Magnetic Resonance Imaging Radiomics Analyses for Prediction of High-Grade Histology and Necrosis in Clear Cell Renal Cell Carcinoma: Preliminary Experience

IntroductionPercutaneous renal mass biopsy results can accurately diagnose clear cell renal cell carcinoma (ccRCC); however, their reliability to determine nuclear grade in larger, heterogeneous tumors is limited. We assessed the ability of radiomics analyses of magnetic resonance imaging (MRI) to predict high-grade (HG) histology in ccRCC.Patients and MethodsSeventy patients with a renal mass underwent 3 T MRI before surgery between August 2012 and August 2017. Tumor length, first-order statistics, and Haralick texture features were calculated on T2-weighted and dynamic contrast-enhanced (DCE) MRI after manual tumor segmentation. After a variable clustering algorithm was applied, tumor length, washout, and all cluster features were evaluated univariably by receiver operating characteristic curves. Three logistic regression models were constructed to assess the predictability of HG ccRCC and then cross-validated.ResultsAt univariate analysis, area under the curve values of length, and DCE texture cluster 1 and cluster 3 for diagnosis of HG ccRCC were 0.7 (95% confidence interval [CI], 0.58-0.82, false discovery rate P = .008), 0.72 (95% CI, 0.59-0.84, false discovery rate P = .004), and 0.75 (95% CI, 0.63-0.87, false discovery rate P = .0009), respectively. At multivariable analysis, area under the curve for model 1 (tumor length only), model 2 (length + DCE clusters 3 and 4), and model 3 (DCE cluster 1 and 3) for diagnosis of HG ccRCC were 0.67 (95% CI, 0.54-0.79), 0.82 (95% CI, 0.71-0.92), and 0.81 (95% CI, 0.70-0.91), respectively.ConclusionRadiomics analysis of MRI images was superior to tumor size for the prediction of HG histology in ccRCC in our cohort.     

First-Line Treatments for Metastatic Clear Cell Renal Cell Carcinoma: An Ever-Enlarging Landscape

Treatment paradigm for metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically over the recent decades. From cytokines, interleukin-2 and interferon-α to tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors, during the last decade, combinations of immune checkpoint inhibitors have taken over first-line treatment of mccRCC. These combinations are approved based on results from large phase III clinical trials, all of which used sunitinib as the comparator. These trials include CheckMate214 (ipilimumab plus nivolumab), KEYNOTE 426 (pembrolizumab plus axitinib), JAVELIN Renal 101 (avelumab plus axitinib), CheckMate 9ER (nivolumab plus cabozantinib), and the CLEAR study (lenvatinib and pembrolizumab). Results from these studies constitute milestones for newer therapeutic approaches in mccRCC. The broadening spectrum of treatment options for patients with mccRCC with multiple first-line options currently available also means that treating physicians will need to consider each option carefully, balance clinical factors, financial considerations, and weigh toxicity profiles of each drug before deciding the optimal treatment regimen for each individual patient. We describe each frontline treatment option in detail through this review to aid the decision-making process.     

Expression and Prognostic Role of MEKK3 and pERK in Patients with Renal Clear Cell Carcinoma

Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 3 (MEKK3) is animportant serine/threonine protein kinase and a member of the MAPK family. MEKK3 can effectively activate theMEK/ERK signaling pathway and promote an autocrine growth loop critical for tumor genesis, cell proliferation,terminal differentiation, apoptosis and survival. To explore the relationship between MEKK3 and cell apoptosis,clinicopathology and prognosis, we characterize the expression of MEKK3, pERK and FoxP3 in the renal clearcell carcinoma (RCCC). Protein expression was detected by tissue microarray and immunochemistry in 46 casesof RCCC and 28 control cases. Expression levels of CD3+ ,CD3+CD4+,CD3+CD8+,CD4+CD25+, CD4+CD25+FoxP3+ were assessed by flow cytometry and analyzed for their association with pathological factors, correlationand prognosis in RCCC. Expression of MEKK3, pERK and FoxP3 was significantly up-regulated in RCCCas compared to control levels (p<0.01), associated with pathological grade (p<0.05)and clinical stage (p<0.05).CD4+CD25+ Foxp3+ Treg cells were also significantly increased in RCCC patients (p<0.05). Cox multivariateregression analysis showed that MEKK3, pERK expression and patholigical stage were independent prognosticfactors in patients with RCCC (p<0.05). MEKK3 can be used as an important marker of early diagnosis andprognostic evaluation in RCCC. It may be associated with imbalance of anti-tumor immunity and overexpressionof pERK. Expression of MEKK3 and pERK are significantly increased in RCCC, with protein expression andclinical stage acting as independent prognostic factors.     

