway, have recently demonstrated significant activity in clear-cell RCC. Historically, chemotherapy has shown limited activity in advanced-stage RCC; however, clinical trials to date have failed to individualize treatment based on histologic subtype. In this article, we will review the literature and present our experience with the use of chemotherapy in patients with non-clear-cell kidney cancer by histologic subtype.     

MSCT多期扫描在肾脏乏脂肪血管平滑肌脂肪瘤与透明细胞癌鉴别诊断中的应用价值

目的 探讨肾脏乏脂肪血管平滑肌脂肪瘤(fpAML)和透明细胞癌(ccRCC)多排螺旋CT(MSCT)平扫及多期增强扫描表现,提高诊断准确率.方法 选取2015年1月至2019年12月江苏省中医院经手术病理确诊的fpAML和ccRCC患者各20例,测量肿瘤的短径和长径、CT平扫及多期增强的肿瘤CT值及邻近肾皮质的CT值,...     

透明细胞乳头状肾细胞癌7例报告并文献复习

背景与目的：透明细胞乳头状肾细胞癌是最近发现的一种少见的肾脏上皮源性恶性肿瘤,其生物学行为惰性,预后较好,该研究旨在分析透明细胞乳头状肾细胞癌的临床及病理学特点,与其他亚型鉴别,以免过度治疗。方法：收集7例透明细胞乳头状肾细胞癌病例,应用组织病理学、免疫组织化学法并结合相关文献分析其镜下及临床特点。结果：7例患者肿块均位于肾内,切面灰红或灰黄色,实性或囊实性,镜下肿瘤组织呈腺管状、微囊状或乳头状结构,肿瘤以一种结构为主或多种结构混合存在。细胞质透明,细胞核圆形或卵圆形,世界卫生组织（World Health Organization,WHO）/国际泌尿病理协会（International Society of Urological Pathology,ISUP）细胞核分级为1或2级。免疫表型：7例均表达CK7、CK8、vimentin、PAX-8、CA9和CK34βE12,Ki-67增殖指数为5%~10%,7例均不表达CD117、TFE3和CD10。对本组7例患者随访2个月至4年,均无复发及转移。结论：透明细胞乳头状肾细胞癌是一种少见的低度恶性肿瘤,形态学上与多种具有透明细胞和（或）乳头状细胞的肾癌有重叠,需要借助免疫组织化学进行鉴别。     

Hypothyroidism in patients with renal cell carcinoma

BACKGROUND:

Sunitinib and sorafenib are tyrosine kinase inhibitors that have important antitumor activity in metastatic renal cell carcinoma (mRCC). Hypothyroidism constitutes a commonly reported side effect of both drugs, and particularly of sunitinib. The objective of this analysis was to investigate whether the occurrence of hypothyroidism during treatment with sunitinib and sorafenib affects the outcome of patients with mRCC.

METHODS:

Eighty‐seven consecutive patients with mRCC who were to receive treatment with sunitinib or sorafenib were included in a prospective analysis. Thyroid function was assessed in each patient every 4 weeks during the first 2 months of treatment and every 2 to 4 months thereafter. Assessment included serum levels of thyroid‐stimulating hormone (TSH), tri‐iodthyronine (T3), and thyroxine (T4). Subclinical hypothyroidism was defined as an increase in TSH above the upper limit of normal (>3.77 μM/mL) with normal T3 and T4 levels.

RESULTS:

Subclinical hypothyroidism was evident in 5 patients at baseline and occurred in 30 patients (36.1%) within the first 2 months after treatment initiation. There was a statistically significant correlation between the occurrence of subclinical hypothyroidism during treatment and the rate of objective remission (hypothyroid patients vs euthyroid patients: 28.3% vs 3.3%, respectively; P < .001) and the median duration of survival (not reached vs 13.9 months, respectively; hazard ratio, 0.35; 95% confidence interval, 0.14‐0.85; P = .016). In multivariate analysis, the development of subclinical hypothyroidism was identified as an independent predictor of survival (hazard ratio, 0.31; P = .014).

CONCLUSIONS:

The current results indicated that hypothyroidism may serve as a predictive marker of treatment outcome in patients with mRCC. Thus, the interpretation of hypothyroidism during treatment with sunitinib and sorafenib as an unwanted side effect should be reconsidered. Cancer 2011. © 2010 American Cancer Society.     

