Artificial intelligence to improve cytology performance in urothelial carcinoma diagnosis: results from validation phase of the French, multicenter, prospective VISIOCYT1 trial.

PURPOSE: Cytology and cystoscopy, the current gold standard for diagnosing urothelial carcinomas, have limits: cytology has high interobserver variability with moderate or not optimal sensitivity (particularly for low-grade tumors); while cystoscopy is expensive, invasive, and operator dependent. The VISIOCYT1 study assessed the benefit of VisioCyt® for diagnosing urothelial carcinoma. METHODS: VISIOCYT1 was a French prospective clinical trial conducted in 14 centers. The trial enrolled adults undergoing endoscopy for suspected bladder cancer or to explore the lower urinary tract. Participants were allocated either Group 1: with bladder cancer, i.e., with positive cystoscopy or with negative cystoscopy but positive cytology, or Group 2: without bladder cancer. Before cystoscopy and histopathology, slides were prepared for cytology and the VisioCyt® test from urine samples. The diagnostic performance of VisioCyt® was assessed using sensitivity (primary objective, 70% lower-bound threshold) and specificity (75% lower-bound threshold). Sensitivity was also assessed by tumor grade and T-staging. VisioCyt® and cytology performance were evaluated relative to the histopathological assessments. RESULTS: Between October 2017 and December 2019, 391 participants (170 in Group 1 and 149 in Group 2) were enrolled. VisioCyt®'s sensitivity was 80.9% (95% CI 73.9-86.4%) and specificity was 61.8% (95% CI 53.4-69.5%). In high-grade tumors, the sensitivity was 93.7% (95% CI 86.0-97.3%) and in low-grade tumors 66.7% (95% CI 55.2-76.5%). Sensitivity by T-staging, compared to the overall sensitivity, was higher in high-grade tumors and lower in low-grade tumors. CONCLUSION: VisioCyt® is a promising diagnostic tool for urothelial cancers with improved sensitivities for high-grade tumors and notably for low-grade tumors.

Silicone-hydrocoated ureteral stents encrustation and biofilm formation after 3-week dwell time: results of a prospective randomized multicenter clinical study.

OBJECTIVE: To explore the risk of encrustation and biofilm formation for silicone ureteral stents compared to percuflex polymer stents, through a randomized multicenter study. PATIENTS AND METHODS: Design, setting and participants: A Multicenter, prospective, randomized, single blind, comparative study of hydrocoated silicone stent (Coloplast Imajin® hydro) versus Percuflex™ Plus stent (Boston Scientific), in 141 patients treated by flexible URS for a kidney stone. The study had ethical committee approval in the respective hospitals. Outcome measurements and statistical analysis: Endpoints related to encrustation were biofilm formation and mineral encrustation after a period of 3-week indwelling time. They were evaluated at removal through a scoring scale of ureteral stents encrustation, infrared spectroscopy and optical microscopy of inner and outer surfaces of tips, angles and along the stent's body. Comparison was performed using ANOVA. RESULTS: 119 stents were available after removal for analysis, 56 in the silicone and 63 in the Percuflex TM Plus group. Mean dwelling duration was 21.8 days for silicone, 22.1 days for PercuflexTM Plus. There was significantly more biofilm on Percuflex™ Plus compared to silicone (1.24 ± 0.08 vs 0.93 ± 0.09, p = 0.0021), and more mineral encrustation (1.22 ± 0.10 vs 0.78 ± 0.11, p = 0.0048), respectively. CONCLUSIONS: This multicenter randomized study shows that silicone-hydrocoated stents are less prone to encrustation than PercuflexTM Plus after a 3-week dwelling period and confirms the low encrustation potential of silicone.

Apalutamide, darolutamide and enzalutamide in nonmetastatic castration-resistant prostate cancer: a meta-analysis.

