Nathalie Rioux-Leclercq

Positive Surgical Margin Appears to Have Negligible Impact on Survival of Renal Cell Carcinomas Treated by Nephron-Sparing Surgery

BACKGROUND The occurrence of positive surgical margins (PSMs) after partial nephrectomy (PN) is rare, and little is known about their natural history. OBJECTIVE To identify predictive factors of cancer recurrence and related death in patients having a PSM following PN. DESIGN, SETTING, AND PARTICIPANTS Some 111 patients with a PSM were identified from a multicentre retrospective survey and were compared with 664 negative surgical margin (NSM) patients. A second cohort of NSM patients was created by matching NSM to PSM for indication, tumour size, and tumour grade. MEASUREMENTS PSM and NSM patients were compared using student t tests and chi-square tests on independent samples. A Cox proportional hazards regression model was used to test the independent effects of clinical and pathologic variables on survival. RESULTS AND LIMITATIONS Mean age at diagnosis was 61+/-12.5 yr. Mean tumour size was 3.5+/-2 cm. Imperative indications accounted for 39% (43 of 111) of the cases. Some 18 patients (16%) underwent a second surgery (partial or total nephrectomy). With a mean follow-up of 37 mo, 11 patients (10%) had recurrences and 12 patients (11%) died, including 6 patients (5.4%) who died of cancer progression. Some 91% (10 of 11) of the patients who had recurrences and 83% of the patients (10 of 12) who died belonged to the group with imperative surgical indications. Rates of recurrence-free survival, of cancer-specific survival, and of overall survival were the same among NSM patients and PSM patients. The multivariable Cox model showed that the two variables that could predict recurrence were the indication (p=0.017) and tumour location (p=0.02). No other variable, including PSM status, had any effect on recurrence. None of the studied parameters had any effect on the rate of cancer-specific survival. CONCLUSIONS PSM status occurs more frequently in cases in which surgery is imperative and is associated with an increased risk of recurrence, but PSM status does not appear to influence cancer-specific survival. Additional follow-up is needed.

Low CAIX expression and absence of VHL gene mutation are associated with tumor aggressiveness and poor survival of clear cell renal cell carcinoma

We attempted to describe, in a series of clear cell renal cell carcinoma (RCC), the relationship between CAIX expression, VHL gene mutations, tumor characteristics and outcome. Radical nephrectomy was performed in 100 patients. Genomic DNA was extracted from frozen tumor samples. Four amplimers covering the whole coding sequence of the VHL gene were synthesized by PCR and sequenced. The monoclonal antibody M75 was used to evaluate CAIX protein expression immunohistochemically. VHL mutations were identified in 58 patients (58%) and high CAIX expression (>85%) was observed in 78 (78%). Tumors with VHL mutation showed higher CAIX expression than those without (p = 0.02). Low CAIX expression and absence of VHL mutation were associated with a more advanced tumors e.g., higher T stages and presence of metastases. VHL mutation and high CAIX expression predicted longer progression‐free survival (p = 0.037) and disease‐specific survival (p = 0.001), respectively. In combination, they defined three prognostic groups (p = 0.002): (i) good prognosis, defined as VHL mutation and high CAIX (2‐year survival: 86%), (ii) intermediate prognosis with either VHL mutation or high CAIX (69%), and (iii) poor prognosis with no VHL mutation and low CAIX (45%, median survival 18 months). CAIX expression, but not VHL mutational status, was an independent prognostic factor in multivariate analysis. Taken together, CAIX expression and VHL mutational status are able to stratify patients with clear cell RCC into distinct groups with regards to clinicopathological variables and prognosis, with low CAIX expression and absence of VHL mutation being associated with a poor clinicopathological phenotype and diminished survival.

Prognostic significance of the mode of detection in renal tumours

Objective  To evaluate the mode of detection of 400 renal tumours as a prognostic factor compared with the usual clinical and pathological prognostic variables.

Correlation between Symptom Graduation, Tumor Characteristics and Survival in Renal Cell Carcinoma

OBJECTIVES To compare renal tumors with respect to initial clinical presentation and assess the prognostic value of a symptom based classification. MATERIAL AND METHODS Based on symptoms at diagnosis, 388 renal tumors were stratified into three groups: (1) asymptomatic tumors; (2) tumors with local symptoms (3) tumors with systemic symptoms. The three groups were compared for usual clinical and pathological variables using chi(2)-tests and Anova regression, for qualitative and quantitative variables, respectively. Survival assessment was made with univariate and multivariate analysis using the Kaplan-Meier method and Cox regression analysis. RESULTS The three defined groups were significantly different for all analysed variables except for age, sex ratio and pathological subtype. In univariate analysis: ECOG performance status, symptom classification, tumour size, TNM stage and grade, adrenal, perinephric fat or vein invasion were significant prognostic factors (p<0.001). In multivariate analysis, symptom classification, TNM stage, Fuhrman grade and perinephric fat invasion remained independent prognostic factors (p<0.001). CONCLUSION The proposed classification merits further validation through multi-institutional studies before integrating it in further prognosis algorithms.

