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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.

Supplementary Fig S1, S2, S3

Preclinical data show that intravesical instillation of Ty21a/Vivotif, a commercial vaccine against typhoid fever, is an effective alternative option to standard Bacillus Calmette–Guérin (BCG) immunotherapy for non–muscle-invasive bladder cancer (NMIBC). Here, we characterized the inflammatory effects of Ty21a on the bladder and investigated the immune mechanisms underlying tumor regression toward the use of this bacterial vaccine in NMIBC patients. MB49 bladder tumor–bearing mice had significantly improved survival after intravesical instillations of Ty21a doses of 106 to 108 colony-forming units. By IHC and morphology, both BCG and Ty21a instillations were associated with bladder inflammation, which was decreased with the use of low, but effective doses of Ty21a. Flow-cytometry analysis showed a significant infiltration of T cells, natural killer (NK) cells, and myeloid cells, compared with controls, after a single dose of Ty21a, whereas this was only observed after multiple doses of BCG. The induced myeloid cells were predominantly neutrophils and Ly6C+CD103+ dendritic cells (DC), the latter being significantly more numerous after instillation of Ty21a than BCG. Ex vivo infection of human leukocytes with Ty21a, but not BCG, similarly significantly increased DC frequency. CD4+ and CD8+ T cells, but not NK cells nor neutrophils, were required for effective bladder tumor regression upon Ty21a treatment. Thus, the generation of antitumor adaptive immunity was identified as a key process underlying Ty21a-mediated treatment efficacy. Altogether, these results demonstrate mechanisms behind intravesical Ty21a therapy and suggest its potential as a safe and effective treatment for NMIBC patients.

Objectives: We conducted a phase I/II prospective trial to determine whether stereotactic dose escalation to the dominant intra-prostatic nodule (DIN) up to 50 Gy incorporating a rectal balloon spacer is safe, does not affect patient quality of life, and preserves local control in patients with intermediate-high risk PCa. Methods: Eligible patients included males with stage ≤T3b localized disease, a prostate-specific antigen (PSA) level ≤50 , International Prostate Symptom Score (IPSS) ≤14, and a gland volume ≤70 cm3. Patients underwent perirectal spacer placement, followed by a planning MRI and were subsequently treated with SBRT doses of 36.25 Gy in five fractions to the whole prostate while simultaneously escalating doses to the magnetic resonance image visible DIN up to 50 Gy. Primary endpoint: safety. Secondary endpoints: biochemical control, quality of life (QofL), and dosimetry outcome. Results: Nine patients were treated in the Phase I part of the study. Dose limiting toxicities (DLTs) were not observed. Further characterization of tolerability and efficacy was conducted in the subsequent 24 patients irradiated at the recommended Phase II dose (50 Gy, RP2D). At a median follow-up of 61 months, biochemical control is 69%. Grade 1 and 2 acute GU and GI toxicity was 57.5 and 15%, and 24.2 and 6.1%, respectively. Grade 1 and 2 late GU and GI toxicity was 66.6 and 12.1%, and 15.1 and 3%, respectively. No Grade 3 or higher toxicity was reported. QofL data confirmed physician’s reported side effects. Dosimetry analysis showed adherence to the doses prescribed in the protocol. Conclusions SBRT of the whole prostate with 36.25 Gy in 5 fractions and dose escalation to 50 Gy to the DIN, when combined with a peri-rectal balloon spacer, was tolerable and established the RP2D. QofL analysis showed minimal negative impact in GU, GI, and sexual domains. Advances in knowledge: Extreme hypofractionated prostate radiation therapy with focal dose escalation to the DIN is well tolerated with efficacy comparable to normal fractionated radiation therapy.

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

Bacillus Calmette-Guérin (BCG) instillations for the treatment of non-muscle-invasive bladder cancer patients can result in significant side effects and treatment failure. Immune checkpoint blockade and/or decreasing tumor-infiltrating myeloid suppressor cells may be alternative or complementary treatments. Here, we have characterized immune cell infiltration and chemoattractant molecules in mouse orthotopic MB49 bladder tumors. Our data show a 100-fold increase in CD45 + immune cells from day 5 to day 9 tumors including T cells and mainly myeloid cells. Both monocytic myeloid-derived suppressor-cells (M-MDSC) and polymorphonuclear (PMN)-MDSC were strongly increased in day 9 tumors, with PMN-MDSC representing ca. 70% of the myeloid cells in day 12 tumors, while tumor associated macrophages (TAM) were only modestly increased. The kinetic of PD-L1 tumor expression correlated with published data from patients with PD-L1 expressing bladder tumors and with efficacy of anti-PD-1 treatment, further validating the orthotopic MB49 bladder-tumor model as suitable for designing novel therapeutic strategies. Comparison of chemoattractants expression during MB49 bladder tumors grow highlighted CCL8 and CCL12 (CCR2-ligands), CCL9 and CCL6 (CCR-1-ligands), CXCL2 and CXCL5 (CXCR2-ligands), CXCL12 (CXCR4-ligand) and antagonist of C5/C5a as potential targets to decrease myeloid suppressive cells. Data obtained with a single CCR2 inhibitor however showed that the complex chemokine crosstalk would require targeting multiple chemokines for anti-tumor efficacy.

