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Among the growing family of inhibitory receptors regulating immunity, sialic acid-binding immunoglobulin domain-containing lectins (Siglecs) have recently emerged as immunoregulatory receptors recognizing sialylated ligands on tumor cell surface. However, their role in the immunoregulation of bladder cancer (BCa) remains unknown. Here, we determined the presence of eight Siglec ligands (SLs) on bladder nontumor and tumor cell lines. S2L, S3L, and S6L were not expressed, and few bladder tumor cell lines expressed S5L and S14L. In contrast, S7L and S10L were upregulated on all bladder tumor cell lines. We found a discrepency in S9L expression by nontumor cell lines, which is however highly expressed by bladder tumor cell lines. Notably, expression of S5L, S6L, and S14L was increased upon bacillus Calmette-Guerin (BCG) infection. Furthermore, we analyzed the expression of Siglecs on T cells from healthy donors and BCa patients. Circulating T cells only expressed Siglec-6, which is upregulated in non-muscle-invasive BCa patients. In addition, BCG therapy induced the overexpression of Siglec-6 by urinary CD8+ T cells. In vitro functional assays suggested that Siglecs may decrease cytotoxic functions of effector CD8+ T cells. Finally, analyses from two BCa datasets (The Cancer Genome Atlas and UROMOL cohorts) showed that Siglec-6 is associated with tumor progression and poor survival. Our findings indicate that Siglec-6 might be a new target for BCa treatments. PATIENT SUMMARY: We investigated the expression of Siglecs, a family of immunoregulatory receptors, in bladder cancer patients. We observed that the expression of Siglec-6 is increased on circulating and urinary T cells of non-muscle-invasive bladder cancer patients. We also showed that Siglec-6 is associated with lower survival in bladder cancer patients and might contribute to bladder cancer recurrence.

Characteristics of UroV1-A and UroV1-B cases

Supplementary Figure S5: Longitudinal evaluation of vaccine-specific T-cells; Supplementary Figure S6: MAGE-A3-specific CD4+ and CD8+ T-cells in each treatment group before vaccination and after 3 and 5 vaccine doses; Supplementary Figure S7: MAGE-A3 specific urine T cells in each treatment group

Purpose: Treatments with cancer vaccines may be delivered as combination therapies for better efficacy. Addition of intravesical immunostimulation with bacteria promotes vaccine-specific T cells in the bladder and tumor-regression in murine bladder cancer models. Here, we determined whether an adjuvanted cancer vaccine can be safely administered with concomitant standard intravesical Bacillus-Calmette-Guérin (BCG) therapy and how vaccine-specific immune responses may be modulated in patients with non-muscle–invasive bladder cancer (NMIBC).Experimental Design: In a nonrandomized phase I open-label exploratory study, 24 NMIBC patients, apportioned in three groups, received 5 injections of a subunit cancer vaccine (recMAGE-A3 protein+AS15) alone or in two combinations of intravesical BCG-instillations. Safety profiles were compared between the three treatment groups, considering single vaccine injections or BCG instillations and concomitant interventions. Immune responses in blood and urine were compared between treatment groups and upon BCG instillations.Results: The mild adverse events (AE) experienced by all the patients were similar to AE previously reported for this vaccine and standard BCG treatment. AEs were not increased by the double interventions, suggesting that BCG did not exacerbate the AE caused by the MAGE-A3 vaccine and vice-versa. All patients seroconverted after MAGE-A3 vaccination. In half of the patients, vaccine-specific T cells were induced in blood, irrespective of BCG treatment. Interestingly, such T cells were only detected in urine upon BCG-induced T-cell infiltration.Conclusions: Cancer vaccines, including strong adjuvants, can be safely combined with intravesical BCG therapy. The increase of vaccine-specific T cells in the bladder upon BCG provides proof-of-principle evidence that cancer vaccines with local immunostimulation may be beneficial. Clin Cancer Res; 23(3); 717–25. ©2016 AACR.

Supplementary Figure S1: Treatment and sampling schedules; Supplementary Figure S2: Patients-flow diagram

Supplementary Figure S3: Urinary levels of cytokines/chemokines/growth factors in individual patients before and after BCG instillations; Supplementary Figure S4: Serum anti-MAGE-A3 IgG titers in each individual patient