CD248在肾透明细胞癌中的表达及临床意义CSCD

目的探讨内皮唾酸蛋白(CD248)在肾透明细胞癌(ccRCC)组织中的表达及临床意义。方法收集115例ccRCC组织及对应癌旁组织的石蜡标本,同时收集其中17例ccRCC组织及对应癌旁组织的新鲜标本。qRT-PCR检测17例ccRCC组织及对应癌旁组织中CD248 mRNA的表达;免疫组织化学法检测115例ccRCC患者石蜡标本的CD248蛋白水平,分析CD248表达与ccRCC临床病理指标及预后的相关性。结果ccRCC组织中的CD248阳性表达免疫组织化学反应强度显著强于癌旁组织,差异有统计学意义(P=0.0061),且CD248蛋白阳性信号定位于细胞核及细胞质。CD248 mRNA在癌旁组织中的表达水平明显低于ccRCC组织(P=0.0026)。CD248高表达组组间总生存率明显低于CD248低表达组(44.4 vs.57.2月,P=0.017)。结论CD248的表达可能参与ccRCC的发生发展。与癌旁组织比较,CD248在ccRCC组织中高表达;CD248高表达的ccRCC患者术后生存时间较短。     

Hypertension and Circulating Cytokines and Angiogenic Factors in Patients With Advanced Non‐Clear Cell Renal Cell Carcinoma Treated With Sunitinib: Results From a Phase II Trial

Background.

We evaluated the significance of hypertension developing during vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (VEGFR-TKI) treatment and a group of cytokines and angiogenic factors (CAFs) in advanced non-clear cell renal cell carcinoma (nccRCC) patients treated with sunitinib in a phase II study.

Materials and Methods.

Using multiplex assays, we analyzed the levels of 38 CAFs in plasma at baseline and after 4 weeks of sunitinib therapy. Sunitinib benefit was defined as a partial response or stable disease using the Response Evaluation Criteria in Solid Tumors lasting ≥4 months. Cox proportional hazards regression models were used to assess the associations among hypertension, CAFs, and progression-free (PFS) and overall survival (OS).

Results.

Fifty-seven patients were evaluable; 53 had baseline CAF levels available. The median PFS and OS were 2.9 months (95% confidence interval [CI], 1.4–5.5) and 16.8 months (95% CI, 10.7–27.4), respectively. Sunitinib benefit was observed in 21 patients (37%). However, 33 patients (60%) developed hypertension during treatment, although no association was found with survival or response. Elevated baseline soluble tumor necrosis factor (TNF) receptor I, interleukin-8, growth-regulated oncogene, transforming growth factor-α, and VEGFR-2 levels were associated with an increased risk of death on multivariate analysis.

Conclusion.

We found no association between the development of hypertension and survival or sunitinib benefit in advanced nccRCC. TNF and angiogenic/immunomodulatory mediators were identified for evaluation as markers of prognosis and VEGFR-TKI benefit in future studies.

Implications for Practice:

The present study describes the first analysis of hypertension and a relatively large set of circulating cytokines and angiogenic factors in patients with advanced non-clear cell renal cell carcinoma (nccRCC) treated with sunitinib. No association was found between hypertension and patient outcomes. However, a group of candidate circulating biomarkers was identified, in particular, those associated with tumor necrosis factor and CXCR1/2 signaling, with probable biological and clinical significance in nccRCC, warranting confirmation in future studies.     

影像基因组学及其在肾透明细胞癌中的研究进展

 影像基因组学是人工智能在医疗领域的重要应用之一，是近年来蓬勃发展的一门新兴学科，它将影像组学和基因组学结合起来，以一种无创、高效的方式，相对直观地反映出疾病的变化。本综述介绍了影像基因组学的定义、优势、方法和应用领域，重点介绍了影像基因组学在肾透明细胞癌中的研究进展，以期对肾透明细胞癌进行早期精准诊断，为患者制定最佳的个体化治疗方案。     

