Prognostic value of circulating tumor cells and immune-inflammatory cells in patients with renal cell carcinoma

PurposeThe relationships among circulating tumor cells (CTCs), inflammatory cells, and platelets in patients with renal cell carcinoma (RCC) are not transparent. We evaluated the correlations among CTCs, blood inflammatory cells, and platelets in patients with RCC and their prognostic value for metastasis-free survival.MethodsCTC and typical tumor cell chip data were collected and analyzed by the GEO database. The baseline data, survival data, CTCs data, and blood test results were statistically analyzed.ResultsBioinformatics analysis showed that the function of the differentially expressed genes between CTCs and normal tumor cells mainly involved platelets and immune inflammation. A total of 82 patients whose follow-up time was 3 to 68 months were included in the analysis. Clinical data of the patients confirmed that there is a correlation between platelets and mesenchymal CTCs. Simultaneously, there was a correlation between immune inflammatory cells and platelets. The univariate Cox proportional hazards model indicated that staging, mesenchymal CTCs, and the monocyte-to-neutrophil ratio (MNR) had prognostic value. The multivariate Cox proportional hazards model indicated that staging and the MNR had prognostic value and high accuracy.ConclusionsBioinformatics analysis showed that CTCs were related to platelets and immune-inflammatory cells. Furthermore, the clinical data confirmed that platelets were correlated with mesenchymal CTCs and immune-inflammatory cells in the blood. By using mesenchymal CTCs, the MNR, or staging respectively, it is possible to predict the risk of postoperative metastasis in RCC patients. As a compound prognostic factor, staging, and the MNR can provide more convenient and accurate condition monitoring.     

Comparison of two detection systems for circulating tumor cells among patients with renal cell carcinoma

Background/aims

Detection of circulating tumor cells (CTCs) in cancer patients has diagnostic and prognostic importance. However, the clinical implications of CTC detection in patients with renal cell carcinoma (RCC) are still unclear. In this study, we investigated the clinical significance of CTCs using two detection systems, the CellSearch system (CSS) and isolation by size of epithelial tumor cells (ISET), among RCC patients.

Methods

We recruited 36 RCC patients and 22 healthy volunteers as controls. Blood was drawn before treatment. Samples were analyzed using the CSS and ISET. We prospectively followed the RCC patients to determine overall and progression-free survival.

Results

We did not detect CTCs in the control group using either the CSS or ISET. CTCs were detected in 7/36 patients (19.4%) using the CSS and in 13/36 patients (36.1%) using ISET, while circulating microemboli (CTMs) were detected in three patients (8.3%). The presence of ISET-detected CTCs correlated with clinical tumor node metastasis (TNM) stages, while the CSS-detected CTCs did not. After 36 months (median), CTCs detected by both methods failed to correlate with overall and progression-free survival among RCC patients.

Conclusion

We discovered that ISET is more suitable than the CSS for detecting CTCs in RCC patients. The presence of CTCs/CTMs in RCC patients correlated with higher TNM stages, suggesting that the presence of CTCs could be a prognostic marker in RCC patients.

     

循环肿瘤细胞检测在转移性肾细胞癌中的应用

目的:探讨循环肿瘤细胞(circulating tumor cells,CTC)检测在转移性肾细胞癌临床诊断中的应用价值。方法:2013年3月~2015年5月收治的肾癌患者52例,所有患者在治疗前取外周静脉血标本7.5ml,用细胞搜索系统(cell search system,CSS)对患者外周血进行CTC定量检测,其中男41例,女11例。结果:CTC检测总体阳性率为48.1%(25/52),存在淋巴结转移及远处转移的患者,其CTC阳性率明显高于无淋巴转移及远处转移的患者,中晚期患者(Ⅲ期+Ⅳ期)其阳性率明显高于早期患者(Ⅰ期+Ⅱ期)。结论:CTC检测结果和传统上用来评价肾癌患者的预后的指标其结果一致,CTC的检测可以用来评估肾癌患者的预后,为肾癌患者术后是否应早期进行干预提供依据。     

C-reactive protein and neutrophil-lymphocyte ratio are prognostic in metastatic clear-cell renal cell carcinoma patients treated with nivolumab

ObjectiveTo evaluate the impact of markers of systemic inflammation such as C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) on outcomes of metastatic clear-cell renal cell carcinoma (m-ccRCC) patients treated with nivolumab.Patients and methodsWe retrospectively evaluated m-ccRCC patients treated with nivolumab and collected known prognostic factors and survival data. We used Kaplan-Meier survival analysis and cox proportional hazards regression analysis to study prognostic factors for overall survival (OS) and progression-free survival (PFS) since start of nivolumab. Harrell's C-index was used to evaluate the models.ResultsWe included 113 patients. Median OS and PFS after initiation of nivolumab was 15 (interquartile range 7–28) and 4 months (interquartile range 3–11), respectively.Elevated baseline CRP was associated with worse OS (HR per 25 mg/l 1.35, 95% CI 1.16–1.52, P < 0.001) and PFS (HR per 25 mg/l 1.19, 95% CI 1.08–1.35, P = 0.001), independent from the international metastatic renal cell carcinoma database consortium (IMDC) prognostic criteria, increasing the model's C-index from 0.72 to 0.77 for OS and 0.59 to 0.62 for PFS.Elevated NLR was associated with worse OS (HR 1.10, 95% CI 1.04–1.17, P = 0.002) and PFS (HR 1.06, 95% CI 1.01–1.11, P = 0.03) independent from the other IMDC prognostic criteria. The model's C-index decreased from 0.72 to 0.70 for OS and increased from 0.59 to 0.60 for PFS.ConclusionsElevated baseline CRP and NLR predict worse OS and PFS on nivolumab in m-ccRCC patients. Including baseline CRP in the IMDC prognostic model improves its discriminatory power to predict OS and PFS since start of nivolumab.     