Aberrant glycosylation actively contributes to tumor progression and is a key hallmark of cancer. Most of the glycan moieties expressed on the surface of cancer cells are sialic acids that may modulate antitumor immune responses via binding to sialic acid–binding immunoglobulin-like lectins (Siglecs) expressed by immune cells. Here we show that Siglecs may decrease the bladder tumor immune response mediated by natural killer (NK) cells. We observed higher NK cell activity against desialylated bladder tumor cell lines. We therefore determined the expression of nine Siglecs on circulatory NK cells from healthy donors and patients with bladder cancer (BCa). NK cells from blood mainly express Siglec-7, which is highly upregulated in non–muscle-invasive BCa (NMIBC), as well as Siglec-6, albeit at a much lower level. However, both Siglecs are expressed by urinary NK cells from NMIBC patients undergoing bacillus Calmette-Guerin therapy. Ex vivo analysis of Siglec-6 and Siglec-7 expression levels on tumor-infiltrating NK cells (TINKs) from BCa patients showed that only Siglec-7 is expressed by TINKs. Finally, analyses for The Cancer Genome Atlas data set revealed that BCa patients with high expression levels of Siglec-7 have a poor survival rate. This work indicates that Siglec-7 may restrain NK-mediated antitumor immunity in BCa. Patient summary We investigated the expression of proteins called Siglecs in natural killer (NK) cells from patients with bladder cancer. We showed that levels of the protein Siglec-7 in blood, urine, and tumors from patients with bladder cancer are associated with poor clinical outcomes. Thus, Siglec-7 may be involved in the regulation of antitumor immunity mediated by NK cells in bladder cancer.

To evaluate Enhanced recovery after surgery (ERAS®) protocol on oncological outcomes for patients treated with radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB).A prospectively maintained single-institutional database comprising 160 consecutive UCB patients who underwent open RC from 2012 to 2020 was analyzed. Patients receiving chemotherapy and those with a urinary diversion other than ileal conduit were excluded. Patients were divided into two groups according to the perioperative management (ERAS® and pre-ERAS®). The study aimed to evaluate the impact of the ERAS® protocol on survival at five years after surgery using a Kaplan-Meier log-rank test. A multivariable Cox proportional hazards model was used to identify prognostic factors for cancer-specific (CSS) and overall survival (OS).Of the 107 patients considered for the final analysis, 74 (69%) were included in the ERAS® group. Median follow-up for patients alive at last follow-up was 28 months (interquartile range [IQR] 12-48). Five-years CSS rate was 74% for ERAS® patients, compared to 48% for the control population (P = 0.02), while 5-years OS was 31% higher in the ERAS® (67% vs. 36%, P = .003). In the multivariable analysis, ERAS® protocol and tumor stage were independent factors of CSS, while ERAS®, tumor stage so as total blood loss were independent factors for OS.A dedicated ERAS® protocol for UCB patients treated with RC has a significant impact on survival. Reduction of stress after a major surgery and its potential improvement of perioperative patient's immunity may explain these data.

Hematuria is frequently encountered in clinical practice. Its diagnostic spectrum is wide: urinary tract infection, lithiasis, malignant tumor and nephropathy. In the absence of one of these causes, the nutcracker syndrome must be evoked. It results from compression of the left renal vein between the abdominal aorta and the superior mesenteric artery. Knowing how to diagnose it can avoid morbid consequences (chronic renal disease, renal vein thrombosis). In addition to hematuria, its main symptoms are left lumbago, varicoceles, and orthostatic proteinuria. The clinical picture and complementary examinations (ultrasound-doppler, computed tomography angiography, magnetic resonance angiography, and phlebography) generally allow the diagnosis to be made. Treatment varies according to age and severity of symptoms.L’hématurie est fréquemment rencontrée en pratique clinique. Son spectre diagnostique est large : infection urinaire, lithiase, tumeur maligne et néphropathie. En l’absence de l’une de ces causes, le syndrome du casse-noisette doit être évoqué. Il résulte de la compression de la veine rénale gauche entre l’aorte abdominale et l’artère mésentérique supérieure. Savoir le diagnostiquer permet d’éviter des conséquences morbides (maladie rénale chronique, thrombose veineuse rénale). Outre l’hématurie, ses principaux symptômes sont la lombalgie gauche, les varicocèles et la protéinurie orthostatique. Le tableau clinique et les examens complémentaires (échographie-doppler, angioscanner, angio-IRM et phlébographie) permettent généralement de poser le diagnostic. Le traitement varie en fonction de l’âge et de la sévérité des symptômes.

Towards the development of vaccines against urinary tract infections (UTI), we determined the ability of intramuscular (i.m.) immunization to result in antigen-specific antibodies in urine. As a model antigen/vaccine, levels of total and vaccine-specific antibodies were determined in urine as a spin-out study of a phase 1 trial. Non-muscle-invasive bladder cancer (NMIBC) patients at different risks of progression, undergoing intravesical bacillus Calmette-Guérin (BCG) immunotherapy or not, received an adjuvanted recombinant protein vaccine that resulted in high titers of vaccine-specific serum immunoglobulin G (IgG) in all patients, regardless of the risk group. Vaccine-specific IgG and immunoglobulin A (IgA) were detected in urine of half of the patients at low risk of progression NMIBC and in all the intermediary/high- (int/high) risk patients. Vaccine-specific IgG titers were correlated to total urinary IgG levels, the latter being higher in the int/high-risk patients. In contrast, vaccine-specific IgA did not correlate to urinary IgA levels. Furthermore, vaccine-specific antibodies were transiently increased by intravesical BCG instillations. Altogether, our data show that a standard i.m. immunization can effectively induce antigen-specific antibodies in urine, which, upon selection of optimal vaccine targets, may provide protection against UTI. Vaccine-specific IgG titers were dependent on conditions affecting total urinary IgG levels, while production of vaccine-specific IgA in situ might independently contribute to protection against infections in the bladder. PATIENT SUMMARY: Towards the development of vaccines able to protect against urinary tract infections, we examined the potential of the intramuscular vaccination using a model antigen. We found two types of specific antibodies in the urine, which together may locally contribute to protection against infections, thus supporting the use of such a standard immunization route.

