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ABSTRACT: Metastatic renal cell carcinoma is resistant to current therapies. The phosphoinositide 3-kinase (PI3K)/Akt signaling cascade induces cell growth, cell transformation, and neovascularization. We evaluated whether targeting this pathway could be of therapeutic value against human renal cell carcinoma. The activation of the PI3K/Akt pathway and its role in renal cell carcinoma progression was evaluated in vitro in seven human cell lines by Western blot, cell counting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, terminal deoxyribonucleotide transferase-mediated nick-end labeling assays, and fluorescence-activated cell sorting analysis, using two PI3K inhibitors, LY294002 and wortmannin, as well as by transfection with various Akt constructs and through Akt knockdown by small interfering RNA (siRNA). In vivo nude mice bearing human renal cell carcinoma tumor xenografts were treated with LY294002 (75 mg/kg/wk, 4 weeks, i.p.). Tumor growth was measured and tumors were subjected to Western blot and immunohistochemical analysis. Akt was constitutively activated in all cell lines. Constitutive phosphorylation of glycogen synthase kinase-3 (GSK-3) was observed in all cell lines, whereas forkhead transcription factor and mammalian target of rapamycin, although expressed, were not constitutively phosphorylated. Exposure to LY294002 or wortmannin decreased Akt activation and GSK-3 phosphorylation and reduced cell growth by up to 70% through induction of cell apoptosis. These effects were confirmed by transfection experiments with Akt constructs or Akt siRNA. Importantly, LY294002 induced up to 50% tumor regression in mice through tumor cell apoptosis. Tumor neovascularization was significantly increased by LY294002 treatment. Blood chemistries showed no adverse effects of the treatment. Our results suggest an important role of PI3K/Akt inhibitors as a potentially useful treatment for patients with renal cell carcinoma.
Cancer Research 06/2006; 66(10):5130-42. · 7.86 Impact Factor
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ABSTRACT: Functional inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene occurs in 40-80% of human conventional renal cell carcinomas (RCCs). We showed recently that VHL-deficient RCCs expressed large amounts of parathyroid hormone-related protein (PTHrP), and that PTHrP, acting through the PTH1 receptor (PTH1R), plays an essential role in tumor growth. We also showed that PTHrP expression is negatively regulated by the VHL gene products (pVHL). Our goal was to determine whether blocking the PTHrP/PTH1R system might be of therapeutic value against RCC, independent of VHL status and PTHrP expression levels. The antitumor activity of PTHrP neutralizing antibody and of PTH1R antagonist were evaluated in vitro and in vivo in a panel of human RCC lines expressing or not pVHL. PTHrP is upregulated compared with normal tubular cells. In vitro, tumor cell growth and viability was decreased by up to 80% by the antibody in all cell lines. These effects resulted from apoptosis. Exogenously added PTHrP had no effect on cell growth and viability, but reversed the inhibitory effects of the antibody. The growth inhibition was reproduced by a specific PTH1R antagonist in all cell lines. In vivo, the treatment of nude mice bearing the Caki-1 RCC tumor with the PTHrP antibody inhibited tumor growth by 80%, by inducing apoptosis. Proliferation and neovascularization were not affected by the antiserum. Anti-PTHrP treatment induced no side effects as assessed by animal weight and blood chemistries. Current therapeutic strategies are only marginally effective against metastatic RCC, and adverse effects are common. This study provides a rationale for evaluating the blockade of PTHrP signaling as therapy for human RCC in a clinical setting.
Carcinogenesis 02/2006; 27(1):73-83. · 5.70 Impact Factor
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ABSTRACT: The Fuhrman system is the most widely used nuclear grading system for renal cell carcinoma (RCC). Although Fuhrman nuclear grade is widely accepted as a significant prognostic factor, its reproducibility, as reported in the limited number of series available in the literature, appears to be low.
Between 1980 and 1990, 255 cases of RCC (pT1-3bN0M0) were treated with radical nephrectomy at the Department of Urology, University Hospital, Strasbourg, France. In a retrospective multicenter study, 3 pathologists independently classified 241 of these 255 cases according to the Fuhrman grading system. The authors searched for optimal interobserver agreement by collapsing the grading system to a three-tiered scheme and then to a two-tiered scheme. In addition, overall survival curves were generated according to the classic four-tiered scheme and also according to the best collapsed scheme. The kappa index was used to assess the level of agreement between each pair of observers, and the Cox model was used for multivariate survival analyses.
The mean interobserver kappa value was 0.22 (range, 0.09-0.36). The best concordance was obtained by collapsing to a system in which low-grade (Grade 1-2) disease was compared with high-grade (Grade 3-4) disease. Doing so improved the mean interobserver kappa value to 0.44 (range, 0.32-0.55). Fuhrman grade was an independent prognostic factor for all 3 pathologists (P = 0.01, P < 0.0001, and P = 0.004, respectively), and nuclear grade continued to have independent prognostic value after the optimal collapsing algorithm was performed (P = 0.004, P = 0.0003, and P = 0.005).
Collapsing of the Fuhrman grading system to a two-tiered scheme led to an improvement in interobserver agreement while preserving the independent prognostic value of nuclear grade.
Cancer 03/2005; 103(3):625-9. · 4.77 Impact Factor
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Progrès en Urologie 12/2004; 14(4 Suppl 1):997, 999-1035. · 0.58 Impact Factor
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ABSTRACT: To assess the prognostic value of microscopic venous invasion (MVI) in a long-term follow-up series.