Clinical factors associated with outcome in patients with metastatic clear-cell renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy

BACKGROUND: Therapy targeted against the vascular endothelial growth factor (VEGF) pathway is a standard of care for patients with metastatic renal cell carcinoma (RCC). The identification of patients who are more likely to benefit from these agents is warranted. METHODS: In total, 120 patients with metastatic clear-cell RCC received bevacizumab, sorafenib, sunitinib, or axitinib on 1 of 9 prospective clinical trials at the Cleveland Clinic. Clinical features associated with outcome were identified by univariate analysis; then, a stepwise modeling approach based on Cox proportional hazards regression was used to identify independent prognostic factors and to form a model for progression-free survival (PFS). A bootstrap algorithm was used to provide internal validation. RESULTS: The overall median PFS was 13.8 months, and the objective response according to the Response Criteria in Solid Tumors was 34%. Multivariate analysis identified time from diagnosis to current treatment <2 years; baseline platelet and neutrophil counts >300 K/microL and >4.5 K/microL, respectively; baseline corrected serum calcium <8.5 mg/dL or >10 mg/dL; and initial Eastern Cooperative Oncology Group performance status >0 as independent, adverse prognostic factors (PF) for PFS. Three prognostic subgroups were formed based on the number of adverse prognostic factors present. The median PFS in patients with 0 or 1 adverse prognostic factor was 20.1 months compared with 13 months in patients with 2 adverse prognostic factors and 3.9 months in patients with >2 adverse prognostic factors. CONCLUSIONS: Five independent prognostic factors for predicting PFS were identified and were used to categorize patients with metastatic RCC who received VEGF-targeted therapies into 3 risk groups. These prognostic factors can be incorporated into patient care and clinical trials that use such novel, VEGF-targeted agents.     

胰腺转移性肾透明细胞癌的临床病理特征和预后分析

目的探讨胰腺转移性肾透明细胞癌患者的临床病理特征和预后。方法回顾性分析2000年1月至2018年12月在北京协和医院收治的经病理确诊的18例胰腺转移性肾透明细胞癌患者的临床病理资料。结果18例患者中,男11例,女7例;确诊肾透明细胞癌的平均年龄为51.4岁。其中左肾8例(44.4%),右肾10例(55.6%);同时性转移3例,异时性转移15例,从确诊肾透明细胞癌到发现胰腺转移的中位发生转移的时间为156个月,主要临床表现有腹痛、黄疸、消化道出血、恶心、乏力、体重下降等。其中胰腺单病灶患者7例(38.9%),多病灶患者11例(66.1%),9例患者(50.0%)除胰腺外还同时存在其他部位转移。5例患者行胰腺转移灶切除,15例患者服用靶向药物治疗。随访时间1~361.5个月,平均随访时间为171.7个月,死亡5例,生存13例,中位生存时间为122个月,5年生存率为81.4%。是否为同时性转移、是否为10年后复发、纪念斯隆-凯特琳癌症中心模型预后评分以及国际转移性肾细胞癌联合数据库评分是影响胰腺转移性肾透明细胞癌患者预后的因素。结论胰腺转移性肾透明细胞癌罕见,但预后较好,尤其是10年后复发转移至胰腺的患者,行手术切除胰腺转移灶未发现明显的生存获益。     

CXC chemokine receptor 2 is associated with postoperative recurrence and survival of patients with non-metastatic clear-cell renal cell carcinoma

BackgroundAberrant CXC chemokine receptor 2 (CXCR2) expression has been shown to promote angiogenesis and proliferation in renal cell carcinoma (RCC). Our current study aims to evaluate the prognostic significance of CXCR2 in patients with non-metastatic clear-cell renal cell carcinoma (ccRCC).MethodsWe retrospectively enrolled 375 patients with non-metastatic ccRCC undergoing nephrectomy at Zhongshan Hospital, Fudan University between 2003 and 2008. The cohort was split into a training set (n = 184) and a validation set (n = 191). CXCR2 expression was assessed by immunohistochemical staining and its association with clinicopathologic features and prognosis were evaluated.ResultsCXCR2 expression was significantly associated with tumour size (P = 0.036 and P = 0.016, respectively) and Fuhrman grade (P = 0.009 and P = 0.001, respectively) in the training and validation sets. Moreover, high CXCR2 expression indicated poor overall survival (OS) (P < 0.001 and P = 0.001, respectively) and recurrence-free survival (P < 0.001 and P < 0.001, respectively) in the training and validation sets. The incorporation of CXCR2 into the T stage and Fuhrman grade would help to refine individual risk stratification. Furthermore, CXCR2 expression was identified as an independent adverse prognostic factor for survival (P < 0.001) and recurrence (P < 0.001). A predictive nomogram was generated with identified independent prognosticators to assess patient recurrence-free survival at 5 and 10 years.ConclusionsCXCR2 is a potential independent adverse prognostic biomarker for recurrence and survival of patients with non-metastatic ccRCC after nephrectomy.