BACKGROUND VPM1002BC is a genetically modified Mycobacterium bovis bacillus Calmette-Guérin (BCG) strain with potentially improved immunogenicity and attenuation. OBJECTIVE To report on the efficacy, safety, tolerability and quality of life of intravesical VPM1002BC for the treatment of non-muscle-invasive bladder cancer (NMIBC) recurrence after conventional BCG therapy. DESIGN, SETTING, AND PARTICIPANTS We designed a phase 1/2 single-arm trial (NCT02371447). Patients with recurrent NMIBC after BCG induction ± BCG maintenance therapy and intermediate to high risk for cancer progression were eligible. INTERVENTION Patients were scheduled for standard treatment of six weekly instillations with VPM1002BC followed by maintenance for 1 yr. Treatment was stopped in cases of recurrence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary endpoint was defined as the recurrence-free rate (RFR) in the bladder 60 wk after trial registration. The sample size was calculated based on the assumption that ≥30% of the patients would be without recurrence at 60 wk after registration. RESULTS AND LIMITATIONS After exclusion of two ineligible patients, 40 patients remained in the full analysis set. All treated tumours were of high grade and 27 patients (67.5%) presented with carcinoma in situ. The recurrence-free rate in the bladder at 60 wk after trial registration was 49.3% (95% confidence interval [CI] 32.1-64.4%) and remained at 47.4% (95% CI 30.4-62.6%] at 2 yr and 43.7% (95% CI 26.9-59.4%) at 3 yr after trial registration. At the same time, progression to muscle-invasive disease had occurred in three patients and metastatic disease in four patients. Treatment-related grade 1, 2, and 3 adverse events (AEs) were observed in 14.3%, 54.8%, and 4.8% of the patients, respectively. No grade ≥4 AEs occurred. Two of the 42 patients did not tolerate five or more instillations during induction. Limitations include the single-arm trial design and the low number of patients for subgroup analysis. CONCLUSIONS At 1 yr after treatment start, almost half of the patients remained recurrence-free after therapy with VPM100BC. The primary endpoint of the study was met and the therapy is safe and well tolerated. PATIENT SUMMARY We conducted a trial of VPM100BC, a genetically modified bacillus Calmette-Guérin (BCG) strain for treatment of bladder cancer not invading the bladder muscle. At 1 year after the start of treatment, almost half of the patients with a recurrence after previous conventional BCG were free from non-muscle-invasive bladder cancer (NMIBC). The results are encouraging and VPM1002BC merits further evaluation in randomised studies for patients with NMIBC.

Purpose To compare the clinical outcome of males with low-risk and favorable intermediate-risk prostate cancer managed within a standardized modern protocol of active surveillance. Materials and Methods This was a prospective cohort study with strict and expanded active surveillance criteria in males with prostate cancer. Baseline assessment included multiparametric magnetic resonance imaging (mpMRI), extended systematic biopsy, and software-based MR-targeted biopsy. Follow-up included biannual prostate-specific antigen (PSA) check, mpMRI, and control biopsy once a year for the first 2 years, and afterward mpMRI every 2 years with additional tests as clinically indicated. The primary outcome was the transition rate to active treatment. Results A total of 51 patients were included: 17 (33%) and 34 (67%) followed protocols of strict (study arm 1) and expanded (study arm 2) active surveillance criteria, respectively. Median age and PSA were 65 years (IQR, 60–69 years) and 5.3 ng/mL (IQR, 4.5–7.7 ng/mL), respectively. At baseline, a median of 2 (IQR, 1–3) cores were positive out of 13 (IQR, 12–14) cores; 22 males (43%) had visible mpMRI lesions. Eight males (24%) in study arm 2 had Gleason score 3+4. After a median follow-up of 36 months (IQR, 24–48 mo), no patient in study arm 1 compared with 17 patients (33%) in arm 2 underwent active treatment (p, Graphical Abstract

