Potentiating Vascular-Targeted Photodynamic therapy through CSF-1R modulation of myeloid cells in a preclinical model of prostate cancer

La photothérapie dynamique à visée vasculaire utilisant le WST11 (VTP) induit la destruction rapide des tissus ciblés et constitue un traitement prometteur pour le cancer de la prostate. Cependant, la réponse immunitaire qui en résulte, qui peut jouer un rôle important dans la potentialisation ou l’atténuation des effets de la VTP, n’a toujours pas été comprise. Les cellules myéloïdes, telles que les MDSC et les macrophages, sont souvent présentes dans les tumeurs et sont largement associées à l'angiogenèse, au remodelage tissulaire et à l'immunosuppression. On sait également que ces cellules jouent un rôle essentiel dans la cicatrisation des plaies, induite lors de la destruction rapide des tissus. Nous avons étudié les effets de la VTP sur le recrutement de cellules myéloïdes infiltrant la tumeur (TIM), en particulier les MDSC et les macrophages associés aux tumeurs (TAM), dans les modèles de cancer de la prostate murin Myc-Cap et TRAMP C2. Nous rapportons que la VTP augmentait à la fois l'infiltration de cellules myéloïdes dans les tumeurs, mais aussi l’expression de CSF1R ; CSF1R étant un récepteur nécessaire à la différenciation, à la prolifération et à la migration des cellules myéloïdes. Comme un traitement anti-CSF1R avait déjà été utilisé pour diminuer l’infiltration de cellules myéloïdes dans d'autres modèles murins de cancer de la prostate, nous avons émis l'hypothèse que l'association d'un anti-CSF1R à un traitement par VTP entraînerait une diminution de la repousse tumorale et une amélioration de la survie. Nous avons constaté que le ciblage des cellules myéloïdes en utilisant un anti-CSF1R en association avec la VTP diminuait le nombre de MDSC et de TAM, et en particulier les macrophages M2. De plus cette association induisait une infiltration accrue de cellules T CD8+, diminuait la croissance tumorale et prolongeait la survie globale. Ces résultats suggèrent que le ciblage des cellules myéloïdes via le récepteur CSF1R est une stratégie prometteuse pour potentialiser les effets anti-tumoraux de la VTP.Vascular-targeted photodynamic therapy (VTP) induces rapid destruction of targeted tissues and is a promising therapy for prostate cancer. However, the resulting immune response, which may play an important role in either potentiating or blunting the effects of VTP, is still incompletely understood. Myeloid cells such as myeloid-derived suppressor cells (MDSCs) and macrophages are often found in tumors and are widely reported to be associated with cancer angiogenesis, tissue remodelling and immunosuppression. These cells are also known to play a critical role in wound-healing, which is induced by rapid tissue destruction. In this study, we investigated the effects of VTP on the recruitment of tumor infiltrating myeloid cells, specifically MDSCs and tumor-associated macrophages (TAMs), in the Myc-Cap and TRAMP C2 murine prostate cancer models. We report that VTP increased the infiltration of myeloid cells into the tumors, as well as their expression of CSF1R, a receptor required for myeloid differentiation, proliferation and tumor migration. As anti-CSF1R treatment has previously been used to deplete these cells types in other murine models of prostate cancer, we hypothesized that combining anti-CSF1R with VTP therapy would lead to decreased tumor regrowth and improved survival. Importantly, we found that targeting myeloid cells using anti-CSF1R in combination with VTP therapy decreased the number of tumor MDSCs and TAMs, especially M2 macrophages, as well as increased CD8+ T cell infiltration, decreased tumor growth and improved overall survival. These results suggest that targeting myeloid cells via CSF1R targeting is a promising strategy to potentiate the anti-tumor effects of VTP

Tolérance et faisabilité de la photothérapie dynamique par WST11 pour le traitement des cancers localisés de la prostate: Etude prospective sur 56 patients

ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Assessment of the Compliance of Cystitis Management According to French Recommendations through the Analysis of Prescriptions Collected in Community Pharmacies