索坦治疗14例晚期肾透明细胞癌的疗效和安全性临床观察

目的观察苹果酸舒尼替尼胶囊(索坦)对晚期肾透明细胞癌患者常用化疗剂量的疗效和安全性。方法设置2个剂量观察组:4/2方案组按50 mg·d^(-1),用4周歇2周,6周为1周期;持3方案组按37.5mg·d^(-1),持续治疗直至疾病进展;出现不良事件后,4/2方案可调整为2/1方案(按25 mg·d^(-1),用2周停1周,3周为1周期)。每组7例,若每组≥2例出现剂量限制性毒性(DLT),将停止继续用药。结果 14例可评价疗效患者中3例PR,8例SD,3例PD。4/2方案组7例患者中,出现2例严重不良事件和2例次DLT,而持3方案组7例患者未出现DLT。结论索坦具有显著抗肿瘤活性,DLT是手足皮肤毒性和血小板减少。持3方案患者耐受性较好。对中国人而言,4/2方案出现不良事件后调整为2/1方案较为安全,而对于年轻和体质好的患者优先采用4/2方案。     

环状核糖核酸调节肾透明细胞癌生物学行为的研究进展

肾细胞癌作为十种多发癌症之一,其发病率与死亡率二十多年来一直在增加.肾透明细胞癌(ccRCC)是其最常见的组织病理学亚型.环状核糖核酸(CircRNAs)是一种非编码核糖核酸,分布广泛,细胞功能多样化,并有器官及组织特异性表达模式.最近研究表明,CircRNAs在ccRCC中异常表达,作为其发生与发展的重要调节因子.目...     

Overexpression of Cyclooxygenase-1 Correlates with Poor Prognosis in Renal Cell Carcinoma

The aim of this study was to evaluate expression of COX-1 in renal cell carcinoma (RCC) and its prognosticvalue. mRNA of COX-1 was detected in 42 paired RCC and adjacent normal tissues with quantitative realtimepolymerase chain reaction (qRT-PCR). Expression of COX-1 was also evaluated in 196 RCC sections and91 adjacent normal tissues with immunohistochemistry. Statistical analysis was performed to assess COX-1expression in RCC and its prognostic significance. The results of qRT-PCR showed mRNA levels of COX-1 inRCC tissues to be significantly higher than that in adjacent normal tissues (p < 0.001). Immunohistochemicalassays also revealed COX-1 to be overexpressed in RCC tissues (p < 0.001). Statistical analysis demonstrated highexpression of COX-1 was correlated with tumour size (p = 0.002), pathological stage (p = 0.003), TNM stage (p= 0.003, 0.007, 0.027, respectively), and tumour recurrence (p < 0.001). Survival analysis indicated patients withhigh expression of COX-1 had shorter survival time (p < 0.001), and COX-1 was an independent predictor. Thisis the first study to reveal overexpression of COX-1 in RRC and point to use as a prognostic marker in affectedpatients.     

Higher Serum C-reactive Protein Level Represents the Immunosuppressive Tumor Microenvironment in Patients With Clear Cell Renal Cell Carcinoma

Introduction

C-reactive protein (CRP), a representative inflammatory marker, could serve as a biomarker in renal cell carcinoma because CRP is an important prognostic factor. However, its detailed mechanism remains unknown. This study showed that higher CRP levels correlated with the tumor immune microenvironment, which leads to a worse prognosis. These findings can help to clarify the underlying mechanisms between the presence of systemic inflammatory reaction and prognosis. The aim of this study is to investigate the association between tumor immune microenvironment and CRP in patients with renal cell carcinoma (RCC) to explore the underlying mechanisms between CRP level and prognosis.

AQP-1、MMP-9在肾透明细胞癌组织中的表达

目的探讨水通道蛋白-1(AQP-1)、基质金属蛋白酶-9(MMP-9)在肾透明细胞癌组织中表达及其临床意义。方法采用免疫组织化学法检测29例肾透明细胞癌组织和20例正常肾脏组织中AQP-1、MMP-9的表达。结果 AQP-1主要表达于肾透明细胞癌新生毛细血管或正常肾脏组织毛细血管细胞膜上,而MMP-9主要表达于细胞质和间质中,均呈黄褐色。肾透明细胞癌组织和正常肾脏组织中AQP-1阳性率分别为89.7%和60.0%,差异有统计学意义(P<0.05);MMP-9的阳性率分别为65.5%和46.8%,差异有统计学意义(P<0.05)。AQP-1与MMP-9在肾透明细胞癌组织中的表达呈正相关(r=0.535,P<0.05)。结论 AQP-1、MMP-9的异常表达与肾透明细胞癌的发生及浸润转移有密切关系。     

Low Expression of ATM Indicates a Poor Prognosis in Clear Cell Renal Cell Carcinoma

