Transcriptomic Profiling of Upper Tract Urothelial Carcinoma: Bladder Cancer Consensus Classification Relevance, Molecular Heterogeneity, and Differential Immune Signatures.

Analyses of large transcriptomics data sets of muscle-invasive bladder cancer (MIBC) have led to a consensus classification. Molecular subtypes of upper tract urothelial carcinomas (UTUCs) are less known. Our objective was to determine the relevance of the consensus classification in UTUCs by characterizing a novel cohort of surgically treated ≥pT1 tumors. Using immunohistochemistry (IHC), subtype markers GATA3-CK5/6-TUBB2B in multiplex, CK20, p16, Ki67, mismatch repair system proteins, and PD-L1 were evaluated. Heterogeneity was assessed morphologically and/or with subtype IHC. FGFR3 mutations were identified by pyrosequencing. We performed 3'RNA sequencing of each tumor, with multisampling in heterogeneous cases. Consensus classes, unsupervised groups, and microenvironment cell abundance were determined using gene expression. Most of the 66 patients were men (77.3%), with pT1 (n = 23, 34.8%) or pT2-4 stage UTUC (n = 43, 65.2%). FGFR3 mutations and mismatch repair-deficient status were identified in 40% and 4.7% of cases, respectively. Consensus subtypes robustly classified UTUCs and reflected intrinsic subgroups. All pT1 tumors were classified as luminal papillary (LumP). Combining our consensus classification results with those of previously published UTUC cohorts, LumP tumors represented 57.2% of ≥pT2 UTUCs, which was significantly higher than MIBCs. Ten patients (15.2%) harbored areas of distinct subtypes. Consensus classes were associated with FGFR3 mutations, stage, morphology, and IHC. The majority of LumP tumors were characterized by low immune infiltration and PD-L1 expression, in particular, if FGFR3 mutated. Our study shows that MIBC consensus classification robustly classified UTUCs and highlighted intratumoral molecular heterogeneity. The proportion of LumP was significantly higher in UTUCs than in MIBCs. Most LumP tumors showed low immune infiltration and PD-L1 expression and high proportion of FGFR3 mutations. These findings suggest differential response to novel therapies between patients with UTUC and those with MIBC.

Clinical outcomes of adapted hypofractionated radiotherapy for bladder cancer in elderly patients.

OBJECTIVE: To investigate the feasibility, efficacy, and safety of trimodal therapy (TMT) using a bifractionated split-course hypofractionated radiotherapy (RT) for non-metastatic muscle-invasive bladder cancer (MIBC) in elderly patients. PATIENTS AND METHODS: We retrospectively reviewed the characteristics and outcomes of patients aged >75 years with non-metastatic MIBC suitable or not for radical cystectomy (RC) and treated with transurethral resection of bladder tumour followed by concomitant radio-chemotherapy (platinum salt and 5-fluorouracil) at two institutions (Saint Louis Hospital, Paris, France and European Georges Pompidou Hospital, Paris, France) between 1990 and 2021. RT consisted of an adapted bifractionated split-course hypofractionated RT. Acute toxicities were reported according to Common Terminology Criteria for Adverse Events version 5.0 and late toxicities were reported according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer late radiation morbidity scoring schema. The primary end-point was overall survival (OS). Secondary end-points included other survivals outcomes and safety. RESULTS: A total of 122 patients were identified, with a median (range) follow-up of 51.1 (0.5-210.8) months. In all, 83.5% of patients completed radio-chemotherapy. The OS rate was 61.7% at 3 years and 51.2% at 5 years. In multivariate analysis, the completion of RT and concomitant chemotherapy were significantly associated with better OS and cancer-specific survival. For patients fit for RC, a complete histological response was achieved for 77 patients (91.7%) with radio-chemotherapy and the bladder conservation rate was 90.5%. Acute and late Grade ≥3 toxicities were <5%. CONCLUSION: Bifractionated split-course hypofractionated RT with concomitant chemotherapy regimen appears to be well-tolerated and effective. Trimodal treatment seems to be a curative option for elderly patients unfit for radical surgery compared with palliative care and may contribute to improved survival in these patients.