Objectives To evaluate the utility of in-bore multiparametric magnetic resonance-guided biopsy of the prostate (IB) in patients with visible lesion/s and previous negative software-based multiparametric magnetic resonance imaging/ultrasonography fusion-targeted biopsy of the prostate (FTB). Patients and methods We retrospectively analysed prospectively maintained database including consecutive men undergoing IB from March 2013 to October 2017 in 2 European centres expert in this procedure. We selected men with the following criteria: No previous treatment for prostate cancer (CaP), multiparametric magnetic resonance imaging (mpMRI) lesion(s) PIRADS score ≥ 3, FTB showing no clinically significant cancer (csCaP), and subsequent IB. Patient's characteristics, mpMRI findings, biopsy technique, and histopathological results were extracted. The primary outcome was to determine the detection rate of csCaP, defined as any Gleason pattern ≥ 4. A multivariable analysis was performed to identify predictors of positive findings at IB. Results Fifty-three men were included. Median age was 68 years (interquartile range [IQR] 64–68), median Prostate-Specific Antigen (PSA) was 7.6 ng/ml (IQR 5.2–10.9), and median prostate volume was 59 ml (IQR 44–84). Fifty-six lesions with PIRADS score 3 in 9 cases (16%), 4 in 30 cases (54%), and 5 in 17 cases (30%) were detected. FTB was performed in all cases using a transrectal approach with 3 different platforms (Toshiba, Koelis, and Artemis). Median time between FTB and IB was 3 months (IQR 1–7). A median of 2 cores per lesion were collected with IB (IQR 2–3). No cancer, clinically insignificant and clinically significant cancer were found in 33 (59%), 9 (16%), and 14 (25%) targeted lesions, respectively. Median maximum cancer core length and maximum positive percentage were 9 mm (3–13) and 55% (21%–80%). The only predictor of csCaP on IB was prostate volume (P = 0.026) with an ideal cut-off at 70 ml. Conclusion One in 4 patients with previous negative FTB, IB was able to detect csCaP. According to this study, IB would be of particularly useful in patients with large glands.

Purpose Overexpression of Caveolin-1 has been associated with cancer growth, migration, and metastases in several malignancies, but only few data are available on its role in bladder cancer (BCa). The aim of this study is to validate Caveolin-1 as a prognosticator of recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) in a large cohort of patients treated with radical cystectomy (RC) for BCa. Methods Caveolin-1 expression was evaluated by immunochemistry on a tissue microarray from 424 patients treated with RC for UCB at a single institution. Caveolin-1 was considered overexpressed when at least 50% of the tumor cells stained positively. Univariable and multivariable Cox proportional hazards regression models were used to assess the association of Caveolin-1 expression with RFS, OS, and CSS. Results Overexpression of Caveolin-1 was observed in 116 (27.4%) patients and was associated with lymph node metastasis ( P = 0.003). Median follow-up for patients alive at last follow-up was 129 months (interquartile range [IQR]: 82–178). Patients with overexpression of Caveolin-1 had significant worse RFS, OS, and CSS compared to those with normal expression (log-rank test, P = 0.008, P = 0.001, and P = 0.005, respectively). At multivariable analyses that adjusted for the effects of standard clinicopathologic features, Caveolin-1 remained associated with OS (hazard ratio = 1.47, P = 0.002) and CSS (hazard ratio = 1.42, P = 0.03). Conversely, no association with RFS was found ( P = 0.1). Addition of Caveolin-1 in a model for prediction of survival did not improve the accuracy of the prognostic model. Actually, C-index did not differ among models with or without Caveolin-1 (0.72 for a model predicting RFS, 0.65 for OS, and 0.71 for CSS). Conclusions Caveolin-1 is overexpressed in one-third of patients with BCa treated with RC. Overexpression of Caveolin-1 is significantly associated with OS and CSS, but not with RFS, in patients with BCa treated with RC. However, it is not clinically useful as it does not improve upon the predictive accuracy of survival achieved by pathologic variables alone.

Background and objectives Focal high intensity focused ultrasound (HIFU) is an emerging treatment for selected men with localized prostate cancer. A limitation of HIFU is the absence of a reliable tool to measure treatment effect intraoperatively. Contrast-enhanced ultrasound (CEUS) has been shown to be a promising modality for assessing the extent and boundaries of tissue ablation. The aim of this study was to assess the value of CEUS immediately after focal HIFU. Materials and methods Retrospective analysis of a prospectively maintained registry including consecutive men undergoing focal HIFU (Focal One). Candidates for focal HIFU were treatment naive men with ≥10 years life expectancy, prostate-specific antigen (PSA) ≤ 20 ng/ml, TNM primary tumor, regional lymph nodes, distant metastasis stage ≤ T2c N0 M0 with a multiparametric MRI (mpMRI) visible lesion concordant with histologically proven prostate cancer. CEUS evaluation was performed immediately at the end of the procedure. Based on the surgeon's estimation of CEUS imaging, re-HIFU was performed, followed by another CEUS evaluation. To test our hypothesis, the results of the CEUS were compared to the results of early mpMRI to rule out clinically significant cancer. The concordance between the 2 tests was measured using the Cohen's kappa. The best model including relevant predictors was calculated with CEUS or with mpMRI to determine their respective added value. Results Of 66 men who underwent HIFU, 32 met eligibility criteria. Bifocal treatment was performed in 1 man, increasing the number of treated lesions to 33. Further ablation based on CEUS was delivered intraoperatively to 13 lesions (39%). The positive biopsy rate for clinically significant cancer in the treated zones was 30% (10/33). The negative predictive value of CEUS and early mpMRI was 71% (95% confidence interval: 59%–82%). Concordance between CEUS and mpMRI was significant with a 72.7% agreement (P = 0.001). The model with CEUS showed the best accuracy with an area under the curve of 0.881. Conclusion CEUS has a higher added value compared to early mpMRI in ruling out clinically significant cancer after focal HIFU. It should be evaluated whether the use of CEUS intraoperatively enhances the efficacy of focal HIFU.