Aim: Comparison of the efficacy/safety/health-related quality of life of apalutamide, enzalutamide and darolutamide in Phase III clinical trials involving patients with nonmetastatic castration-resistant prostate cancer was performed. Materials & methods: Relevant studies were identified by searching PubMed as well as conference abstracts reporting updated overall survival. Three pivotal trials were identified, SPARTAN (apalutamide), PROSPER (enzalutamide) and ARAMIS (darolutamide), and form the basis of this analysis. Results: All three drugs significantly prolonged metastasis-free survival, prostate-specific antigen response and overall survival versus placebo, and were generally well tolerated. Conclusion: Drug selection will likely be influenced by tolerability/safety and other factors, such as the propensity for drug-drug interactions and the presence of comorbidities, that affect the risk-benefit balance in individual patients.

Effects of Silicone Hydrocoated Double Loop Ureteral Stent on Symptoms and Quality of Life in Patients Undergoing Flexible Ureteroscopy for Kidney Stone: A Randomized Multicenter Clinical Study.

PURPOSE: We compared the hydrocoated silicone stent (Coloplast Imajin® hydro) to Percuflex™ Plus stent (Boston Scientific) in terms of patient comfort and quality of life after flexible ureteroscopy for stone disease over a 5-week prospective followup. MATERIALS AND METHODS: This is a multicenter, single-blind, prospective, randomized trial of 141 patients treated with flexible ureteroscopy for renal stones. Primary outcome was Ureteral Stent Symptom Questionnaire (USSQ) Body Pain Index recorded before Double-J® stent removal at day (D) 20. Secondary endpoints were USSQ scores at intermediate dates (D2, D7, D20) and 2 weeks after stent withdrawal (D35), occurrence of adverse events and stent encrustation. RESULTS: The trial was completed by 113 (80.1%) patients. Mean (SD) USSQ body pain scores were 25% lower at D20 for the silicone stent at 18.7 (11.4) vs 25.1 (14.2) (p=0.015). No difference in terms of adverse events and safety profile was observed. USSQ urinary symptoms scores at D2, D7 and D20 were lower in the silicone stent group at 26.4 (7.7) vs 31.8 (8.1) at D20 (p <0.001). The use of USSQ self-questionnaires was associated with a limited number of missing or incomplete answers. CONCLUSIONS: The primary results of this large sample prospective randomized controlled study comparing the silicone Imajin hydro stents to the Percuflex Plus stent show that silicone stents are associated with significantly less patient discomfort. We would recommend their use in patients who require stenting for stone disease.

Radical Prostatectomy after Vascular Targeted Photodynamic Therapy with Padeliporfin: Feasibility, and Early and Intermediate Results.

PURPOSE: Vascular targeted photodynamic therapy with TOOKAD® is a new therapeutic option for localized prostate cancer management. The objectives of this study were to assess the feasibility of radical prostatectomy after vascular targeted photodynamic therapy and describe functional and oncologic outcomes. MATERIALS AND METHODS: We retrospectively included in study 45 patients who underwent salvage radical prostatectomy after vascular targeted photodynamic therapy for recurrent prostate cancer at a total of 14 surgical centers in Europe between October 2008 and March 2017. Of the 42 radical prostatectomies performed 16 were robot-assisted, 6 were laparoscopic and 20 were open surgery. Primary end points were morbidity and technical difficulties. Secondary end points were early and intermediate postoperative functional and oncologic outcomes. RESULTS: Median operative time was 180 minutes (IQR 150-223). Median blood loss was 200 ml (IQR 155-363). According to the surgeons the surgery was easy in 29 patients (69%) and difficult in 13 (31%). Nerve sparing was feasible in 14 patients (33%). Five postoperative complications (12%) were found, including 2 Clavien I, 2 Clavien II and 1 Clavien IIIB complications. Of the cases 13 (31%) were pT3 and 21 (50%) were pT2c. Surgical margins were positive in 13 patients (31%). Prostate specific antigen was undetectable at 6 to 12 months in 37 patients (88%). Nine patients underwent complementary radiotherapy. Four patients had final prostate specific antigen greater than 0.2 ng/ml at a median followup of 23 months (IQR 12-36). At 1 year 27 patients (64%) were completely continent (no pads) and 10 (24%) had low incontinence (1 pad). Four patients (11%) recovered potency without treatment and 23 (64%) recovered potency with appropriate treatment. CONCLUSIONS: Salvage radical prostatectomy after vascular targeted photodynamic therapy treatment was feasible and safe without difficulty for most of the surgeons.

