Molecular alterations during bladder urothelial carcinogenesis

Le cancer de vessie représente la sixième cause de mortalité par cancer en France. Son incidence a augmenté ces 20 dernières années, mais les taux de survie restent inchangés. La carcinogénèse vésicale fait intervenir différents mécanismes moléculaires qui agissent en réseau comme c’est le cas dans de nombreux cancers. Le développement récent de nouveaux traitements prenant spécifiquement pour cible certaines voies de signalisation apportent de nouveaux espoirs thérapeutiques. Nous nous sommes intéressés dans ce travail à trois axes de recherche pour tenter d’identifier, dans les carcinomes urothéliaux, de nouveaux marqueurs pronostiques moléculaires et de nouvelles cibles thérapeutiques potentielles: l’angiogénèse, la voie de signalisation Hedgehog et les microARNs. Nous avons choisi la RT-PCR quantitative en temps réel à grande échelle permettant d’évaluer le niveau d’expression de nombreux gènes, avec une quantification précise et reproductible des transcrits. L’expression de ces gènes a été corrélée aux données de suivi clinique afin d’identifier de nouveaux biomarqueurs moléculaires prédictifs de l’évolution des tumeurs de vessie.Nous avons ainsi pu démontrer que les niveaux d’expression de certains de ces gènes variaient de façon significative dans les tumeurs de vessie, confirmant le rôle de l’angiogénèse dans la carcinogénèse urothéliale, et plus particulièrement de la voie du VEGF, et suggérant une implication majeure de la voie de signalisation Hedgehog et des microARNs. Par ailleurs, nous avons également pu identifier plusieurs biomarqueurs ayant une valeur pronostique en terme de survie globale dans les tumeurs infiltrantes. C’est le cas du VEGF, qui semble être un biomarqueur moléculaire particulièrement intéressant puisqu’il existe des thérapies ciblées spécifiquement dirigées contre ce ligand ou ses récepteurs avec plusieurs essais cliniques actuellement en cours dans le cancer de vessie. C’est également le cas d’une signature moléculaire associant 3 miARNs (miR-9, miR-182 et miR-200b) ayant une valeur péjorative dans les tumeurs infiltrantes, ouvrant la voie vers de nouvelles stratégies thérapeutiques.L’ensemble de ces études confirment l’intérêt majeur d’une meilleure compréhension des bases moléculaires de la carcinogénèse urothéliale vésicale débouchant sur l’utilisation rationnelle de nouvelles thérapies ciblées dans le cancer de vessie, avec l’espoir d’en améliorer la prise en charge et l’évolution.Bladder cancer is the sixth cause of cancer mortality in France and its incidence is increasing since the last 20 years, with no improvement in survival outcomes. Bladder carcinogenesis involves different molecular mechanisms such as in many cancers. The recent development of new targeted therapies targeting signaling pathways provides new therapeutic hopes.In this work, we choose to study three molecular pathways in order to identify new prognostic markers and new therapeutic targets in urothelial carcinoma: angiogenesis, Hedgehog signaling pathway, and microRNAs. Real-time quantitative RT-PCR was performed to measure simultaneously expression levels of several genes with precise and reproductible RNA quantification. Our results were correlated with clinical outcomes to identify new molecular markers associated with bladder cancer evolution and to guide the potential use of targeted therapies.We were able to demonstrate that expression levels of several transcripts differ significantly in bladder tumors as compared to normal bladder and that some of them may have a prognostic implication. This is the case of VEGF, which appears to be an interesting molecular marker since there are targeted therapies specifically targeting the pathway and several ongoing trials in bladder cancer. The Hedgehog pathway also appears to be altered in bladder tumors, with a ligand-dependent activation. Then, we were able to identify several deregulated microRNAs and describe a molecular 3 miRNA-signature (miR-9, miR-182 and miR-200b) having a prognostic value in muscle-invasive bladder tumors. All these studies confirm the major interest of molecular biology and new targeted therapies in the treatment of bladder cancer, with the hope of improving management and evolution

Facteurs prédictifs du risque d'insuffisance rénale chronique après néphrectomie partielle pour cancer sur rein unique

