Development of a preclinical model of donation after circulatory determination of death for translational application

BACKGROUND: Extracorporeal membranous oxygenation is proposed for abdominal organ procurement from donation after circulatory determination of death (DCD). In France, the national Agency of Biomedicine supervises the procurement of kidneys from DCD, specifying the durations of tolerated warm and cold ischemia. However, no study has determined the optimal conditions of this technique. The aim of this work was to develop a preclinical model of DCD using abdominal normothermic oxygenated recirculation (ANOR). In short, our objectives are to characterize the mechanisms involved during ANOR and its impact on abdominal organs. METHODS: We used Large White pigs weighing between 45 and 55 kg. After 30 minutes of potassium-induced cardiac arrest, the descending thoracic aorta was clamped and ANOR set up between the inferior vena cava and the abdominal aorta for 4 hours. Hemodynamic, respiratory and biochemical parameters were collected. Blood gasometry and biochemistry analysis were performed during the ANOR procedure. RESULTS: Six ANOR procedures were performed. The surgical procedure is described and intraoperative parameters and biological data are presented. Pump flow rates were between 2.5 and 3 l/min. Hemodynamic, respiratory, and biochemical objectives were achieved under reproducible conditions. Interestingly, animals remained hemodynamically stable following the targeted protocol. Arterial pH was controlled, and natremia and renal function remained stable 4 hours after the procedure was started. Decreased hemoglobin and serum proteins levels, concomitant with increased lactate dehydrogenase activity, were observed as a consequence of the surgery. The serum potassium level was increased, owing to the extracorporeal circulation circuit. CONCLUSIONS: Our ANOR model is the closest to clinical conditions reported in the literature and will allow the study of the systemic and abdominal organ impact of this technique. The translational relevance of the pig will permit the determination of new biomarkers and protocols to improve DCD donor management

Les complications génito-urinaires de la curiethérapie de prostate pour cancer (analyse de l'expérience de l'Hôpital Saint-Louis (Paris))

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

Troubles du bas appareil urinaire et de la statique pelvienne chez les candidats et receveurs d’une transplantation rénale

International audienceOBJECTIVES:To describe lower urinary tract symptoms (LUTS) and their management in renal transplant candidates and recipients.MATERIAL AND METHODS:Relevant publications were identified through Medline (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) database using the following keywords, alone or in association: "transplantation", "prostate hyperplasia", "transurethral resection of prostate", "urinary incontinence", "LUTS", "pelvic floor dysfunction". Articles were selected according to methods, language of publication and relevance. The reference lists were used to identify additional historical studies of interest. Both prospective and retrospective series, in French and English, as well as review articles and case reports were selected. In addition, French national transplant and health agencies (http://www.agence-biomedecine.fr and http://www.has-sante.fr) databases were screened using identical keywords. A total of 991 articles were analyzed and after careful selection, 47 publications were eligible for our review.RESULTS:Reduction of bladder capacity, due to dialysis and anuria, is correlated with dialysis duration. This reduction is reversible after renal transplantation and does not seem to put renal transplant recipients at risk for medical complications. Transplant procedure generally allows restoration of bladder maximal output, normal bladder capacity and compliance. Medical treatment of LUTS related to prostate hyperplasia (BPH) includes alpha-blockers and finasteride. Silodosin and dutasteride have not been evaluated in that setting. Antimuscarinics may be used with caution, and favor the use of solifenacin at 5mg per day. Surgical treatment of BPH requires a preserved urine output, otherwise must be delayed after transplantation; it may thus be performed safely in the early postoperative course. Botulinum toxin injections and surgical treatment of stress incontinence and prolapse are barely reported in this population.CONCLUSION:Precise assessment and optimal management of LUTS in renal transplant candidates and recipients are critical to improve quality of life and to preserve allotransplant function. Literature data lack evidence to propose robust recommendations. However, knowledge of reported specificities in this peculiar setting is mandatory for urologists to provide patients with finest options and optimal treatment timing

La transplantation rénale et ses défis

International audienceOBJECTIVES:To describe kidney transplantation surgical techniques and to propose strategies in high-risk recipients.MATERIAL AND METHODS:Relevant publications were identified through Medline (http://www.ncbi.nlm.nih.gov/) and Embase (http://www.embase.com/) database using the following keywords, alone or in association, "renal transplantation; peripheral arterial disease; obesity; third and fourth transplantation; robotic-assisted kidney transplant; anticoagulant therapy; dual kidney transplant". Articles were selected according to methods, language of publication and relevance. The reference lists were used to identify additional historical studies of interest. Both prospective and retrospective series, in French and English, as well as review articles and case-reports were selected. A total of 1949 articles were analyzed for arterial disease and anticoagulant therapy, 1083 for obesity, 663 for dual kidney transplants, 458 for third and subsequent procedures and 84 for robotic-assisted kidney transplantation. After careful selection, 304 publications were eligible for our review.RESULTS:Surgical assessment of future recipients is a pivotal step to anticipate technical difficulties, to interrupt clopidogrel or direct oral anticoagulants and to propose a revascularization procedure when necessary. Lack of data regarding obese recipients does not allow us to conclude about best surgical care or optimal timing but suggest that an early global management of obesity in chronic kidney disease patients is mandatory to improve access to a successful transplantation. In neurologic bladder and congenital anomalies, urodynamics and bladder function must be assessed prior to the onset of oliguria to intend an early treatment. Urinary diversion may be performed prior to or after transplantation with similar survival outcome and comparable rates of infections. Because of a rigorous selection of donors, the French dual kidney transplant program provides satisfactory outcomes, but fails in convincing surgical teams nationwide. Third and subsequent transplant procedures remain a surgical and immunological challenge, with an increased morbidity and a moderate decline in transplant survival only when donors are extended criteria' with extensive duration of waiting time between procedures. Robotic-assisted kidney transplantation is a recent technique requiring methodical evaluation.CONCLUSION:Kidney transplantation in challenging recipients implies a global understanding of patients' prognosis and benefits versus dialysis, in the context of the attribution of a valuable resource awaited by other patients on waiting list

Treatment with Sunitinib Enabled Complete Resection of Massive Lymphadenopathy not Previously Amenable to Excision in a Patient with Renal Cell Carcinoma.

