DCC protein expression in clear cell renal cell carcinoma

OBJECTIVES: To investigate whether the expression of protein from the "deleted in colorectal cancer" (DCC) gene, which predicts a poor outcome for patients with colorectal carcinoma, can also serve as a prognostic factor in renal cell carcinoma (RCC). PATIENTS AND METHODS: The expression of DCC was evaluated immunohistochemically in 94 paraffin-embedded tumour samples from patients with stage T1, T2, and T3 clear cell RCC. The mean follow-up was 52.3 months. The endpoints of the study were recurrence of disease and death from disease. RESULTS: The under-expression of DCC protein was detected in 63% of patients who died from the disease and in 36% with no evidence of disease. DCC protein under-expression was detected in all patients with T1 tumours who died from the disease, in half the T2 tumours and in two-thirds of T3 tumours. CONCLUSION: DCC protein under-expression correlated with more aggressive tumour behaviour and a greater risk of death from RCC. However, a larger cohort of patients should be assessed before drawing definitive conclusions.     

蛋白激酶C活性及δ亚型在肾透明细胞癌的表达

目的　探讨蛋白激酶C(PKC)、PKC δ在肾透明细胞癌中的表达及其临床意义。方法　采用PKC比活性测定和WesternBlotting方法检测 38例肾透明细胞癌和 5例正常肾组织中PKC比活性和PKC δ的表达。结果　癌组织和正常组织胞浆PKC比活性值分别为 ( 6 .97± 2 .6 5 )10 - 2 pmol·ml- 1 ·min- 1 和 ( 14 .16± 5 .6 7) 10 - 2 pmol·ml- 1 ·min- 1 ;而胞膜中的比活性值分别为( 2 7.90± 7.5 8) 10 - 2 pmol·ml- 1 ·min- 1 和 ( 5 7.0 6± 18.13) 10 - 2 pmol·ml- 1 ·min- 1 ;PKC δ在癌组织细胞胞浆中的相对灰度值小于 1,在胞膜中则大于 1,各病理分期和细胞分级间差异均有显著性 (P<0 .0 5 )。结论　PKC活性在肾透明细胞癌中下降 ,PKC δ表达与病理分期、细胞分级相关 ,是判断肾细胞癌预后的指标。     

HLA-G和Fas配体在肾透明细胞癌中的表达及意义

目的：探讨两种免疫抑制分子人类白细胞表面抗原HLA—G和Fas配体（FasL）与经典型肾透明细胞癌（ccRCC）分级和分期的相关性。方法：采用免疫组织化学方法对60例ccRCC标本石蜡切片进行检测,数据由SPSS软件进行统计分析。结果：肿瘤旁正常肾组织中无HLA—G表达;肾癌组织中,40例（66．7％）表达HLA—G,36例（60．0％）表达FasL。31例（51．7％）两者均表达,15例（25．0％）两者均不表达。在同一标本中,肿瘤侵犯脉管或淋巴结后,其HLA-G或FasL表达较原位肿瘤明显增强。统计分析显示HLA—G表达的阳性率和表达强度与肿瘤的分期、分级均呈正相关（P〈0．01）。FasL表达的阳性率与肿瘤分级呈正相关（P〈0．05）,而表达强度与肿瘤分期呈正相关（P〈0．01）。结论：ccRCC中HLAG和FasL的表达与肿瘤的分期、分级均呈正相关,与淋巴结转移有一定关系;晚期ccRCC高表达免疫抑制分子的机制需进一步研究。     

MicroRNA profile in stage I clear cell renal cell carcinoma predicts progression to metastatic disease

ObjectiveThis study sought to identify microRNA (miRNA) profiles of small, pathologically confirmed stage 1 clear cell renal cell carcinoma (ccRCC) tumors that are associated with progression to metachronous metastatic disease.Materials and methodsFifty-five pathologic stage 1 ccRCC tumors ≤5cm, from 2 institutions, were examined in a miRNA screening, followed by a validation study. For the screening phase 752 miRNA were evaluated on each sample to identify those with differential expression between tumors that subsequently did (n = 10) or did not (n = 10) progress to metastatic disease. For the validation, 35 additional samples (20 nonprogressors and 15 with distant progression) were utilized to investigate 20 miRNA to determine if a miRNA panel could differentiate aggressive tumors: associations of miRNA expression with cancer specific survival was also investigated.ResultsIn the screening analysis, 35 miRNA were differentially expressed (P < 0.05, FDR < 0.1) between the groups. In the validation, 11 miRNA were confirmed to have differential expression. The miRNA -10a-5p, -23b-3p, and -26a-5p differentiated nonprogressive and distant progressive disease with a sensitivity of 73.3% and a specificity of 85% (AUC=0.893). In addition, levels of miR-30a-3p and -145-5p were identified as independent prognostic factors of cancer specific survival.ConclusionsThis investigation identified miRNA biomarkers that may differentiate between non-progressive ccRCC tumors and those that progress to metastatic disease in this group of stage I tumors. The miRNA profiles determined in this study have the potential to identify patients with small renal masses who are likely to have progressive ccRCC. Such information may be valuable to incorporate into predictive models.     