Survival after sequential neoadjuvant chemotherapy followed by trimodal treatment or radical cystectomy for muscle-invasive bladder cancer.

PURPOSE: to assess the respective outcomes of patients with localized muscle-invasive bladder cancer (MIBC) treated by either radical cystectomy (RC) or trimodal treatment (TMT) depending on pathological response to previous neoadjuvant chemotherapy (NAC) assessed on cystectomy specimen or post-NAC transurethral resection (TURB) specimen, respectively. PATIENT AND METHODS: We retrospectively included all consecutive patients treated in one academic center with cisplatin-based NAC followed by RC or TMT for cT2-3N0M0 MIBC between 2014 and 2021. Primary endpoint was metastasis-free survival (MFS) in both treatment groups and according to pathological response to NAC. Local recurrence-free survival and conservative management failure (metastasis-free bladder-intact survival) for patients treated with TMT were assessed. RESULTS: 104 patients were included, 26 treated with TMT and 78 with RC. The rate of complete pathological response was 47.4% in patients treated with RC (ypT0) and 66.7% in patients treated with TMT (ycT0). Median follow-up was 34.9 months. Four-year MFS was 72% in both treatment groups. Four-year MFS was 85% in both ypT0 RC patients and ycT0 TMT patients. ycT0 stage was associated with low rates of intravesical recurrence and conservative management failure. CONCLUSION: Patients with post-NAC ycT0 stage treated with TMT have favorable oncological outcomes similar to those of ypT0 patients treated with RC. Assessment of complete histological response with TURB after NAC may help in selecting the best candidates for bladder preservation with TMT.

Safety and efficacy of preoperative chemotherapy for muscle-invasive bladder cancer in elderly patients.

PURPOSE: This study aimed at describing the feasibility and oncological outcomes of standard cisplatin-based neoadjuvant chemotherapy (C-NAC) for muscle-invasive bladder cancer (MIBC) in patients aged ≥ 75 and assess the impact of baseline geriatric parameters. METHODS: This retrospective study included patients with stage cT2-4NanyM0 MIBC aged 75 and older treated with ≥ 1 cycle of C-NAC from 2011 to 2021 at a high-volume academic center. Primary outcome was overall survival (OS). Secondary outcomes were chemotherapy feasibility (administration of ≥ 4 cycles), safety, and pathological downstaging. RESULTS: Fifty-six patients were included. Median age was 79 (range 75-90). C-NAC regimen was ddMVAC in 41 patients and GC in 15. Seventy-three percent of patients received ≥ 4 cycles of C-NAC. Grade ≥ 3 toxicity was observed in 55% of patients. The febrile neutropenia rate was 7%. Thirty patients underwent cystectomy, and 13 underwent chemoradiotherapy. Three-year OS was 63%. Geriatric parameters polypharmacy, undernutrition, and age-adjusted Charlson comorbidity index ≥ 8 predicted worse OS. CONCLUSION: Standard-of-care C-NAC and local treatments are feasible in selected elderly MIBC patients, with efficacy and safety findings similar to that observed in pivotal trials with younger patients. The prognostic impact of geriatric parameters underlines the need for specialized evaluation before treatment initiation.

BK virus genotypes and humoral response in kidney transplant recipients with BKV associated nephropathy.

BACKGROUND: Among kidney transplant recipients (KTR) with BK virus associated nephropathy (BKVN), BKV genotypes' evolution and anti-BKV humoral response are not well established. We aim to analyze BKV replication and genetic evolution following transplantation, and characterize concomitant anti-BKV-VP1 humoral response. METHODS: We retrospectively analyzed 32 cases of biopsy-proven BKVN. Stored plasma and kidney biopsies were tested for BKV viral load, and VP1 sequencing performed on positive samples. BKV-VP1 genotype-specific neutralizing antibodies (NAbs) titers were determined at transplantation and BKVN. RESULTS: At the time of BKVN diagnosis, BKV viral load was 8.2 log10 IU/106 cells and 5.4 log10 IU/mL in kidney and plasma, respectively. VP1 sequencing identified the same BKV-subtype in both compartments in 31/32 cases. At the time of transplantation, 8/20 (40%) of biopsies tested positive for BKV detection, whereas concomitant BKV viremia was negative. VP1 sequencing identified a different subtype compared to BKVN in 5/6 of these samples. This was confirmed following transplantation: 8 patients had a BKV+ biopsy before BKV viremia, and VP1 sequencing identified a different subtype compared to BKVN in all of them. After the onset of BKV viremia and prior to BKVN diagnosis, the BKV subtype in BKV+ plasma and kidney biopsy was the same as the one isolated at BKVN. BKV-VP1 NAbs titers were significantly higher at the time of BKVN compared to transplantation (p = .0031), with similar titers across genotypes. CONCLUSION: Altogether, our data suggest that among some KTR with BKVN, the BKV genotype from the donor may not be responsible for BKVN pathogenesis.