Down-regulation of A-FABP predicts non-muscle invasive bladder cancer progression: investigation with a long term clinical follow-up.

BACKGROUND: Non-muscle invasive bladder cancers (NMIBC: pTa, pT1) are characterised by a high risk of recurrence and/or progression. Identification of prognostic markers is needed to improve both diagnosis and management of the disease. The aim of this study was to analyse the expression of A-FABP (adipocyte-fatty acid binding protein) and to evaluate its prognostic value in bladder cancer with a long term clinical follow-up. METHODS: A-FABP expression was investigated by immunohistochemistry in 236 tumours (114 pTa, 61 pT1, 61 pT2-4). Immunostaining was classified as negative (absent or weak immunostaining and moderate or strong staining on ≤10% of cells) or positive (moderate or strong staining on > 10% of cells). Event-free survival (EFS) and overall survival (OS) were determined with a 87.3 months median follow-up in the overall cohort. Recurrence-free survival (RFS) and progression-free survival (PFS) were established in NMIBC. RESULTS: Loss of A-FABP was associated with higher mean age, high stage/grade, and the presence of metastatic lymph nodes. It was correlated with shorter median EFS (17.5 vs 62.5 months; p = 0.001) and mean OS (76.7 vs 154.2 months; p = 0.009) and with higher risk of progression in the pTa/pT1 subgroup (HR, 0.36; 95% CI, 0.13-0.96; p = 0.041) and importantly in the pTa tumours (HR, 0.34; 95% CI, 0.10-0.97; p = 0.045). CONCLUSION: These results demonstrated that loss of A-FABP expression following a long follow-up was predictive of pTa and pTa/pT1 progression. Immunohistochemistry on diagnostic biopsy is easy to use and could be of value to help clinicians to propose appropriate treatment for these tumours.

Testicle-sparing surgery versus radical orchiectomy in the management of Leydig cell tumors: results from a multicenter study.

OBJECTIVE: To compare the oncological outcomes of testicle-sparing surgery (TSS) and radical orchiectomy (RO) in patients with Leydig cell tumor (LCT) of the testis. PATIENTS AND METHODS: A multicenter retrospective clinical study was conducted in 12 centers in France. All the patients with histologically proven LCT were included and analyzed according to treatment (organ-sparing surgery or radical orchiectomy). Patients underwent preoperative clinical, biological and imaging assessment. Demographic, clinical, and pathological variables were collected at baseline and compared between groups according to surgical treatment. Follow-up was calculated using the reverse Kaplan-Meier estimation and was updated at the end of 2015. RESULTS: Between 1986 and 2014, 56 patients presented with LCT were identified and included in the study. Twenty-one patients (37.5%) underwent TSS and 35 (62.5%) RO. Demographics and tumor characteristics were not significantly different between the groups. Median follow-up was 62 months after TSS, but only 35 months after RO. Two patients (9.5%) developed local recurrence 15 and 34 months after TSS and underwent secondary RO. No local recurrence or metastasis was observed after complementary treatment. No recurrence was observed after RO. Disease-free survival did not differ between the groups (95.2% in TSS versus 77.1% in the RO group, p = 0.23). No patient died in the TSS group, but three patients (8.6%) in the RO group died from other diseases without evidence of relapse. One patient (4.8%) in the TSS group versus five (14.3%) in the RO group were lost to follow-up. CONCLUSION: Long-term follow-up suggests that testicle-sparing surgery does not compromise relapse-free survival in the treatment of Leydig cell tumor of the testis.

Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial.