International audienceWe present a case of previously unresectable lymphadenopathy in a patient with renal cell carcinoma treated with sunitinib. Complete resection of a 15-cm left renal cell carcinoma was initially impossible due to massive retroperitoneal disease and encasement of the great vessels and mesenteric vessels. Residual retroperitoneal disease from a radical nephrectomy was treated with the oral, multitargeted receptor tyrosine kinase inhibitor, sunitinib. Tumour shrinkage following five cycles of treatment allowed uncomplicated complete resection of the lymphadenopathy. Follow-up after 6 mo showed no evidence of disease recurrence

Combined Chemoradiation Therapy With Twice-Weekly Gemcitabine and Cisplatin for Organ Preservation in Muscle-Invasive Bladder Cancer: Long-Term Results of a Phase 1 Trial.: Conservative bladder cancer treatment

International audiencePURPOSE: Concomitant treatment with radiation therapy and cisplatin (CDDP) remains the gold standard for bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC). We present the long-term results of a phase 1 clinical trial to assess the association of twice-weekly gemcitabine with CDDP and radiation therapy in this setting. METHODS AND MATERIALS: Patients with pT2-pT4N0M0 MIBC without hydronephrosis or diffuse carcinoma in situ were enrolled in this study. After maximal transurethral resection of the bladder tumor, patients received concomitant radiation therapy (63 Gy in 1.8 fractions) and chemotherapy (CDDP 20 mg/m²/day over 4 days every 21 days and gemcitabine twice a week). The starting dose of gemcitabine was 15 mg/m² with dose escalation to 20, 25, and 30 mg/m². The primary endpoint was the maximum tolerated dose (MTD). Secondary endpoints included toxicity and tumor control. RESULTS: Fourteen patients were enrolled. Dose-limiting toxicity occurred in 2 patients treated with 30 mg/m² gemcitabine (grade 4 thrombocytopenia and severe impairment of World Health Organization performance status, respectively). Nine patients received the complete chemoradiation therapy protocol. The recommended dose of gemcitabine was 25 mg/m². The median follow-up time was 53 months, and the overall and disease-specific 5-year survival rates were 62% and 77%, respectively. Among the patients who received the complete treatment, bladder-intact survival was 76% at 5 years, and the median overall survival was 69.6 months. CONCLUSIONS: This regimen was well tolerated. The gemcitabine MTD was 25 mg/m². Bladder preservation and disease control were promising. A multicenter phase 2 randomized trial is ongoing

Concurrent treatment with everolimus (RAD001) and hormonoradiotherapy in high-risk locally advanced prostate cancer: Results of a phase I trial.

International audience150 Background: Everolimus is able to stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving everolimus together with hormonotherapy and radiation therapy may kill more tumor cells. Methods: We conducted a phase I trial to evaluate the impact of everolimus (RAD001), an mTOR inhibitor, in patients treated concurrently with radiotherapy (RT) and ablative androgen treatment in high-risk locally advanced prostate cancer. Inclusion criteria were high-risk locally advanced non metastatic prostate cancer defined as clinical stage ≥ T3 or Gleason score ≥ 8 or PSA ≥ 20. The week before the beginning of RT, RAD001 was administered at different dose levels, twice daily, until the last day of irradiation. A nonsteroid antiandrogen was also given for 1 month at the beginning of RT. Prostate and seminal vesicle were irradiated up to 74Gy in 37 fractions of 2Gy with concomitant long-term LHRH analogue. The starting dose of RAD001 was 5mg/d with subsequent dose levels of 7.5 and 10 mg/d. The primary endpoint was the determination of the maximum tolerated dose (MTD). Dose escalation was implemented according to the continual reassessment method (CRM). Results: Fifteen patients were enrolled and 14 were assessable for toxicity and response. Significant toxicities were demonstrated at the 7.5 and 10 mg/d dose levels. Dose-limiting toxicity (DLT) occurred in two patients at dose level 7.5 mg/d and characterized by a grade 3 diarrhea and a grade 3 hydronephrosis due to dehydration and kidney lithiasis. DLT also occurred in two patients at dose level 10 mg/d (grade 3 diarrhea and grade 3 laryngopharyngeal infection). The MTD was reached at 7.5 mg/day (dose-level II). The recommended dose of RAD001 was 5 mg/d. After a median follow-up of 22 months, 12 patients are alive, 1 is dead (not related to cancer) and 2 patients had relapsed. Conclusions: Concomitant hormone-radiotherapy and everolimus is well-tolerated with mucositis, hypercholesterolemia, and urinary disorders. The recommended phase-II trial dose of everolimus in this combined setting is 5 mg/day. Clinical trial information: NCT00943956