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To analyze, in patients with prostate cancer (PC) potentially eligible for active surveillance (AS), whether multiparametric-MRI (mp-MRI) predicts presence of clinically significant cancer on radical prostatectomy (RP) specimen.We identified 77 men with PC eligible for AS (PSA≤15ng/mL, stage≤T2a, Gleason score≤6, up to 3 positive cores, maximal cancer core length≤5mm) who underwent RP between 01/2008 and 08/2015. All patients had prebiopsy mp-MRI followed by systematic±targeted biopsies. For each patient, the likelihood of the presence of cancer on mp-MRI was assigned using Likert scale (1 to 5). The predictive factors for the presence of significant cancer on RP specimen (Gleason score≥7 and/or tumoral maximal diameter10mm) were evaluated using logistic regression.Median age was 61 and median PSA was 6.7ng/mL. Overall, 49 (64%) patients had a positive mp-MRI (score≥3). Clinically significant cancer on RP specimen was found in 45 (58%) patients (69% in MRI-positive patients vs 39% in MRI-negative patients). In multivariate analysis, a positive MRI was a predictive factor for the presence of significant cancer on the surgical specimen (OR=3.0; CI95% [1.01-8.88]; P=0.04), as was age (OR=1.17; CI95% [1.05-1.31]; P=0.004) and PSAD (OR=1.10; CI95% [1.01-1.20]; P=0.02).Mp-MRI is a useful exam for selecting patients eligible for AS even if the situation remains unclear after prostate biopsies including targeted biopsies. Upon confirmation by further studies, mp-MRI should be considered as an independent criterion before entering an AS program.4.

Salvage radical prostatectomy (sRP) for radiorecurrent prostate cancer (PCa) is a challenging procedure. To report our experience with sRP for selected patients with local recurrence after primary treatment for localised PCa.From 2005 to 2015, 24 patients underwent sRP for recurrent PCa in our center and were included in this retrospective study. Local recurrence was suspected by PSA increasenadir+2ng/mL and was confirmed by biopsy. Perioperative complications according to Clavien-Dindo classification, oncological and functional results were analysed.Overall, 24 patients with a median age of 59 years (IQR: 55-60) were included. Median follow-up was 25 months (IQR: 9-26). Procedures were performed with open-retropubic approach in 50 % and robot-assisted laparoscopic approach in 50 %. Overall, 5 (21 %) and 2 (8 %) patients experienced grade≤IIIa and grade≥IIIb postoperative complication, respectively. Surgical margins were positive in 46 % of cases. Three out of 4 patients with postoperatively detectable PSA (0.2ng/mL) had positive surgical margins. Seven patients experienced biochemical recurrence in a median delay of 19 months (9-62). Seventy-one percent (5) of these patients experienced clinical recurrence in a median delay of 24 months (10-113). Severe urinary incontinence (≥3 pads/day) and erectile dysfunction were reported in 25 % and 63 %, respectively.sRP for patients is a feasible procedure with encouraging local control rate and acceptable morbidity. This technique should be discussed as a treatment option for locally recurrent PCa in well-selected patients.4.

Introduction and hypothesis Symptoms of endometriosis of the urinary tract consist of nonspecific signs that are often trivialized. However, late diagnosis may be responsible for an upstream impact. The aim of this study is to describe a population of patients who received ureterovesical reimplantation for deep infiltrating endometriosis. We evaluate the preoperative clinical and radiological symptoms and long-term surgical outcomes. Methods All the endometriotic patients who underwent ureterovesical reimplantation at Lille university hospital between 2003 and 2013 were included retrospectively. Results Seventeen patients were included. Urological symptoms of endometriosis were present in 53% of patients and 29% had a history of urological surgery. Delay between diagnosis and ureteral reimplantation was 64 ± 65 months on average. Forty-seven percent of patients had urinary functional symptoms consisting mainly of lower back pain. The ureteral lesion was known preoperatively and associated with hydroureteronephrosis in 82% of cases. Thirty-five percent of patients had renal atrophy and renal function was impaired in 23% of cases. Mean follow-up was 45 ± 27 months. Forty-one percent of patients presented at least one immediate postoperative complication–fistula, postoperative infection or nerve compression. Also, urinary functional symptoms, dyspareunia and dysmenorrhea were maintained in 47%. Conclusion Ureterovesical reimplantation in a context of endometriosis is major surgery with frequent complications. It requires close collaboration between gynecologists, radiologists and urologists. Prior comprehensive patient information is essential. Diagnosis and early treatment of ureteral endometriosis lesions should help reduce the morbidity of this disease.