碳酸酐酶IX表达在肾透明细胞癌预后评估中的价值

目的 评估肾透明细胞癌组织中碳酸酐酶IX(CA IX)表达在患者预后判断中的价值.方法 应用免疫组织化学P-V方法检测 120例肾透明细胞癌和25例正常肾组织石蜡标本中CA IX的表达.以肿瘤特异性生存率作为最终和主要的评估目标.运用Cox回归模型行CA IX表达与预后关系的单因素和多因素分析,以P＜0.05为差异有统计学意义.结果 112例(93.3%)获随访,随访6～94个月,中位时间45个月,无瘤生存75例,带瘤生存3例,死亡34例,其中死于肿瘤28例.正常肾组织均不表达CA IX.120例肾透明细胞癌组织中CA IX高表达89例(74.2%),高表达者中获随访82例,无瘤生存62例(75.6%),带瘤生存2例(2.4%),死亡18例(22.0%),死于肿瘤13例(15.9%),复发和(或)转移9例(11.0%),中位生存期为92个月.肾透明细胞癌CA IX低表达31例(25.8%),其中获随访30例,无瘤生存13例(43.3%),带瘤生存1例(3.3%),死亡16例(53.3%),死于肿瘤15例(50.0%),中位生存期为53个月,复发和(或)转移8例(26.7%).2组肿瘤特异性生存率比较经log-rank检验,差异有统计学意义(P=0.000,χ2=15.950),CA IX高表达组1、3、5、7年肿瘤特异性生存率分别为95.2%、83.9%、81.2%、78.2%,CA IX低表达组分别为89.5%、63.9%、46.8%、40.1%.2组术后肿瘤复发和(或)转移率比较差异有统计学意义(P=0.040,χ2=4.200).多因素Cox 回归模型分析显示CA IX表达是影响肾透明细胞癌预后的指标(RR=0.186).结论 CA IX高表达与肾透明细胞癌患者术后死亡率及肿瘤复发和(或)转移率呈负相关,CA IX可作为判断肾透明细胞癌预后的指标.

Abstract：

Objective To evaluate the prognostic significance of carbonic anhydrase IX (CA IX) expression in patients with clear cell renal cell carcinoma (ccRCC). Methods CA IX expression in a cohort of 120 patients with ccRCC was evaluated by P-V immunohistochemistry with a rabbit CA IX polyclonal antibody. Twenty-five normal kidney tissues were used as a control. The relationship between CA IX expression and prognosis was analyzed by univariate and multiple-factor analysis (Cox regression model). The primary end point was cancer specific survival. Results One hundred and twelve (93.3%) patients were followed up with the median follow-up time of 45 months (range, 6 to 94 months). Seventy-five patients survived without evidence of tumor recurrence, 3 patients survived with tumor recurrence, and 34 patients died, 28 of the 34 died of cancer. CA IX expression was negative in all normal renal tissue. High CA IX expression was observed in 89 (74.2%) patients, among which 82 patients were followed up, and the disease free survival was 75.6% (62/82). Two (2.4%) patients survived with tumor recurrence, and 18 (22.0%) patients died, of which 13 (15.9%) died of cancer. Tumor recurrence and (or) metastasis occurred in 9 (11.0%) patients, with a median survival of 92 months in this high expression group. Low CA IX expression was observed in 31 (25.8%) patients, among which 30 patients were followed up, and the disease free survival was 43.3% (13/30). One (3.3%) patient survived with tumor recurrence, and 16 (53.3%) patients died, of which 15 (50.0%) died of cancer. Tumor recurrence and (or) metastasis occurred in 8 (26.7%) patients with a median survival of 53 months in this low expression group. Cancer specific survival between CA IX high expression group and low expression group was significantly different (P=0.000, χ2=15.950), and tumor relapse and (or) metastasis rates were significantly different (P=0.040, χ2=4.200). The 1, 3, 5 and 7 year cancer specific survival rates were 95.2%, 83.9%, 81.2% and 78.2% respectively in the high CA IX expression group, and 89.5%, 63.9%, 46.8% and 40.1% respectively in the low expression group. Multivariate analysis with Cox regression model showed that CA IX expression was a prognostic factor (RR=0.186). Conclusions High CA IX expression is negatively correlated with postoperative mortality, relapse and (or) metastasis in ccRCC. CA IX expression could be used as a prognostic biomarker in ccRCC.     

