Evaluation de l'expression de la E-cadherine, N-cadherine et de la protéine TWIST dans les tumeurs de vessie à haut risque

Les tumeurs de vessie sont dans 75 % des cas non infiltrantes et parmi celles-ci, 20 à 25 % d'entre elles envahissent la lamina propria (catégorie T 1). Ces tumeurs posent le problème de la récidive mais surtout de la progression vers le mode infiltrant dans 10-30 % des cas avec alors un pronostic réservé. Nous nous intéressons dans cette étude aux tumeurs à haut risque (T1 de haut grade) dont le traitement est un challenge pour l'urologue puisque d'évolution et de pronostic très variables. Des facteurs et des scores pronostiques sont utiles afin d'éviter un retard de recours à la cystectomie sur une tumeur agressive et à l'inverse une prise en charge trop agressive sur une tumeur de faible degré de malignité. Afin d'affiner ces facteurs pronostiques classiques, les recherches s'orientent vers les marqueurs moléculaires : outils pronostiques mais aussi dans l'avenir à l'origine du développement de thérapies ciblées. Nous avons étudié l'expression de la E-cadhérine, de la N-cadhérine et de la protéine TWIST chez 123 patients porteurs d'une tumeur T1 de haut grade. Ces marqueurs sont au coeur de la transition épithélio-mésenchymateuse où la E-cadhérine (marqueur épithélial) peut se transformer en N-cadhérine (marqueur mésenchymateux) avec la protéine TWIST qui est un des régulateurs de cette transition avec un rôle de répresseur de la transcription de la E-cadhérine. La E-cadhérine n'était pas exprimée par 71,5 % des tumeurs et associée à la présence de CIS (p = 0,01), ce qui est un signe d'agressivité, mais elle n'a pas été retrouvée comme marqueur pronostique. Il semble cependant que la perte de son expression soit une condition nécessaire à l'expression de novo de la N-cadhérine. Cette dernière est retrouvée comme le facteur pronostique le plus puissant sur la progression et sur la survie spécifique. La protéine TWIST était aussi retrouvée comme marqueur pronostique de progression (p < 0,02) mais son expression n'était pas liée au tabagisme. La combinaison des 3 marqueurs a permis d'affiner encore le pronostic. Ces résultats significatifs prouvent bien que nous sommes rentrés dans l'aire des marqueurs moléculaires même s'ils sont encore trop peu utilisés en pratique courante dans la décision thérapeutique du fait du manque d'études, de la standardisation de la méthode et de la population cible à définir.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Molecular targeting in the treatment of either advanced or metastatic bladder cancer or both according to the signalling pathways.

International audiencePURPOSE OF REVIEW: An estimated 300,000 new cases of bladder cancer worldwide are diagnosed annually. Although new cytotoxic chemotherapeutic agents for either advanced or metastatic bladder cancer or both are used, no improvement in survival has been observed. Indeed, the 5-year survival rate of metastatic bladder cancer is very low (6%). The target-directed approach is an attractive challenge for treating specific genetic alterations involved in progression and metastasis development. This article aims to describe the new targeted therapies available to cure advanced cancer or metastatic bladder cancer or both according to the signalling pathways potentially involved. RECENT FINDINGS: The rapidly expanding understanding of the pathogenesis of bladder cancer at the molecular level has led to the identification of signalling pathways involved in this disease and provided molecular targets for new biological agents directed against tumorigenesis and progression. The recent results of clinical trials have not only highlighted the need to select patients who could benefit from such a therapy but also the fact that oncology has completely entered into a new era. SUMMARY: Toxic chemotherapeutic agents are slowly being supplemented by a new generation of drugs that recognize specific targets in or on cancer cells. Recent technological advances in pharmacogenomics and proteomics have led to an improvement in identifying biomarkers predictive of response and thereby to identify patients who would be more likely to respond to such a therapy. There is a real hope to improve both the efficiency and the tolerability of bladder cancer treatment

Recherche de marqueurs diagnostiques et/ou pronostiques du cancer de la vessie (étude des mutations des gènes p53/FGFR3 et de l'expression de la E- et de la N-cadhérine)

Les mutations de p53 et FGFR3 définissent 2 voies moléculaires distinctes dans la carcinogenèse vésicale. Les mutations de p53 étaient associées à des tumeurs de haut stade et de haut grade alors que celles de FGFR3 étaient présentes dans les tumeurs de bas stade et de bas grade. Ces mutations étaient retrouvées exclusives. Le tabagisme affecte la nature des mutations de p53 alors qu'il n'a aucune influence sur les mutations de FGFR3. Nous avons évalué la valeur pronostique des mutations de ces deux gènes dans les tumeurs à haut risque T1G3. Les mutations de FGFR3 sont associées à un faible taux de progression et une meilleure survie spécifique. Le phénotype tumoral FGFR3 muté / p53 normal a le meilleur pronostic. La néo-expression de la molécule d'adhérence N-cadhérine à la surface de cellules tumorales est associée à un comportement infiltrant et constitue une cible moléculaire. Son expression tumorale est un facteur de mauvais pronostic.P53 and FGFR3 mutations showed two different molecular pathways in bladder carcinogenesis. We demonstrated that p53 mutations were more frequent in high stage high grade bladder tumors and that smoking influenced the nature of p53 mutations. However, FGFR3 mutations were associated with low stage low grade tumors and as smoking did not have any effect on this gene, it may suggest that FGFR3 mutations were probably endogeneous. Moreover, we investigated the prognostic value of the N-cadherin expression in bladder tumor. N-cadherin was associated with an agressive behaviour of bladder cancer cells and could be considered as a potential molecular target against invasive bladder tumor. In a cohort of 30 patients, we showed that N-cadherin expression was a marker of bad prognosis.PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