Item does not contain fulltext BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

Context The urologic community has embraced robot-assisted laparoscopic radical prostatectomy (RALP) using the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA, USA) as a surgical therapeutic approach to localised prostate cancer (PCa). Safety, efficacy, and potential complications of RALP should be clearly known and emphasised in order to improve outcomes. Objective To provide an overview of the prevention and reduction of complications in RALP to aid the understanding of the multivariable nature of a surgical procedure incorporating highly developed technology. Evidence acquisition The present manuscript is based on a presentation on the prevention of complications in robotic prostatic surgery held at the European Association of Urology Section of Oncological Urology meeting in Vienna, Austria, in January 2010. The scope of this article is such that no attempt has been made to include all available evidence on the topic but rather a selection based on practical considerations. Experience with RALP gained at the Institut Montsouris is also reflected in the body of the manuscript. Evidence synthesis Despite the lack of standardisation when talking about complications, RALP seems to be at least equivalent to laparoscopic radical prostatectomy, and recently, it appears to provide even better results. To prevent complications, RALP should be considered in its entirety from patient evaluation to postoperative care, not just the surgery itself. The surgeon remains the first actor, and no place is left for improvisation. Thus, every step of the procedure must be perfectly understood and mastered. One must remember that years of training stand behind these high levels of control and technique. Conclusions Prevention and management of complications in RALP require a high level of team expertise. Perfect standardisation of the procedure and the communication of the procedure's results are mandatory to lowering the incidence of complications and to facilitating its diffusion to the urologic community.

To assess long term biochemical recurrence free survival after radical prostatectomy according to open, laparoscopic and robot-assisted surgical approach and clinicopathological stage.A cohort study of 1313 consecutive patients treated by radical prostatectomy for localized or locally advanced prostate cancer between 2000 and 2013. Open surgery (63.7%), laparoscopy (10%) and robot-assisted laparoscopy (26.4%) were performed. Biochemical recurrence was defined by PSA0,1ng/mL. The biochemical recurrence free survival was described by Kaplan Meier method and prognostic factors were analysed by multivariable Cox regression.Median follow-up was 57 months (IQR: 31-90). Ten years biochemical recurrence free survival was 88.5%, 71.6% and 53.5% respectively for low, intermediate and high-risk D'Amico groups. On multivariable analysis, the worse prognostic factor was Gleason score (P0.001). Positive surgical margins rate was 53% in pT3 tumours and 24% in pT2 tumours (P0.001). Biochemical recurrence free survival (P=0.06) and positive surgical margins rate (P=0.87) were not statistically different between the three surgical approaches.Biochemical recurrence free survival in our study does not differ according to surgical approach and is similar to published series. Ten years biochemical recurrence free survival for high-risk tumours without hormone therapy is 54% justifying the role of surgery in the therapeutic conversations in this group of tumours.3.

Docetaxel has been the cornerstone in the treatment of castration- resistant prostate cancer (CRPC) since 2004. The recent and almost simultaneous arrival of new and effective molecules - several of which are already available on the market - has added to the CRPC treatment arsenal. Several studies have explored the optimal order in which these new treatments should be administered. The aim of this review was to present their respective predictive and evaluative factors and suggest potential administration sequences.The PubMed medical literature citations database was searched using the following key words: prostate cancer, castration resistant, metastatic, targeted therapy, treatment sequence, immunotherapy and clinical trials. The reports of the most recent European and North American congresses were also included.While no predictive factors have been clearly identified for these new therapies to date, a Gleason score of not less than 8 and one or more chemotherapy sessions seemed to be predictive of lower efficacy for abiraterone. Promising elements for further investigation include the circulating tumour cell count and variation in this count per treatment, ERG mutation status or the intratumoural androgen status. Substitution criteria have not yet been reported but, as is the case with all hormone therapies, changes in PSA levels emerge as a valuable indicator of the efficacy of abiraterone. The best treatment sequence for patients who develop castration-resistance remains to be defined.Although new molecules have recently become available, the experience with their use is limited. Thus, no predictive markers of response rates and treatment outcomes or data concerning the best treatment sequence to use in patients with CRPC are as yet available.