肾透明细胞癌孤立转移瘤的手术治疗

目的探讨肾透明细胞癌转移瘤的手术治疗及预后。方法回顾性分析5例肾透明细胞癌转移瘤行手术治疗患者的临床资料。本组5例,男3例,女2例,发病年龄42～73岁。转移部位:肺转移3例(其中1例肺转移2次),骨转移1例,脑转移1例(该患者发生2次脑转移),局部复发1例,鼻腔转移1例(该患者发生4次鼻腔转移)。均手术切除患肾及转移瘤。结果随访7月～16年,3例存活大于15年,1例已存活超过1年,1例肾切除术后7月死亡。结论对肾透明细胞癌孤立的转移瘤和局部复发灶应积极手术切除,可以延长患者生存期和提高生活质量。     

P-glycoprotein activity in renal clear cell carcinoma

BackgroundThe mechanism by which renal cancer patients show poor response to chemotherapy has not been well understood. The aim of this study was to evaluate the functional activity of P-glycoprotein (P-gp) in renal clear cell carcinoma (RCCC) and its possible role in chemotherapy resistance.MethodsWe studied 11 patients who underwent radical nephrectomy due to RCCC; from each patient we obtained a sample from the cancer tissue, and another from normal renal tissue. These biopsies were mechanically disaggregated to allow individual cells analysis. Cells were incubated with daunorubicin (a fluorescent drug extruded by P-gp) at 37°C and 4°C for 30 min. P-gp activity was analyzed using flow cytometry. Results were expressed as the percentage of cells with P-gp activity (i.e., low fluorescence).ResultsThe analysis of renal cells showed that there was no significant difference in size between normal and cancer cells; however there were clusters of cells with different granularities. We divided the cells according to their granularity. The proportion of cells capable of extruding daunorubicin was significantly higher on tumor cells than in normal renal cells independently of the cell granularity. Our results are congruent with those obtained when mRNA or immunohistochemical test were used. This is the first report quantifying the P-gp activity from fresh samples obtained from kidney cancer in humans.ConclusionsPercentage of cells extruding daunorubicin in RCCC is elevated, indicating that P-gp activity may contribute to multidrug resistance in RCCC.     

嫌色细胞癌与透明细胞癌混合性肾癌的诊断

目的 探讨嫌色细胞癌与透明细胞癌混合性肾肿瘤的诊断及鉴别诊断。 方法 回顾性分析1例嫌色细胞癌与透明细胞癌混合性肾肿瘤的临床资料，结合文献复习进行讨论。结果 病理检查证实该肿瘤为嫌色细胞癌与透明细胞癌混合性肾肿瘤，免疫组织化学揭示嫌色细胞癌可能来源于肾集合小管，Hale胶体铁染色阳性。电镜下胞浆内见大量小囊泡是嫌色细胞癌特征表现。结论 该类肿瘤临床无特异性，需借助病理、免疫组织化学和超微结构特征等明确诊断及相关组织来源。     

CA9 expression as a prognostic factor in renal clear cell carcinoma

INTRODUCTION: We investigated whether CA9 protein could be used as a prognostic tumor marker as well as a diagnostic biomarker in renal clear cell carcinoma. MATERIALS AND METHODS: Nephrectomy specimens from 92 patients were used in this study. 80 of these were renal cell carcinomas, 10 adenomas and 2 oncocytomas. Of the renal cell carcinomas, 67 were clear cell carcinomas. Immunohistochemical analysis using CA9 monoclonal antibody (M75) was performed on paraffin-embedded specimens. CA9 staining was correlated with tumor stage, grade, lymph node involvement, distant metastasis and cumulative survival time. RESULTS: CA9 was present in 91.2% of clear cell carcinomas. Low staining was a poor prognostic factor, and conversely high staining a good prognostic one. CA9 expression was found to be the best prognostic factor when compared with T stage and grade. Even in low-grade and stage tumors, the presence of low expression correlated with lowered survival times. CONCLUSIONS: On the basis of our study, CA9 is a significant molecular marker in renal clear cell carcinomas. Decreased CA9 expression is independently associated with poor survival. CA9 can be used to predict clinical outcome and identify high-risk patients in need for adjuvant immunotherapy and CA9 targeted therapies.     

