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.     

Carbonic anhydrase IX and the future of molecular markers in renal cell carcinoma

The use of carbonic anhydrase IX as a promising molecular marker in RCC is described by authors from Los Angeles, who discuss the promise that molecular markers hold to improve diagnosis, staging, treatment, surveillance and survival of patients with RCC. There is a whole range of new treatments being introduced in the management of metastatic renal cancer. The use of VEGF-targeted therapy has particular importance, especially as it has a strong genetically linked rationale for its potential success in this area. Authors from the USA show that substantial clinical activity has been reported in initial clinical trials. In prostate cancer, drugs targeting microtubules, such as taxanes, have already been introduced clinically, and their success has received widespread attention. A new group of drugs, the epothilones, have similar but not identical binding properties to microtubules, and authors from the USA describe how they have shown activity in hormone-refractory prostate cancer, and are moving to phase III testing.     

PLIN3 is up-regulated and correlates with poor prognosis in clear cell renal cell carcinoma

Background

PLIN3, one of the members of the perilipin family, has been reported to be involved in the formation and accumulation of lipid droplets. However, the expression levels and diagnostic and prognostic value of PLIN3 in renal cell carcinoma (RCC) remain unclear.

Prognostic impact of carbonic anhydrase IX expression in human renal cell carcinoma

OBJECTIVE: To evaluate the prognostic information of carbonic anhydrase (CA) IX expression in patients with renal cell carcinoma (RCC), as increased expression of CA IX is correlated with a worse prognosis in several malignancies. PATIENTS AND METHODS: CA IX expression was assessed in RCC tumours from 228 patients, using a tissue microarray technique on archival material. The expression was related to RCC cell type, Tumour-Node-Metastasis (TNM) stage, nuclear grade and survival. RESULTS: CA IX expression was significantly higher (P < 0.001) in 183 conventional than in 31 papillary RCC and 14 chromophobe RCC. For conventional RCC there was no correlation of CA IX expression with TNM stage or nuclear grade. To evaluate the prognostic information conventional RCC tumours were subdivided arbitrarily into three groups according to the CA IX expression, of 0-10%, 11-90% and 91-100% expression, respectively. Patients with tumours with 0-10% expression had a less favourable prognosis than those with 11-90% and 91-100% expression (P = 0.012, and 0.001), respectively. A multivariate analysis of prognostic factors for patients with conventional RCC showed that TNM stage, nuclear grade and CA IX were independent predictors of prognosis. CONCLUSION: These results show that CA IX expression is higher in conventional than other RCC cell types; furthermore, patients with conventional RCC with low CA IX expression had a less favourable prognosis.     

Carbonic anhydrase IX and pathological features as predictors of outcome in patients with metastatic clear‐cell renal cell carcinoma receiving vascular endothelial growth factor‐targeted therapy

Study Type – Prognosis (retrospective cohort)
Level of Evidence 2b

OBJECTIVE

To investigate the utility of tumour carbonic anhydrase IX (CAIX) expression and histological features for predicting the outcome in patients with metastatic clear‐cell renal cell carcinoma (mRCC) treated with vascular endothelial growth factor (VEGF)‐targeted therapy.

PATIENTS AND METHODS

We identified 118 patients with mRCC initiating first‐line VEGF‐targeted therapy, including 94 with clinical and histological data, and available tissue. The primary endpoint was to detect an interaction between sorafenib vs sunitinib treatment and CAIX status on tumour shrinkage. Other treatment outcomes were also assessed.

RESULTS

There was heterogeneity in tumour responsiveness to sunitinib or sorafenib according to CAIX status; the mean shrinkage was –17% vs –25% for sunitinib‐treated patients with high vs low tumour CAIX expression, compared to –13% vs +9% for sorafenib‐treated patients (P interaction, 0.05). A higher tumour clear‐cell component was independently associated with greater tumour shrinkage (P= 0.02), response (P= 0.02) and treatment duration (P= 0.02).

CONCLUSIONS

Although CAIX expression had no prognostic value in patients with clear‐cell mRCC treated with VEGF‐targeted therapy, it might be a predictive biomarker for response to sorafenib treatment. Patients with a higher clear‐cell component in their tumours are likely to have a superior clinical benefit from VEGF‐targeted therapy.     

Loss of BAP1 expression in metastatic tumor tissue is an event of poor prognosis in patients with metastatic clear cell renal cell carcinoma

Purpose

To evaluate the prognostic impact of the protein expression of both PBRM1 and BAP1 in metastatic tissue of patients with metastatic clear cell renal cell carcinoma (ccRCC).