New drugs have recently been developed, through a better understanding of the mechanisms involved in the progression of prostate cancer, including castration-resistant ones (CRPC). This article aims to describe the mechanisms of action of these new hormonal treatments and their major clinical outcomes and development programs.A bibliographic research in French and English using Medline(®) and Embase(®) using the keywords "castration-resistant prostate cancer", "abiraterone acetate", "orteronel", "enzalutamide", and "clinical trials" was performed.the androgen signaling pathway remains the cornerstone of advanced cancers management. Hence, some molecules target the androgen biosynthesis, as abiraterone acetate and orteronel, which are selective inhibitors of the enzyme CYP17. Others act as antagonists of the androgen receptor: the enzalutamide, RNA-509 and ODM201. Finally, galeterone combines the two effects.Progress conferred by these molecules in terms of overall survival and quality of life in patients with metastatic CRPC, suggest that their use at earlier stages of the disease could reduce morbidity and mortality from prostate cancer. Determining the best strategy for sequence or combination therapy to optimize the use of these new molecules should be investigated.

Fc epsilonRI gamma (Fc gamma) is a member of the zeta family of signal transducing molecules that function as components of both the TCR and Fc receptors (FcR). While the majority of thymocytes and T cells express TCRs containing zeta-chain homodimers, certain unique populations of T cells express TCRs that contain both zeta and Fc gamma. To examine the ability of Fc gamma to substitute for zeta-chain in T cell development and function, we introduced a transgene encoding Fc gamma into mice made genetically deficient for zeta-chain (zeta(e)-/-). Analysis of thymocyte development in zeta(e)-/-;Fc gamma Tg mice demonstrated that Fc gamma was able to support the maturation of both gammadelta TCR+ and alphabeta TCR+ T cells. However, positive selection of alphabeta TCR+ thymocytes was less efficient in zeta(e)-/-;Fc gamma Tg mice than in zeta(e)-/- mice reconstituted with zeta-chain. This difference may be due to the fact that Fc gamma contains a single immunoreceptor tyrosine-based activation motif (ITAM) whereas zeta-chain contains three ITAMs. Interestingly, the peripheral T cells that develop in zeta(e)-/- mice reconstituted with Fc gamma are functional and respond to TCR-specific stimuli. These data suggest that Fc gamma and zeta are interchangeable in their ability to mediate T cell development and function, however zeta-chain is more efficient at promoting positive selection and T cell maturation. The difference in efficiency between zeta and Fc gamma may be responsible in part for the unusual developmental and functional properties of T cells that constitutively express Fc gamma as a signaling component of their TCRs.

In France, organ donation refusal rates approach 32% of eligible brain deaths. Outright family refusal represents the primary barrier reason for declining organ donation. This retrospective study evaluated factors influencing this decision.A retrospective chart review at Lille Hospital, France, was conducted on brain-death patients eligible for organ donation between 2010 and 2011. Data were collected regarding patient characteristics, death conditions and reasons for refusal based upon family interview. Descriptive statistic analyses were conducted to identify circumstances associated with family refusal.Of 227 eligible organ donors identified, 70 families (30.8%) refused organ donation. The most frequent reason for refusal was desire to keep the body's wholeness (46.3%), followed by religion (16.4%), mistrust of the medical community (13.4%), and revolt against society (6%). The most common causes of death associated with refusal were brutality and suddenness of death (44.8%), early age (23.9%), denial of death (17.9%), and the family culpability (11.9%). In 30% of cases, the family followed the deceased's wishes before his death.Family refusal remains a significant factor associated with the approximately one third of declined eligible organ donations. This retrospective analysis suggested that the most important cause for refusal was a desire to keep the body's wholeness, and the brutality and suddenness of the potential donor's death. Additional research addressing these factors, and their underlying causes, paired with measures to improve professional training and public awareness are warranted to improve organ donation rates.