BACKGROUND: Vascular-targeted photodynamic therapy, a novel tissue-preserving treatment for low-risk prostate cancer, has shown favourable safety and efficacy results in single-arm phase 1 and 2 studies. We compared this treatment with the standard of care, active surveillance, in men with low-risk prostate cancer in a phase 3 trial. METHODS: This randomised controlled trial was done in 47 European university centres and community hospitals. Men with low-risk, localised prostate cancer (Gleason pattern 3) who had received no previous treatment were randomly assigned (1:1) to vascular-targeted photodynamic therapy (4 mg/kg padeliporfin intravenously over 10 min and optical fibres inserted into the prostate to cover the desired treatment zone and subsequent activation by laser light 753 nm with a fixed power of 150 mW/cm for 22 min 15 s) or active surveillance. Randomisation was done by a web-based allocation system stratified by centre with balanced blocks of two or four patients. Best practice for active surveillance at the time of study design was followed (ie, biopsy at 12-month intervals and prostate-specific antigen measurement and digital rectal examination at 3-month intervals). The co-primary endpoints were treatment failure (histological progression of cancer from low to moderate or high risk or death during 24 months' follow-up) and absence of definite cancer (absence of any histology result definitely positive for cancer at month 24). Analysis was by intention to treat. Treatment was open-label, but investigators assessing primary efficacy outcomes were masked to treatment allocation. This trial is registered with ClinicalTrials.gov, number NCT01310894. FINDINGS: Between March 8, 2011, and April 30, 2013, we randomly assigned 206 patients to vascular-targeted photodynamic therapy and 207 patients to active surveillance. Median follow-up was 24 months (IQR 24-25). The proportion of participants who had disease progression at month 24 was 58 (28%) of 206 in the vascular-targeted photodynamic therapy group compared with 120 (58%) of 207 in the active surveillance group (adjusted hazard ratio 0·34, 95% CI 0·24-0·46; p<0·0001). 101 (49%) men in the vascular-targeted photodynamic therapy group had a negative prostate biopsy result at 24 months post treatment compared with 28 (14%) men in the active surveillance group (adjusted risk ratio 3·67, 95% CI 2·53-5·33; p<0·0001). Vascular-targeted photodynamic therapy was well tolerated. The most common grade 3-4 adverse events were prostatitis (three [2%] in the vascular-targeted photodynamic therapy group vs one [<1%] in the active surveillance group), acute urinary retention (three [2%] vs one [<1%]) and erectile dysfunction (two [1%] vs three [1%]). The most common serious adverse event in the vascular-targeted photodynamic therapy group was retention of urine (15 patients; severe in three); this event resolved within 2 months in all patients. The most common serious adverse event in the active surveillance group was myocardial infarction (three patients). INTERPRETATION: Padeliporfin vascular-targeted photodynamic therapy is a safe, effective treatment for low-risk, localised prostate cancer. This treatment might allow more men to consider a tissue-preserving approach and defer or avoid radical therapy. FUNDING: Steba Biotech.

Endoscopic lithotripsy and vaginal excision of a calcified bladder-mesh extrusion.

INTRODUCTION AND HYPOTHESIS: Synthetic meshes have proven to increase efficacy of pelvic organ prolapse (POP) repair, but associated complications are not rare. Bladder mesh extrusion is one of the most serious adverse events following POP surgery with mesh. The aim of this video was to describe endoscopic and vaginal approaches for treating a bladder-mesh extrusion. METHODS: A 52-year-old female patient with a history of vaginal POP surgery with mesh was referred for severe pelvic and perineal pain, dyspareunia, and dysuria. She was found to have a bladder calculus on a mesh extrusion. The calculus was removed by endoscopic lithotripsy before vaginal mesh excision was performed. CONCLUSIONS: With the use of synthetic vaginal mesh, the incidence of bladder-mesh extrusion could increase. This didactic video will be helpful to surgeons required to manage such cases using a minimally invasive treatment.

Clinicopathological characteristics of incidental prostate cancer discovered from radical cystoprostatectomy specimen: a multicenter French study.