The HLA-G immune checkpoint: a new immuno-stimulatory role for the α1-domain-deleted isoform.

The heterogeneity of cancer cells, in part maintained via the expression of multiple isoforms, introduces significant challenges in designing effective therapeutic approaches. In this regard, isoforms of the immune checkpoint HLA-G have been found in most of the tumors analyzed, such as ccRCC, the most common human renal malignancy. In particular, HLA-G∆α1, which is the only HLA-G isoform described that lacks the α1 extracellular domain, has been newly identified in ccRCC and now here in trophoblasts. Using a cellular model expressing HLA-G∆α1, we have uncovered its specific and overlapping functional roles, relative to the main HLA-G isoform, i.e., the full-length HLA-G1. We found that HLA-G∆α1 has several particular features: (i) although possessing the α3 domain, it does not associate with ß2-microglobulin; (ii) it may not present peptides to T cells due to absence of the peptide-binding groove; and (iii) it exerts immune-stimulatory activity towards peripheral blood NK and T cells, while all known isoforms of HLA-G are immune-inhibitory checkpoint molecules. Such immune-stimulatory properties of HLA-G∆α1 on the cytotoxic function of peripheral blood NK cells are individual dependent and are not exerted through the interaction with the known HLA-G receptor, ILT2. Importantly, we are faced here with a potential antitumor effect of an HLA-G isoform, opposed to the pro-tumor properties described for all other HLA-G isoforms, which should be taken into account in future therapeutic designs aimed at blocking this immune checkpoint.

Operative and Midterm Oncological Outcome of Focal Salvage Cryotherapy for Localized Prostate Cancer.

BACKGROUND: Local recurrence after radiation therapy for prostate cancer is a major clinical issue. Various local treatments are available with mitigated functional and oncological outcomes. The aim of the present study was to evaluate perioperative and oncological results of salvage cryotherapy (CT) as treatment of local recurrence of prostate cancer. METHODS: We retrospectively reviewed all patients treated with hemi-prostatic salvage CT for local recurrence of prostate cancer in 1 academic hospital between November 2011 and April 2019. Local recurrence was defined according to the Phoenix criteria (prostate-specific antigen [PSA] nadir + 2 ng/mL), associated with a prostatic MRI target lesion and confirmed by biopsy. Perioperative and functional complications were collected. Cox regression was conducted to assess factors associated with time to initiation of androgen deprivation therapy (ADT). Statistical analyses were conducted using R Studio. RESULTS: A total of 29 patients were treated with an average follow-up of 37.6 months. Median age at CT was 77 years. Median PSA before CT was 5.1 ng/mL (min-max: 2.74-18). 17.2% of patients displayed a high D'Amico risk group. Median hospital stay was 1.4 days. Four patients (13.8%) experienced postoperative acute urinary retention. Nineteen patients (65.5%) experienced late functional complications (3 erectile dysfunctions, 3 stress incontinence, and 13 urinary frequency). Fourteen patients displayed recurrence after salvage treatment (48.2%). Median time to introduction of ADT was 15.1 months. ADT-free survival at 1 and 2 years was, respectively, 74% and 61%. In multivariate analysis, ISUP score 4 and PSA nadir <1 ng/mL after CT were significantly associated with time to ADT initiation. CONCLUSIONS: Salvage focal CT may delay the use of ADT in locally recurrent prostate cancer after RT and offers an alternative for eligible patients. The technique was feasible with acceptable perioperative morbidity and acceptable midterm oncological outcome.