Although major improvements in surgical and anesthetic techniques occurred over the past 30 years, radical cystectomy (RC) remains burdened with high morbidity. Postoperative ileus is a concern in open RC, often resulting in prolonged length of stay and increased costs. Strategies to promote bowel function recovery, such as opioid-sparing anesthesia, pain management, early mobilization, oral feeding, and appropriate use of intravenous fluids, are in the forefront. The need for a multidisciplinary approach is also enlightened.

Elderly patients with urologic cancer are often undertreated because of their age. Recently, many studies showed that advanced age is not an absolute contraindication to radical surgery for bladder and prostate cancer patients. For small renal cancers, instead, active surveillance with a close follow-up may be a valid alternative to surgery because of a low risk of progression. Patients' selection remains a crucial step to define the best treatment. This article summarizes the new tendencies of urologic cancer management in elderly patients.Les personnes âgées avec un cancer urologique sont souvent traitées de façon sous-optimale en se basant uniquement sur leur âge avancé. Récemment, plusieurs chercheurs se sont intéressés à cette classe de la population et ont montré que l’âge avancé n’est pas forcément une contre-indication à réaliser une chirurgie majeure. Cependant, l’évaluation des bénéfices et des risques est déterminante car la grande majorité des néoplasies du rein et de la prostate ont une lente évolution et un faible risque de progression, raison pour laquelle, une surveillance active avec des examens réguliers peut donc être la meilleure alternative. La sélection du patient reste une étape cruciale afin de proposer la meilleure option thérapeutique. Cet article résume les nouvelles tendances de prise de charge des 3 pathologies onco-urologiques les plus fréquentes.

The immune system plays a central role in cancer development, showing both anti-tumor and pro-tumor activities depending on the immune cell subsets and the disease context. While CD8 T cells are associated with a favorable outcome in most cancers, only T helper type 1 (Th1) CD4 T cells play a protective role, in contrast to Th2 CD4 T cells. Double positive (DP) CD4 + CD8 + T cells remain understudied, although they were already described in human cancers, with conflicting data regarding their role. Here, we quantified and phenotypically/functionally characterized DP T cells in blood from urological cancer patients. We analyzed blood leukocytes of 24 healthy donors (HD) and 114 patients with urological cancers, including bladder (n = 54), prostate (n = 31), and kidney (n = 29) cancer patients using 10-color flow cytometry. As compared to HD, levels of circulating DP T cells were elevated in all urological cancer patients, which could be attributed to increased frequencies of both CD4 high CD8 low and CD4 + CD8 high DP T-cell subsets. Of note, most CD4 high CD8 low DP T cells show a CD8αα phenotype, whereas CD4 + CD8 high cells express both CD8α and CD8β subunits. Functional properties were investigated using ex-vivo generated DP T-cell clones. DP T cells from patients were skewed toward an effector memory phenotype, along with enhanced Th2 cytokine production. Interestingly, both CD8αα and CD8αβ DP T cells were able to trigger Th2 polarization of naïve CD4 T cells, while restraining Th1 induction. Thus, these data highlight a previously unrecognized immunoregulatory mechanism involving DP CD4 + CD8 + T cells in urological cancers.

Objective To develop a preoperative multivariable decision-making tool to predict nonorgan-confined urothelial carcinoma of the bladder (NOC-UCB) using standard clinical and pathological factors as well as biomarkers of systemic inflammatory response. Materials and Methods We retrospectively analyzed a prospectively maintained single-institutional database comprising 310 patients with clinically N0 M0 UCB who underwent radical cystectomy (RC) with pelvic lymph node dissection without neoadjuvant cisplatin-based chemotherapy (NAC). NOC-UCB was defined as pT3-4/Nany or pTany/N + disease. A predictive nomogram was built based on significant variables in a bootstrap-corrected multivariable logistic regression model. The accuracy was measured by the area under the curve. Decision-curve analysis was used to evaluate the clinical net benefit. Results NOC-UCB was found in 147 (47%) of the 310 patients. On multivariable analysis, T stage at transurethral resection of the bladder, lymphovascular invasion, abnormal imaging, and Glasgow prognostic score (GPS) were all independent predictors of NOC-UCB and formed the basis of the nomogram. By adding the GPS, the accuracy of the nomogram improved by 4.7% to 81.7%. The decision curve analysis showed a net benefit of this model compared with the Green model and the strategies of treating all patients or no patient with NAC. Limitations include the retrospective design and the lack of a validation cohort. Conclusion NOC-UCB at radical cystectomy can be accurately predicted. The accuracy of preoperative models can be improved by adding biomarkers of systemic inflammatory response, such as the GPS. The use of this nomogram may help physicians to accurately identify patients with NOC-UCB who may benefit from NAC.