PURPOSE: The present study assessed the incidence and histopathological features of incidentally diagnosed prostate cancer (PCa) in specimens from radical cystoprostatectomy (RCP) for bladder cancer. The patient outcomes also were evaluated. METHODS: We retrospectively reviewed the histopathological features and survival data of 4,299 male patients who underwent a RCP for bladder cancer at 25 French centers between January 1996 and June 2012. No patients had preoperative clinical or biological suspicion of PCa. RESULTS: Among the 4,299 RCP specimens, PCa was diagnosed in 931 patients (21.7%). Most tumors (90.1%) were organ-confined (pT2), whereas 9.9% of them were diagnosed at a locally advanced stage (≥pT3). Gleason score was <6 in 129 cases (13.9%), 6 in 575 cases (61.7%), 7 (3 + 4) in 149 cases (16.0%), 7 (4 + 3) in 38 cases (4.1%), and >7 in 40 cases (4.3%). After a median follow-up of 25.5 months (interquartile range 14.2-47.4), 35.4% of patients had bladder cancer recurrence and 23.8% died of bladder cancer. Only 16 patients (1.9%) experienced PCa biochemical recurrence during follow-up, and no preoperative predictive factor was identified. No patients died from PCa. CONCLUSIONS: The rate of incidentally diagnosed PCa in RCP specimens was 21.7%. The majority of these PCas were organ-confined. PCa recurrence occurred in only 1.9% of cases during follow-up.

ProACT™ (Uromedica, Plymouth, USA) balloons for male urinary incontinence: A fourteen-year-old cohort.

BACKGROUND: Male urinary incontinence is attributed to SUI consecutive to benign prostate hypertrophy surgery, trauma, neurological diseases, or injury. Medical devices are developed to treat male urinary incontinence among them proACT® balloons. This technique was chosen in our center to achieve continence. Our study aims to evaluate safety and efficacy of proACT® balloons implanted in our center by measuring the rate of efficacy. METHODS: We performed a retrospective and single centre study. A single expert surgeon performed all surgeries. Seventy-one balloons were implanted in 57 male patients between 2007 and 2020. Primary endpoint was the efficacy time lapse of the balloons after surgery. The analysis was performed using Kaplan-Meier method. Factors, which could affect the efficacy of the balloons, were analysed using a Cox regression analysis. RESULTS: In all, 45 balloons successfully cured stress urinary incontinence among the 57 men implanted resulting in a 63.38% success rate. Twenty-six balloons failed to treat stress urinary incontinence and were retrieved out of the 71 implanted. Ten balloons failed to treat urinary stress incontinence without organic cause, 6 balloons deflated, 5 balloons migrated out of the initial implantation site, 2 eroded, and 3 ended up infected. Fifty percent of the balloons were successful for a median time of 95 months. Univariate analysis did not reveal any predictive factor of failure. CONCLUSIONS: Our study showed 50% success rate at 95 months follow-up, therefore allowing a life expectancy of 7.9 years for the balloons. This safe mini-invasive technique ensured stress urinary incontinence in men.

Urinary tract infection after flexible ureterorenoscopy for urolithiasis in patients with positive treated preoperative urinalysis.

Prevalence of kidney stones is increasing worldwide, flexible ureterorenoscopy (f-URS) is the most common surgical treatment. Postoperative urinary tract infection (PUTI) is the primary complication. Some risk factors are classically associated with PUTI, especially preoperative positive urinalysis (POPU). We aimed to identify risk factors for PUTI after f-URS for urolithiasis in patients with treated POPU, and to identify the different pre and postoperative pathogens. Retrospective, single-center study of all f-URS for urolithiasis between January 2004 and December 2020. Procedures with treated POPU were categorized as PUTI or no PUTI (NPUTI). We examined demographics, preoperative, perioperative and postoperative characteristics in each group. Among 1934 procedures analyzed, 401 (20.7%) had POPU; these were categorized into NPUTI (n = 352, 87.8%) and PUTI (n = 49, 12.2%). By univariate analysis, only preoperative stenting duration (76.3 in NPUTI group vs 107.7 days in PUTI group, p = 0.001) was significantly associated with a higher risk of PUTI in univariate analysis. Germ distribution was similar in both groups. We compared pre- and postoperative microbiological data for interventions with PUTI, and found that only 8.7% of pathogens were identical between pre and postoperative urinalysis. Our study shows that the rate of PUTI is higher for patients with a POPU and that preoperative stent duration is the sole risk factor in patients with POPU. The low concordance rate (8.7%) between POPU and post-operative pathogens highlights the need for further research on obtaining sterile preoperative urinalysis, or performing intraoperative culture (urines, stent or stone), to treat PUTI early with an adapted antibiotic therapy.

