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We report the observation of Brillouin backscattering in a 50-cm long spiral high-index doped silica chip waveguide and measured a Brillouin frequency shift of 16 GHz which is in very good agreement with theoretical predictions and numerical simulations based on the elastodynamics equation. © 2023.

The main objective of the French GETUG/AFU V05 VESPER randomized phase III study was to assess the efficacy of dd-MVAC and GC in term of progression-free survival in patients for whom chemotherapy has been decided, before or after surgery.A total of 500 patients have been randomized in 28 reference centers. Inclusion criteria were urothelial carcinoma without neuro-endocrine variant, disease defined by a T2, T3 or T4a N0 (pelvic lymph node ≤ 10 mm on CT scan) M0 staging for patients receiving neoadjuvant chemotherapy or pT3 or pT4 or pN+ and M0 for patients receiving adjuvant chemotherapy. Secondary endpoints include overall survival, safety, response rate. The peri-operative chemotherapy schedule was experimental arm dd-MVAC for a total of 6 cycles versus standard arm GC 4 cycles. The toxicity was evaluated according to NCI CTCAE (v 4.0). The progression-free survival rate will be estimated at 3 years by the Kaplan-Meier method. All the patients will be followed for 5 years.The last patient was randomized in March 2018 and the primary endpoint results are expected for mid-2021. As the dd-MVAC schedule is associated with higher response rates in metastatic disease, the real question today is to confirm such benefit in the peri-operative setting, taking also in consideration the chemotherapy toxicity. Tomorrow, the challenge may be the best chemotherapy and immunotherapy association, the authors hope that final Vesper Trial results will help to determine the gold standard chemotherapy. Keywords: Bladder cancer, Peri-operative chemotherapy

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 langerin high , but not langerin low , 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., (© 2022. The Author(s), under exclusive licence to Society for Mucosal Immunology.)

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 (C trough ) 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 C trough (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 C trough 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 C trough . In 4 patients (18%) who required ENZA dose reduction because of severe clinical toxicity, an increased ENZA plasma C trough 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 C trough 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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The complexity of signal transduction resulting from the contact of human immunodeficiency virus type 1 (HIV-1)-infected cells and mucosal cells has hampered our comprehension of HIV-1 mucosal entry. Such process is driven efficiently only by viral synapse contacts, whereas cell-free HIV-1 remains poorly infectious. Using CD4 + T-cells expressing only HIV-1 envelope inoculated on human adult foreskin tissues, we designed methodologies to identify the signals transduced in foreskin keratinocytes following HIV-1-envelope-dependent viral synapse formation. We find that the viral synapse activates the MyD88-independent TLR-4-nuclear factor (NfκB) signaling pathway in keratinocytes and the subsequent secretion of cytokines including thymic stromal lymphopoietin (TSLP), a cytokine linking innate and T-helper type 2-adaptive immune responses. Moreover, the viral synapse upregulates the non-coding microRNA miR-375, known to control TSLP, and transfection of keratinocytes with anti-miR-375 blocks significantly TSLP secretion. Thus, the secretion of TSLP by keratinocytes is induced by the viral synapse in a miR-375 controlled manner. At the tissue level, these signals translate into the epidermal redistribution of Langerhans cells and formation of conjugates with T-cells, recapitulating the initial events observed in human foreskin infection by HIV-1. These results open new possibilities for designing strategies to block mucosal HIV-1 transmission, the major pathway by which HIV-1 spreads worldwide.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Tissue-based markers improve the accuracy of prediction models in urothelial carcinoma of the bladder (UCB). Current smoking status and cumulative exposure also affect outcomes. To evaluate whether the combination of molecular markers and smoking features further improved the prognostication of patients who underwent radical cystectomy (RC) for UCB., Materials and Methods: A total of 588 patients underwent RC and bilateral lymphadenectomy for UCB from 1995 to 2005. Immunohistochemistry for p53, p21, pRB, p27, Ki-67, and survivin was performed on tissue microarrays from the RC specimen. Smoking features were routinely assessed at diagnosis. Multivariable Cox regression models assessed time to disease recurrence and cancer-specific mortality., Results: Of the 588 patients, 128 were never (22%), 283 former (48%), and 177 current smokers (30%). In total, 227 patients experienced disease recurrence, whereas 190 died of UCB. Smoking status was independently associated with both outcomes (hazard ratio [HR] = 1.48 and 2.62, for former and current vs. never smokers, respectively, P<0.001). All markers were significantly associated with both outcomes (P<0.05) except for survivin. The combination of the 4 cell cycle markers p53, p21, pRB, and p27 increased the discrimination of clinicopathologic model for former and current vs. never smokers with c-indices 0.779 and 0.780, respectively (base model c-indices of 0.741 and 0.740 for former and current vs. never smokers, respectively). The further addition of smoking features and biomarker status improved the discrimination of the model (c-indices of 0.783 and 0.786 for former and current vs. never smokers, respectively)., Conclusions: We confirmed that smoking information and tissue markers status improve prognostication of UCB outcomes after RC; the combination of both reaching the highest level of discrimination., (© 2013 Published by Elsevier Inc.)