IntroductionThe study was carried out to examine the expression of ataxia telangiectasia mutant (ATM) of clear cell renal cell carcinoma (ccRCC), and to explore the relationship between the expression of ATM and the clinicopathologic parameters and prognosis of ccRCC.Materials and MethodsClinicopathologic data of the patients with ccRCC were collected from January 2011 to August 2015 in Xiangya Hospital, Central South University. The immunohistochemical method was used to detect the expression of ATM in ccRCC and adjacent tissues. The Kaplan-Meier survival method and log-rank test were used to analyze the relationship between ATM expression and the survival time of the patients with ccRCC. Univariate and multivariate Cox regression analysis was used to evaluate the risk factors for the prognosis of ccRCC.ResultsA total of 110 patients were selected in this study, including 73 men and 37 women. The expression of ATM in ccRCC is significantly lower than that in adjacent tissues. Further analysis found that the expression of ATM in the ccRCC tissues above grade II was lower than that of grade II or below. Kaplan-Meier survival analysis showed that the total survival time of the ATM low expression group was significantly shorter than that of the ATM high expression group. The multivariate Cox regression analysis showed that expression of ATM and clinical stage were independent factors affecting the prognosis of ccRCC.ConclusionATM expression level could serve as an independent risk factor for the prognosis of ccRCC and could be considered as a potential therapeutic target of ccRCC.     

Computed Tomography Texture Analysis for Predicting Clinical Outcomes in Patients With Metastatic Renal Cell Carcinoma Treated With Immune Checkpoint Inhibitors

BackgroundThe treatment responses of immune checkpoint inhibitors in metastatic renal cell carcinoma (mRCC) vary, requiring reliable prognostic biomarkers. We assessed the prognostic ability of computed tomography (CT) texture analysis in patients with mRCC treated with programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors.Materials and MethodsSixty-eight patients with mRCC treated with PD-1/PD-L1 inhibitors between 2012 and 2019 were revaluated. Using baseline and first follow-up CT, baseline and follow-up texture models were developed to predict overall survival (OS) and progression-free survival (PFS) using least absolute shrinkage and selection operator Cox-proportional hazards analysis. Patients were divided into high-risk or low-risk group, and the survival difference was assessed using Kaplan-Meier and log-rank test. Multivariable Cox models were constructed by including only the clinical variables (clinical models) and by combining the clinical variables and the texture models (combined clinical-texture models), and their predictive performance was evaluated using Harrell’s C-index.ResultsThe baseline texture models distinguished longer- and shorter-term survivors for both OS (median, 60.1 vs. 17.0 months; P = .048) and PFS (5.2 vs. 2.8 months; P = .003). The follow-up texture models distinguished longer- and shorter-term overall survivors (40.3 vs. 15.2 months; P = .008) but not for PFS (5.0 vs. 3.6 months; P = .25). The combined clinical-texture model outperformed the clinical model in both predicting the OS (C-index, 0.70 vs. 0.63; P = .03) and PFS (C-index, 0.63 vs. 0.55; P = .04).ConclusionCT texture analysis performed at baseline and early after starting PD-1/PD-L1 inhibitors is associated with clinical outcomes of patients with mRCC.     

Renal Cell Carcinoma is More Aggressive in Turkish Patients with the Metabolic Syndrome

Background: Metabolic syndrome (MetS) is a multifactorial disease characterized by impaired glucosetolerance/diabetes, obesity, high triglyceride levels, low HDL levels, and hypertension. In this study we evaluatethe relationship between tumor size and grade, and presence of the metabolic syndrome in patients with renal cellcarcinoma. Materials and Methods: Between 2007-2013, radical nephrectomy was performed for 310 patients withrenal tumors in our clinic and those with pathology reported renal cell carcinoma were enrolled and divided intotwo groups, with and without metabolic syndrome diagnosed on the basis of the National Cholesterol EducationProgram (NCEP) Adult Treatment Panel III (ATP III) criteria. The relationship between tumor size and gradeof the two groups (Fuhrman nuclear degree) was evaluated statistically. Results: The metabolic syndrome wasfound in 70 patients, with a mean age of 65.5 (40-87), as compared to 58.8 (31-84) years in the non-metabolicsyndrome group. Tumor size over 7 cm was found in 54% and 33%, respectively, and tumor grade over Fuhrman3 in 56% and 32% of patients. Patients with metabolic syndrome had significantly higher tumor size and grade(p<0.05). In the presence of hypertension, diabetes and high triglyceride levels, significant assocations wereagain observed (p<0.05). Tumor size and degree also increased with increasing body mass index but this wasnot statistically significant (p>0.05). Conclusions: Renal cancer is more aggressive in patients with metabolicsyndrome. Lifestyle and risk factors were revealed to be significant influences in renal cancer patients.     