Perioperative outcomes of transurethral resection for t1 bladder tumors: quality evaluation based on patient, tumor and surgeon criteria.

INTRODUCTION: Transurethral resection of bladder tumor (TURBT) is a fundamental but challenging step in the diagnosis and treatment of non-muscle invasive bladder cancer (NMIBC). The first- and second-look TURBT are central in the management of T1 tumors. MATERIALS AND METHODS: We retrospectively reviewed all patients treated with TURBT for T1 urothelial cell carcinoma (UCC) of the bladder in one academic institution between 2007 and 2017. Quality of TURBT was evaluated based on the presence/absence of muscle on pathology report, the presence/absence of residual tumor on the second look and the occurrence of complications. Patient-, surgeon- and tumor-related factors were investigated for their association with TURBT quality. RESULTS: 283 patients were included. Second-look resection was performed after a mean delay of 54 days. Muscle was observed in 85.9% of the samples on the first TURBT. On the second-look resection, UCC was observed in 52.3% of the samples. 38 complications were reported after the first TURBT (13.4%). Surgeon's experience was the only factor significantly associated with occurrence of post-operative complications (OR = 0.40; p = 0.04). Location of the tumor at the bottom of the bladder was a risk factor for not finding muscle at pathological analysis (OR = 0.20; p = 0.06). Male gender, multiplicity and tumor located at the bottom of the bladder were significantly associated with residual disease on reTURBT. In multivariate analysis, only male gender (OR = 4.71; p = 0.02) and tumor multiplicity remained significant (OR for unique tumor = 0.36; p = 0.02). CONCLUSION: TURBT is a challenging procedure and surgeon's experience is crucial in reducing the rate of post-operative complications. Technical difficulties resulting from patient's gender, tumor location or number of tumors may be as important as oncological factors in deciding whether or not to perform a second-look resection.

Comprehensive landscape of immune-checkpoints uncovered in clear cell renal cell carcinoma reveals new and emerging therapeutic targets.

Clear cell renal cell carcinoma (ccRCC) constitutes the most common renal cell carcinoma subtype and has long been recognized as an immunogenic cancer. As such, significant attention has been directed toward optimizing immune-checkpoints (IC)-based therapies. Despite proven benefits, a substantial number of patients remain unresponsive to treatment, suggesting that yet unreported, immunosuppressive mechanisms coexist within tumors and their microenvironment. Here, we comprehensively analyzed and ranked forty-four immune-checkpoints expressed in ccRCC on the basis of in-depth analysis of RNAseq data collected from the TCGA database and advanced statistical methods designed to obtain the group of checkpoints that best discriminates tumor from healthy tissues. Immunohistochemistry and flow cytometry confirmed and enlarged the bioinformatics results. In particular, by using the recursive feature elimination method, we show that HLA-G, B7H3, PDL-1 and ILT2 are the most relevant genes that characterize ccRCC. Notably, ILT2 expression was detected for the first time on tumor cells. The levels of other ligand-receptor pairs such as CD70:CD27; 4-1BB:4-1BBL; CD40:CD40L; CD86:CTLA4; MHC-II:Lag3; CD200:CD200R; CD244:CD48 were also found highly expressed in tumors compared to adjacent non-tumor tissues. Collectively, our approach provides a comprehensible classification of forty-four IC expressed in ccRCC, some of which were never reported before to be co-expressed in ccRCC. In addition, the algorithms used allowed identifying the most relevant group that best discriminates tumor from healthy tissues. The data can potentially assist on the choice of valuable immune-therapy targets which hold potential for the development of more effective anti-tumor treatments.