Les TNE renales sont rares, de spectre histologique etendu, de pronostic mal determine Nous en rapportons un cas d’exerese complete, mais cependant evolutif. Une femme de 39 ans, sans antecedent, mere d’un enfant, consulte pour douleurs abdominales. Echographie, scanner et IRM montrent une lesion tissulaire bien limitee (45 × 50 × 43 mm), du cote droit d’un rein en fer a cheval, comprimant l’uretere, sans envahissement a distance. La piece d’hemi-nephrectomie correspond a une TNE de 6 cm comportant necrose et emboles vasculaires, marquee par la chromogranine A et la synaptophysine (Ki6710 % ; 13 mitoses/10 champs), classee G2 (OMS 2010–TNE digestives) ou carcinome neuroendocrine a grandes cellules (OMS 1999–TNE pulmonaires), stade pT1b pNx R0 (TNM 2010). Curieusement, une hypertrophie thymique, captant physiologiquement en PET-FDG est constatee comparativement au scanner preoperatoire, mais l’imagerie et les dosages post-operatoires des marqueurs neuro-endocrines sont normaux. La neurone-specific enolase (NSE) initialement a 18 μg/L (N

The aim of this work is to study variations of prostate cancer incidence by stage as a function of time and place in a region of France.Retrospective observational survey conducted in five private and public urology centres representative of the various demographic features of the Nord-Pas-de-Calais region. In each centre, the medical records of the first 25 cases of prostate cancer diagnosed in 1998, 2002 and 2004, identified from histology laboratory data, were studied by means of a case report form evaluating the circumstances of diagnosis, PSA level, grade, stage (TNM 97, classification) and initial management.This analysis was based on 123, 124 and 125 patients in five centres in 1998, 2002 and 2004, respectively. The age at diagnosis ranged from 71.14 to 68.9 years between 1998 and 2004 (p=0.054). Median PSA decreased over this six-year period from 18 to 10.8 ng/ml. Between 1998 and 2004, the percentage of patients with localized cancer (PSA20 ng/ml) increased from 44.8 to 66.4% (p0.05), the percentage of patients with locally advanced cancer (PSA between 20 and 50 ng/ml) decreased from 17 to 9.6% (p0.05), the percentage of patients with regional or distant metastatic disease (N1 and/or M1 and/or PSA50 ng/ml) decreased from 29.4 to 22.4% (p0.05) and the percentage of patients receiving curative treatment increased from 30 to 54.4% (p0.005).The prostate cancer incidence by stage varied between 1998 and 2004, with a significantly higher proportion of localized stages, which can be explained by the increased use of screening and diagnostic tests. Routine surveys can measure trends and the amplitude of incidence variations in the population of a region. A representative survey conducted in centres throughout France would allow evaluation of national trends between two publications of incidence by stage results in French registries.

Chronic rejection remains a leading cause of allograft loss. Histologically, it is characterized by arterial intimal thickening and parenchymal fibrosis. The immune mechanisms triggering chronic rejection are still uncompletely understood.We performed major histocompatibility complex (MHC) class H-incompatible skin grafts from C-H2bm12 (bm12, H2bm12) into C57BL/6 (C57BL/6, H2b) recipients immunosuppressed with a short course of anti-CD3 monoclonal antibodies to prevent acute rejection.More than 80% of grafts survived for prolonged periods, but eventually all displayed macroscopic and microscopic evidence of chronic rejection. At histology, there was a progressive arterial intimal thickening as well as intense dermal fibrosis. This was accompanied by an inflammatory infiltrate consisting of lymphocytes and macrophages, but also of a considerable number of eosinophils. Mice with chronic rejection were unable to generate anti-donor MHC class II cytotoxic T lymphocyte activity at either 20 or 60 days after transplant. Furthermore, transplantation of bm12 skins on C57BL/6-congenic, Ig knock-out mice was associated with the development of a chronic rejection that was identical to that occurring in wild-type C57BL/6 animals, indicating that alloantibodies are not necessary in this model.(1) Skin grafts may undergo chronic rejection with the characteristic lesions of vasculopathy and fibrosis; (2) chronic rejection of MHC class II-disparate skins may occur in the absence of direct cytotoxic T lymphocyte activity or alloantibodies.

To investigate the consequences of CD40 engagement on the neonatal induction of transplantation tolerance, BALB/c mice were injected at birth with (A/J x BALB/c) F1 spleen cells together with activating anti-CD40 mAb and grafted 4 wk later with A/J skin. Whereas A/J allografts were accepted in mice neonatally injected with F1 cells and control Ab, they were acutely rejected in mice injected with F1 cells and anti-CD40 mAb. Neonatal administration of anti-CD40 mAb resulted in enhanced anti-A/J CTL activity, increased IFN-gamma, and decreased IL-4 production by donor-specific T cells in vitro. Experiments using anti-cytokine mAb and IFN-gamma-deficient mice demonstrated that CD40 ligation prevents neonatal allotolerance through an IFN-gamma- and IL-12-dependent pathway. Finally, we found that newborn T cells express less CD40L than adult T cells upon TCR engagement. Taken together these data indicate that insufficiency of CD40/CD40L interactions contribute to neonatal transplantation tolerance.