GW501516-Mediated Targeting of Tetraspanin 15 Regulates ADAM10-Dependent N-Cadherin Cleavage in Invasive Bladder Cancer Cells.

Bladder cancer aggressiveness is correlated with abnormal N-cadherin transmembrane glycoprotein expression. This protein is cleaved by the metalloprotease ADAM10 and the γ-secretase complex releasing a pro-angiogenic N-terminal fragment (NTF) and a proliferation-activating soluble C-terminal fragment (CTF2). Tetraspanin 15 (Tspan15) is identified as an ADAM10-interacting protein to induce selective N-cadherin cleavage. We first demonstrated, in invasive T24 bladder cancer cells, that N-cadherin was cleaved by ADAM10 generating NTF in the extracellular environment and leaving a membrane-anchored CTF1 fragment and that Tspan15 is required for ADAM10 to induce the selective N-cadherin cleavage. Targeting N-cadherin function in cancer is relevant to preventing tumor progression and metastases. For antitumor molecules to inhibit N-cadherin function, they should be complete and not cleaved. We first showed that the GW501516, an agonist of the nuclear receptor PPARß/δ, decreased Tspan15 and prevented N-cadherin cleavage thus decreasing NTF. Interestingly, the drug did not modify ADAM10 expression, which was important because it could limit side effects since ADAM10 cleaves numerous substrates. By targeting Tspan15 to block ADAM10 activity on N-cadherin, GW501516 could prevent NTF pro-tumoral effects and be a promising molecule to treat bladder cancer. More interestingly, it could optimize the effects of the N-cadherin antagonists those such as ADH-1 that target the N-cadherin ectodomain.

Concomitant decrease of E- and A-FABP expression predicts worse survival in urothelial bladder cancer patients.

Non-muscle invasive bladder cancers (NMIBC) pTa-pT1 are depicted by a high risk of recurrence and/or progression with an unpredictable clinical evolution. Our aim was to identify, from the original resection specimen, tumors that will progress to better manage patients. We previously showed that A-FABP (Adipocyte- Fatty Acid Binding Protein) loss predicted NMIBC progression. Here we determined by immunohistochemistry the prognostic value of E-FABP (Epidermal-Fatty Acid Binding Protein) expression in 210 tumors (80 pTa, 75 pT1, 55 pT2-T4). Thus, E-FABP low expression was correlated with a high grade/stage, the presence of metastatic lymph nodes, and visceral metastases (p < 0.001). Unlike A-FABP in NMIBC, E-FABP low expression was not associated with RFS or PFS in Kaplan-Meier analysis. But patients of the overall cohort with a high E-FABP expression had a longer mOS (53.8 months vs. 29.3 months, p = 0.029). The immunohistochemical analysis on the same NMIBC tissue sections revealed that when A-FABP is absent, a high E-FABP expression is detected. E-FABP could compensate A-FABP loss. Interestingly, patients, whose original tumor presents both low E-FABP and negative A-FABP, had the worse survival, those maintaining the expression of both markers had better survival. To conclude, the combined evaluation of A- and E-FABP expression allowed to stratify patients with urothelial carcinoma for optimizing treatment and follow-up.

Young urologists and kidney transplantation training: A survey designed by the French Transplantation Committee of the French Association of Urology (CTAFU) and the French Association of Urologists in training (AFUF).

OBJECTIVE: In France, kidney transplantations (KT) are mainly performed by urologist. Young urologists and residents are involved in this activity mostly performed in emergency. How do they feel about KT training? Is KT an attractive part of the urologist activity? METHODS: This survey has been designed in the form of a questionnaire by the French Committee of Kidney Transplantation (CTAFU) and the French Association of Urologists in training (AFUF). It has been sent by e-mail to all the AFUF members. Interest in KT and performance of the training were evaluated. RESULTS: In total, 126 members filed the form. Among the residents, 51.5% feel secure to perform KT at the end of their residency. KT is considered as an interesting surgery for 92.1% of the participants: 76.5% are willing to get involved in KT during their residency/fellowship. Among the participants, 44% are willing to continue a long-term involvement. Among the residents, 65.9% consider their practical training insufficient: 56.8% have been supervised for a KT performance during their residency and 86% declare a lack of practical training and had a patient-based learning. Among the residents, 92.1% declare an insufficient theorical training. Among the residents, 33.3% say the schedules of transplantation limit their interest in KT. Among the participants, 34.4% receive a transplant bonus in addition to the usual on-call salary. CONCLUSION: Young urologists wish to continue their involvement in KT activity, but improved theoretical and practical training are essential. In addition, the conditions under which this activity is performed and remunerated are a matter of concern.