[Conservative management of Corynebacterium urealyticum encrusted cystitis]

International audienceThe authors report the case of a 75-year-old patient who developed Corynebacterium urealyticum encrusted cystitis six months after open prostatectomy, complicated by vesicocutaneous fistula, which required bladder catheterization for several days. Encrustation of the bladder wall induced marked bilateral ureteropyelocaliceal dilatation without renal failure. Medical treatment by antibiotic therapy and oral acidification of the urine allowed regression of the plaques and resolution of the dilatation

[Conservative management of Corynebacterium urealyticum encrusted cystitis]

International audienceThe authors report the case of a 75-year-old patient who developed Corynebacterium urealyticum encrusted cystitis six months after open prostatectomy, complicated by vesicocutaneous fistula, which required bladder catheterization for several days. Encrustation of the bladder wall induced marked bilateral ureteropyelocaliceal dilatation without renal failure. Medical treatment by antibiotic therapy and oral acidification of the urine allowed regression of the plaques and resolution of the dilatation

[Urologic cancer in patients with kidney transplantation]

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[Urologic cancer in patients with kidney transplantation]

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[Atypical cysts and risk of renal cancer: value and danger of the Bosniak classification]

International audienceOBJECTIVE: The objective of this study was to devaluate the risk of renal cancer in patients with atypical renal cysts and to compare radiological data used to establish the Bosniak classification with clinical or histological data. MATERIAL AND METHOD: We performed a retrospective study on 37 patients managed in our establishment for atypical renal cyst between January 1995 and April 2003. The following criteria were analysed: gender, age, clinical examination and circumstances of discovery imaging findings, Bosniak classification, treatment modalities and follow-up data. These criteria were compared in two populations according to the presence or absence of associated renal cancer. RESULTS: In this series, 6 patients presented a stage II cyst. No cancer was demonstrated in this group of cysts. Ten patients presented a stage IIF cyst and 2 cancers were detected in this group (i.e. 20%). Fourteen patients presented a stage III cyst, with a cancer in 4 cases (30%) and 7 patients presented a stage IV cyst with 6 cancers (86%). CONCLUSION: The Bosniak classification is currently the reference classification fr the diagnosis of cystic diseases of the kidney. Although stages I and II (cysts with minor changes not requiring surveillance) and stages III and IV (suspicious malignant cysts which require surgical exploration) raise few diagnostic problems, stage IIF (indeterminate cyst requiring radiological surveillance) may be the source of diagnostic difficulties with a risk of missing an associated renal cancer

[Simultaneous embolization of a large arteriovenous fistula and a renal pseudoaneurysm]

International audienceThe authors report the cases of a 41-year-old woman with a large arteriovenous fistula between a branch of the renal artery and the main renal vein in the renal hilum and a peripheral pseudoaneurysm secondary to a knife wound to the kidney. These lesions were successfully treated by embolization. In the light of this case, the authors illustrate the possibility of performing more than one embolization on the same kidney and emphasize the successful embolization of a large, high-flow arteriovenous fistula

N-cadherin as a novel prognostic marker of progression in superficial urothelial tumors.

International audiencePURPOSE: Loss of intercellular adhesion and increased cell motility promote tumor cell invasion and spreading. In bladder cancer, loss or reduced E-cadherin expression has been associated with poor survival, and aberrant expression of N-cadherin has been associated with the invasive phenotype of bladder carcinoma cells. The purpose of this study was to investigate whether N-cadherin expression was associated with the bladder tumor progression. EXPERIMENTAL DESIGN: E-cadherin and N-cadherin expression was evaluated by immunohistochemistry in 101 tumors (pT1 and pT2-T3) and by reverse transcription-PCR analysis and immunohistochemistry in 28 other fresh frozen tumors (pT(a), pT1, and pT2-T3). RESULTS: N-cadherin expression was absent in normal urothelium, appeared in stage pT1, and increased in pT2-pT3 tumors. In most cases, increased N-cadherin expression in invasive tumors was associated with loss of E-cadherin expression. Progression-free survival and multivariate analyses revealed that N-cadherin expression is an independent prognostic marker for pT1 tumor progression. Analysis of the 28 frozen tumors by immunohistochemistry and reverse transcription-PCR showed a good correlation between protein and gene expression in pT1 and pT2-T3 tumors. Interestingly, in pT(a) tumors, N-cadherin was not immunodetected, whereas mRNA was present in 50% of cases. CONCLUSION: Regulatory defects in the N-cadherin promoter, abnormalities at the translational, or protein processing levels could explain the discrepancies between protein and mRNA expression. Most importantly, this study identified N-cadherin as a novel prognostic marker of progression in superficial urothelial tumors. Clearly, N-cadherin acts in an invasive mode in bladder cancer, but whether it has a primary role in urothelial neoplastic progression has yet to be investigated