长链非编码 RNA MIAT 在肾透明细胞癌中的表达情况和预后意义

目的 探讨长链非编码RNAMIAT在肾透明细胞癌中的表达情况及与患者临床指标的相关性,分析其作为肾透明细胞癌分子标记物的可能性。方法 通过荧光定量PCR方法 检测MIAT在40例肾透明细胞癌组织和40例癌旁正常组织中的表达情况,同时结合TCGA数据库分析MIAT表达水平与肾透明细胞癌患者临床指标和预后的关系。结果 MIAT在肾透明细胞癌组织中的表达明显高于癌旁正常组织,在肾癌细胞系中的表达明显高于正常肾小管上皮细胞,差异均具有统计学意义（P<0.05）。TCGA数据库资料分析表明,MIAT表达水平与肾癌患者T分期（P<0.001）、M分期呈正相关（P<0.05）。Kaplan-Meier生存分析表明,高表达MIAT的肾癌患者总体生存时间明显低于低表达MIAT的肾癌患者（Log-rankP<0.05）。结论 MIAT在肾透明细胞癌组织和肾癌细胞系中高表达,有可能成为肾透明细胞癌的分子标记物。     

RCC5基因在肾透明细胞癌中的表达及临床意义

目的明确RCC5在肾透明细胞癌（ccRCC）组织中的表达水平及其对肾癌患者预后的影响。方法通过荧光定量PCR方法对54对ccRCC患者标本（包括癌组织和癌旁正常组织）的RCC5mRNA进行分析;并运用免疫组化对82对配对的癌组织和癌旁正常组织切片及161例癌组织切片进行染色;运用统计学方法分析RCC5的表达量和患者的临床特点之间关系。结果荧光定量PCR结果显示92.59%（50/54））的肾癌组织中RCC5表达水平明显高于癌旁正常组织（P〈0.001）;82对癌组织及癌旁正常组织切片免疫组化显示,92.68%（76/82）的癌组织RCC5表达水平高于癌旁正常组织（P〈0.001）;同时发现RCC5的表达水平与性别、肿瘤直径、病理分期、分级、TNM分期和复发率相关;RCC5高表达的患者预后一般较低表达者差,多元分析显示RCC5表达上调是ccRCC的独立预后因素。结论 RCC5的表达水平和ccRCC预后之间存在明显相关性;研究发现RCC5表达上调的患者预后较差,RCC5可能是一个新颖并且有临床价值的预后标志物。     

Dicer表达与肾透明细胞癌发生及转移的关系

目的：探讨Dicer在肾透明细胞癌发生及转移中的作用。方法：选取正常肾小管上皮细胞株HKC、非转移性肾透明细胞癌细胞株769P、转移性肾透明细胞癌细胞株Caki-1以及36例肾透明细胞癌手术标本（其中11例已发生远处转移）和相应癌旁正常肾组织,应用实时定量PCR和Western blot方法检测Dicer在肾透明细胞癌细胞株和组织中mRNA和蛋白的表达情况,并分析Dicer的mRNA水平与临床病理资料的关系。结果：和正常肾小管上皮细胞株HKC相比;Dicer的mRNA水平在肾透明细胞癌细胞株769-P和Caki-1中均降低（P〈0．001）,而转移性肾透明细胞癌细胞株Caki-1比非转移性肾透明细胞癌细胞株769-P表达水平更低（P〈0．001）;和癌旁正常肾组织相比,Dicer的mRNA水平在‘肾透明细胞癌手术标本中明显降低（P〈0．001）,且已发生远处转移的。肾癌标本比未发生远处转移的肾癌标本表达水平更低（P=0．04）;Dicer在细胞株和组织中的蛋白水平的变化与mRNA水平的变化一致（P〈0．001）;Dicer的mRNA水平在不同年龄、性别、组织学分级、肿瘤大小及T分期组间无统计学差异（P〉0．05）。结论：Dicer表达降低可能在。肾透明细胞癌的肿瘤发生中发挥作用,且其表达的进一步下降可能与肾透明细胞癌的远处转移有关。     

Immunohistochemical negative expression of ezrin predicts poor prognosis in clear cell renal cell carcinoma