Objective: The data describing the urologic extracolonic cancers associated with Lynch syndrome (hereditary non-polyposis colorectal cancer [HNPCC]) are variable. The aim of our study was to establish the frequency of mutations in mismatch repair (MMR) genes in patients with upper urinary tract transitional cell carcinoma (UUT-TCC) and to evaluate the clinical benefits of a systematic screening., Methods: Specimen blocks were obtained from 146 patients treated for UUT-TCC in our center. Clinicopathological characteristics and survival data of patients were collected (median follow-up = 42.5 months). Immunohistochemistry was performed by tissue microarray (TMA), in order to detect mutations in mismatch repair genes. Results obtained after TMA analysis were confirmed at a molecular level by microsatellite instability (MSI) analysis., Results: Mutations in mismatch repair genes were detected in seven patients (4.8%) at immunohistochemistry screening, and confirmed by MSI analysis for five of them (3.4%). Clinicopathological characteristics and survival data did not differ significantly in patients with instability compared with patients without. After a median follow-up of 42.5 months, none of them experienced a new HNPCC manifestation., Conclusion: The frequency of mutations in mismatch repair genes in UUT-TCC was very low, with a good accuracy of immunohistochemistry. Systematic screening should not be proposed in daily practice.

Background: The purpose of this study was to evaluate morbidity, functional, and oncological outcomes after NSS in renal tumors > 7 cm., Materials and Methods: We retrospectively analyzed data from 168 patients with tumors > 7 cm who were treated using NSS between 1998 and 2012., Results: Imperative and elective indications accounted for 76 (45.2%) and 92 (54.8%) patients, respectively. Major perioperative complications and renal function deterioration occurred in 33 (19.6%) and 51 patients (30.4%), respectively. In multivariate analysis, age older than 60 years (P = .001; hazard ratio [HR], 5) and tumor malignancy (P = .014; HR, 6.7) were prognostic factors for renal function deterioration whereas imperative indication was a risk factor for major postoperative complications (P = .0019; HR, 2.7). In 126 (75%) patients with malignant tumors, after a median follow-up of 30 months (range, 1-254 months), 25 patients (20.2%) died. In multivariate analysis, imperative indication (P = .023; HR, 4.2), positive surgical margin (P = .021; HR, 3.3), and Fuhrman grade > II (P = .013; HR, 3.7) were prognostic indicators for cancer-free survival (CFS). Imperative indication (P = .04; HR, 8.5) and Fuhrman grade > II (P = .04; HR, 3.9) were predictive factors of cancer-specific survival (CSS). In case of elective indication, positive surgical margin, local recurrence, and cancer-related death occurred in 4 (7.6%), 1 (1.1%), and 1 (1.1%) cases, respectively. For elective indication, 5-year estimates of CFS, CSS, and overall survival rates were: 85.7%, 98%, and 93.9%, respectively., Conclusion: In this selected population, imperative vs. elective indication status seems to play a critical role in oncologic outcomes. Oncologic results for elective indications are close to those reported with radical nephrectomy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: Expression of T-cell co-regulatory proteins has been associated with worse outcomes in patients with UCB. We aimed to confirm these findings., Materials and Methods: The study comprised tissue microarrays from 302 consecutive UCB patients treated with RC and lymphadenectomy between 1988 and 2003, 117 matched lymph nodes, and 50 cases of adjacent normal urothelium controls, which were evaluated for B7-H1, B7-H3, and PD-1 protein expression by immunohistochemistry., Results: B7-H3 and PD-1 expression were increased in cancers compared to adjacent normal