Prognostic ability of simplified nuclear grading of renal cell carcinoma.

The Fuhrman grading system is an established predictor of survival in patients with renal cell carcinoma (RCC). The predictive accuracy of various Fuhrman grading schemes was tested with the intent of improving the prediction of RCC‐specific survival (RCC‐SS).

Value of immunohistochemical Ki-67 and p53 determinations as predictive factors of outcome in renal cell carcinoma☆

OBJECTIVES Nuclear grade and tumor stage are important prognostic factors in renal cell carcinoma, but tumors of similar stage and grade can exhibit a wide variation in biologic behavior and clinical outcome. In this retrospective study, we evaluated the immunologic markers, Ki-67 (MIB1) and p53, in 73 cases of conventional (clear cell) renal cell carcinoma and compared these markers with the accepted prognostic features of grade, stage, and tumor size in predicting outcome. METHODS Specimens of 73 renal cell carcinomas of different nuclear grade (20 Furhman I/II, 32 Fuhrman III, and 21 Fuhrman IV) and different stage (10 pT1, 23 pT2, 36 pT3, and 4 pT4) were immunostained with monoclonal antibodies against Ki-67 and p53. RESULTS Univariate statistical analysis showed that tumor size (P <0. 001), nuclear grade (P <0.01), tumor stage (P <0.01), Ki-67 index (P <0.001), and p53 immunostaining (P <0.03) correlated significantly with a poor prognosis. A Ki-67 index of 20% was a powerful predictor of survival in all patients (P <0.00001), with strong predictive values. On multivariate analysis, the Ki-67 index and metastases were significant independent prognostic factors (P <0.02 and <0.01, respectively). CONCLUSIONS Ki-67 immunostaining appeared to be an additional prognostic indicator of biologic aggressiveness in renal cell carcinoma. Immunohistochemical assessment of tumor antigens could be used to identify patients at high risk of tumor progression in addition to conventional prognostic factors.

Prognostic Value of Thrombocytosis in Renal Cell Carcinoma

PURPOSE We correlated platelet count to renal tumor characteristics, and evaluated the potential prognostic value of thrombocytosis in localized and metastatic tumors. MATERIALS AND METHODS A total of 804 patients operated on for a renal tumor in 2 French centers were included in this study. In all cases TNM stage, Fuhrman grade, tumor size, nodal invasion, ECOG score, histological subtype and platelet count were recorded. Survival estimates were compared with the Kaplan-Meier method and multivariate analysis was performed using a Cox model. RESULTS There were 538 (66.9%) males and 266 (33%) females (ratio 2.02) in the patient group. Median age was 62 years. T stages were T1, T2, T3 and T4 in 284 (35.3%), 116 (14.4%), 387 (48.1%) and 17 (2.1%), respectively. There were 112 (13.9%) and 126 (15.7%) patients with nodal and metastatic invasion, respectively. Platelet count was strongly correlated with T stage (p < 0.001), Fuhrman grade (p < 0.001), tumor size (p < 0.001), nodal invasion (p < 0.001) and the presence of distant metastasis (p = 0.01). In univariate analysis all studied factors were significantly predictive of survival (p = 0.0001). Thrombocytosis had an impact on prognosis in localized (p < 0.001) and metastatic (p = 0.003) disease. Several factors were retained in multivariate analysis, namely TNM stage, Fuhrman grade, tumor size, ECOG score and platelet count. In cases with a platelet count of less than 450,000/mm3, the 5-year survival rate was 70%, compared to 38% when the platelet count was 450,000/mm3 or greater. CONCLUSIONS Platelet count appears to be an independent prognostic factor in renal cell carcinoma. It reflects a cascade of biological events correlated with tumor aggressiveness. This observation opens new perspectives for exploring carcinogenesis mechanisms and tumor progression in renal cell carcinoma.

Sunitinib combined with angiotensin-2 type-1 receptor antagonists induces more necrosis: a murine xenograft model of renal cell carcinoma.

