TRPV1 activation in human Langerhans cells and T cells inhibits mucosal HIV-1 infection via CGRP-dependent and independent mechanisms.

Upon its mucosal transmission, HIV type 1 (HIV-1) rapidly targets genital antigen-presenting Langerhans cells (LCs), which subsequently transfer infectious virus to CD4+ T cells. We previously described an inhibitory neuroimmune cross talk, whereby calcitonin gene-related peptide (CGRP), a neuropeptide secreted by peripheral pain-sensing nociceptor neurons innervating all mucosal epithelia and associating with LCs, strongly inhibits HIV-1 transfer. As nociceptors secret CGRP following the activation of their Ca2+ ion channel transient receptor potential vanilloid 1 (TRPV1), and as we reported that LCs secret low levels of CGRP, we investigated whether LCs express functional TRPV1. We found that human LCs expressed mRNA and protein of TRPV1, which was functional and induced Ca2+ influx following activation with TRPV1 agonists, including capsaicin (CP). The treatment of LCs with TRPV1 agonists also increased CGRP secretion, reaching its anti-HIV-1 inhibitory concentrations. Accordingly, CP pretreatment significantly inhibited LCs-mediated HIV-1 transfer to CD4+ T cells, which was abrogated by both TRPV1 and CGRP receptor antagonists. Like CGRP, CP-induced inhibition of HIV-1 transfer was mediated via increased CCL3 secretion and HIV-1 degradation. CP also inhibited direct CD4+ T cells HIV-1 infection, but in CGRP-independent manners. Finally, pretreatment of inner foreskin tissue explants with CP markedly increased CGRP and CCL3 secretion, and upon subsequent polarized exposure to HIV-1, inhibited an increase in LC-T cell conjugate formation and consequently T cell infection. Our results reveal that TRPV1 activation in human LCs and CD4+ T cells inhibits mucosal HIV-1 infection, via CGRP-dependent/independent mechanisms. Formulations containing TRPV1 agonists, already approved for pain relief, could hence be useful against HIV-1.

Robot-Assisted Surgery vs Robotic Stereotactic Body Radiotherapy in Prostate Cancer: A Cost-Utility Analysis.

Prostate cancer is the most common men cancer in France. Continuous progress in oncology led to develop robot-assisted Radical Prostatectomies (rRP) and robot-assisted stereotactic body radiotherapy (rSBRT). The present study aims at comparing economic and clinical impacts of prostate cancer treatments performed either with rSBRT or rRP in France. A Markov model using TreeAge Pro software was chosen to calculate annual costs; utilities and transition probabilities of localized prostate cancer treatments. Patients were eligible for radiotherapy or surgery and the therapeutic decision was a robot-assisted intervention. Over a 10-year period, rSBRT yielded a significantly higher number of quality-adjusted life years than rRP (8.37 vs 6.85). In France, rSBRT seemed more expensive than rRP (€19,475 vs €18,968, respectively). From a societal perspective, rRP was more cost-saving (incremental cost effectiveness ratio = €332/QALY). The model was sensitive to variations of costs of the initial and recurrence state in one-way sensitivity analyses. Robot-assisted stereotactic body radiotherapy seems more cost-effective than Radical Prostatectomy in terms of QALY despite the slightly higher initial cost due to the use of radiotherapy. It would be interesting to conduct comparative quality of life studies in France over longer periods of time.

CGRP inhibits human Langerhans cells infection with HSV by differentially modulating specific HSV-1 and HSV-2 entry mechanisms.

Herpes simplex virus (HSV) is widespread globally, with both HSV-1 and HSV-2 responsible for genital herpes. During sexual transmission, HSV targets epithelial cells, sensory peripheral pain neurons secreting the mucosal neuropeptide calcitonin gene-related peptide (CGRP), and mucosal immune cells including Langerhans cells (LCs). We previously described a neuro-immune crosstalk, whereby CGRP inhibits LCs-mediated human immunodeficiency virus type 1 (HIV-1) transmission. Herein, to further explore CGRP-mediated anti-viral function, we investigated whether CGRP affects LCs infection with HSV. We found that both HSV-1 and HSV-2 primary isolates productively infect monocyte-derived LCs (MDLCs) and inner foreskin LCs. Moreover, CGRP significantly inhibits infection with both HSV subtypes of MDLCs and langerinhigh, but not langerinlow, inner foreskin LCs. For HSV-1, infection is mediated via the HSV-1-specific entry receptor 3-O sulfated heparan sulfate (3-OS HS) in a pH-depended manner, and CGRP down-regulates 3-OS HS surface expression, as well as abrogates pH dependency. For HSV-2, infection involves langerin-mediated endocytosis in a pH-independent manner, and CGRP up-regulates surface expression of atypical langerin double-trimer oligomers. Our results show that CGRP inhibits mucosal HSV infection by differentially modulating subtype-specific entry receptors and mechanisms in human LCs. CGRP could turn out useful for prevention of LCs-mediated HSV infection and HSV/HIV-1 co-infection.