urothelium (58.6% vs 6% and 65% vs 0%, respectively; both p values < 0.001). Meanwhile, B7-H1 was expressed in 25% of cancers (n = 76). Expression of B7-H3, B7-H1, and PD-1 were highly correlated between the primary tumors and metastatic nodes, with concordance rates of 90%, 86%, and 78% for B7H3, B7H1 and PD-1, respectively. Expression was not associated with clinicopathologic features, disease recurrence, cancer-specific or overall mortality. However, for the subgroup of patients with organ-confined disease (n = 96), B7-H1 expression was associated with an increased risk of overall mortality (p = 0.02) on univariate and trended toward an association on multivariate analyses (p = 0.06)., Conclusions: B7-H1, B7-H3 and PD-1 are altered in a large proportion of UCB. B7-H1 and PD-1 expression are differentially upregulated in cancer versus normal urothelium. High correlation between expression in LN and expression in RC specimens was observed. While expression was not associated with clinicopathologic features or standard outcomes in all patients, B7-H1 expression predicted overall mortality after RC in the subset of patients with organ-confined UCB., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: The objective of the study was to evaluate the effect of a history of bladder cancer (BC) or synchronous BC on the prognosis and survival of patients who have undergone radical nephroureterectomy (RNU)., Methods and Materials: Using a multi-institutional, retrospective database, we identified 662 patients with upper urinary tract urothelial carcinoma (UUT-UC) treated by radical nephroureterectomy, between 1995 and 2010. We analyzed clinicopathologic characteristics and outcomes according to the history of BC or concomitant BC or both, at the time of diagnosis. BC was evaluated as a prognostic factor for bladder recurrence and survival., Results: Overall, 83 (12.5%) patients had previous BC, 62 (9.4%) exhibited concomitant BC, and 75 (11.3%) presented with both previous and current BC. A history of BC was less seen in women and nonsmokers (P<0.0001 and P = 0.013, respectively). The patients with associated BC had more tumors located in the ureter (P<0.0001), as well as more multiple locations in the upper tract (P<0.0001). The tumors without concomitant BC were more likely to be associated with locally advanced stages (P = 0.024). At a median follow-up time of 37.3 months, 31.4% of patients experienced BC recurrence and 2.9% developed contralateral upper tract tumor. Using multivariate analyses, the previous or synchronous BC (P = 0.01) and positive surgical margins (P = 0.03) are independent prognostic factors for BC recurrence. The metastasis-free survival and cancer-specific survival rates did not significantly differ according to the associated BC status., Conclusions: In patients without previous or concomitant BC, the upper tract tumors are more frequently localized in the renal pelvis and are associated with a more invasive status at the time of diagnosis. Nevertheless, the presence of UUT-UC without previous or synchronous BC did not significantly affect the survival rates after nephroureterectomy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Abiraterone acetate and cabazitaxel have shown an overall survival benefit in patients with metastatic castration-resistant prostate cancer following docetaxel failure. Both have been approved in this indication. The search, follow-up and characterisation of circulating tumor cells should help for the response evaluation and the choice between the two treatments. Recently, alpharadin (radium-223 chloride) has demonstrated also an overall survival advantage in a large phase III trial. Other hormone therapies as MDV3100 or TAK700 are very promising. In undifferentiated cancers with neuroendocrine features, etoposide and platinum salts combinations have shown low efficiency.