Background. Angiotensin-2 type-1 receptor antagonists not are only antihypertensive drugs but also can inhibit VEGF production. We hypothesised that adding telmisartan to sunitinib could potentiate the antiangiogenic effects. Material and Methods. 786-O cell lines were injected in nude mice. After tumor development, mice were divided into 4 groups: the first was the control group (DMSO), the second group was treated with sunitinib alone, the third group was treated with telmisartan alone, and the fourth group was treated with the combination. Drugs were orally administered every day for four weeks. Animals were sacrificed after treatment. Blood and tumor tissues were collected for analysis by immunohistochemistry, Western Blot, and ELISA methods. Results. All animals developed a ccRCC and ten in each group were treated. Using a kinetic model, tumors tended to grow slower in the combination group compared to others (P = 0.06). Compared to sunitinib alone, the addition of telmisartan significantly increased tissue necrosis (P = 0.038). Central microvascular density decreased (P = 0.0038) as well as circulating VEGF (P = 0.003). There was no significant variation in proliferation or apoptosis markers. Conclusion. The combination of sunitinib and telmisartan revealed an enhancement of the blockage of the VEGF pathway on renal tumor resulting in a decrease in neoangiogenesis and an increase in necrosis.

Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting

Purpose: Selecting patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) who might benefit from treatment with targeted tyrosine kinase inhibitors (TKI) is a challenge. Our aim was to identify molecular markers associated with outcome in patients with m-ccRCC treated with sunitinib. Experimental Design: We performed global transcriptome analyses on 53 primary resected ccRCC tumors from patients who developed metastatic disease and were treated with first-line sunitinib. We also determined chromosome copy-number aberrations, methylation status, and gene mutations in von Hippel–Lindau and PBRM1. Molecular data were analyzed in relation with response rate (RR), progression-free survival (PFS), and overall survival (OS). Validation was performed in 47 additional ccRCC samples treated in first-line metastatic setting with sunitinib. Results: Unsupervised transcriptome analysis identified 4 robust ccRCC subtypes (ccrcc1 to 4) related to previous molecular classifications that were associated with different responses to sunitinib treatment. ccrcc1/ccrcc4 tumors had a lower RR (P = 0.005) and a shorter PFS and OS than ccrcc2/ccrcc3 tumors (P = 0.001 and 0.0003, respectively). These subtypes were the only significant covariate in the multivariate Cox model for PFS and OS (P = 0.017 and 0.006, respectively). ccrcc1/ccrcc4 tumors were characterized by a stem-cell polycomb signature and CpG hypermethylation, whereas ccrcc3 tumors, sensitive to sunitinib, did not exhibit cellular response to hypoxia. Moreover, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong inflammatory, Th1-oriented but suppressive immune microenvironment, with high expression of PDCD1 (PD-1) and its ligands. Conclusions: ccRCC molecular subtypes are predictive of sunitinib response in metastatic patients, and could be used for personalized mRCC treatment with TKIs, demethylating or immunomodulatory drugs. Clin Cancer Res; 21(6); 1329–39. ©2015 AACR.

Absence of VHL gene alteration and high VEGF expression are associated with tumour aggressiveness and poor survival of renal-cell carcinoma

Background:The von Hippel–Lindau gene (VHL) alteration, a common event in sporadic clear-cell renal-cell carcinoma (CCRCC), leads to highly vascularised tumours. Vascular endothelial growth factor (VEGF) is the major factor involved in angiogenesis, but the prognostic significance of both VHL inactivation and VEGF expression remain controversial. The aims of this study were to analyse the relationship between VHL genetic and epigenetic alterations, VHL expression and VEGF tumour or plasma expression, and to analyse their respective prognostic value in patients with CCRCC.Methods:A total of 102 patients with CCRCC were prospectively analysed. Alterations in VHL were determined by sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA) and methylation-specific MLPA. Expression of pVHL and VEGF was determined by immunohistochemistry. Plasma VEGF was measured by enzyme-linked immunosorbent assay (ELISA).Results:VHL mutation, deletion and promoter methylation were identified in 70, 76 and 14 cases, respectively. Overall, at least one VHL-gene alteration occurred in 91 cases (89.2%). Both VEGF tumour and plasma expression appeared to be decreased in case of VHL alteration. Median progression-free survival and CCRCC-specific survival were significantly reduced in patients with wild-type VHL or altered VHL and high VEGF expression, which, therefore, represent two markers of tumour aggressiveness in CCRCC.Conclusion:Stratifying CCRCCs according to VHL and VEGF status may help tailor therapeutic strategy.