Objectif : Etudier les facteurs prédictifs d insuffisance rénale chronique (IRC) de patients opérés par néphrectomie partielle (NP) sur rein unique. Patients et méthodes : Entre 1979 et 2010, 259 patients opérés dans 13 centres internationaux ont été inclus. Résultats : Sur l ensemble des patients, 106 (40,9%), 53 (20,5%) et 100 (38,6%) ont été respectivement opérés en ischémie chaude, en ischémie froide et sans clampage pédiculaire. Parmi eux, 30 patients ont évolué vers l IRC de stade 4 ou 5. En analyse multi-variée, Le DFG préopératoire (p<0,0001), l Insuffisance cardiaque (p=0,02), les pertes sanguines (p=0,02) et les complications médicales (p=0,04) étaient des facteurs de risques d IRC. Le clampage pédiculaire, le temps d ischémie chaude et le refroidissement rénal n étaient pas liés à une évolution vers l IRC.Conclusion : Dans cette étude, l évolution de la fonction rénale après NP sur rein unique était essentiellement liée à des facteurs non modifiables.PARIS13-BU Serge Lebovici (930082101) / SudocSudocFranceF

Warm ischaemia: the ultimate enemy for partial nephrectomy?

International audienc

A Giant Paratesticular Liposarcoma: Case Report and Literature Review

Liposarcoma of the spermatic cord (LSC) is a very rare disease. In literature, are reported less than 350 cases. Genitourinary sarcomas account for &lt;5% of all soft-tissue sarcomas and &lt;2% of malignant urologic tumours. An inguinal mass is the clinical presentation, which can mimic a hernia or hydrocele. Since it is such a rare disease, there are insufficient data on chemotherapy and radiotherapy, and in any case, the data come from low-level scientific evidence. Here, we report the case of a patient who came to the observation for a giant inguinal mass, in which a definitive diagnosis was obtained with the histological examination

Encrusted Uretero-pyelitis: Case Report

Encrusted uretero-pyelitis is a rare and serious disease, related to the presence of calcifications in the pelvicalyceal system and ureter, associated with chronic urinary tract infection. In most cases, the causal agent of this infection lithiasis is corynebacterium urealyticum. The specific aspect of calcifications on CT scan can help to suggest diagnosis. To avoid a delay in diagnosis (which is frequent), an accurate exploration by the bacteriologist is crucial. The combination of a glycopeptides antibiotherapy and urine acidification has proved its effectiveness, as described in the medical literature. We report the case of a 77-year-old male patient, successfully treated for a bilateral encrusted uretero-pyelitis by local acidification (Thomas's solution) followed by oral acidification (ammonium chloride)

Les complications de la néphrectomie totale et de la néphrectomie partielle : quelles sont-elles, comment les prévenir et les prendre en charge ?

International audienceINTRODUCTION: Surgical techniques of radical and partial nephrectomy have changed over the last 20years. Indications for partial nephrectomy have widened and mini-invasive surgery (laparoscopy and robotic assistance) has become widely used. However, both still have a significant morbidity. The objective of this article is to review complications of renal surgery and their predictive factors and to offer algorithms of management. METHODS: Recent literature regarding complications of radical and partial nephrectomy was queried using Pubmed engine search. The most relevant articles were analyzed and served as a basis for this work. RESULTS: The literature on complications of radical and partial nephrectomy has a low level of evidence. There are only retrospective series. The most frequent complications of radical nephrectomy occur during surgery in 5-10% of the cases: wound of the pedicle or of an adjacent organ. The management can often be conservative. Laparoscopy has a similar morbidity compare to the open approach but has greatly increased postoperative outcomes and comfort. Partial nephrectomy has a 20% complication rate. Many factors have an impact on the risk of complications (tumor size, inflammation of perirenal fat, access, surgeon experience, centre volume, comorbidities and age of the patient) and must be taken into consideration before advising partial nephrectomy. The two most feared complications of partial nephrectomy are bleeding (per- or postoperative, 10% of the cases) and urinary fistula (<5% of the cases). Robotic assistance is associated with a lower morbidity in many publications. CONCLUSION: Complications after partial and radical nephrectomy are quite frequent but have decreased with the improvement of surgical techniques. French urologists should maintain their interest in novel technologies and simplification of perioperative pathway to further improve patients' outcomes. Copyrigh

Laparoscopic Partial Nephrectomy: Is It Worth Still Performing the Retroperitoneal Route?