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.

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.

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.

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.

Contains fulltext : 220960.pdf (Publisher’s version ) (Open Access) BACKGROUND: Dendritic cells (DCs) are the most efficient antigen-presenting cells, hence initiating a potent and cancer-specific immune response. This ability (mainly using monocyte-derived DCs) has been exploited in vaccination strategies for decades with limited clinical efficacy. Another alternative would be the use of conventional DCs (cDCs) of which at least three subsets circulate in human blood: cDC1s (CD141(bright)), cDC2s (CD1c(+)) and plasmacytoid DCs. Despite their paucity, technical advances may allow for their selection and clinical use. However, many assumptions concerning the DC subset biology depend on observations from mouse models, hindering their translational potential. In this study, we characterise human DCs in patients with ovarian cancer (OvC) or prostate cancer (PrC). PATIENTS AND METHODS: Whole blood samples from patients with OvC or PrC and healthy donors (HDs) were evaluated by flow cytometry for the phenotypic and functional characterisation of DC subsets. RESULTS: In both patient groups, the frequency of total CD141(+) DCs was lower than that in HDs, but the cDC1 subset was only reduced in patients with OvC. CD141(+) DCs showed a reduced response to the TLR3 agonist poly (I:C) in both groups of patients. An inverse correlation between the frequency of cDC1s and CA125, the OvC tumour burden marker, was observed. Consistently, high expression of CLEC9A in OvC tissue (The Cancer Genome Atlas data set) indicated a better overall survival. CONCLUSIONS: cDC1s are reduced in patients with OvC, and CD141(+) DCs are quantitatively and qualitatively impaired in patients with OvC or PrC. CD141(+) DC activation may predict functional impairment. The loss of cDC1s may be a bad prognostic factor for patients with OvC.

Surgical treatments for female stress urinary incontinence is in perpetual evolution. This article reviews the current surgical treatments for stress urinary incontinence in female. Bulking agents, Burch colposuspension, autologous sling, midurethral slings, single incision slings, artificial urinary sphincter and adjustable continence therapy (ACT) are discussed.Les traitements chirurgicaux de l’incontinence urinaire d’effort chez la femme sont en perpétuelle évolution. Cet article passe en revue les options actuelles de traitement chirurgical de l’incontinence urinaire d’effort chez la femme. Les injections péri-urétrales d’agents de comblement, la colposuspension selon Burch, la bandelette sous-urétrale aponévrotique, les bandelettes sous-urétrales synthétiques, les mini-bandelettes (

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.

Introduction: Urologists have to master a variety of techniques to be able to offer the most appropriate surgical stone treatment for each individual patient. Therefore, we performed a survey among board-certified Swiss urologists to assess the availability of the different surgical methods, the current practices of surgical treatment of urolithiasis and the adherence to evidence-based guideline recommendations in Switzerland. Methods: A 14-question survey assessed the working environment, equipment, perioperative settings and decision trees for specific stone scenarios. Data was analyzed using descriptive statistics and chi-square tests to determine differences between frequencies of answers. Results: Hundred and five members of Swiss Urology (38%) completed the survey. All treatment modalities are available for the majority of respondents. Ureterorenoscopy was found to have the highest availability (100%) and was the preferred choice in the majority of stone scenarios. A high adherence to the guidelines was found for the treatment of ureteral stones 10 mm (69% proximal, 94% distal). All respondents answered in accordance with the guidelines regarding the treatment of middle and upper pole stones 20 mm, and 63% for middle/upper pole stones >20 mm. Conclusion: This survey provides a detailed insight into current stone treatment practices in Switzerland. The full spectrum of urinary stone treatment options is available for the majority of Swiss urologists. The choice of treatment shows a high accordance with evidence-based guidelines and a preference for retrograde endoscopic surgery in the majority of stone scenarios.