Conditional estimates provide a dynamic prediction of outcomes but to our knowledge there are no data on nonmuscle invasive bladder cancer. We assessed changes in conditional recurrence and progression rates after transurethral resection of the bladder and explored the prognostic impact of established factors and risk groups with time.We retrospectively analyzed data on 1,292 consecutive patients with newly diagnosed Ta/T1 bladder cancer who underwent transurethral resection of the bladder. Study end points were time to first recurrence and time to progression.The 2-year recurrence rate at baseline was 36%, which improved as a function of the time that patients were free of disease recurrence. After 6, 12, 24, 36 and 48 months the 2-year conditional recurrence rate improved to 31% (14% improvement vs baseline), 22% (39% improvement), 16% (56% improvement), 13% (64% improvement) and 11% (69% improvement), respectively. Comparably, conditional progression rates improved with increasing followup, although relative differences were less distinct. The prognostic impact of established factors and nonmuscle invasive bladder cancer risk groups progressively decreased with time and finally disappeared. However, bacillus Calmette-Guérin had a protective effect on progression even after 3 years. We provide tables with dynamic prognostic information at all analyzed time points.In patients with primary Ta/T1 bladder cancer recurrence and progression rates improve with time. The prognostic impact of established factors and risk groups decreases and finally disappears. The effect of bacillus Calmette-Guérin on progression is long-lasting. Conditional outcome estimates may improve patient counseling and individualize surveillance planning.

Background Prediction of outcomes in patients with renal cell carcinoma (RCC) is crucial for clinical decision-making. The limited accuracy of conventional prognostic factors such as stage and grade may be increased by the use of biomarkers. Objective To evaluate the association of serum adiponectin and leptin and polymorphisms in the leptin and leptin receptor genes with RCC histopathology and prognosis. Design, setting, and participants Adiponectin and leptin levels were measured in preoperative serum samples from 131 consecutive patients with sporadic unilateral RCC. The polymorphisms G–2548A (rs7799039 ) in the leptin gene ( LEP ) and Gln223Arg (Q223R, A668G, rs1137101) in the leptin receptor gene ( LEPR ) were genotyped in 233 patients. Outcome measurements and statistical analysis Multivariable associations with RCC-specific survival were analyzed using Cox models. Results and limitations Median preoperative serum adiponectin was 15.8μg/ml (interquartile range 10.0–23.1). Adiponectin was lower in patients with distant metastases ( p =0.017) or histologic tumor necrosis ( p =0.015). On multivariable analysis adjusted for the effects of variables in the Karakiewicz nomogram, each 1-μg/ml increase in adiponectin was associated with a 8% decrease in the hazard of death from RCC (hazard ratio 0.92, 95% confidence interval 0.86–0.98; p =0.007). The discrimination of the Karakiewicz nomogram increased by 0.6% on inclusion of adiponectin. Leptin levels, LEP G–2548A and LEPR Q223R were not associated with either RCC pathology or outcomes. Limitations include the retrospective study design, the low numbers of patients, and a lack of standardized follow-up. Conclusions This study suggests that lower preoperative serum adiponectin is associated with features of biologically aggressive RCC, metastasis, and survival. Patient summary We assessed the relationship between outcomes and blood levels of adiponectin and leptin and genetic changes in leptin and leptin receptor genes. We found that patients with lower adiponectin levels have more aggressive tumors and poorer survival.

International audience; OBJECTIVE: To assess the association of smoking status with standard clinicopathological features and overall survival (OS) in a large multi-institutional cohort of patients with metastatic renal cell carcinoma (mRCC) treated with cytoreductive nephrectomy (CNT). METHODS: A total of 613 patients with mRCC treated with CNT in US and Europe institutions between 1990 and 2013 were included. Smoking history comprised smoking status, smoking duration in years, number of cigarettes per day and years since smoking cessation. Cumulative smoking exposure was categorized as light short term, heavy long term and moderate. Association between smoking history and OS was assessed by Cox regression logistic analysis. RESULTS: One hundred and seventy-one patients (27.9 %) never smoked, 193 (31.5 %) were former smokers and 249 (40.6 %) were current smokers. Smoking status was associated with a higher number of metastases (p \textless 0.001) and an abnormal preoperative corrected calcium level (p = 0.01). Median follow-up was 16 (IQR 7-24) months. Current smokers had a shorter OS than never and former smokers (log rank, p = 0.004). Smoking status was significantly associated with OS in univariable analysis (HR 1.45; 95 % CI 1.16-1.82; p \textless 0.001), and in multivariable analysis that adjusted for established prognostic factors (HR 1.46; 95 % CI 1.16-1.84; p = 0.002). Daily consumption of more than 20 cigarettes, more than 20 years of smoking exposure and heavy long exposure were all independent prognosticators of worse OS. CONCLUSIONS: Current smoking and a higher cumulative smoking exposure are associated with a higher risk of death in patients with mRCC treated with CNT. Even at this stage, smoking negatively affects kidney cancer outcomes