Mast cells and basophils, which are activated by IgE and allergens through the high affinity IgE receptor (Fc epsilon RI), play a prominent role in anaphylaxis in the mouse. Mice deficient in this receptor become resistant to passive anaphylaxis. As a first step in developing an in vivo model that more closely mimics the IgE-mediated responses in man, we used a combination of transgenic and embryonic stem cell technology to generate a mouse line in which the murine Fc epsilon RI alpha-chain has been replaced with its human homologue. We demonstrate here that these mice express a tetrameric high affinity IgE receptor, in which the human alpha-chain associates with the murine beta- and gamma-chains, and that upon triggering with relevant Ag, this receptor mediates the initiation of the expected intracellular events. In addition, we show that the human alpha-chain restores an anaphylactic response to the nonresponsive alpha-deficient parental mouse line. This "humanized" mouse represents a potentially important model system, not only for studying the role of IgE in human immune responses, but also for testing potential therapeutic reagents that can interfere with responses mediated through the human Fc epsilon RI receptor.

The hamster mAb 145-2C11 specific for the CD3 complex of murine T lymphocytes shares many properties with OKT3, including the induction of T cell activation. In vivo, the injection of 145-2C11 entails a variety of pathologic changes in relation to the systemic release of cytokines. We tested the effects on this cytokine release syndrome of different doses of methylprednisolone (m-PDS) given at various intervals of time before the 145-2C11 mAb. The administration of high doses of m-PDS (50 mg/kg) 2 to 3 h before the mAb resulted in an almost complete inhibition of the systemic release of TNF-alpha, IL-2, and IL-6. As far as the pathologic changes are concerned, the hypothermia, the acute renal tubular necrosis, and the fatty infiltration of the liver were completely prevented whereas the hypoglycemia was only partially attenuated. The protective effect of m-PDS on the toxicity of 145-2C11 was confirmed by the reduction of the mortality rate among galactosamine-sensitized mice. The inhibition of the release of cytokines by m-PDS did not affect the immunosuppression triggered by 145-2C11 as assessed by the CTL activity against alloantigens measured 48 h after the injection of the mAb. We conclude that the administration of very high doses of glucocorticoids 2 to 3 h before 145-2C11 prevents the release of cytokines and attenuates the acute toxicity of the mAb. Similar protocols could allow mitigation of the cytokine-release syndrome induced by the OKT3 mAb in man.

Recently, functional heterogeneity among Th cells has been recognized. Based on pattern of lymphokine secretion, two mutually exclusive subsets of CD4+ cells have been defined and designated Th1 (secreting IL-2 and IFN-gamma) and Th2 (secreting IL-4 and IL-5). Identification of these subsets was mostly based on the study of long term cultured T cell lines and clones, and little is known about the Th heterogeneity in vivo. In particular, it has been suggested that IL-4 producing cells cannot be detected in vivo or in primary stimulations in vitro unless responder cells had been previously primed. Our data however, indicate that anti-CD3 mediated stimulation can induce T cells isolated from unprimed animals to IL-4 production. An assay system based on the ability of IL-4 to increase Ia expression of B cells present in the environment of activated T cells was found to be more sensitive than detection of secreted IL-4 in the supernatant by conventional bioassays and was used to study IL-4 production by unprimed lymphocytes polyclonally stimulated in vivo and in vitro by anti-CD3 mAb. The results obtained indicate that CD4+ CD8- T cells able to produce IL-4 upon receptor-specific stimulation exist in the preimmune pool of adult animals. Remarkably, these cells can also be stimulated in vivo by treating animals with anti-CD3 mAb, as indicated by the in vivo induction of IL-4 specific mRNA and hyper-Ia expression on B cells. These results indicate that the inability to detect IL-4 in primary cultures is not due to different activation requirements of Th2 cells but may simply result from their lower frequency in unprimed animals.