分子靶向药物Pazopanib治疗转移性肾癌的效果观察

目的探讨抑制血管生成的分子靶向药物酪氨酸激酶抑制剂Pazopanib治疗晚期肾透明细胞癌的疗效。方法分析解放军总院2006年6月至2007年5月参与的Pazopanib治疗晚期肾透明细胞癌随机临床药物试验的门诊病例14例，分为Pazo—panib组（10例）和安慰剂组（4例），分别接受Pazopanib800mg／d和安慰剂，持续治疗12周后，根据服药前后的CT检查结果判定疗效。结呆Pazopanib组和安慰剂组患者可测量病灶的平均缩小比值分别为27．6％、-2．8％（P〈O．05）；Pazopanib组和安慰剂组的疾病控制率分别为100％和25％。结论分子靶向血管生成抑制药酪氨酸激酶抑制剂Pazopanib能够在短期内对转移性肾透明细胞癌具有明显的治疗效果且安全性较高。     

Primary tumor response to targeted agents in patients with metastatic renal cell carcinoma

Background

The recent development of multiple targeted agents for metastatic renal cell carcinoma (mRCC) has changed the treatment paradigm; hence the benefit and optimal timing of cytoreductive nephrectomy is being reevaluated.

Objective

To determine primary tumor response to treatment with targeted agents in patients with mRCC.

Design, setting, and participants

We reviewed the clinical and radiographic data of all mRCC patients seen at our institution between November 2004 and December 2009 without prior systemic treatment who received targeted therapy with their primary tumor in situ.

Measurements

Two independent reviewers measured the diameter of primary and metastatic tumors at baseline and subsequent scans, using Response Evaluation Criteria Solid Tumors (RECIST) v.1.1 to assess disease response.

Results and limitations

We identified 168 consecutive patients with a median 15 mo of follow-up and a median maximum tumor diameter of 9.6 cm. Median maximum primary tumor response was −7.1% (interquartile range: −14.0 to −0.1).A total of 61 patients had multiple studies available for evaluation. In 43 patients with <10% decrease in primary tumor within in the first 60 d, median maximum response was −7.2% at 154 d versus −24.5% maximum response at 174.5 d for 18 patients with ≥10% decrease in primary tumor during the initial 60 d.

Conclusions

Decrease in primary tumor diameter >30% while on targeted therapy for mRCC is rare, with most patients demonstrating minimal or no decrease in primary tumor diameter. Early response predicts a better overall primary tumor response.     

Role of nephrectomy in metastatic renal cell carcinoma

Metastatic kidney cancer is still a devastating disease but it represents a very heterogeneous situation. Some patients will have a median survival limited to some months, while others will live several years. If the initial diagnosis of kidney cancer at metastatic stage is quite uncommon, it raises the question of whether or not performing initial nephrectomy. The point was long debated as it was suggested that initial nephrectomy could result in a spontaneous metastase regression and protect against local complications (hematuria, local pain,...). Today, nephrectomy must not be systematic, as effective alternative treatments are often available. Furthermore spontaneous postoperative metastasis regression is unusual. Two recent prospective randomized trials clarified the impact of initial nephrectomy. It is now accepted that initial surgery prior to systemic immunotherapy results in 30% survival benefit. However this procedure should only be considered for highly selected cases: patients in otherwise good condition (ECOG 0-1), macroscopically complete local resection, no supra-hepatic caval thrombus, and patients suitable for systemic immunotherapy treatment. Several questions remain unanswered, such as lymph node dissection to be performed, and its real survival impact. Furthermore the definition of "suitable" patients for immunotherapy has to be clarified, based on the recent results from the Percy Quatro study. It would probably be more effective to consider only patients with an expected good survival benefit using immunotherapy, such as those classified as "good prognosis" based on the CRECY criteria. Finally the development of new drugs, targeting mainly the angiogenic pathway may lead to different future indications in this setting.     