255 patients had a radical nephrectomy between 1980 and 1990 for pT1 to pT3b N0 M0 renal cell carcinoma. We reviewed the disease free, specific and overall survival after 183 months of median follow-up. Survival analyses using Kaplan-Meier and Log-rank models for univariate comparisons and Cox proportional hazards model for multivariate analyses were performed. The studied variables were: age, size, side, extracapsular invasion, renal vein invasion, local stage, Fuhrman's grade and MVI.
MVI was found in 74 cases (29%). The MVI was strongly correlated to metastases appearance and survival (p < 0.0001). Multivariate analysis of disease free survival showed the following independent variables: size (p < 0.0001) and Fuhrman's grade (p < 0.0001). For cancer specific survival, the analysis found size (p < 0.0001), age (p = 0.0005), Fuhrman's grade (p = 0.0035) and MVI (p = 0.016) with a relative risk of cancer related death of 2.16. Independent prognostic factors of overall survival were age (p < 0.0001), size (p < 0.0001), MVI (p = 0.015) and Fuhrman's grade (p = 0.045). The relative risk of cancer related death for MVI is 1.82.
It seems that MVI is an independent prognostic factor of survival for patients with pT1 to pT3b N0 M0 renal cell carcinoma.
European Urology 10/2004; 46(3):331-5. · 8.49 Impact Factor
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ABSTRACT: Incidence of multifocality in Renal Cell Carcinoma (RCC) is estimated at between 5 and 25%. Multifocality has been largely studied because of the growing interest in conservative surgery which is a risk of local recurrence. The aim of this study is to evaluate the relationship between multifocality and other prognostic parameters and whether it is an independent prognostic factor.
From 1980 to 1990, 255 patients (median age: 60.9 years) were treated by radical nephrectomy for pT1 to pT3b N0M0 RCC. The median follow-up time was 183 months. Multifocality was defined as the existence of at least one other tumoral localization, macroscopically and microscopically diagnosed as renal cell carcinoma, in the same kidney. Studied parameters were: age, sex, side, size, stage, Fuhrman's grade, capsular invasion, renal vein involvement and microvascular invasion. Survival was assessed with Kaplan-Meier and Cox models.
37 cases of multifocal RCC were diagnosed (14.5%). There was only a significant correlation with stage (p=0.002) and with capsular invasion (p=0.002). No other factor was correlated with multifocality. It had no influence on the risk of metastatic progression, overall or specific survival.
There is a significant correlation between capsular invasion and multifocality that has to be considered before proposing conservative surgery for a localized RCC. Multifocality has no influence on survival or metastatic progression in case of radical nephrectomy.
European Urology 07/2004; 45(6):749-53. · 8.49 Impact Factor
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ABSTRACT: To evaluate the benefits obtained during the learning phase of laparoscopic nephrectomy (LN) for clinical stage cT1 and cT2 renal cancers.
We retrospectively compared our first 25 cases of LN (13 right, 12 left) with 32 nephrectomies performed by Conventional Surgery (CS) (17 right, 15 left) between May 2000 and December 2001. The LN group comprised 18 men and 7 women with a mean age of 63.8 years. The CS group comprised 18 men and 14 women with a mean age of 67.7 years. Preoperative, intraoperative, postoperative and histological parameters were compared by analysis of the variance or nonparametric Mann-Whitney U test for quantitative variables and Chi-square test for qualitative data.
Preoperative and histological parameters, blood loss, quantity and duration of analgesics and the complication rate were similar in the two groups. Resection was complete in every case. The mean duration of radical nephrectomy was significantly shorter by CS (p < 0.001). Return of bowel sounds was more rapid (p = 0.002) and patients were discharged from hospital earlier (p = 0.004) after LN.
Laparoscopic nephrectomy for cancer must be performed by an operator experienced in laparoscopy. During the learning phase, this procedure provided benefits in terms of return of bowel sounds and length of hospital stay, which should encourage teams performing laparoscopy to perform radical nephrectomy by laparoscopy.
Progrès en Urologie 09/2003; 13(4):569-76. · 0.58 Impact Factor
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ABSTRACT: A 46-year-old healthy man presented to the emergency room with an abscess of corpus cavernosum. The patient was successfully treated by a surgical drainage and antibiotics. The two causes which are discussed are the trauma due to fellatio or hematogenous spread of a periodontal abscess because of bacteria of the oral commensal flora (Streptoccoccus constellatus and Peptostreptococcus) founded in the abscess. Ten months later, the patient had an erectile dysfunction as sequel.
Current Urology. 08/1970; 3(4):217-219.
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Jean-Jacques Patard,
Bernard Escudier,
Philippe Paparel,
Yann Neuzillet,
Jean-Alexandre Long,
Hervé Baumert,
Jean-Michel Corréas, Hervé Lang,
Laura Poissonnier,
Nathalie Rioux-Leclercq,
Michel Soulié
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ABSTRACT: During the recent congress of urology and oncology key topics discussed were the evolution of survival data in metastatic kidney cancer which median is now around 40 months, persistent questions about the role of nephrectomy, including access to the systemic treatment of nephrectomized patients and tumor resectability induced by systemic therapies, the emergence of new prognostic models which are adapted to new therapeutic standards, and the emergence of promising new drugs including pazopanib. This article describes these advances.
Progrès en urologie : journal de l'Association française d'urologie et de la Société française d'urologie.