The immune-checkpoint HLA-G/ILT4 is involved in the regulation of VEGF expression in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC), the most aggressive renal cancer, is characterized by early lymph node metastases and bad prognosis. Most therapies targeting advanced or metastatic ccRCC are based, as first-line treatment, on the administration of the vascular endothelial growth factor (VEGF) neutralizing antibody termed Bevacizumab. Despite proven benefits, the expected results were not obtained for the majority of patients. The possibility that an intricate interplay between angiogenesis and immune-checkpoints might exist lead us to evaluate tumor angiogenesis, by means of VEGF expression together with the immune checkpoint HLA-G/ILT4. METHODS: Tumor specimens were obtained from patients from two separate cohorts: One from "Evita Pueblo" Hospital from Berazategui, (Buenos Aires, Argentina) and the second includes patients surgically operated at the Urology Department of Saint-Louis Hospital (Paris, France) with a confirmed ccRCC diagnosis. Immunohistochemistry was performed with specific antibodies directed against HLA-G, VEGF-A, VEGF-C, D240, CD34, ILT4 and Ca-IX. In addition, gene expression levels were measured in a cell line derived from a ccRCC patient by semi-quantitative RT-PCR. RESULTS: Our results show that the highly vascularized tumors of ccRCC patients express high levels of VEGF and the immune-checkpoint HLA-G. In addition, ILT4, one of the HLA-G receptors, was detected on macrophages surrounding tumor cells, suggesting the generation of an immune-tolerant microenvironment that might favor tumorigenesis. Notably, RT-qPCR analysis provided the first evidence on the transcriptional relationship between HLA-G/ILT4 and the VEGF family. Namely, in the presence of HLA-G or ILT4, the levels of VEGF-A are diminished whereas those of VEGF-C are increased. CONCLUSIONS: In an effort to find new therapeutic molecules and fight against metastasis dissemination associated with the poor survival rates of ccRCC patients, these findings provide the rationale for co-targeting angiogenesis and the immune checkpoint HLA-G.

Peri-operative and local control outcomes of robot-assisted partial nephrectomy vs percutaneous cryoablation for renal masses: comparison after matching on radiological stage and renal score.

OBJECTIVES: To compare the oncological outcomes of percutaneous cryoablation (PCA) vs robot-assisted partial nephrectomy (RAPN) for the treatment of T1 renal tumours. PATIENTS AND METHODS: We conducted a retrospective study in all patients treated by RAPN or PCA for malignant renal tumours in one of four centres between 2009 and 2016. Tumours were paired one by one using radiological tumour stage and RENAL nephrometry score (package matchit, R software version 3.2.2). Malignancy was confirmed by biopsy for all patients in the PCA group. Patient characteristics before and after matching and oncological results were compared between the two groups. Cox regression, adjusted for age, treatment type, histological type and margins, was used to identify factors associated with time to local recurrence. Positive margins were defined histologically in the RAPN group and radiologically in the PCA group. RESULTS: A total of 647 patients were identified; 470 underwent RAPN and 177 underwent PCA. After matching, there was no significant difference between the two groups (RAPN, n = 177; PCA, n = 177) with regard to tumour stage, RENAL nephrometry score, tumour size (27.6 vs 25.9 mm; P = 0.07) and gender ratio. Patients in the PCA group remained significantly older (69.9 vs 59.8 years; P < 0.001). The absolute recurrence rate was 2.8% in the RAPN group vs 8.4% in the PCA group (P = 0.03). The 5-year recurrence-free survival rate was 85% in the PCA group vs 95% in the RAPN group (log-rank P = 0.02). In multivariate analysis, the presence of positive margins and the type of treatment were the two factors significantly associated with local recurrence (P < 0.001 and P = 0.046, respectively). CONCLUSION: The local recurrence rate after PCA was significantly higher than after RAPN for T1 renal tumours. Incomplete treatment was the main criterion associated with recurrence. The recurrence rate may have been overestimated in the PCA group because of closer radiological follow-up in these patients.

[Lower urinary tract disorders in men: which management?] / Troubles du bas appareil urinaire chez l'homme : comment les traiter ?

Lower urinary tract disorders in men: which management? Initial management of men lower urinary tract symptoms is based on a well conducted interview and the realization of a frequency-volume chart. Dietary intervention associated with behavioral reeducation can be of great efficacy in combination with usual drug treatments. In case of failure, transuretral electrical resection of the prostate remains the reference, with possible emerging instrumental alternatives such as Urolift or prostatic embolization.