肾癌循环肿瘤细胞检测及临床应用的研究进展

肾癌是泌尿系统常见的恶性肿瘤之一。其中20%~30%的患者会出现远处转移。但目前用于肾癌诊断、监测复发和评估预后的生物标志物仍不确定。循环肿瘤细胞(CTCs)是从原发肿瘤或转移灶脱落、侵入并存在于外周血管的肿瘤细胞。因此CTCs被认为是肿瘤转移的关键环节。然而,目前肾癌CTCs的相关研究面临检测方法不统一、临床应用较局限等问题。本文就肾癌CTCs检测和临床应用的研究进展作一综述。     

Using tumor markers to predict the survival of patients with metastatic renal cell carcinoma

PURPOSE: Approximately 30% of renal cell carcinomas (RCCs) present as metastatic disease. Molecular markers have the potential to characterize accurately the biological behavior of tumors and they may be useful for determining prognosis. MATERIALS AND METHODS: A custom tissue array was constructed using clear cell RCC from 150 patients with metastatic RCC who underwent nephrectomy prior to immunotherapy. The tissue array was stained for 8 molecular markers, namely Ki67, p53, gelsolin, carbonic anhydrase (CA)9, CA12, PTEN (phosphatase and tensin homologue deleted on chromosome 10), epithelial cell adhesion molecule and vimentin. Marker status and established clinical predictors of prognosis were considered when developing a prognostic model for disease specific survival. RESULTS: On univariate Cox regression analysis certain markers were statistically significant predictors of survival, namely CA9 (p <0.00001), p53 (p = 0.0072), gelsolin (p = 0.030), Ki67 (p = 0.036) and CA12 (p = 0.043). On multivariate Cox regression analysis that included all markers and clinical variables CA9 (p = 0.00002), PTEN (p <0.0001), vimentin (p = 0.0032), p53 (p = 0.028), T category (p = 0.0025) and performance status (p = 0.0013) were significant independent predictors of disease specific survival and they were used to construct a combined molecular and clinical prognostic model. The bias corrected concordance index (C-index) of this combined prognostic model was C = 0.68, which was significantly higher (p = 0.0033) than that of a multivariate clinical predictor model (C = 0.62) based on the UCLA Integrated Staging System (T category, histological grade and performance status). CONCLUSIONS: In patients with clear cell RCC a prognostic model for survival that includes molecular and clinical predictors is significantly more accurate than a standard clinical model using the combination of stage, histological grade and performance status.     

Predicting survival of patients with metastatic renal cell carcinoma

The relationship between pretreatment clinical features and survival was studied from patients treated on clinical trials for metastatic renal cell carcinoma (RCC) at the Memorial Sloan-Kettering Cancer Center. The primary analysis was performed on 670 patients treated with cytokines or chemotherapy, from which a multivariate model was derived to predict survival. Studies which followed addressed: (1) the survival of patients given interferon-alpha as first-line therapy; (2) a comparison of survival for patients treated with chemotherapy versus cytokine therapy; and (3) survival of patients with non-clear cell histology. Prospective identification of patients more likely to benefit from cytokine therapy is important as a stratification factor in phase III trials, and in risk-directed therapy.     

Predicting survival of patients with metastatic renal cell carcinoma

The relationship between pretreatment clinical features and survival was studied from patients treated on clinical trials for metastatic renal cell carcinoma (RCC) at the Memorial Sloan-Kettering Cancer Center. The primary analysis was performed on 670 patients treated with cytokines or chemotherapy, from which a multivariate model was derived to predict survival. Studies which followed addressed: (1) the survival of patients given interferon-α as first-line therapy; (2) a comparison of survival for patients treated with chemotherapy versus cytokine therapy; and (3) survival of patients with non-clear cell histology. Prospective identification of patients more likely to benefit from cytokine therapy is important as a stratification factor in phase III trials, and in risk-directed therapy.     

The value of tumor nephrectomy in metastatic renal cell carcinoma

In the case of an organ-confined RCC, tumor nephrectomy is the undisputed therapy of choice even though overall 5-year survival has not surpassed the 60% threshold. Further improvement will most likely have to await the development of more effective systemic treatment strategies. For an exclusively surgical therapy of metastatic RCC, tumor nephrectomy, sometimes in combination with metastasectomy, can be applied. However, more commonly used is a multimodality approach consisting of a cytoreductive operation followed by immunotherapy. Alternatively, one may select immunotherapy first followed by adjuvant nephrectomy in the case of a response, or one may proceed directly to immunotherapy only. Long-term survival does not exceed 5-10%, and patient selection appears to have a higher prognostic impact than any treatment strategy available. Concepts and progress in the field clearly are of increasing value for modern oncologic urologists. The current standard, a multimodality treatment of metastatic RCC, in which an operation becomes necessary at a certain point in time, easily justifies a central role for the urologic surgeon.     

Surgical considerations for patients with metastatic renal cell carcinoma

Among patients with renal cell carcinoma (RCC), 25–30% present with metastatic disease at the time of initial diagnosis. Despite the ever-increasing array of treatment options available for these patients, surgery remains one of the cornerstones of therapy. Proper patient selection for cytoreductive surgery is paramount to its effective use in the management of patients with metastatic RCC despite the decrease in reported morbidity rates. We explore the evolving role cytoreductive surgery in metastatic RCC spanning the immunotherapy era to the targeted therapy era. Despite significant advances in the management of patients with metastatic RCC, further evidence on the definitive role of cytoreductive surgery in the targeted therapy era is awaited through large randomized trials.