Native CGRP Neuropeptide and Its Stable Analogue SAX, But Not CGRP Peptide Fragments, Inhibit Mucosal HIV-1 Transmission.

Background: The vasodilator neuropeptide calcitonin gene-related peptide (CGRP) plays both detrimental and protective roles in different pathologies. CGRP is also an essential component of the neuro-immune dialogue between nociceptors and mucosal immune cells. We previously discovered that CGRP is endowed with anti-viral activity and strongly inhibits human immunodeficiency virus type 1 (HIV-1) infection, by suppressing Langerhans cells (LCs)-mediated HIV-1 trans-infection in-vitro and mucosal HIV-1 transmission ex-vivo. This inhibition is mediated via activation of the CGRP receptor non-canonical NFκB/STAT4 signaling pathway that induces a variety of cooperative mechanisms. These include CGRP-mediated increase in the expression of the LC-specific pathogen recognition C-type lectin langerin and decrease in LC-T-cell conjugates formation. The clinical utility of CGRP and modalities of CGRP receptor activation, for inhibition of mucosal HIV-1 transmission, remain elusive. Methods: We tested the capacity of CGRP to inhibit HIV-1 infection in-vivo in humanized mice. We further compared the anti-HIV-1 activities of full-length native CGRP, its metabolically stable analogue SAX, and several CGRP peptide fragments containing its binding C-terminal and activating N-terminal regions. These agonists were evaluated for their capacity to inhibit LCs-mediated HIV-1 trans-infection in-vitro and mucosal HIV-1 transmission in human mucosal tissues ex-vivo. Results: A single CGRP intravaginal topical treatment of humanized mice, followed by HIV-1 vaginal challenge, transiently restricts the increase in HIV-1 plasma viral loads but maintains long-lasting higher CD4+ T-cell counts. Similarly to CGRP, SAX inhibits LCs-mediated HIV-1 trans-infection in-vitro, but with lower potency. This inhibition is mediated via CGRP receptor activation, leading to increased expression of both langerin and STAT4 in LCs. In contrast, several N-terminal and N+C-terminal bivalent CGRP peptide fragments fail to increase langerin and STAT4, and accordingly lack anti-HIV-1 activities. Finally, like CGRP, treatment of human inner foreskin tissue explants with SAX, followed by polarized inoculation with cell-associated HIV-1, completely blocks formation of LC-T-cell conjugates and HIV-1 infection of T-cells. Conclusion: Our results show that CGRP receptor activation by full-length CGRP or SAX is required for efficient inhibition of LCs-mediated mucosal HIV-1 transmission. These findings suggest that formulations containing CGRP, SAX and/or their optimized agonists/analogues could be harnessed for HIV-1 prevention.

Feasibility and safety of targeted focal microwave ablation of the index tumor in patients with low to intermediate risk prostate cancer: Results of the FOSTINE trial.

OBJECTIVE: To assess the feasibility, safety and precision of organ-based tracking (OBT)-fusion targeted focal microwave ablation (FMA), in patients with low to intermediate risk prostate cancer. PATIENTS AND METHOD: Ten patients with a visible index tumor of Gleason score ≤3+4, largest diameter <20mm were included. Transrectal OBT-fusion targeted FMA was performed using an 18G needle. Primary endpoint was the evidence of complete overlap of the index tumor by ablation zone necrosis on MRI 7 days after ablation. Urinary and sexual function were assessed with IPSS, IIEF5 and MSHQ-EjD-SF. Oncological outcomes were assessed with PSA at 2 and 6 months, and re-biopsy at 6 months. RESULTS: Median [IQR] age was 64.5 [61-72] years and baseline PSA was 5 [4.3-8.1] ng/mL. Seven (70%) and 3 (30%) patients had a low and intermediate risk cancer, respectively. Median largest tumor axis was of 11 [9.0-15.0] mm. Median duration of procedure was of 82 [44-170] min. No patient reported any pain or rectal bleeding, and all 10 patients were discharged the next day. Seven days after ablation, total necrosis of the index tumor on MRI was obtained in eight (80% [95%CI 55%-100%]) patients. One patient was treated with radical prostatectomy. Re-biopsy at 6 months in the other 9 did not show evidence of cancer in 4 patients. IPSS, IIEF-5 and MSHQ-EjD-SF were not statistically different between baseline and 6 months follow up. CONCLUSIONS: OBT-fusion targeted FMA was feasible, precise, and safe in patients with low to intermediate risk localized prostate cancer.

Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer.

This study evaluated the prognostic value of a panel of 29 oncogenes derived from the analysis of The Cancer Genome Atlas (TCGA data) or from the recent literature on bladder tumors on a well-characterized series of muscle-invasive bladder cancer (MIBC) and non-MIBC (NMIBC) samples and tried to identify molecular prognostic markers. Mutations of HRAS, FGFR3, PIK3CA and TERT were found in 2.9%, 27.2%, 14.9% and 76.7% of tumor samples, respectively. Concerning NMIBC, on multivariate analysis, RXRA and FGFR3 levels were associated with recurrence-free survival (RFS) (p = 0.0022 and p = 0.0069) and RXRA level was associated with progression to muscle-invasive disease (p = 0.0068). We identified a 3-gene molecular signature associated with NMIBC prognosis. FGFR3 overexpression was associated with reduced response to Bacillus Calmette-Guerin treatment (p = 0.037). As regards MIBC, on multivariate analysis, ERCC2 overexpression was associated with RFS (p = 0.0011) and E2F3 and EGFR overexpression were associated with overall survival (p = 0.014 and p = 0.035). RT-PCR findings were confirmed by IHC for FGFR3. Genomic alterations in MIBC revealed in TCGA data also concern NMIBC and seem to be associated with prognosis in terms of recurrence and progression. Correcting these alterations by targeted therapies seems a promising pharmacological approach.

Pharmacokinetic/Pharmacodynamic Relationship of Enzalutamide and Its Active Metabolite N-Desmethyl Enzalutamide in Metastatic Castration-Resistant Prostate Cancer Patients.

INTRODUCTION: Enzalutamide (ENZA) is an oral androgen receptor inhibitor approved by the Food and Drug Administration and the European Medicines Agency for the treatment of metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). ENZA is extensively metabolized by cytochrome P450 3A4 into N-desmethyl ENZA (NDE), an active metabolite. We aimed to explore the pharmacokinetic/pharmacodynamic relationship for ENZA and NDE in metastatic CRPC patients from a real-world setting. PATIENTS AND METHODS: Trough plasma concentration (Ctrough) of ENZA and NDE were assayed using liquid chromatography coupled with UV detection. The relationship between ENZA, NDE, and composite (ENZA with NDE) plasma concentration and requirement of ENZA dose reduction was investigated using the Mann-Whitney test. A survival univariate analysis was conducted to explore association between progression-free survival (PFS), overall survival (OS), and plasma Ctrough (ENZA, NDE, and composite). RESULTS: Twenty-two metastatic CRPC patients treated with ENZA (median age, 75.5 years; 13 patients (59%) with Eastern Cooperative Oncology Group status 0-1) were prospectively included. Mean plasma Ctrough of ENZA and NDE were 12.4 ± 3.0 µg/mL and 8.8 ± 2.1 µg/mL, respectively. Neither PFS nor OS were statistically associated with ENZA, NDE, or composite plasma Ctrough. In 4 patients (18%) who required ENZA dose reduction because of severe clinical toxicity, an increased ENZA plasma Ctrough was observed compared with 18 remaining patients (16.1 ± 2.4 µg/mL vs. 11.6 ± 2.6 µg/mL, respectively; P = .027). CONCLUSION: The low interindividual variability in ENZA and NDE Ctrough and the lack of relationship with survival do not support the need for plasma drug monitoring. Severe asthenia might be related to higher exposure and could be improved by decreasing ENZA dosing.

PLEKHS1: A new molecular marker predicting risk of progression of non-muscle-invasive bladder cancer.

Promoter mutations of pleckstrin homology domain-containing S1 (PLEKHS1) are frequent in several cancer types. To evaluate the DNA mutations, the mRNA expression and prognostic value of PLEKHS1 was evaluated in bladder cancer. We investigated DNA mutations and mRNA expression of PLEKHS1 in a first series of 154 bladder tumors [71 non-muscle-invasive bladder cancer (NMIBC) and 83 muscle-invasive bladder cancers (MIBC)] from patients who underwent transurethral bladder resection or radical cystectomy between 2001 and 2006, and 20 normal bladder samples. Results were then validated in a second series of 181 bladder tumors (91 NMIBC and 90 MIBC). All patients have signed an informed consent form. DNA mutations were analysed by high-resolution melt analysis and sanger sequencing. The mRNA expression was measured by real-time reverse-transcriptase quantitative PCR. The results of the molecular analysis were compared with survival data. PLEKHS1 mutations occurred in 25.0 and 32.2% of NMIBC and MIBC, respectively in the first series. These results were confirmed in the second series (33.0 and 37.8% of NMIBC and MIBC, respectively). In MIBC, DNA mutations were significantly more frequent with the basal than non-basal phenotype (61.5 vs. 27.1%; P=0.0025). The PLEKHS1 mRNA level was increased in 22.5 and 27.7% of NMIBC and MIBC tumors but was not associated with DNA mutations. In NMIBC, PLEKHS1 mRNA overexpression was significantly associated with progression to muscle-invasive disease (P=0.0069) and remained an independent prognostic factor on multivariate analysis (P=0.034). DNA mutations of PLEKHS1 occurred in one-third of bladder tumors and was frequent in the basal MIBC phenotype. PLEKHS1 mRNA overexpression may be an independent prognostic factor of progression-free survival in NMIBC.