Troubles du bas appareil urinaire chez l'homme : comment les traiter ? La prise en charge initiale des troubles mictionnels de l'homme repose sur un entretien bien conduit et la réalisation d'un calendrier mictionnel. Des règles hygiénodiététiques associées à une rééducation comportementale peuvent rendre de grands services en association avec les traitements médicamenteux habituels. En cas d'échec, la résection endoscopique électrique de la prostate reste la référence, avec de possibles alternatives instrumentales émergentes comme le système Urolift ou l'embolisation prostatique.

Prostatic injection of botulinum toxin is not inferior to optimized medical therapy in the management of lower urinary tract symptoms due to benign prostatic hyperplasia: results of a randomized clinical trial.

OBJECTIVE: To explore efficacy and safety of Botulinum Neurotoxin Type A (BoNT-A) prostatic injection in patients with lower urinary tract symptoms (LUTS) due to benign prostatic hyperperplasia. MATERIALS AND METHODS: A phase 3 multicenter open-labeled study randomised patients to receive BoNT-A prostatic injection or optimized medical therapy. BoNT-A injection consisted in trans-rectal injections of 200 UI in the transitional zone of the prostate. Optimal medical therapy consisted in oral medication with any drug patented for LUTS. One month (M1) after randomisation patients in the BoNT-A group were asked to stop any medical therapy related to LUTS. The main judgment criterion was the IPSS score at M4. Per-protocol analysis was performed with a non-inferiority hypothesis (ΔIPSS < 3). RESULTS: 127 patients were randomised to BoNT-A (n = 64) or medical therapy (n = 63). At randomisation mean IPSS was 16.9 ± 7.2 in the BoNT-A group vs 15.7 ± 7.3 in control. In the BoNT-A group, 44 patients (73.3%) could interrupt medical therapy for LUTS from M1 to M4. At M4, mean IPSS score was 12.0 ± 6.7 in the BoNT-A group vs 11.8 ± 6.9 in control. After adjustment for baseline IPSS, delta IPSS between groups was 0.01; 95% CI [- 2.14; 2.11] leading to accept the non-inferiority hypothesis. CONCLUSIONS: Four months after BoNT-A injection, most of the patients could interrupt LUTS-related medical treatments. In these patients, IPSS improvement was not inferior to optimized medical treatment, but the study design did not allow to conclude that this improvement was related with study drug rather than with sustained placebo effect. TRIAL REGISTRATION: NCT01275521.

[Total or partial nephrectomy for renal tumors?] / Néphrectomie totale ou partielle dans le cancer du rein ?

Total or partial nephrectomy for renal tumors? Due to the raising incidence of small renal masses in the past decades and long term consequences of enlarged nephrectomy on renal function, partial nephrectomy has been recommended as reference treatment for renal tumors less than 4 cm. Partial nephrectomy has shown to allow equivalent oncological control compared to enlarged nephrectomy and allows preservation of the patient's nephronic capital. However, this surgery is technically demanding and requires experience and rapidity to limit renal ischemia.

Néphrectomie totale ou partielle dans le cancer du rein ? L'augmentation de l'incidence des tumeurs rénales de petite taille et les conséquences à long terme de la néphrectomie élargie sur la fonction rénale ont conduit la chirurgie partielle à s'imposer comme traitement de référence des tumeurs rénales de moins de 4 cm. La néphrectomie partielle a démontré être équivalente d'un point de vue carcinologique à la néphrectomie élargie et permet une préservation du capital néphronique du patient. Elle n'en reste pas moins une chirurgie techniquement difficile nécessitant expérience et rapidité d'exécution afin de limiter la durée d'ischémie rénale.

[Cryoablation under local anesthesia of renal tumors]. / Cryothérapie sous anesthésie locale des tumeurs rénales.

Cryoablation under local anesthesia of renal tumors. The incidence of small renal tumors is increasing. These small tumors measuring less than 4 cm are typically slow-growing. The development of non-invasive percutaneous ablative techniques represents an alternative to active surveillance or surgery in at risk patients who are candidates to nephron sparing techniques. The intrinsic anesthetic properties of cryoablation make the procedure feasible under local anesthesia.

