49 research outputs found
Cytogénétique des carcinomes rénaux [Cytogenetics profiles of renal carcinoma]
National audienc
Cytoplasmic PAR-3 protein expression is associated with adverse prognostic factors in clear cell renal cell carcinoma and independently impacts survival.
International audienceClear cell renal cell carcinomas (ccRCCs) represent 70% of renal cancers, and several clinical and histolopathological factors are implicated in their prognosis. We recently demonstrated that the overexpression of PAR-3 protein encoded by the PARD3 gene could be implicated in renal oncogenesis. The object of this work was to study the association of intratumoral PAR-3 expression with known prognostic parameters and clinical outcome. In this aim, PAR-3 expression was assessed by immunohistochemistry in ccRCC tumors of 101 patients from 2003 to 2005. The immunostaining of PAR-3 was scored either as membranous (mPAR-3) or as both membranous and cytoplasmic (cPAR-3). Cytoplasmic PAR-3 was significantly associated with worse histopathological and clinical prognostic factors: Fuhrman grades 3 and 4, tumor necrosis, sarcomatoid component, adrenal invasion, renal and hilar fat invasion, eosinophilic component, a noninactivated VHL gene, higher tumor grade, lymph node involvement, metastasis, and worse clinical Eastern Cooperative Oncology Group and S classification scores. After multivariate analysis, 2 parameters were independently associated with cPAR-3: necrosis and eosinophilic components. In addition, cPAR-3 patients had shorter overall and progression-free survivals independently from strong prognostic validated factors like metastases. A cytoplasmic expression of PAR-3 is therefore implicated in worse clinical and pathological cancer features in ccRCC and could be useful to identify patients with high-risk tumors
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
Comparative analysis of clear cell renal cell carcinomas and their metastases
Le carcinome Ă cellules claires du rein (ccRCC) est une tumeur trĂšs hĂ©tĂ©rogĂšne. Le taux de mĂ©tastase est de lâordre de 50% et les mĂ©tastases des ccRCC sont peu frĂ©quemment opĂ©rĂ©es. Lâobjectif de la thĂšse est dâune part dâanalyser les facteurs prĂ©dictifs de mĂ©tastases dans la tumeur primitive, et dâautre part de comparer le phĂ©notype des tumeurs primitives et de leurs mĂ©tastases dans le ccRCC par diffĂ©rentes approches histopathologiques et gĂ©nomiques. Parmi les facteurs prĂ©dictifs de mĂ©tastases, la nouvelle classification OMS/ISUP remplace lâancienne classification de Fuhrman. LâintĂ©rĂȘt pronostique de la nĂ©crose tumorale est Ă©galement mis en Ă©vidence. Une tumeur avec un grade donnĂ© associĂ©e Ă la prĂ©sence de nĂ©crose a un pronostic qui se rapproche dâune tumeur de grade plus Ă©levĂ© sans nĂ©crose. Le pourcentage des cellules de grade 4 pourrait Ă©galement contribuer Ă la stratification pronostique des patients. Une diffĂ©rence de survie avec un pronostic dĂ©favorable est observĂ©e pour les tumeurs dont le pourcentage des cellules de grade 4 est plus Ă©levĂ© (>50% vs. <10%). Au niveau molĂ©culaire le statut du gĂšne VHL, gĂšne suppresseur de tumeur inactivĂ© par un « double hit », est impliquĂ© dans le pronostic des patients. Les ccRCC sans aucune altĂ©ration de VHL sont des tumeurs plus agressives, quâil convient dâisoler. Il existe une similaritĂ© morphologique et immunohistochimique entre les mĂ©tastases et la composante de plus haut grade des tumeurs primitives correspondantes. Le profil chromosomique des mĂ©tastases nâest pas totalement superposable Ă celui des tumeurs primitives. Il existe anomalies cytogĂ©nĂ©tiques rĂ©currentes dans des mĂ©tastases de ccRCC Ă des sites diffĂ©rents (+2p, +3q, +5, +8q, +12, +20). LâhĂ©tĂ©rogĂ©nĂ©itĂ© tumorale retrouvĂ©e au niveau des tumeurs primitives est Ă©galement retrouvĂ©e au niveau des mĂ©tastases sous forme dâhĂ©tĂ©rogĂ©nĂ©itĂ© inter- et intra-mĂ©tastatique. Lâanalyse combinĂ©e des profils gĂ©nomiques et transcriptomiques de 14 Ă©chantillons prĂ©levĂ©s au sein dâun ccRCC primitif et de ses mĂ©tastases ont permis dâidentifier trois classes de clones tumoraux distincts, ne suivant aucune logique gĂ©ographique. Enfin il semble exister un phĂ©nomĂšne de multi-colonisation, qui implique non pas un, mais plusieurs clones tumoraux qui pourraient agir conjointement dans le processus mĂ©tastatique.Clear cell renal cell carcinoma (ccRCC) is a heterogeneous tumor. The metastatic rate is 50% and metastases are only rarely surgically excised. The objective of this thesis was to analyze the predictive factors of metastasis in the primary tumor on one hand; and to compare primary and metastatic phenotypes on the other hand. We combined different histopathological and genomic approaches. Considering prognostic factors, the new WHO/ISUP classification replaces the previous Fuhrman grade. The interest of tumor necrosis is also highlighted. A tumor of a certain grade with necrosis has a prognosis that is close to a tumor of higher grade without necrosis. The percentage of grade 4 cells could additionally help in stratifying patients. A significant difference in survival is observed between tumors with more than 50% grade 4 cells and tumors with less than 10%. At a molecular level, the VHL gene status (tumor suppressor gene inactivated by a double hit) could be implicated in the prognosis of patients. ccRCCs with no alteration of the gene are more aggressive tumors that need to be identified. There exists a morphological and immunohistochemical similarity between metastases and the high-grade component in corresponding primary tumors. Moreover, the chromosomal profile of metastases differs from those of the corresponding primary tumors. Recurrent cytogenetic events are observed in different metastatic sites (+2p, +3q, +5, +8q, +12, +20). The tumor heterogeneity phenomenon in primary tumors is also observed in metastases with inter- and intra- metastatic heterogeneity. The combined analysis of transcriptomic and genomic analyses of 14 specimens extracted from a single ccRCC and its metastases divided samples into three classes of sub-clones with no spatial link. We observe a multi-colonization process that implies not only one but several tumor clones that could cooperate in the metastatic process
Is the UICC/AJCC pT2 staging category for clear cell renal cell carcinoma meaningful?