Purpose: To establish the accurate surgical anatomy of endonasal dacryocystorhinostomy (DCR) based on the radiological analysis of underlying bony structures., Design: Prospective noncomparative observational case series study., Participants: Fifty-nine patients with complete nasolacrimal stenosis underwent a computed tomodensitometry (CT) scan before endonasal DCR., Methods: High-resolution CT scanning with contrast injection of the lacrimal sac was performed. Image reconstruction was performed to obtain continuous 1.0-mm axial and coronal sections for review., Main Outcome Measures: Relationship of the lacrimal fossa (LF) to the operculum of the middle turbinate (OMT), the uncinate process (UP), and the frontal recess (FR); symmetry of the right and left anatomies; location of the OMT; position of the most anterior insertion of the UP with respect to 2 main references (the posterior lacrimal crest and the junction between the maxillary and lacrimal bones) on axial sections at 3 different levels (upper, intermediate, and lower of the LF); height of the LF; and distance of the OMT from the lower limit of the LF., Results: The OMT, the UP, and the FR were adjacent to the LF in 41 (53.2%), 73 (94.8%), and 23 cases (29.9%), respectively. There was a right-left symmetry in 10 of 18 patients (55%). The OMT was always anterior to the junction between the maxillary bone and the lacrimal bone. The UP was more frequently posterior (32.5%) or adjacent (45.5%) to the LF at the lower level, adjacent to the maxillary bone (55.8%) at the intermediate level, and adjacent to the middle turbinate (61%) at the upper level. The height of the LF was 12.06+/-1.93 mm. The OMT was located 5.96+/-2.05 mm upward from the lower limit of the LF., Conclusion: The almost constant overlapping of the UP onto the LF at the level of the common canaliculus indicates that the most effective approach for successful DCR osteotomy is via a submucosal cleavage and resection of the anterior part of the UP. The management of these landmark structures should be an integral part of the endonasal DCR method.

A radical prostatectomy for localized prostate cancer is indicated after evaluation of the disease (initial PSA, clinical stage, biopsy mapping, results of radiologic explorations with an endorectal MRI) and the patient (age, morbidity, life expectancy and wishes of potency conservation). The surgical approaches, retropubic or laparoscopic, depend on the surgeon's experience. Radical prostatectomy provides good disease-free survival for organ-confined disease close to the natural life expectancy. Post-radical prostatectomy morbidity is essentially represented by orthostatic incontinence (up to 6.8%), stress incontinence (up to 27%) and impotence (30 to 95%), depending on the published series and patient age.

Aim of the Study: Retrospective analysis of result of radical cystectomy at Cochin Hospital., Patients and Methods: We report the results of a 106 patients series treated by radical cystectomy for bladder carcinoma after a 5-year period follow-up., Results: The extent of the tumour invasion according to pathological analysis was: pT1 or less: 26%, pT2 and pT3a: 33%, pT3b and over: 41%. Morbidity rate was 19% with a 7.5% reintervention rate. Long term complication rate was 31%, concerning essentially ureteral stenosis. A local recurrence or distant metastasis occurred in 35% of patients. Local recurrence rate was 10.7%. Cancer specific survival rates were 88%, 81% and 42% for pT1, pT2-pT3a, and pT3b patients respectively., Conclusion: The present results confirm that radical cystectomy is the most effective curative treatment for invasive bladder carcinoma.

The most effective chemotherapy of metastatic bladder cancer in M-VAC (methotrexate, vinblastine, cisplatin), as it was shown M-VAC by phase III trials. The complete remission rate is 15-20%. The toxicity is severe, and M-VAC cannot be delivered to fragile patients. Survival is improved. This increase in survival results in an increased incidence in brain metastases. The Cochin Hospital experience with 50 patients treated with M-VAC for a metastatic bladder cancer is presented.

Two homosexuals with advanced HIV infection and testicular seminoma stage IIb and IIc were treated with irradiation associated with chemotherapy in one patient. Subdiaphragmatic irradiation was followed by moderate diarrhoea. Initial chemotherapy consisted of cisplatinum, vinblastine, bleomycin replaced by cyclophosphamide after radiotherapy. The use of cyclophosphamide was discontinued after 2 courses due to neutropenia (less than 1500/mm3). Complete tumor remission was achieved in both patients without infection in spite of an aggravation of the CD4 deficit (5/mm3, 52/mm3). The patients died of opportunistic infections 14 and 12 months after terminating treatment. We conclude that cytotoxic and radiation treatment can be administered safely if carefully monitored in these severely immunodepressed patients.