Cryothérapie sous anesthésie locale des tumeurs rénales. L'incidence du cancer du rein localisé et de petite taille est en constante augmentation. Ces tumeurs de moins de 4 cm sont classiquement peu agressives et leur potentiel de croissance est faible. Le développement des techniques ablatives percutanées comme la cryoablation a permis de proposer une alternative à la surveillance et à la chirurgie chez les patients fragiles nécessitant une préservation du capital néphronique. Les propriétés anesthésiques intrinsèques de la cryothérapie rendent la procédure faisable sous anesthésie locale.

Complement-binding anti-HLA antibodies and kidney-allograft survival.

BACKGROUND: Anti-HLA antibodies hamper successful transplantation, and activation of the complement cascade is involved in antibody-mediated rejection. We investigated whether the complement-binding capacity of anti-HLA antibodies plays a role in kidney-allograft failure. METHODS: We enrolled patients who received kidney allografts at two transplantation centers in Paris between January 1, 2005, and January 1, 2011, in a population-based study. Patients were screened for the presence of circulating donor-specific anti-HLA antibodies and their complement-binding capacity. Graft injury phenotype and the time to kidney-allograft loss were assessed. RESULTS: The primary analysis included 1016 patients. Patients with complement-binding donor-specific anti-HLA antibodies after transplantation had the lowest 5-year rate of graft survival (54%), as compared with patients with non-complement-binding donor-specific anti-HLA antibodies (93%) and patients without donor-specific anti-HLA antibodies (94%) (P<0.001 for both comparisons). The presence of complement-binding donor-specific anti-HLA antibodies after transplantation was associated with a risk of graft loss that was more than quadrupled (hazard ratio, 4.78; 95% confidence interval [CI], 2.69 to 8.49) when adjusted for clinical, functional, histologic, and immunologic factors. These antibodies were also associated with an increased rate of antibody-mediated rejection, a more severe graft injury phenotype with more extensive microvascular inflammation, and increased deposition of complement fraction C4d within graft capillaries. Adding complement-binding donor-specific anti-HLA antibodies to a traditional risk model improved the stratification of patients at risk for graft failure (continuous net reclassification improvement, 0.75; 95% CI, 0.54 to 0.97). CONCLUSIONS: Assessment of the complement-binding capacity of donor-specific anti-HLA antibodies appears to be useful in identifying patients at high risk for kidney-allograft loss.

Promoter hypermethylation of HS3ST2, SEPTIN9 and SLIT2 combined with FGFR3 mutations as a sensitive/specific urinary assay for diagnosis and surveillance in patients with low or high-risk non-muscle-invasive bladder cancer.

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) is a high incidence form of bladder cancer (BCa), where genetic and epigenetic alterations occur frequently. We assessed the performance of associating a FGFR3 mutation assay and a DNA methylation analysis to improve bladder cancer detection and to predict disease recurrence of NMIBC patients. METHODS: We used allele specific PCR to determine the FGFR3 mutation status for R248C, S249C, G372C, and Y375C. We preselected 18 candidate genes reported in the literature as being hypermethylated in cancer and measured their methylation levels by quantitative multiplex-methylation specific PCR. We selected HS3ST2, SLIT2 and SEPTIN9 as the most discriminative between control and NMIBC patients and we assayed these markers on urine DNA from a diagnostic study consisting of 167 NMIBC and 105 controls and a follow-up study consisting of 158 NMIBC at diagnosis time's and 425 at follow-up time. ROC analysis was performed to evaluate the diagnostic accuracy of each assay alone and in combination. RESULTS: For Diagnosis: Using a logistic regression analysis with a model consisting of the 3 markers' methylation values, FGFR3 status, age and known smoker status at the diagnosis time we obtained sensitivity/specificity of 97.6 %/84.8 % and an optimism-corrected AUC of 0.96. With an estimated BCa prevalence of 12.1 % in a hematuria cohort, this corresponds to a negative predictive value (NPV) of 99.6 %. For Follow-up: Using a logistic regression with FGFR3 mutation and the CMI at two time points (beginning of the follow-up and current time point), we got sensitivity/specificity/NPV of 90.3 %/65.1 %/97.0 % and a corrected AUC of 0.84. We also tested a thresholding algorithm with FGFR3 mutation and the two time points as described above, obtaining sensitivity/specificity/NPV values of, respectively, 94.5 %/75.9 %/98.5 % and an AUC of 0.82. CONCLUSIONS: We showed that combined analysis of FGFR3 mutation and DNA methylation markers on urine can be a useful strategy in diagnosis, surveillance and for risk stratification of patients with NMIBC. These results provide the basis for a highly accurate noninvasive test for population screening and allowing to decrease the frequency of cystoscopy, an important feature for both patient quality of life improvement and care cost reduction.