肾透明细胞癌患者血清中可溶性白细胞介素-2受体水平变化及临床意义

目的 分析可溶性白细胞介素-2受体在肾透明细胞癌患者血清中的水平变化及临床意义.方法 选取60例肾透明细胞癌患者作为研究对象,作为实验组;对照组则为60例健康成人.采用酶联免疫吸附试验,检验实验组和对照组血清中可溶性白细胞介素-2受体的水平变化.结果 实验组血清中可溶性白细胞介素-2受体水平为(951.6±49.3) ng/L,明显高于对照组的(442.2±75.8) ng/L,其差异有统计学意义;影响肾透明细胞癌预后的危险因素有临床分期、血清中可溶性白细胞介素-2受体水平及是否发生远处转移.结论 肾透明细胞癌患者血清中可溶性白细胞介素-2受体水平明显增高,血清中高水平的可溶性白细胞介素-2受体可能预示预后较差.     

肾嫌色细胞癌影像检查与病理检查的诊断价值比较

目的：比较分析肾嫌色细胞癌的影像检查与病理检查的诊断价值。方法回顾性分析经手术病理检查证实的51例肾脏嫌色细胞癌的临床资料。结果51例患者肿瘤大小1．5～18 cm,平均6．1 cm,影像检查与病理检查结果,显示与相似肾肿瘤较为明显的差异表现。其中5例予以肾部分切除,其余46例行根治性肾切除。术后经随访3个月到4年,3例广泛转移,7例失访,其余41例均未见局部肿瘤复发、转移。结论肾脏嫌色细胞癌术前影像学检查具有较大程度的意义,能与大多数相似肾脏肿瘤进行鉴别;确诊主要依据术后病理组织学检查。     

肾细胞癌的分子遗传学改变研究进展

肾细胞癌（RCC）是肾癌最重要的一种病理分型,其中又以透明细胞性肾细胞癌（ccRCC）最常见,其次是乳头状肾细胞癌（PRCC）和嫌色性肾细胞癌（ChRCC）。随着二代测序技术的普遍运用,关于ccRCC中VHL、PBRM1等常见突变基因以及3p缺失等拷贝数变异（CNV）的研究越来越多;另外,PRCC和ChRCC中的基因突变和CNV研究也不断出现。本文将对ccRCC、PRCC和ChRCC等几种常见RCC的基因突变、CNV和基因融合等分子遗传学改变研究进展作一综述。     

Association of Leptin Receptor Lys109Arg and Gln223Arg Polymorphisms with Increased Risk of Clear Cell Renal Cell Carcinoma

Background: Although roles of genetic polymorphisms of leptin receptor (LEPR) gene in several cancershave been documented, the association between polymorphisms of LEPR and clear cell renal cell carcinoma(CC-RCC) remains unknown. The aim of this study was to explore any relation. Materials and Methods: Thestudy population consisted of 77 patients with CC-RCC and 161 healthy control subjects. Polymorphism analysesof Lys109Arg and Gln223Arg were performed by direct DNA sequencing and PCR-restriction fragment lengthpolymorphism approaches respectively. Results: Comparisons of allelic and genotypic frequencies in Lys109Argand Gln223Arg showed no significant difference between the cases and controls. However, when evaluating thecombined genotype of Lys109Arg and Gln223Arg, risk with GG/GG was increased (OR=1.85, 95%CI=1.04-3.30)and with GA/GG or GG/GA was decreased (OR=0.07, 95%CI=0.01-0.54; OR and 95%CI of the latter could notbe calculated for a value of zero) . Furthermore, the G-G haplotype frequency of Lys109Arg and Gln223Arg inthe cases was higher (OR=1.68; 95%CI=1.02-2.76). In contrast, the A-G and G-A haplotype frequencies in thecases were lower than those in the controls (OR=0.06; 95%CI=0.01 to 0.47; OR and 95%CI of the latter couldnot be calculated for a value of zero). In addition, the Lys109Arg A allele was in LD with the Gln223Arg A allele(d’=0.9399) in the CC-RCC subjects, but not in the controls. Conclusions: Our data suggest that the GG/GGcombined genotype and G-G haplotype of Lys109Arg and Gln223Arg can act as evaluating factors for CC-RCCrisk.