This study was undertaken to determine the association between extrarenal tumor spread and size in a series of well-sampled clear cell renal cell carcinoma (ccRCC). In a series of 917 cases of ccRCC, 178 were >7 cm in maximum extent. Assessment of tumors >7 cm in size showed 72 (40.4%) to have renal sinus infiltration, the tumor infiltrating perirenal fat in 7 (3.9%) cases, and both in 96 (53.9%) cases. In the remaining 3 (1.7%) cases, no extrarenal extension of the tumor was seen. These 3 cases with organ-confined ccRCC were all cystic tumors. Two showed extensive infarction with associated hemorrhage and the presence of a thick investing pseudocapsule, while the third was a cystic ccRCC arising in the upper pole of the kidney. For the ccRCCs in the series that were â€7 cm in maximum extent, division of cases according to tumor size and pT staging category showed an increase in the proportion of tumors showing extrarenal spread with increasing size, ranging from 0% for tumors 6 to 7 cm. The study has shown that for ccRCC, the extrarenal spread of tumor is strongly associated with the size of the primary tumor. The study has also shown that renal sinus invasion and/or perirenal fat infiltration by tumor is commonplace in tumors >7 cm in maximum extent and that tumors of this dimension are rarely organ-confined. These findings provide evidence that the defining features of pT1, pT2, and pT3a staging categories for ccRCC require revision
Characterization of membrane-localized and cytosolic Rac-GTPase-activating proteins in human neutrophil granulocytes: contribution to the regulation of NADPH oxidase
An unusual case of adrenocortical carcinoma with liver metastasis that occurred at 23 years after surgery
International audienceAdrenocortical carcinoma (ACC) is an uncommon and aggressive cancer occurring more frequently in women; local or distant recurrences occur in 80% of cases, typically within 1 year after curative resection. Liver is the preferred metastatic site. Herein, we report the case of a unique liver metastasis from ACC occurring 23 years after the curative prior tumor surgery. A 45-year-old woman was operated in 1991 for adrenocortical stage II without microvascular involvement or capsular infiltration. At that time, no adjuvant treatment was indicated. The initial surgery consisted on a left adrenalectomy with contemporaneous left nephrectomy and regional lymphadenectomy. Five years after surgery, the patient was considered cured. However, 23 years later, the patient presented an atypical right subcostal pain. A 4 cm liver ACC metastasis involving the segment 4 and initially diagnosed as a hemangioma was discovered. A curative resection of the segment 4 was performed. Final pathological examination confirmed the diagnosis of ACC metastasis with a complete R0 resection; no lymph node metastases were observed. This case is the latest metachronous ACC metastasis ever reported in literature. To date, the patient is alive with no signs of recurrence after a post-surgical follow-up of 13 month
Electrical Behavior of Vertical Pt/Au Schottky Diodes on GaN Homoepitaxy
International audienceSchottky barrier diodes on GaN on GaN substrates are fabricated for the purposeof material and technology characterization. The epitaxial layers are grown byMOCVD. IâV measurements as a function of the temperature in the range80â480 K show ideality factor (n) and barrier height (ÏB) variations not following athermionic (TE) model. Consequently, barrier height fluctuations are considered.In the temperature range 280â480 K, an average barrier height of 1.31 eV with arelatively large standard deviation (Ï) of 0.15 eV is extracted using this model. Then(T ) variation is also analyzed in order to extract the field sensibility of 1) themean barrier height variation (Ï2 = -0.1) and 2) the barrier height standarddeviation (Ï3 = -15mV). The corrected Richardson plot usingÏB and Ï values islinear and gives a Richardson constant of 31.5 A cmÂČ KÂČ close to the theoreticalvalue of 26.4 A cmÂČ KÂČ. For a deeper understanding of ÏB fluctuation origins,micro-Raman mapping of the epitaxial layers and deep-level transient spectroscopy(DLTS) are used. ÎŒ-RS mappings show compressive strain for diodeshaving suffered electrical breakdown. DLTS analysis shows the presence of ninelevels whose signatures are extracted and nature discussed