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

International audienceWe 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

Wild-type VHL Clear Cell Renal Cell Carcinomas Are a Distinct Clinical and Histologic Entity: A 10-Year Follow-up

International audienceBackground: Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor with 50% risk of metastases at initial diagnosis or at follow-up. An inactivation of the tumor-suppressor gene von Hippel-Lindau (VHL) is present in >70% of sporadic cases by two of three different mechanisms: locus deletion, gene mutation, or promoter hypermethylation. Objective: To correlate the complete status of the VHL gene with clinical and pathologic criteria. Design, setting, and participants We retrospectively included 98 patients with ccRCC who underwent surgery between 2002 and 2005. VHL gene deletions (71 of 98; 72.4%), mutations (68 of 98; 69.4%), and promoter hypermethylations (13 of 98; 13.3%) were screened by gene copy analysis, gene sequencing, and methylation-specific multiplex ligation-dependent probe amplification, respectively. Outcome measurements and statistical analysis Relationships between VHL subgroups and the studied criteria were analyzed using chi-square and Student t tests. Survival was analyzed with the log-rank test and Kaplan-Meier curves. Results and limitations: Compared with ccRCCs with two events (66.3%), tumors with no or one genetic event (33.6%) were associated with a higher nuclear grade IV (p = 0.02), metastases (p = 0.04), sarcomatoid component (p = 0.01), dense lymphocyte infiltrate (p = 0.013), and vascular endothelial growth factor overexpression (>30%) (p = 0.003), which was also an independent factor after multivariate analysis. Furthermore, wild-type VHL tumors (no inactivating event, 11.2%) were associated with nodal involvement (p = 0.019), and patients with this type of tumor had a specific survival of 33 mo compared with patients with ccRCCs having one or two VHL inactivating events (107 mo; p = 0.016). The retrospective design with small number of wild-type tumors was a limitation of this work. Conclusions: This long-term study (10-yr clinical follow-up) confirms that ccRCCs with wild-type VHL are highly aggressive tumors that need to be formally identified. Patient summary Among activated VHL tumors, the wild-type subgroup defines an aggressive phenotype with worse survival rates, suggesting that these tumors must be more thoroughly screene

Cytoreductive Nephrectomy in the Tyrosine Kinase Inhibitor Era: A Question That May Never Be Answered.

Despite great interest, two randomised controlled trials (RCTs) of cytoreductive nephrectomy in the tyrosine kinase inhibitor setting in metastatic renal cell carcinoma have either closed early (SURTIME) or are recruiting very slowly (CARMENA) after 7 yr. Challenges in RCT delivery in uro-oncologic surgery are many. Multiple steps are needed to ensure strong recruitment to trials addressing important urologic cancer questions. Feasibility/pilot studies are key stepping stones towards successful delivery of surgical RCTs.CARMENA is sponsored by Assistance Publique-Hôpitaux de Paris (APHP). CARMENA-UK was funded by Cancer Research UK and administered by the CRUK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow. SURTIME was sponsored by the European Organisation for Research and Treatment of Cancer (EORTC)

Dendritic cells are defective in breast cancer patients: a potential role for polyamine in this immunodeficiency

INTRODUCTION: Dendritic cells (DCs) are antigen-presenting cells that are currently employed in cancer clinical trials. However, it is not clear whether their ability to induce tumour-specific immune responses when they are isolated from cancer patients is reduced relative to their ability in vivo. We determined the phenotype and functional activity of DCs from cancer patients and investigated the effect of putrescine, a polyamine molecule that is released in large amounts by cancer cells and has been implicated in metastatic invasion, on DCs. METHODS: The IL-4/GM-CSF (granulocyte–macrophage colony-stimulating factor) procedure for culturing blood monocyte-derived DCs was applied to cells from healthy donors and patients (17 with breast, 7 with colorectal and 10 with renal cell carcinoma). The same peroxide-treated tumour cells (M74 cell line) were used for DC pulsing. We investigated the effects of stimulation of autologous lymphocytes by DCs pulsed with treated tumour cells (DC-Tu), and cytolytic activity of T cells was determined in the same target cells. RESULTS: Certain differences were observed between donors and breast cancer patients. The yield of DCs was dramatically weaker, and expression of MHC class II was lower and the percentage of HLA-DR(-)Lin(- )cells higher in patients. Whatever combination of maturating agents was used, expression of markers of mature DCs was significantly lower in patients. Also, DCs from patients exhibited reduced ability to stimulate cytotoxic T lymphocytes. After DC-Tu stimulation, specific cytolytic activity was enhanced by up to 40% when DCs were from donors but only up to 10% when they were from patients. IFN-γ production was repeatedly found to be enhanced in donors but not in patients. By adding putrescine to DCs from donors, it was possible to enhance the HLA-DR(-)Lin(- )cell percentage and to reduce the final cytolytic activity of lymphocytes after DC-Tu stimulation, mimicking defective DC function. These putrescine-induced deficiencies were reversed by treating DCs with all-trans retinoic acid. CONCLUSION: These data are consistent with blockade of antigen-presenting cells at an early stage of differentiation in patients with breast cancer. Putrescine released in the microenvironmement of DCs could be involved in this blockade. Use of all-trans retinoic acid treatment to reverse this blockade and favour ex vivo expansion of antigen-specific T lymphocytes is of real interest

Toward Standardized Anatomical Classifications of Small Renal Tumors.