Novel approaches in the therapy of metastatic renal cell carcinoma

Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC.     

Renal tubular acidosis and osteopetrosis with carbonic anhydrase II deficiency: pathogenesis of impaired acidification

Renal tubular acidosis with osteopetrosis is an autosomal recessive disorder due to deficiency of carbonic anhydrase II (CAII). A 3.5-year-old Egyptian boy with osteopetrosis and cerebral calcification had a persistent normal anion gap type of metabolic acidosis (plasma pH 7.26) and a mild degree of hypokalemia. A baseline urine pH was 7.0; ammonium (NH₄ ⁺) excretion was low at 11 μmol/min per 1.73 m²; fractional excretion of bicarbonate HCO₃ (FE_HCO3) was high at 9%, when plasma HCO₃ was 20 mmol/l; citrate excretion rate was high for the degree of acidosis at 0.35 mmol/mmol creatinine. Intravenous administration of sodium bicarbonate led to a urine pH of 7.6, a FE_HCO3 of 14%, a urine-blood PCO₂ difference of 7 mmHg, NH₄ ⁺ excretion fell to close to nil, and citrate excretion remained at 0.38 mmol/mmol creatinine. Intravenous administration of arginine hydrochloride caused the urine pH to fall to 5.8, the FE_HCO3 to fall to 0, the NH₄ ⁺ excretion rate to rise to 43 μmol/min per 1.73 m², and citrate excretion to fall to <0.01 mmol/mmol creatinine. These results show that our patient had a low rate of NH₄ ⁺ excretion, a low urine minus blood PCO₂ difference in alkaline urine, and a low urinary citrate excretion, but only when he was severely acidotic. He failed to achieve a maximally low urine pH. These findings indicate that his renal acidification mechanisms were impaired in both the proximal and distal tubule, the result of his CA_II deficiency. Received October 24, 1996; received in revised form and accepted February 20, 1997     

Thymidine phosphorylase/platelet-derived endothelial cell growth factor (PD-ECGF) associated with prognosis in renal cell carcinoma

We investigated the correlation between thymidine phosphorylase (TP)/platelet-derived endothelial cell growth factor (PD-ECGF) expression, angiogenesis, and prognosis in renal cell carcinoma (RCC) patients. We prepared paraffin block specimens from 56 postradical nephrectomy RCC patients. The preparations were immunohistochemically stained using anti-CD34 antibody and anti-TP antibody. Angiogenic findings were evaluated based on both microvessel density (MVD) and renal arteriography findings as classified by Roosen et al. TP expression showed heterogeneity in 56 patients: 11 (19.6%) were negative, 28 (50.0%) weak, and 17 (30.4%) positive. There was no correlation between TP expression, MVD, and renal arteriography. There was no TP expression in chromophobe types. Univariate analysis showed a significant correlation between survival and TP expression, patient age, tumor infiltration type, pathologic T- and N-stages, venous involvement, distant metastasis, and tumor grade. There was no correlation between survival and MVD or renal arteriography. Multivariate analysis showed a significant correlation between survival and pathologic T-stage, distant metastasis, tumor infiltration type, and TP expression. TP expression in RCC may be an independent prognostic factor rather than just an index for angiogenesis. Received: 26 June 2000 / Accepted: 11 October 2000     

Low preoperative lymphocyte-monocyte ratio (LMR) represents a potentially poor prognostic factor in nonmetastatic clear cell renal cell carcinoma