High Prevalence of a Hotspot of Noncoding Somatic Mutations in Intron 6 of GPR126 in Bladder Cancer.

Numerous pangenomic studies identified protein-coding genes and signaling pathways involved in bladder carcinogenesis. However, noncoding somatic alterations remain unexplored. A recent study revealed a mutational hotspot in intron 6 of GPR126 gene in 2.7% of a large breast cancer series. As GPR126 is highly expressed in bladder tissues, we investigated here the prevalence and the prognostic significance of these mutations in bladder cancer. We analyzed a cohort of 103 bladder cancers including 44 nonmuscle-invasive bladder cancers (NMIBC) and 59 muscle-invasive bladder cancers (MIBC). GPR126 mutations were analyzed by high-resolution melting and Sanger sequencing, and GPR126 expression levels were assessed using real-time quantitative RT-PCR. In NMIBC, somatic GPR126 noncoding mutations occurred in 47.7% of samples and were negatively associated with GPR126 mRNA levels. GPR126 mutations had higher frequencies in nonsmoker patients and were associated with a prior history of NMIBC. GPR126 overexpression was detected in 70.5% of samples. GPR126 mutation and overexpression status were not associated with outcome. In MIBC, somatic GPR126 mutations occurred in 44.1% of samples. Mutations were more frequent in females. GPR126 overexpression was detected in 27.1% of the sample. A trend toward significance was observed between GPR126 overexpression and better outcome. We identified the second most frequent mutational hotspot after TERT promoter (∼70%) in bladder cancer, with a mutation rate of approximately 50%. IMPLICATIONS: The GPR126 intronic mutational hotspot could be a promising clinical biomarker candidate to monitor tumor burden using circulating tumor DNA in bladder cancer.

Criteria for indication and treatment modification in a cohort of patients with prostate cancer treated with hormone therapy.

BACKGROUND: No published studies have specifically assessed whether treatment modifications to androgen deprivation therapy (ADT) for prostate cancer (PCa) are frequently carried out in routine clinical practice. The current study was conducted to determine what proportion of patients who had initiated hormone therapy with a gonadotropin-releasing hormone (GnRH) analogue then had their treatment regimen modified during the first 24 months. METHODS: A prospective, noninterventional study was carried out in routine clinical practice in France. Patients with locally advanced or metastatic PCa were followed up for 2 years after treatment initiation with a GnRH analogue. The primary endpoint was the proportion of patients with a modification to their initial hormone therapy. RESULTS: In total, 1301 patients were enrolled into the study by 204 physicians, and the primary endpoint could be evaluated for 891 patients. The GnRH analogue treatment was initiated for metastatic PCa (24.2%), locally advanced PCa without planned local treatment (20.6%), locally advanced PCa in association with radiotherapy (31.6%), and biochemical recurrence after local treatment (21.4%). Hormonal treatment was modified in 43.8% (390/891) of patients during the 24-month follow-up period after GnRH analogue initiation. In 61.3% of cases (239/390), the type of modification involved a change of GnRH analogue formulation or switch to another GnRH analogue. A total of five significant predictive factors for GnRH analogue treatment modification were identified: metastatic stage; physician sector; physician speciality; presence or absence of urinary symptoms; and intermittent versus continuous ADT. CONCLUSIONS: This study shows that in 43.8% of the patients with advanced PCa, ADT is modified in the first 2 years after initiation in routine clinical practice. Predictive factors for alteration of ADT were metastatic stage and the choice of an intermittent schedule.

Neoadjuvant Chemotherapy in Patients With Muscle-Invasive Bladder Cancer and Its Impact on Surgical Morbidity and Oncological Outcomes: A Real-World Experience.