Urinary tract infections, especially cystitis, are common infections; they are the second most prevalent cause of antibiotic prescriptions in community pharmacies. To reduce antimicrobial resistance, guidelines are revised regularly. This study aims to assess compliance between prescriptions collected in community pharmacies and French cystitis guidelines. A treatment is considered compliant if the nature, dosage, and duration of the antibiotics are correct. Only women aged 18–65 years with a diagnosis of cystitis were eligible. The participation of 16 pharmacies resulted in 303 prescriptions. Most infections were classified as uncomplicated cystitis (79.2%), general practitioners were the prescribers in more than 9 out of 10 cases, and fosfomycin trometamol was the antibiotic dispensed for 1 in 2 women. An average compliance of 66% was observed, but with disparities according to the type of cystitis. Two-thirds of cases of uncomplicated cystitis and recurrent cystitis followed the recommendations, whereas only 15% of cystitis cases that were at risk of complication did so. The inclusion of a urine examination in uncomplicated cystitis decreased the overall compliance rate to 5.8%. These results show the essential role played by pharmacists; they are the last line of defence before dispensing antibiotics. They must know the recommendations in order to apply them

Impact of retrograde flexible ureteroscopy and intracorporeal lithotripsy on kidney functional outcomes

ABSTRACT Objective: The aim of the study was to evaluate renal function and to identify factors associated with renal function deterioration after retrograde intrarenal surgery (RIRS) for kidney stones. Materials and Methods: We retrospectively analyzed patients with renal stones treated by RIRS between January 2010 and June 2013 at a single institute. We used the National Kidney Foundation classification of chronic kidney disease (CKD) to classify Glomerular Filtration Rate (GFR) in 5 groups. The baseline creatinine level was systematically pre-operatively and post-operatively evaluated. All patients had a creatinine blood measurement in June 2013. A change toward a less or a more favorable GFR group following RIRS was considered significant. Results: We included 163 patients. There were 86 males (52.8%) and 77 females (47.3%) with a mean age of 52.8±17 years. After a mean follow-up of 15.5±11.5 months, median GFR was not significantly changed from 84.3±26.2 to 84.9±24.5 mL/min (p=0.675). Significant renal function deterioration occurred in 8 cases (4.9%) and significant renal function amelioration occurred in 23 cases (14.1%). In univariate analysis, multiple procedures (p=0.023; HR: 5.4) and preoperative CKD (p=0.011; HR: 6.8) were associated with decreased renal function. In multivariate analysis these factors did not remain as predictive factors. Conclusion: Stone management with RIRS seems to have favorable outcomes on kidney function; however, special attention should be given to patients with multiple procedures and preoperative chronic kidney disease

Quantitative proteomic determination of diethylstilbestrol action on prostate cancer

International audienceDiethylstilbestrol (DES) has a direct cellular mechanism inhibition on prostate cancer. Its action is independent from the oestrogen receptors and is preserved after a first-line hormonal therapy. We aimed to identify proteins involved in the direct cellular inhibition effects of DES on prostate cancer. We used a clonogenic assay to establish the median lethal concentration of DES on 22RV1 cells. 22RV1 cells were exposed to standard and DES-enriched medium. After extraction, protein expression levels were obtained by two-dimensional differential in-gel electrophoresis (2D-DIGE) and isotope labelling tags for relative and absolute quantification (iTRAQ). Proteins of interest were analysed by quantitative RT-PCR and western blotting. The differentially regulated proteins (P$$1.3 fold; P$<$0.05). The iTRAQ analyses allowed the identification of 895 proteins. Among these proteins, 65 had a modified expression due to DES exposure (i.e., 23 overexpressed and 42 underexpressed). Most of these proteins were implicated in apoptosis and redox processes and had a predicted mitochondrial expression. Additionally, ingenuity pathway analysis placed the OAT and HSBP1 genes at the centre of a highly significant network. RT-PCR confirmed the overexpression of OAT (P50.006) and HSPB1 (P50.046)