PurposeTo analyze the immunohistochemical expression of ezrin and moesin in clear cell renal cell carcinoma (ccRCC). These proteins, as part of the ezrin-radixin-moesin complex link the cell membrane to the actin cytoskeleton, affecting such processes as cell adhesion, cell survival, cell motility, and signal transduction. Our aim was to examine the impact of their expression on clinical outcomes and survival rates.Patients and methodsFive hundred seventy-five consecutive patients who had been treated surgically for ccRCC in a single center between 1985 and 2016 were selected. A single pathologist reviewed all cases to perform a uniform reclassification and determined the most representative tumor areas for construction of a tissue microarray.ResultsOf all ccRCC specimens, 106 (18.3%) were negative for ezrin, and 469 (81.7%) had positive ezrin expression; 16 (2.8%) were negative and 559 (97.2%) were positive for moesin, respectively. Ezrin expression was associated with pT stage (P < 0.001), clinical stage (P = 0.012), synchronic metastasis (P < 0.001), incidental tumors (P = 0.007), and International Society of Urological Pathology histological grade (P = 0.025). There was a correlation between moesin expression and clinical stage (P = 0.027), pT stage (P = 0.025), and pN stage (P = 0.007). Ezrin expression significantly influenced tumor-related deaths. By multivariate analysis, negative ezrin expression was an independent risk factor for disease-specific survival (HR 1.89; 95% CI 1.11–3.20).ConclusionsNegativity for ezrin in ccRCC patients significantly impacts survival rates. We encourage further prospective studies to analyze ezrin analysis to evaluate its significance in the prognosis of ccRCC.     

Gastric metastasis of clear cell renal carcinoma

We report the case of a patient operated in 2003 for renal clear cell carcinoma (CCRC), when left nephrectomy was performed. In the years following occur: lung (2004) and brain (2006) metastasis, pathological bone fracture in right femur (2007), which needed a complex treatment: polichimiotherapy, cobaltotherapy, right temporal metastasectomy, right femoral fixation with metal rod. In our clinic was hospitalised for serious upper gastrointestinal bleeding, severe anaemia (haemoglobin 5.8 g%, hematocrit 18.3%) produced by a ulcerated gastric metastasis. The inefficiency of medical treatment, patient and family desire to operate, have led us to practise Péan type gastrectomy necessary for palliative role (raising the hemorrhagic metastasis). Scarcity of the gastric metastasising of CCRC are discussed and also the surgical indication in the context of a plurimetastatic patient.     

NDUFA4L2 expression predicts poor prognosis in clear cell renal cell carcinoma patients

Background: NDUFA4L2 is overexpressed in VHL-deficient cell lines and neuroblastoma. The clinical significance of NDUFA4L2 in clear cell renal cell carcinoma (ccRCC) has not been well studied. Therefore, we evaluated the prognostic value of NDUFA4L2 in ccRCC patients.

Methods: In our study, NDUFA4L2 expression in 86 cases of ccRCC and adjacent normal tissues was monitored by immunohistochemistry, semi-quantitative RT-PCR, and Western blot analyses. The relationship between NDUFA4L2 expression and the clinical features of ccRCC was assessed.

Results: The results showed that NDUFA4L2 protein expression was found to be higher in ccRCC tissues 81.4% (70/86) than in normal tissues 26.7% (23/86) (p?=?0.021). The average level of NDUFA4L2 mRNA expression was found to be 122.23?±?6.018 and 21.34?±?1.036 in ccRCC tissue and adjacent normal tissue (p?Conclusions: Our study has provided the significant clinical relevance of NDUFA4L2 in ccRCC and suggested that ccRCC patients with NDUFA4L2 overexpression may be suitable as a potential therapeutic target for ccRCC patients.     

肿瘤-睾丸抗原基因在肾透明细胞癌中的表达

目的 研究6种肿瘤.睾丸抗原(CT)基因在肾透明细胞癌中的表达及其临床意义.方法 采用逆转录-聚合酶链反应(RT-PCR)技术检测42例肾透明细胞癌患者癌组织(新鲜标本,T1期16例,12期12例,T3期10例,T4期4例;G1 10例,G2 18例,G3 14例)及其中14例患者癌旁组织的cTAGE-1、cTAGE-2、MAGE-A1、MAGE-A3、MAGE-A12及NY-ESO-1基因mRNA的表达.结果 42例肾透明细胞癌组织中100%(42/42)至少表达6种CT基因中一种,14例癌旁组织表达均阴性.肾透明细胞癌组织中MAGE-A12表达最高,其次为MAGE-A3,MAGE-A1,cTAGE-1,cTAGE-2及NY-ESO-1,分别为71%(30/42),69%(29/42),67%(28/42),64%(27/42),60%(25/42)及48%(20/42).肿瘤不同分期、不同分级之间6种CT基因表达的差异均无统计学意义(Pearson x2检验法,P＞0.05).结论 CT基因在肾透明细胞癌中有较高表达,可望成为肾透明细胞癌特异性免疫治疗的靶基因.