Objectives: The purpose of this study was to investigate the impact of neoadjuvant chemotherapy (NAC) on perioperative morbidity and on oncological outcomes according to the type of chemotherapy regimen administered to patients with muscle-invasive bladder cancer (MIBC) who subsequently underwent radical cystectomy (RC). Methods: Data were collected retrospectively on 40 patients with bladder urothelial carcinoma who had at least two cycles of NAC, followed by RC, from 2011 to 2015 at our institution. The outcomes evaluated were NAC toxicity, perioperative complications, cancer-specific, and overall survival. Results: Among these cases, 23 patients (57.5%) received methotrexate, vinblastine, doxorubicin and cisplatin (MVAC), 4 patients (10%) received gemcitabine and cisplatin (GC), and 13 patients (32.5%) received other regimes. The early and late postoperative complication rates were 35% and 12.5%. Regarding toxicity, 85% of patients had at least one side effect of NAC, but only 21.7% discontinued therapy in the MVAC group. The pathological complete response (pCR) rates for cisplatin-based regimens (MVAC and GC) and other regimens were 44.4 and 15.4%, respectively, (p = 0.09). The pathological partial response (pPR) rates for cisplatin-based regimens and other regimens were 66.7 and 15.4%, respectively, (p = 0.002). Patients treated with a cisplatin-based chemotherapy regimen had longer overall survival than those treated with other regimen (median 38.1 vs. 18.4 months, p = 0.01). Conclusions: NAC administration was not associated with high toxicity or surgical morbidity. The pathological response rates and survival outcomes in the cisplatin-based regimens were higher than with those with non-cisplatin-based regimens. These data support the use, in patients elective to a neoadjuvant setting prior to RC for MBIC, of a cisplatin-based regimen.

The visual prostate symptom score is a simple tool to identify and follow up in general practice patients with lower urinary tract symptoms associated with benign prostatic hyperplasia (a study with 1359 patients).

INTRODUCTION: The IPSS (International Prostate Symptom Score), a structured self-administered questionnaire is the reference test for evaluation of lower urinary tract symptoms (LUTS). A 5-pictogram score entitled Score Visuel Prostatique en Images (SVPI) was proposed in France and evaluated by urologists. We assessed the interest of the SVPI for the identification and monitoring of benign prostatic hyperplasia (BPH)-related LUTS in general practice, and compared it with the IPSS. METHODS: A prospective observational survey was carried out with general practitioners (GPs) throughout France. The first 4consecutive patients aged over 60years, with BPH-related LUTS (IPSS score greater than 8) for whom the GP freely intended to prescribe an alpha-blocker, were enrolled. Two self-administered questionnaires were used at baseline and at follow-up visit (between 1 and 3months): French language version of the IPSS (8questions) and the SVPI. The 5pictograms of the SVPI were: How many times do you urinate during the day (score of 0 to 5)? How many times do you urinate during the night (score of 0 to 5)? Do you experience an urgent need to urinate (score of 0 to 4)? How strong is the stream (response from 0 to 4)? Do you urinate in a satisfactory manner (score of 0 to 6)? The primary objective was to assess and validate the sensitivity to change of the SVPI at baseline and follow-up visit by the study of the correlation of its changes according to the changes of LUTS evaluated with the IPSS. RESULTS: Five hundred and forty seven GPs enrolled at least one patient and returned information. 2261patients completed the inclusion questionnaire, and 1359 were included in the statistical analysis. Under treatment with alpha-blocker, the IPSS average decreased from 17.7±4.9 to 10.5±4.4 (P<0.0001) with an average diminution of 7.2±4.0, which corresponded to an improvement of 40.7%. This significant decrease of the IPSS involved all its components. The total SVPI was evaluated to 13.8±3.1, the irritative sub-score to 7.4±2.0, and the obstructive sub-score to 2.4±0.8. The internal consistency of the SVPI was good with a value of the Cronbach Alpha coefficient of 0.74. Under treatment with alpha-blocker, the value of the total SVPI decreased from 13.8±3.1 to 8.2±3.0 (P<0.0001) between enrolment and the follow-up visit. The Pearson coefficients assessing the correlations in 1359 patients with benign prostatic hypertrophy were statistically significant at enrolment, and at the follow-up visit. Their variations were all significant. The correlations were weak for the obstructive subscores. Four hundred and fifty-one GPs gave their opinion on the SVPI compared to IPSS: for 36.8% of them, the SVPI was completed a little more rapidly than the IPSS, for 34.6% more rapidly, and for 22.8% of them the SVPI was completed much more rapidly. For 5.8% of them, there was no difference. With regard to ease of understanding for the patient, the 451 GPs responded: much easier for 27.3%, easier for 37.3%, a little easier for 27.1%, and 8.4% had no opinion. CONCLUSION: This study showed the SVPI to be a simple and useful tool for identifying and monitoring BPH-related LUTS. Total SVPI was correlated with total IPSS, even if the obstructive subscore correlation was weaker. The good sensitivity of the SVPI to change showed its potential interest for monitoring LUTS. Given the underuse of the IPSS and the interest expressed by GPs and urologists, the SVPI might be used alone to analyse patient complaints.