ObjectivesTo explore the potential prognostic significance of the lymphocyte-monocyte ratio (LMR) in patients with nonmetastatic renal cell carcinoma (RCC), as the LMR has been repeatedly proposed to have a negative effect on patient?s survival in various hematological and solid cancers. However, findings about LMR?s prognostic significance in RCC have not been reported yet.Methods and materialsWe retrospectively evaluated the prognostic significance of the LMR in a cohort comprising 678 patients with nonmetastatic clear cell RCC, who were operated between 2000 and 2010 with curative radical or partial nephrectomy at a single tertiary academic center. Preoperative LMR was calculated 1 day before surgical intervention. Patients were categorized using an LMR cutoff of 3.0. Cancer-specific survival (CSS), metastasis-free survival, and overall survival were assessed using the Kaplan-Meier method. To evaluate the independent prognostic significance of the LMR, multivariate Cox regression models were applied. Additionally, the influence of the LMR on the predictive accuracy of the Leibovich prognosis score was determined using the Harrell concordance index (c-index) and decision curve analysis.ResultsLow LMR was statistically significantly associated with older patients (≥65 y), high tumor grade (G3+G4), advanced pathologic T category (pT3+pT4), the presence of histologic tumor necrosis, and male gender (P<0.05). Multivariate analysis identified a low LMR as an independent prognostic factor for patients? CSS (hazard ratio = 2.33; 95% CI: 1.10–4.94; P = 0.027). The estimated c-index was 0.83 using the Leibovich prognosis score and 0.86 when the LMR was added.ConclusionsRegarding CSS of patients with RCC, a decreased LMR represents an independent prognostic factor. Adding the LMR to well-established prognostic models, such as the Leibovich prognosis score, might improve their predictive ability.     

High cytoplasmic expression of p27(Kip1) is associated with a worse cancer-specific survival in clear cell renal cell carcinoma

What's known on the subject? and What does the study add? The loss of p27^Kip1 correlates with poor prognosis in various human cancers, and was postulated as a biomarker in RCC. Up to now p27^Kip1 analysis in RCC was focused on its nuclear localization. We confirmed higher p27^Kip1 expression in the nucleus and cytoplasm of RCC and correlated high cytoplasmic p27^Kip1 with an unfavourable clinic and a reduced survival.

OBJECTIVES

• ? To analyse the cytoplasmic and nuclear differences of p27^Kip1 expression and localization in benign and clear cell renal cell carcinoma (ccRCC) with regard to overall survival (OS) and cancer‐specific survival (CSS).
• ? p27^Kip1 is considered to contribute to the progression of ccRCC and is targeted by next generation dual‐therapies.

PATIENTS AND METHODS

• ? In 140 patients, ccRCC and corresponding benign kidney tissue were analyzed for nuclear and cytoplasmic staining of p27^Kip1 by immunohistochemistry using a tissue microarray technique.
• ? Staining intensity and percentage of positive stained cells are given as expression scores. p27^Kip1 expression was categorized as high if ccRCC tissue stained stronger than the respective level of the corresponding benign tissue and categorized as low if ccRCC tissue stained less than or equal to the corresponding benign tissue.
• ? Differences in OS and CSS were analyzed by log‐rank analysis and expression levels were correlated with tumour and patient characteristics using Fisher's exact test.

RESULTS

• ? Cytoplasmatic (mean [sd ]: 13.8% [1.2%] vs 10.7% [1.7%]; P= 0.04) and nuclear (mean [sd ]: 75.6% [2.7%] vs 13.6% [2.1%]; P < 0.001) staining of p27^Kip1 were significantly stronger in ccRCC tissues compared to benign tissue.
• ? High cytoplasmic p27^Kip1 expression was significantly associated with a higher T and N stage, Fuhrman grade and the presence of metastatic disease (P < 0.001).
• ? The median follow‐up time was 38.2 months.
• ? There was no difference in OS between the low and high expression groups, although CSS was significantly lower in patients with high cytoplasmic p27^Kip1 (P < 0.001) and CSS heavily tended to be lower in the nuclear low expression group (P= 0.069).

CONCLUSIONS

• ? High cytoplasmic p27^Kip1 levels in renal cancer tissues are associated with advanced disease and reduced cancer specific survival, whereas low nuclear expression levels appear to be beneficial.
• ? The present study corroborates the consideration of cytoplasmic p27^Kip1 for future diagnostic and targeted therapeutic approaches in RCC establishing a potential protective shift of p27^Kip1 from the cytoplasm to the nucleus.

     

肾癌患者外周血中碳酸酐酶9 mRNA表达的临床意义

目的：探讨肾细胞癌患者外周血中碳酸酐酶9（MN）mRNA表达的临床意义。方法：应用RT－PCR技术，对30例肾细胞癌患者及30例非肾细胞癌患者外周血中肾癌细胞标志物MN mRNA进行检测。结果：非肾癌组外周血中均不表达MN mRNA。肾癌患者外周血MN mRNA阳性表达13例（43％），其中肾癌转移8例，局限性肾癌5例；肾透明细胞癌12例，混合型癌1例。外周血MN mRNA表达与肾癌的临床分期无相关性（P＞0．05）；而肾透明细胞癌阳性率（12／22）明显高于其他组织类型（P＜0．05）。结论：RT－PCR技术可较敏感地检测到血液中肾癌细胞，有助于早期诊断肾癌微小转移。MN可被视为透明细胞癌特异的相关蛋白。     