Effectiveness and safety of silodosin in the treatment of lower urinary tract symptoms in patients with benign prostatic hyperplasia: A European phase IV clinical study (SiRE study).

OBJECTIVES: To assess the benefit-risk balance of silodosin in a real-life setting of benign prostatic hyperplasia patients with lower urinary tract symptoms. METHODS: A phase IV trial including men aged ≥60 years with a clinical diagnosis of benign prostatic hyperplasia with an International Prostate Symptom Score ≥12 was carried out. Patients received silodosin 8 mg for 24 weeks. The primary end-point was a decrease ≥25% in the total International Prostate Symptom Score. Secondary end-points were: changes in total, storage and voiding, and quality of life International Prostate Symptom Scores; changes in the International Continence Society-male questionnaire; changes in the frequency/volume chart; and satisfaction according to the Patient Perception of Study Medication questionnaire. Treatment-emergent adverse events were recorded. RESULTS: Overall, 1036 patients were enrolled. Of these, 766 patients (77.1%) had a decrease ≥25% in the total International Prostate Symptom Score. The mean total International Prostate Symptom Score, and storage and voiding symptoms subscores decreased from 18.9, 8.1 and 10.8 to 10.6, 4.9 and 5.7. Nocturia decreased from 85.7% to 52.4%. The mean International Prostate Symptom Score quality of life score decreased from 4.0 to 2.2. Half of the patients reported an improvement in the frequency and bothersomeness of the most frequent symptoms reported at baseline (all P < 0.001). A reduction in the number of voids was documented by the frequency/volume chart data. The most common treatment-emergent adverse event was ejaculation failure (185 patients; 17.9%), which led to study discontinuation in 2.4% of patients. Overall, 74.2% of patients were satisfied with the medication. CONCLUSIONS: Silodosin improved lower urinary tract symptoms in three out of four patients, including diurnal voiding and storage symptoms, nocturia, and quality of life. This treatment showed a favorable safety profile in this setting.

Association between metabolic syndrome and severity of lower urinary tract symptoms (LUTS): an observational study in a 4666 European men cohort.

OBJECTIVES: To evaluate the relationship between metabolic syndrome and the frequency and severity of lower urinary tract symptoms (LUTS). PATIENTS AND METHODS: In all, 4666 men aged 55-100 years consulting a general practitioner during a 12-day period in December 2009 have been included in this observational study. LUTS were defined according to the International Prostate Symptom Score (IPSS) and metabolic syndrome with the National Cholesterol Education Program/Adult Treatment Panel III definition. We studied the correlation between metabolic syndrome and its individual components, and the severity of LUTS (IPSS and treatment for LUTS). Analyses were adjusted for body mass index, age, and prostate-specific antigen level. RESULTS: Metabolic syndrome was reported in 51.5% of the patients and 47% were treated for LUTS. There was a significant link between metabolic syndrome and treated LUTS (P < 0.001). The risk of being treated for LUTS also increased with an increasing number of metabolic syndrome components present. Metabolic syndrome was positively correlated with the severity of the LUTS (P < 0.001) for overall IPSS and both voiding and storage scores (P < 0.001). Each component of the metabolic syndrome (except high-density lipoprotein-cholesterol) appeared as an independent risk factor of high IPSS and of LUTS treatment in multivariate analysis. Metabolic syndrome was positively correlated with prostate volume. CONCLUSIONS: Our results suggest a significant relationship between LUTS linked to benign prostatic hyperplasia and metabolic syndrome, in terms of frequency and severity. The risk of being treated for LUTS also increased with an increasing number of metabolic syndrome components present. The prevention of such modifiable factors by the promotion of dietary changes and regular physical activity practice may be of great importance for public health.