Impact of body mass index on the oncological outcomes of patients treated with radical nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To evaluate the association between body mass index (BMI) and oncological outcomes in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). METHODS: We retrospectively reviewed 237 consecutive patients treated with RNU for UTUC at our institution between 1990 and 2012. Univariable and multivariable cox regression models investigated the association of BMI with disease recurrence, cancer-specific mortality, and overall mortality. RESULTS: From the 237 patients, 104 (44%) had a BMI < 25 kg/m2, 88 (37%) had a BMI between 25 and 29.9 kg/m2, and 45 (19%) had a BMI ≥ 30 kg/m2 at the time of surgery. Within a median follow-up of 44 months (IQR: 24-79), 53 patients (22.4%) experienced a disease recurrence, 85 patients (35.9%) had bladder recurrence, and 44 patients (18.6%) died from the disease. The 5 year recurrence-free and cancer-specific survival rates were, respectively, 32 and 56% for BMI ≥ 30 kg/m2, 45 and 74% for patients with BMI 25-29.9 kg/m2, and 69 and 81% for patients with BMI < 25 kg/m2. In multivariable analyses that adjusted for the effects of the standard clinico-pathological features, BMI ≥ 30 kg/m2 was associated with a higher risk of disease recurrence (HR 3.23; 95% CI 2.3-6.6, p < 0.001) and cancer-specific mortality (HR 3.84; 95% CI 2.8-6.5; p < 0.001). CONCLUSIONS: Obesity was independently associated with higher risks of disease recurrence and cancer-specific mortality in patients treated with RNU for UTUC.

mRNA Expression levels of genes involved in antitumor immunity: Identification of a 3-gene signature associated with prognosis of muscle-invasive bladder cancer.

Immunotherapy for bladder cancer has given promising results. Here we aimed to evaluate the possible involvement and prognostic value of 33 genes involved in the immune response during bladder carcinogenesis. Expression levels were assessed by quantitative real-time RT-PCR in normal and tumor human bladder samples. Immunohistochemistry was performed to evaluate the protein expression of 2 genes and relation of the mRNA and protein levels was analyzed. Tumors were obtained from 154 patients (83 with muscle-invasive bladder cancer [MIBC] and 71 non-MIBC [NMIBC]) who underwent transurethral bladder resection or radical cystectomy between 2002 and 2006. All patients signed an informed consent. Results of molecular analyses were coupled with survival analyses. Overall, 25 genes (75.8%) were significantly overexpressed in MIBC and 15 (45.5%) were deregulated in NMIBC as compared with normal tissue. On multivariate analysis, risk of NMIBC recurrence was increased with high FOXP3/CD8 ratio and overexpression of OX40L (p = 0.016 and p = 0.0039, respectively). In MIBC, a molecular signature of 3 genes (OX40L, CD8 and TIGIT) was significantly associated with prognosis in terms of recurrence-free and overall survival (p = 0.0007 and p = 0.007). RT-PCR findings were confirmed by immunohistochemistry for CD8 and FOXP3, with high association between mRNA and protein levels. Finally, risk of recurrence of non-muscle-invasive bladder cancer was increased with high FOXP3/CD8 ratio and OX40L overexpression. We identified a 3 gene molecular signature associated with prognosis of muscle-invasive bladder cancer. These results confirm the useful role of immune checkpoints in bladder carcinogenesis and suggest targets for therapy.

Correlation between messenger RNA expression and protein expression of immune checkpoint-associated molecules in bladder urothelial carcinoma: A retrospective study.

OBJECTIVES: Immunotherapy for bladder cancer seems to have promising results. Here, we evaluated the association between messenger RNA (mRNA) and protein levels and possible prognostic value of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) immune checkpoint pathways during bladder carcinogenesis. METHODS AND MATERIALS: Tumor samples were obtained from 155 patients (84 with muscle-invasive bladder cancer [MIBC], and 71 non-muscle-invasive bladder cancer [NMIBC]) and normal bladder tissue from 15 patients. We evaluated the mRNA expression of 3 genes in the PD-1 pathway (PD-1, PD-L1, and PD-L2) and 4 in the CTLA4 pathway (CTLA4, CD28, CD80, and CD86) in normal and tumoral human bladder samples by quantitative real-time reverse transcription polymerase chain reaction, with immunohistochemistry used to evaluate the protein expression of PD-1 and PD-L1 in tumor and immune cells. Results of molecular analyses were compared with survival analyses. RESULTS: As compared with normal bladder tissue, MIBC tissue showed PD-1, PD-L1, CTLA4, and CD80 overexpression (59.5%, 60.7%, 84.5%, and 92.9%, respectively), whereas overexpression was lower in NMIBC tissue (22.5%, 4.2%, 35.2%, and 46.5%, respectively). The results of reverse transcription polymerase chain reaction analysis were confirmed by immunohistochemistry, with a high correlation between mRNA and protein expression. On multivariate analyses, overexpression of the studied genes was not associated with prognosis in relapse or progression of NMIBC or in recurrence-free and overall survival of MIBC. CONCLUSIONS: The CTLA4 pathway appears to be deregulated along with the PD-1/PD-L1 pathway in bladder carcinogenesis, with good correlation between mRNA and protein expression endorsing the useful role of immune checkpoints, especially for a large subgroup of MIBC.