International audienc

Incidental renal tumours.

International audiencePURPOSE OF REVIEW: To analyze the current literature regarding incidental finding of renal cell carcinoma (RCC). RECENT FINDINGS: RCC incidence rates continue to rise among all racial, age, tumour size categories, with the most rapid increase for localized disease and small tumours. In parallel, it seems that mortality from RCC decreases in all these groups. Computed tomography guided tumour biopsies are gaining more accuracy and acceptance, whereas minimal invasive treatments such as cryoablation or radiofrequency ablation are competing with nephron-sparing surgery in certain patient categories. Finally, active surveillance is emerging as a new management modality for elderly patients with small renal masses. SUMMARY: The emergence of incidental diagnosis of renal tumours which is related to the widespread use of imaging has played a pivotal role in the increased incidence of RCC and therefore potentially in improving survival in localized disease. However, a significant proportion of treated tumours are benign or undetermined and active surveillance has proven safe in selected patients. There is the risk in widening the treatment armamentarium that a certain number of patients are overtreated. In conclusion, accurate tools are needed for a proper selection of patients with incidentally detected tumours, so that they can benefit from nephron-sparing surgery, ablative therapies or observation

Facteurs prédictifs de récidive locale après néphrectomie partielle pour cancer du rein

BACKGROUND : Ipsilateral recurrence after Nephron Sparing Surgery (NSS) is rare and little is known about its specific determinants. OBJECTIVE : To determine clinical or pathologic features associated with ipsilateral recurrence after NSS performed for renal cell carcinoma (RCC). DESIGN, SETTINGS AND PARTICIPANTS : 809 NSS procedures for sporadic RCCs, performed at 8 academic institutions, were retrospectively analyzed. MEASUREMENTS : Age, gender, indication, tumour bilaterality, tumour size, tumour location, TNM stage, Fuhrman grade, histological subtype and presence of positive surgical margins (SM) were assessed as predictors for recurrence in univariate and in multivariate analysis by using a Cox proportional hazards regression model. RESULTS AND LIMITATIONS : Among 809 NSS procedures with a median follow-up of 27 (1-252) months, 26 ipsilateral recurrences (3.2 %) occured at a median time of 27 (14.5 - 38.2) months. In univariate analysis, the following variables were significantly associated with recurrence : pT3a stage (p = 0.0489), imperative indication (p 4 cm (p 4 cm and presence of positive SM remained independent predictive factors for RCC ipsilateral recurrence. Hazard ratios were 6.31, 4.57 and 11.5 for tumour bilaterality, tumoour size > 4 cm and positive SM status, respectively. Main limitations of this study included its retrospective nature and a short follow-up. CONCLUSION : RCC ipsilateral recurrence risk after NSS is significantly associated with tumour size > 4 cm, tumour bilaterality (synchronous or asynchronous) and positive SM. Careful follow-up should be advised in patients presenting such characteristics.INTRODUCTION : La récidive locale après néphrectomie partielle (NP) pour cancer du rein est un événement rare dont les déterminants et facteurs de risques potentiels sont méconnus. OBJECTIF : Définir les facteurs cliniques ou histopathologiques associés à la récidive locale dans les suites d'une chirurgie conservatrice réalisée pour cancer du rein. MATERIEL ET METHODES : Nous avons constitué auprès de 8 centres hospitaliers universitaires, une cohorte rétrospective de 809 patients présentant un carcinome à cellules rénales sporadique traité par NP. Les valeurs prédictives en termes de récidive locale, de variables cliniques et histopathologiques telles que l'âge, le sexe, l'indication opératoire, la taille, la bilatéralité ou la localisation tumorales, le stade TNM, le sous-type histologique, le grade de fuhrman et le statut des marges chirurgicales ont été évaluées en analyses uni puis multivariée à l'aide d'un modèle de régression de Cox. RESULTATS : Parmi les 809 procédures analysées et avec un suivi médian de 27 (1-252) mois, 26 récidives locales (3,2 %) sont apparues dans un délai de 27 (14,5-38,2 mois). En analyse univariée, le stade pT3a (p = 0.0489), l'indication opératoire de nécessité (p 4 cm (p = 3 (p = 0,0185) et un statut desmarges chirurgicales positif (p = 4 cm, la bilatéralité tumorale (synchrone ou asynchrone) et la présence d'une marge chirurgicale positive sont des facteurs de risque indépendants de récidive locale d'un cancer du rein traité par NP. Un suivi attentif et prolongé de ces patients devrait être recommandé.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Valeur pronostique du dosage des polyamines eryhtrocytaires dans l'évaluation pré-opératoire et post-opératoire des patients atteints d'un cancer du rein

ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Intérêt de la néphrestomie partielle pour la préservation de la fonction rénale des patients présentant une tumeur rénale de plus de 4 cm (une étude multicentrique française)

RENNES1-BU Santé (352382103) / SudocSudocFranceF