Clinical and molecular findings in a family with the carbonic anhydrase II deficiency syndrome

Carbonic anhydrase II (CA2) deficiency syndrome is an autosomal recessive disorder leading to osteopetrosis, renal tubular acidosis, and cerebral calcifications. Affected members of an Arab family with the CA2 deficiency syndrome carried the Egyptian mutation in CA2, i.e., c.191 del A, H64fsX90. One affected member, homozygote for the mutation, developed primary pulmonary hypertension. Primary pulmonary hypertension was never described before in patients with this unique syndrome. The likelihood of both occurring randomly in a single individual is very low. We therefore speculate that there might be a possibility of an etiologic link between these entities.     

Identification and validation of TGFBI as a promising prognosis marker of clear cell renal cell carcinoma

ObjectiveTo identify prognostic biomarkers in clear cell renal cell carcinoma (ccRCC) using a proteomic approach.Material and methodsWe performed a comparative proteomic profiling of ccRCC and normal renal tissues from 9 different human specimens. We assessed differential protein expression by iTRAQ (isobaric tagging reagent for absolute quantify) labeling with regard to tumor aggressiveness according to the stage, size, grade, and necrosis (SSIGN) score and confirmed our results using Western blot (9 patients) and immunohistochemistry (135 patients) analysis.ResultsAfter proteomic analysis, 928 constitutive proteins were identified. Among these proteins, 346 had a modified expression in tumor compared with that of normal tissue. Pathway and integrated analyses indicated the presence of an up-regulation of the pentose phosphate pathway in aggressive tumors. In total, 14 proteins were excreted and could potentially become biomarkers. Overexpression of transforming growth factor, beta-induced (TGFBI) in ccRCC was confirmed using Western blot and immunohistochemistry analysis. A significant association was found between the presence of TGFBI expression with tumor category T3–4 (P<0.0001), Fuhrman grades III and IV (P<0.0001), tumor size>4 cm (P<0.0001), presence of tumor necrosis (P<0.0001), nodal involvement (n = 0.009), metastasis (P = 0.012), SSIGN score≥5 (P<0.0001), cancer progression (P<0.0001), and cancer-specific death (P<0.0001). Cancer-specific survival was significantly better for patients with no cytoplasmic TGFBI expression (1-, 3-, 5-y cancer-specific survival of 94.7%, 87.8%, and 73.4% vs. 92.9%, 71.2%, and 49.8%, respectively; P<0.0001).ConclusionWe identified 346 proteins involved in renal carcinogenesis and confirmed the presence of a metabolic shift in aggressive tumors. TGFBI was overexpressed in tumors with high SSIGN scores and was significantly associated with oncologic outcomes.     

hZIP1 that is down-regulated in clear cell renal cell carcinoma is negatively associated with the malignant potential of the tumor

ObjectiveThe human ZRT, IRT-like protein 1 (hZIP1) has been associated with tumorigenesis. However, its role in clear cell renal cell carcinoma (ccRCC) has not been yet reported. The objective was to investigate hZIP1 expression in ccRCC and its association with clinicopathological features.Materials and methodsA total of 106 ccRCC tissue samples and corresponding normal kidney tissue samples were examined, along with 3 ccRCC cell lines (ACHN, 769-P, and 786-O). Real-time polymerase chain reaction, Western blot, and immunohistochemistry were used to investigate the expression of hZIP1 and its relationship with clinicopathological features. The ACHN cell line, exhibiting the highest hZIP1 expression, was transfected with hZIP1 small interfering RNA or mock small interfering RNA. Cellular proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Invasion was determined by Transwell assay.ResultsThe level of hZIP1 was decreased in ccRCC tissues when compared with normal tissues. hZIP1 expression significantly decreased with increasing clinical stage and pathological grade in ccRCC samples (P<0.05), showing a significant negative correlation with the histological grade (P<0.05). High hZIP1 expression was associated with a better disease-free survival (P<0.01). Silencing of hZIP1 expression enhanced the proliferative and invasive abilities of ACHN cells.ConclusionsResults suggest that hZIP1 may act as a tumor suppressor in ccRCC. hZIP1 is closely correlated with clinicopathological features. High hZIP1 expression may be an indicator of good prognosis in ccRCC.