Impact of body mass index on the oncological outcomes of patients treated with radical cystectomy for muscle-invasive bladder cancer.

PURPOSE: Body mass index (BMI) has been associated with worse outcomes in several solid malignancies. We aimed to evaluate the association between BMI and oncological outcomes in patients treated with radical cystectomy (RC) for muscle-invasive urothelial carcinoma of the bladder (UCB). METHODS: We retrospectively reviewed 701 consecutive patients treated with RC and pelvic lymphadenectomy for UCB at our institution between 1995 and 2011. Univariable and multivariable Cox regression models investigated the association of BMI with disease recurrence and cancer-specific mortality. BMI was analyzed as both continuous and categorical variable (<25 vs. 25-29 vs. ≥30 kg/m2). RESULTS: From the 701 patients, 275 (39.2 %) had a BMI < 25 kg/m2, 280 (39.9 %) had a BMI between 25 and 29.9 kg/m2, and 146 (20.9 %) had a BMI â©¾ 30 kg/m2. Within a median follow-up of 45 months (IQR 23-75), 163 patients (23.3 %) experienced a disease recurrence and 127 (18.1 %) died from the disease. In univariable analyses, BMI â©¾ 30 kg/m2 was associated with a higher risk of disease recurrence and cancer-specific mortality (both p values <0.01). In multivariable analyses that adjusted for the effects of standard clinicopathological features, BMI â©¾ 30 kg/m2 was associated with both higher risks of disease recurrence (HR 1.58; 95 % CI 1.06-2.34, p = 0.02) and cancer-specific mortality (HR 1.58; 95 % CI 1.01-2.48; p = 0.04). CONCLUSIONS: Obesity was independently associated with higher risks of disease recurrence and cancer-specific mortality in patients treated with RC for muscle-invasive UCB. BMI is a modifiable feature that may have significant individual and public health implications in patients with muscle-invasive UCB.

Gleason Score Determination with Transrectal Ultrasound-Magnetic Resonance Imaging Fusion Guided Prostate Biopsies--Are We Gaining in Accuracy?

PURPOSE: We evaluated the accuracy of prostate magnetic resonance imaging- transrectal ultrasound targeted biopsy for Gleason score determination. MATERIALS AND METHODS: We selected 125 consecutive patients treated with radical prostatectomy for a clinically localized prostate cancer diagnosed on magnetic resonance imaging-transrectal ultrasound targeted biopsy and/or systematic biopsy. On multiparametric magnetic resonance imaging each suspicious area was graded according to PI-RADS™ score. A correlation analysis between multiparametric magnetic resonance imaging and pathological findings was performed. Factors associated with determining the accuracy of Gleason score on targeted biopsy were statistically assessed. RESULTS: Pathological analysis of radical prostatectomy specimens detected 230 tumor foci. Multiparametric magnetic resonance imaging detected 151 suspicious areas. Of these areas targeted biopsy showed 126 cancer foci in 115 patients, and detected the index lesion in all of them. The primary Gleason grade, secondary Gleason grade and Gleason score of the 126 individual tumors were determined accurately in 114 (90%), 75 (59%) and 85 (67%) cases, respectively. Maximal Gleason score was determined accurately in 80 (70%) patients. Gleason score determination accuracy on targeted biopsy was significantly higher for low Gleason and high PI-RADS score tumors. CONCLUSIONS: Magnetic resonance imaging-transrectal ultrasound targeted biopsy allowed for an accurate estimation of Gleason score in more than two-thirds of patients. Gleason score misclassification was mostly due to a lack of accuracy in the determination of the secondary Gleason grade.

Oncological outcomes of advanced muscle-invasive bladder cancer with a micropapillary variant after radical cystectomy and adjuvant platinum-based chemotherapy.