Introduction VPM1002BC is a genetically modified Mycobacterium bovis Bacillus Calmette Guerin (BCG) strain with potentially improved immunogenicity and attenuation. Here, we report on efficacy, safety and tolerability of intravesical VPM1002BC for the treatment of non-muscle invasive bladder cancer (NMIBC). Methods We designed a phase I/II single arm trial (NCT02371447). Patients were eligible with BCG failure (2008 EAU definition) and intermediate to high risk for NMIBC progression after conventional BCG therapy. The primary endpoint of the phase II part was defined as recurrence free survival (RFS) in the bladder 60 weeks after the first VPM1002BC instillation. From September 2015 to April 2018, a total of 40 patients (6 from phase I and 34 from phase II) were included into the trial. Patients were scheduled for a standard treatment of 6 weekly instillations with VPM1002BC followed by a maintenance regimen of 1 year. Results The study population consisted of 4 female and 36 male patients (median age 72 years). Previous maintenance BCG therapy was conducted in 14/40 patients. All recurrent tumours were high grade (2004 WHO definition) and 27 (67.5%) patients presented with carcinoma in situ (CIS). RFS in the bladder at 60 weeks after the first instillation was 49.3 % [95% CI 32.1%, 64.4%]. At the same time, progression in stage, grade or new occurrence of CIS had occurred in 12 (30%) patients, 3 of which had progression to muscle-invasive disease. Two patients died from bladder cancer (> 60 weeks after start of therapy). Over the whole course of therapy, treatment related grade 1, 2 and 3 AEs were observed in 15%, 52.5%, and 5% of the patients, respectively. No adverse events (AEs) grade ≥4 occurred. Two (5%) out of the 40 patients did not tolerate ≥ 5 instillations during induction. Fifteen patients (37.5%) received all scheduled instillations. Conclusion One year after start of treatment, therapy with VPM100BC resulted in freedom from NMIBC recurrence in the bladder in almost half of the patients with recurrence after previous BCG exposure. The treatment is safe and well tolerated.

The volume of ambulatory surgery in urology increases every year. Successful ambulatory care is defined by low hospital (re)admission rates, insuring optimal oncologic and functional outcomes. New medical techniques such as minimally invasive surgical approaches and less side effects of anesthesia have helped the development of ambulatory surgery. Additionally, it is essential to lower the burden of healthcare systems financially, without compromising quality of care. Ambulatory surgery needs a multidisciplinary team involvement, where the general practitioner has a key role.La pratique ambulatoire en urologie augmente chaque année. Les avancées médicochirurgicales ont permis de diminuer les gestes invasifs et les effets secondaires des anesthésiques. Sur le plan financier, il est essentiel de contrôler les dépenses de santé publique, tout en maintenant comme premier objectif la sécurité du patient. Les critères de succès d’une prise en charge ambulatoire se mesurent au faible taux d’hospitalisation et de réadmission, sans compromission quant aux résultats de la chirurgie. La prise en charge ambulatoire exige une équipe pluridisciplinaire et le médecin traitant joue un rôle essentiel dans l’itinéraire clinique de son patient.

Enhanced recovery after surgery (ERAS) is a multimodal concept aiming to reduce surgical stress and prevent postoperative complications. Once adapted to urologic patients in 2013, this protocol evolves continuously and many international centers have now implemented it. This article resumes ERAS key principles for general practitioners as they can have a significant impact on patient's optimization before surgery.Le protocole de réhabilitation améliorée après chirurgie est un concept de prise en charge multimodale visant à anticiper puis gérer de manière optimale le stress chirurgical inhérent à toute intervention. Adapté depuis 2013 à l’urologie, il évolue régulièrement et les centres internationaux qui appliquent ses principes sont toujours plus nombreux. Avant une chirurgie majeure, il existe un potentiel d’optimisation d’un patient auquel le généraliste peut participer activement. Cet article résume à l’attention d’un médecin généraliste les principaux points constituant cette démarche.