Objective. The objective of this study was to compare perioperative, oncologic, and functional outcomes of TLPN (transperitoneal laparoscopic partial nephrectomy) versus RLPN (retroperitoneal). Patients and Methods. From 1997 to 2009, a retrospective study of 153 consecutive patients who underwent TLPN or RLPN for suspicious renal masses was performed. Complications, functional and oncological outcomes were compared between the 2 groups. Results. With a mean followup of 39 and 32 months, respectively, 66 and 87 patients had TLPN and RLPN, respectively. Tumor location was more often posterior in the RLPN and more often anterior in the TLPN. Mean operative time and mean hospital stay were longer in the TLPN group with 190±85 min versus 154±47 (=0.001) and 9.2±6.4 days versus 6.2±4.5 days (<0.05), respectively. Transfusion and urinary fistulas rates were similar in the 2 groups. After 3-year followup, chronic kidney failure occurred in 6 and and 4% (=0.67) in after TLPN and RLPN, respectively. After 3-year followup, recurrence free survival was 96.7% and 96.6% (=0.91) in the TLPN and RLPN groups, respectively. Conclusion. Our study confirmed that TLPN had longer operative time and hospital stay than RLPN. The complication rates were similar. Furthermore, mid-term oncological and functional outcomes were similar

Les complications chirurgicales en urologie adulte : chirurgie de la prostate

International audienceProstate surgery mainly addresses the treatment of the two most common pathologies of the prostate: benign prostatic hypertrophy (BPH), symptomatic or complicated, and prostate cancer (PCa). The objective of this manuscript was to present after review of the literature the main intraoperative and postoperative surgical complications associated with radical prostatectomy and surgery of the BPH whatever the surgical approach. The incidence and type of these complications may vary depending on the patient's comorbidities and the type of surgery. Regarding radical prostatectomy, the main complications are hemorrhagic, digestive and urinary. During or after surgery of BPH, hemorrhagic and urinary complications dominate. The management of these complications relies on general principles based on a low level of evidence, but usually associate a structured diagnostic pathway and an appropriate treatment decision. Copyrigh

Les complications chirurgicales en urologie adulte : chirurgie de la prostate

International audienceProstate surgery mainly addresses the treatment of the two most common pathologies of the prostate: benign prostatic hypertrophy (BPH), symptomatic or complicated, and prostate cancer (PCa). The objective of this manuscript was to present after review of the literature the main intraoperative and postoperative surgical complications associated with radical prostatectomy and surgery of the BPH whatever the surgical approach. The incidence and type of these complications may vary depending on the patient's comorbidities and the type of surgery. Regarding radical prostatectomy, the main complications are hemorrhagic, digestive and urinary. During or after surgery of BPH, hemorrhagic and urinary complications dominate. The management of these complications relies on general principles based on a low level of evidence, but usually associate a structured diagnostic pathway and an appropriate treatment decision. Copyrigh

Development of immunotherapy in bladder cancer: present and future on targeting PD(L)1 and CTLA-4 pathways

International audiencePURPOSE:Over the past 3 decades, no major treatment breakthrough has been reported for advanced bladder cancer. Recent Food and Drug Administration (FDA) approval of five immune checkpoint inhibitors in the management of advanced bladder cancer represent new therapeutic opportunities. This review examines the available data of the clinical trials leading to the approval of ICIs in the management of metastatic bladder cancer and the ongoing trials in advanced and localized settings.METHODS:A literature search was performed on PubMed and ClinicalTrials.gov combining the MeSH terms: 'urothelial carcinoma' OR 'bladder cancer', and 'immunotherapy' OR 'CTLA-4' OR 'PD-1' OR 'PD-L1' OR 'atezolizumab' OR 'nivolumab' OR 'ipilimumab' OR 'pembrolizumab' OR 'avelumab' OR 'durvalumab' OR 'tremelimumab'. Prospectives studies evaluating anti-PD(L)1 and anti-CTLA-4 monoclonal antibodies were included.RESULTS:Evidence-data related to early phase and phase III trials evaluating the 5 ICIs in the advanced urothelial carcinoma are detailed in this review. Anti-tumour activity of the 5 ICIs supporting the FDA approval in the second-line setting are reported. The activity of PD(L)1 inhibitors in the first-line setting in cisplatin-ineligible patients are also presented. Ongoing trials in earlier disease-states including non-muscle-invasive and muscle-invasive bladder cancer are discussed.CONCLUSIONS:Blocking the PD-1 negative immune receptor or its ligand, PD-L1, results in unprecedented rates of anti-tumour activity in patients with metastatic urothelial cancer. However, a large majority of patients do not respond to anti-PD(L)1 drugs monotherapy. Investigations exploring the potential value of predictive biomarkers, optimal combination and sequences are ongoing to improve such treatment strategies