OBJECTIVE: To assess the oncological outcomes of radical cystectomy (RC) and adjuvant chemotherapy to treat muscle-invasive bladder cancer (MIBC) with a micropapillary component (MPC), and to compare outcomes with those from pure urothelial carcinoma (PUC). MATERIALS AND METHODS: A retrospective review of clinicopathological and follow-up data was performed for all patients treated by RC and adjuvant platinum-based chemotherapy for advanced MIBC in three tertiary reference centers between 1999 and 2012. Uni- and multivariate Cox's regression analyses evaluated the association of the presence of MPC with disease recurrence and cancer-specific mortality. RESULTS: Two hundred and thirty-five (88 %) PUC and 31 (12 %) MPC cases were included. Median age was 65 (39-83) years in the PUC group and 62 (45-80) years in the MPC group. Median survival was 29 months in the MPC versus 31 months in the PUC group. No significant difference was observed between the groups regarding main clinical and pathological characteristics. The median number of treatment cycles administered was 6 (3-8) in the PUC versus 5 (3-8) in the MPC group (p = 0.45). Five-year disease-free recurrence and cancer-specific survival (CSS) rates were 15 and 24 %, respectively, in the MPC versus 42 and 47 %, respectively, in the PUC group (p = 0.007 and 0.058). In multivariate analyses, ASA score, soft tissue surgical margins, and MPC were associated with disease recurrence (p = 0.022, 0.001, and 0.015, respectively). We found no association between MPC and cancer-specific mortality (univariate, p = 0.06). CONCLUSION: MPC was associated with higher recurrence rates after RC and platinum-based adjuvant chemotherapy than that with pure urothelial tumors.

The use of partial nephrectomy: results from a contemporary national prospective multicenter study.

PURPOSE: Despite benefits in functional renal outcome and favorable oncological efficacy, previous studies show marked underuse of partial nephrectomy (PN). We investigated national utilization of partial and radical nephrectomy (RN) using a contemporary, prospective population-based cohort. METHODS: Between June and December 2010, 1,237 patients were treated by PN or RN for renal cell carcinoma in 56 French centers. Data were prospectively collected, and statistical analyses were performed. RESULTS: Overall, 667 (53.9 %) and 570 patients (46.1 %) underwent RN and PN, respectively. In case of PN, surgical approach was an open PN in 63.3 % of cases, a laparoscopic PN in 21.0 % of cases and a robot-assisted PN in 15.7 % of cases. PN was used in T1a, T1b, T2 and T3 tumors in 395 (76.7 %), 131 (38.2 %), 29 (14.7 %) and 7 (4.6 %), respectively. Median ischemia time was 16 min [0-60], and mean blood loss was 280.4 ml (±339.9). Tumor characteristics and operative features were significantly different according to the surgical approach. Warm ischemia time was significantly higher in case of laparoscopic or robot-assisted procedure (p < 0.001). There was no statistical significant difference in blood loss and transfusion rate according to surgical approach. Postoperative medical and surgical complications occurred in 8.2 and 10.0 % of PN, respectively, with no significant difference according to surgical approach. CONCLUSIONS: Partial nephrectomy for renal cell carcinoma is commonly used in this French centers sample. Mini-invasive approaches represent also a significant part of all partial nephrectomies with no difference in terms of complication rates.

Prostate cancer incidence on cystoprostatectomy specimens is directly linked to age: results from a multicentre study.

OBJECTIVE: To assess the incidence and age-related histopathological characteristics of incidentally diagnosed prostate cancer from specimens obtained via radical cystoprostatectomy (RCP) for muscle-invasive bladder cancer. PATIENTS AND METHODS: A retrospective review of the histopathological features of 2424 male patients who underwent a RCP for bladder cancer was done at eight centres between January 1996 and June 2012. No patient had preoperative suspicion of prostate cancer. Statistical analyses were performed in different age-related groups. RESULTS: Overall, prostate cancer was diagnosed in 518 men (21.4%). Incidences varied significantly according to age (5.2% in those aged <50 years to 30.5% in those aged >75 years, P < 0.001). Most of the prostate cancers were considered as 'non-aggressive', that is to say organ-confined (≤pT2) and well-differentiated (Gleason score <7). Tumour-Node-Metastasis (TNM) stage and proportion with a Gleason score of ≥7 were significantly greater in older patients (P < 0.001). Apart from age, there were no preoperative predictive factors for 'non-aggressive' prostate-cancer status. At the end of the follow-up, only nine patients (1.7%) had biochemical recurrence of prostate cancer, and no preoperative predictive factors were identified. CONCLUSION: The rate of incidentally diagnosed prostate cancer from RCP specimens is ≈20%, most of them being organ-confined and well-differentiated. The probability of having a 'non-aggressive' prostate cancer decreases in older men.