Loss of central and peripheral CD8+ T-cell tolerance to HFE in mouse models of human familial hemochromatosis.

HFE, an MHC class Ib molecule that controls iron metabolism, can be directly targeted by cytotoxic TCR αß T lymphocytes. Transgenic DBA/2 mice expressing, in a Rag 2 KO context, an αß TCR that directly recognizes mouse HFE (mHFE) were created to further explore the interface of HFE with the immune system. TCR-transgenic mHfe WT mice deleted mHFE-reactive T cells in the thymus, but a fraction of reprogrammed cells were able to escape deletion. In contrast, TCR-transgenic mice deprived of mHFE molecules (mHfe KO mice) or expressing a C282→Y mutated mHFE molecule - the most frequent mutation associated with human hereditary hemochromatosis - positively selected mHFE-reactive CD8(+) T lymphocytes and were not tolerant toward mHFE. By engrafting these mice with DBA/2 WT (mHFE(+)) skin, it was established, as suspected on the basis of similar engraftments performed on DBA/2 mHfe KO mice, that mHFE behaves as an autonomous skin-associated histocompatibility antigen, even for mHFE-C282→Y mutated mice. By contrast, infusion of DBA/2 mHFE(+) mice with naïve mHFE-reactive transgenic CD8(+) T lymphocytes did not induce GVHD. Thus, tolerance toward HFE in mHfe WT mice can be acquired at either thymic or peripheral levels but is disrupted in mice reproducing human familial hemochromatosis.

Positive surgical margins and their locations in specimens are adverse prognosis features after radical cystectomy in non-metastatic carcinoma invading bladder muscle: results from a nationwide case-control study.

OBJECTIVE: To compare the prognoses associated with positive surgical margins (PSMs) according to their urethral, ureteric and/or soft tissue locations in patients with pN0 M0 bladder cancer who have not undergone neoadjuvant chemotherapy. PATIENTS AND METHODS: A retrospective, case-control study was conducted between 1991 and 2011 using data from 17 academic centres in France. A total of 154 patients (cases) with PSMs met the eligibility criteria and were matched according to centre, pT stage, gender, age and urinary diversion method with a population-based sample of 154 patients (controls) from 3651 patients who had undergone cystectomies. The median follow-up period was 23.9 months. Multivariable Cox regression analysis was used to test the effects of PSMs on local recurrence (LR)-free survival, metastatic recurrence (MR)-free survival and cancer-specific survival (CSS). RESULTS: The 5-year LR-free survival and CSS rates of patients with urethral and soft tissue PSMs were lower than those in the control group. A significant decrease in CSS was associated with soft tissue PSMs (P = 0.003, odds ratio = 0.425, 95% confidence interval 0.283-0.647). The prognosis was not affected in cases of ureteric PSMs. CONCLUSIONS: Soft tissue PSMs were associated with poor CSS rates in patients with pN0 M0 bladder cancer. A correlation between urethrectomy and a reduction of the risk of LR in a urethral PSM setting was observed.

Epidemiology and risk factors for febrile ureteral stent-associated urinary tract infections: A prospective observational cohort study.