The aim of the present study was to identify and test a urine marker panel of genes involved in DNA methylation and histone modification for the detection of urothelial carcinoma of the bladder (UCB). RNA samples obtained from the voided urine of 227 patients with asymptomatic microscopic haematuria (AMH) were analysed. Gene array analysis was performed on 18 randomly selected cDNA samples, which revealed that histone deacetylase 9 (HDAC9), HDAC3, tRNA (cytosine-5-)-methyltransferase1 and DNA methyltransferase 1 were differentially expressed between patients with UCB and control subjects. Subsequently, reverse transcription-quantitative polymerase chain reaction analysis was employed to test the performance of the identified four-gene panel on the remaining 209 cDNA samples. In this targeted discovery cohort, all four genes were significantly associated with UCB on univariable analyses [each odds ratio (OR) >2, P

Introduction Bladder cancer (BC) is diagnosed by cystoscopy, which is invasive, costly and causes considerable patient discomfort. MicroRNAs (miR) are dysregulated in BC and may serve as non-invasive urine markers for primary diagnostics and monitoring. The purpose of this study was to identify a urinary miR signature that predicts the presence of BC. Methods For the detection of potential urinary miR markers, expression of 384 different miRs was analyzed in 16 urine samples from BC patients and controls using a Taqman™ Human MicroRNA Array (training set). The identified candidate gene signature was subsequently validated in an independent cohort of 202 urine samples of patients with BC and controls with microscopic hematuria. The final miR signature was developed from a multivariable logistic regression model. Results Analysis of the training set identified 14 candidate miRs for further analysis within the validation set. Using backward stepwise elimination, we identified a subset of 6 miRs (let-7c, miR-135a, miR-135b, miR-148a, miR-204, miR-345) that distinguished BC from controls with an area under the curve of 88.3%. The signature was most accurate in diagnosing high-grade non-muscle invasive BC (area under the curve = 92.9%), but was capable to identify both low-grade and high-grade disease as well as non-muscle and muscle-invasive BC with high accuracies. Conclusions We identified a 6-gene miR signature that can accurately predict the presence of BC from urine samples, independent of stage and grade. This signature represents a simple urine assay that may help reducing costs and morbidity associated with invasive diagnostics.

The regulation of immune responses occurring during Bacillus Calmette-Guerin (BCG) therapy need to be better scrutinized in order to identify new targetable pathways for non-muscle invasive bladder cancer treatment. Immunoregulatory mechanisms have emerged as key players in various cancers. While T lymphocytes are crucial for the control of tumor growth, they often include regulatory subsets known to restrain their anti-tumor activity. In this prospective study, we assessed conventional regulatory T cells (cTregs) and PD-L1-expressing CD4 T cells (PD-L1+ Tregs) levels in blood and urine of urothelial cancer (UCa) patients undergoing BCG treatment. Local cTregs were found at higher frequencies than their counterpart in the periphery and induced by bladder tumor cells in vitro. Interestingly, while circulating PD-L1+ Tregs were hardly detectable in the blood of healthy donors and UCa patients, substantial levels were found in patients' urine. In vitro experiments suggested that BCG infection of urothelial cells could induce PD-L1+ Tregs, partially via an interferon-β-mediated mechanism. Of note, high level of Tregs in urine was associated with rapid recurrence following BCG therapy. Our findings demonstrate that T lymphocytes recruited during BCG therapy encompass a significant fraction of regulatory cells including a non-classical source of PD-L1 and reinforce treatment strategies combining BCG with PD-1/PD-L1 checkpoint inhibitors as promising approaches for non-muscle invasive bladder cancer. Patient summary We investigated the presence of particular immune cell types in the urine of bladder cancer patients undergoing Bacillus Calmette-Guerin (BCG) therapy. We identified a cell type that is strongly enriched in the urine after BCG instillation and that may favor tumor recurrence. This immune subpopulation might be targeted for bladder cancer treatment.

A gender discrepancy exists in the incidence of both urothelial and kidney carcinomas, with more men presenting with these cancers than women. Men have a threefold greater risk of developing bladder cancer than women, but female gender has been identified as an independent adverse prognostic factor for both recurrence and progression of this disease. In particular, women with bladder cancer are often diagnosed with a higher tumour stage than men. Conclusive data on the influence of gender on outcomes of patients with upper tract urothelial carcinoma are currently lacking, although men seem to have a higher disease incidence, whereas survival outcomes might be independent of gender. Patients with renal cell carcinoma are more often men and they typically have larger tumours and higher stage and grade disease than women with this cancer. Smoking habits, tumour biology, occupational risk factors and sex steroid hormones and their receptors could have a role in these observed gender disparities. The majority of data support the theory that gender influences incidence and prognosis of urothelial and kidney cancers; men and women are different genetically and socially, making the consideration of gender a key factor in the clinical decision-making process. Thus, the inclusion of this variable in validated prognostic tables and nomograms should be discussed as a matter of importance.

Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of the human telomerase and plays a key role in telomere restitution and gene regulation. Evidence suggests that hTERT is linked with the risk and progression of several malignancies, but there are no comprehensive data in renal cell carcinoma (RCC). In this case-control study, we assessed seven polymorphic hTERT gene variants (MNS16A, rs2736100, rs2736098, rs7726159, rs2853677, rs13172201, and rs10069690), hTERT serum levels, and the telomere length of 663 individuals, including 243 with clear cell RCC and 420 age- and gender-matched healthy controls. The SL and SS genotypes of MNS16A were associated with a decreased risk for RCC on the multivariable logistic regression analysis (SL-OR 0.72, SS-OR 0.37, P