Preclinical data show that intravesical instillation of Ty21a/Vivotif, a commercial vaccine against typhoid fever, is an effective alternative option to standard Bacillus Calmette-Guérin (BCG) immunotherapy for non-muscle-invasive bladder cancer (NMIBC). Here, we characterized the inflammatory effects of Ty21a on the bladder and investigated the immune mechanisms underlying tumor regression toward the use of this bacterial vaccine in NMIBC patients. MB49 bladder tumor-bearing mice had significantly improved survival after intravesical instillations of Ty21a doses of 10 6 to 10 8 colony-forming units. By IHC and morphology, both BCG and Ty21a instillations were associated with bladder inflammation, which was decreased with the use of low, but effective doses of Ty21a. Flow-cytometry analysis showed a significant infiltration of T cells, natural killer (NK) cells, and myeloid cells, compared with controls, after a single dose of Ty21a, whereas this was only observed after multiple doses of BCG. The induced myeloid cells were predominantly neutrophils and Ly6C + CD103 + dendritic cells (DC), the latter being significantly more numerous after instillation of Ty21a than BCG. Ex vivo infection of human leukocytes with Ty21a, but not BCG, similarly significantly increased DC frequency. CD4 + and CD8 + T cells, but not NK cells nor neutrophils, were required for effective bladder tumor regression upon Ty21a treatment. Thus, the generation of antitumor adaptive immunity was identified as a key process underlying Ty21a-mediated treatment efficacy. Altogether, these results demonstrate mechanisms behind intravesical Ty21a therapy and suggest its potential as a safe and effective treatment for NMIBC patients.

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.

QUALITY PROBLEM As discharge letters (DL) hold important information for healthcare professionals and especially for general practitioners, rapid and efficient finalization is required. We describe a project aiming to reduce DL submission within 8 days in our Urology Department (UD), as required by the local Hospital Board (HB). INITIAL ASSESSMENT AND CHOICE OF SOLUTION A team was built in UD with staff members and one external expert to study the root causes of delayed DL creation and develop sustainable strategies to improve and monitor the process, including habits changing, training and application of Little's Law. IMPLEMENTATION AND EVALUATION The study started on January 2015 and ended up on March 2016, involving 908 and 616 DL for old and new process, respectively. The new process decreased the average delay of DL completion from 24.88 days to 14.7 days. Standard deviation of total average delay for DL completion fell from 10.1 days to 7.5 days. We identified four steps needed to DL creation and allowed maximum 2 days for every step completion. No additional resources were employed. LESSONS LEARNED We were able to improve the process of DL creation, by analysing its steps and reducing their variability. This can be easily transposed to other medical departments.

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 Nd-YAG/KTP laser coagulates and vaporizes prostate tissue. The objective of this study was to investigate the combined effects of both wavelengths and to determine the irradiation parameters allowing the largest lesion volume. Chicken breast tissue was irradiated ex vivo. Consecutive 1064 and 532 nm Nd-YAG/KTP laser irradiations were performed for different combinations (30 W/10 W, 20 W/20 W, 10 W/30 W) with variable total fluence (1200 J, 2400 J, 3600 J) and compared to isofluent single wavelengths at 40 W irradiation. The depths, diameters and volumes of the total lesion as well as the vaporization effects of the 532 nm wavelength on normal and on priorly coagulated tissue were analysed. Maximum total lesion depths (p< 0.001) were found under combined Nd-YAG/KTP (20 W/20 W) irradiation conditions. Ablation efficacy of the 532 nm wavelength was reduced after prior 1064 nm irradiation, but crater depths were increased. Dual wavelength irradiation with the Nd-YAG/KTP laser induces a specific denaturation process. This may represent a new approach to increase the depth of coagulation necrosis, and thus the treated volume, thereby improving long-term results.

Zusammenfassung: Viele Studien bestätigen das klinische Interesse an der photodynamischen Diagnostik (PDD) zur Behandlung des nicht muskelinvasiven Harnblasenkarzinoms. Die PDD oder Fluoreszenzzystoskopie ist bei der Detektion okkulter Urothelkarzinome von großem Wert und mag einen positiven Einfluss auf die rezidivfreie Überlebenszeit und die Prognose haben. Dennoch wird ihre Spezifität mit hoher Variabilität, hauptsächlich in Relation mit den verschiedenen Krankheitsprofilen, in den einzelnen Studien angegeben. Neue Bildgebungstechniken zur Verbesserung der visuellen Beurteilung der Harnblasenwand werden daher entwickelt

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.