OBJECTIVES: We aimed to determine the incidence and risk factors of febrile ureteral stent-associated urinary tract infections (FUSAUTI). METHODS: Hospitalized adult patients with ureteral stent (US) placement or exchange were prospectively enrolled. Patients with kidney transplantation of less than one year were excluded. Patients were followed until US removal/exchange or six months after inclusion. RESULTS: Out of 663 patients included in the study, 48 had at least one FUSAUTI (cumulative incidence 7.24%; 95% confidence interval [CI] 5.39-9.48). The incidence rate of FUSAUTI was 9.04 (95% CI 6.67-12.2) per 10,000 US-days. Ten patients (20.8%) experienced sepsis or septic shock. The most frequently isolated microorganisms were Escherichia coli (38%), Enterococcus spp. (14.5%), Candida spp. (9%) and Pseudomonas aeruginosa (9%). In multivariable logistic regression analysis, female gender, an age adjusted Charlson comorbidity index score> 3, an urethral stent placement concomitant with US placement, and a history of urinary tract infection within three months were significantly associated with a higher risk of FUSAUTI. CONCLUSION: After US placement, 7.24% of patients developed at least one FUSAUTI and, in a quarter of cases, a serious infection. Urethral stent placement was the only modifiable risk factor identified. Future interventional studies are needed to reduce FUSAUTI in these patients.

Renal cell carcinoma (RCC) arising in native kidneys of dialyzed and transplant patients: are they different entities?

UNLABELLED: What's known on the subject? and What does the study add? Patients with end-stage renal disease (ESRD) have an increased risk of developing RCC in their native kidneys. The prevalence of RCC is 3-4% in cases of ESRD in dialyzed and/or transplanted patients, which corresponds to a rate 100-times higher than that in the general population. This is the first study, to our knowledge, comparing the characteristics of kidney cancer in the ESRD population according to their dialysis or transplantation status at the time of diagnosis. The differences in stage and survival we observed may be due to differences in surveillance strategies between transplanted and not transplanted patients, nevertheless, the differences in pathological subtypes suggest they could also be due to differences in the tumorigenesis process. OBJECTIVE: • To compare clinical, pathological and outcome features of renal cell carcinomas (RCCs) arising in patients with chronic renal failure (CRF) with or without renal transplantation. PATIENTS AND METHODS: • In all, 24 French University Departments of Urology and Kidney Transplantation participated in this retrospective study comparing RCCs arising in patients with CRF according to their dialysis or transplantation status at the time of diagnosis. • Information about age, sex, symptoms, duration of CRF, mode and duration of dialysis, renal transplantation, tumour staging and grading, histological subtype and outcome were recorded in a unique database. • Qualitative and quantitative variables were compared by using chi-square and Student statistical analysis. Survival was assessed by Kaplan-Meier and Cox methods. RESULTS: • Data on 303 RCC cases diagnosed between 1985 and 2009 were identified in 206 men (76.3%) and 64 women (23.7%). • Transplanted and not transplanted patients accounted for 213 (70.3%) and 90 cases (29.7%), respectively. • In transplant recipients, RCC was diagnosed at a younger age [mean (sd) 53 (11) vs 61 (14) years, P < 0.001), the mean tumour size was smaller [3.4 (2.3) vs 4.2 (3.1) cm, P= 0.02), pT1a stage (75 vs 60%, P= 0.009) and papillary histological subtype (44 vs 22%, P < 0.001) were more frequent than in their dialysis-only counterparts. • Nodal (1 vs 6%, P= 0.03) and distant metastases rates (0 vs 5%, P < 0.001) were significantly increased in patients who had not had a transplant. However, Fürhman grading, symptoms, tumour multifocality or bilaterality, presence of acquired cystic kidney disease, were not significantly different between the groups. • Estimated 5-year survival rates were 97% and 77% for transplanted and not transplanted patients, respectively (P < 0.001). In univariate analysis, presence of symptoms (P= 0.008), poor performance status (P= 0.04), large tumour size, advanced TNM stage (P < 0.001), high Führman grade (P= 0.005) and absence of transplantation (P < 0.001) were all adverse prognostic factors. In multivariate analysis, only T stage remained an independent predictor for cancer-related death (P < 0.001). CONCLUSION: • RCC arising in native kidneys of transplant patients seems to exhibit many favourable clinical, pathological and outcome features compared with those diagnosed in dialysis-only patients. Further research is needed to determine whether it is due to particular molecular pathways or to biases in relation to mode of diagnosis.