Purpose Although localized prostate cancer (PCa) is multifocal, the dominant intraprostatic nodule (DIN) is responsible for disease progression after radiation therapy. PCa expresses antigens that could be recognized by the immune system. We therefore hypothesized that stereotactic dose escalation to the DIN is safe, may increase local control, and may initiate tumor-specific immune responses. Patients and Methods Patients with localized PCa were treated with stereotactic extreme hypofractionated doses of 36.25 Gy in 5 fractions to the whole prostate while simultaneously escalating doses to the magnetic resonance image–visible DIN (45 Gy, 47.5 Gy, and 50 Gy in 5 fractions). The phase 1a part was designed to determine the recommended phase 1b dose in a “3 + 3” cohort-based, dose-escalation design. The primary endpoint was dose-limiting toxicities defined as ≥grade 3 gastrointestinal (GI) or genitourinary (GU) toxicity (or both) by National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) up to 90 days after the first radiation fraction. The secondary endpoints were prostate-specific antigen kinetics, quality of life (QoL), and blood immunologic responses. Results Nine patients were treated in phase 1a. No dose-limiting toxicities were observed at either level, and therefore the maximum tolerated dose was not reached. Further characterization of tolerability, efficacy, and immunologic outcomes was conducted in the subsequent 11 patients irradiated at the highest dose level (50 Gy) in the phase 1b expansion cohort. Toxicity was 45% and 25% for grades 1 and 2 GU, and 20% and 5% for grades 1 and 2 GI, respectively. No grade 3 or worse toxicity was reported. The average (±standard error of the mean) of the QoL assessments at baseline and at 3-month posttreatment were 0.8 (±0.8) and 3.5 (±1.5) for the bowel (mean difference, 2.7; 95% confidence interval, 0.1-5), and 6.4 (±0.8) and 7.27 (±0.9) for the International Prostate Symptom Score (mean difference, 0.87; 95% confidence interval, 0.3-1.9), respectively. A subset of patients developed antigen-specific immune responses against prostate-specific membrane antigen (n = 2), prostatic acid phosphatase (n = 1), prostate stem cell antigen (n = 4), and prostate-specific antigen (n = 2). Conclusions Irradiation of the whole prostate with 36.25 Gy in 5 fractions and dose escalation to 50 Gy to the DIN was tolerable and determined as the recommended phase 1b dose. This treatment has promising antitumor activity, which will be confirmed by the ongoing phase 2 part. Preliminary QoL analysis showed minimal impact in GU, GI, and sexual domains. Stereotactic irradiation induced antigen-specific immune responses in a subset of patients.

The treatment of urothelial bladder cancer has changed very little in recent years, with high rates of disease recurrence and progression, even in low aggressive urothelial bladder cancer. Immunotherapy has already proven its effectiveness as a treatment for several types of cancer and has been used in high-grade non-muscle-invasive bladder cancer for decades. Recent findings on immune checkpoints inhibitors have opened up a new chapter for treatment of bladder cancer, offering interesting therapeutic perspectives that could revolutionize the management.Le traitement du cancer de la vessie a très peu évolué depuis plusieurs années avec des taux de récidives et de progression élevés, même dans les tumeurs peu invasives. L’immunothérapie a déjà fait ses preuves comme traitement de plusieurs types de cancer et est utilisée dans le cancer de la vessie non musculo-invasif de haut grade depuis des décennies. Les récentes découvertes sur les inhibiteurs de points de contrôle immunitaire (checkpoints inhibitors) ouvrent tout un nouveau chapitre sur le traitement des différents stades du cancer de la vessie, y compris les tumeurs musculo-invasives et métastatiques, offrant des perspectives thérapeutiques, capables de révolutionner la prise en charge.

In the past, it was generally considered that the window of curability had been missed in metastatic solid cancers. At present, novel evidence suggests that oligometastatic cancer might be amenable to a multimodal curative treatment, including ablation of the primary tumour. In this article, we summarise the indications, the controversies and future perspectives of local treatment in oligometastatic urological malignancies.Dans le passé, on considérait le plus souvent que la fenêtre de curabilité dans les cancers solides à un stade métastatique avait été manquée. De nouvelles évidences suggèrent à présent que la maladie à un stade oligométastatique est accessible, dans certains cas, à un traitement multimodal curatif, incluant l’ablation de la tumeur primaire. Dans cet article, nous résumons les indications, les controverses ainsi que les perspectives futures du traitement local dans les cancers oligométastatiques urologiques.

Le carcinome urothelial represente toujours un probleme de sante publique majeur. Il est frequent et les traitements proposes ainsi que l'esperence de vie n'ont que peu evolues ces dernieres annees. Un diagnostic precoce et un staging precis pour la prise en charge et le suivi de cette maladie sont essentiels.

This article summarizes recent advances in the field of urinary infections, bladder function, minimal invasive surgery and genitourinary cancers.Cet article résume les progrès récents dans le domaine des infections urinaires, de la fonction de la vessie, de la chirurgie mini–invasive et des cancers génito-urinaires.