L'effet du vieillissement sur la microcirculation cutanée

The pressure application on the skin leads to an increase of the cutaneous blood flow, called pressure-induced vasodilatation (PIV), that delays the occurrence of tissue ischemia resulting from this pressure. The development of this PIV depends on the activation by pressure of sensory C-fibres, leading to the release of neurotransmitters that acts at the endothelium level to stimulate the synthesis and release of endothelial factors inducing smooth muscle relaxation. This work had for objective to study the modifications of the PIV with the ageing. In old mice, without peripheral neuropathy, the PIV was reduced because of a decrease of the endothelium-dependent vasodilatation and the endothelium factors of the vasodilatation were redistributed with a contribution of Endothelium-Derived Hyperpolarizing Factor because of a decrease of the nitric oxide and the prostacyclin. In old subjects (60-75 years), the PIV was altered in comparison with young subjects (20-35 years) because of a decrease of the endothelium-dependent vasodilatation and a sensory fibres and/or neuromediators alteration. In the presence of a peripheral neuropathy, the PIV was abolished. These modifications of the cutaneous microcirculation with the ageing would lead to an early occurrence of ischemia related to an increased risk for pressure ulcers and the understanding of PIV modifications allow to glimpse of news perceptives of prevention and treatment of pressure ulcers in elderlyL'application d'une pression sur la peau provoque une vasodilatation cutanée, appelée vasodilatation induite par une pression (PIV), et retarde l'apparition de l'ischémie tissulaire liée à cette pression. La pression appliquée sur la peau active les fibres nerveuses capsaïno-sensibles, qui sécrètent en réponse des neurotransmetteurs, qui eux provoquent au niveau de l'endothélium la synthèse et la sécrétion de facteurs endothéliaux qui induisent une relaxation du muscle lisse. Ce travail avait pour objectif d'étudier l'effet du vieillissement sur la PIV.Chez la souris âgée, sans neuropathie périphérique, la PIV était altérée en raison d'une diminution de la vasodilatation endothélium-dépendante ; et la contribution des facteurs endothéliaux de la vasodilatation était modifiée : l'Endothelium-Derived Hyperpolarizing Factor jouait un rôle primordial en raison d'une diminution du monoxyde d'azote et de la prostacycline. Chez les sujets âgés (60-75 ans), la PIV était altérée en comparaison avec les sujets jeunes (20-35 ans) en raison d'une diminution de la vasodilatation endothélium-dépendante mais aussi d'une altération des fibres capsaïno-sensibles et/ou des neurotransmetteurs. En présence d'une neuropathie périphérique, la PIV était abolie. Ces modifications de la microcirculation cutanée au cours du vieillissement expliqueraient la plus grande vulnérabilité de la peau à l'ischémie et l'augmentation du risque d'ulcère de pression liée à l'âge. La compréhension des modifications de la PIV avec l'âge permet d'entrevoir de nouvelles perceptives de prévention et de traitement de l'ulcère de pression chez le sujet âgé

L'effet du vieillissement sur la microcirculation cutanée

L'application d'une pression sur la peau provoque une vasodilatation cutanée, appelée vasodilatation induite par une pression (PIV), et retarde l'apparition de l'ischémie tissulaire liée à cette pression. La pression appliquée sur la peau active les fibres nerveuses capsaïno-sensibles, qui sécrètent en réponse des neurotransmetteurs, qui eux provoquent au niveau de l'endothélium la synthèse et la sécrétion de facteurs endothéliaux qui induisent une relaxation du muscle lisse. Ce travail avait pour objectif d'étudier l'effet du vieillissement sur la PIV. Chez la souris âgée, sans neuropathie périphérique, la PIV était altérée en raison d'une diminution de la vasodilatation endothélium-dépendante ; et la contribution des facteurs endothéliaux de la vasodilatation était modifiée : l'Endothelium-Derived Hyperpolarizing Factor jouait un rôle primordial en raison d'une diminution du monoxyde d'azote et de la prostacycline. Chez les sujets âgés (60-75 ans), la PIV était altérée en comparaison avec les sujets jeunes (20-35 ans) en raison d'une diminution de la vasodilatation endothélium-dépendante mais aussi d'une altération des fibres capsaïno-sensibles et/ou des neurotransmetteurs. En présence d'une neuropathie périphérique, la PIV était abolie. Ces modifications de la microcirculation cutanée au cours du vieillissement expliqueraient la plus grande vulnérabilité de la peau à l'ischémie et l'augmentation du risque d'ulcère de pression liée à l'âge. La compréhension des modifications de la PIV avec l'âge permet d'entrevoir de nouvelles perceptives de prévention et de traitement de l'ulcère de pression chez le sujet âgéThe pressure application on the skin leads to an increase of the cutaneous blood flow, called pressure-induced vasodilatation (PIV), that delays the occurrence of tissue ischemia resulting from this pressure. The development of this PIV depends on the activation by pressure of sensory C-fibres, leading to the release of neurotransmitters that acts at the endothelium level to stimulate the synthesis and release of endothelial factors inducing smooth muscle relaxation. This work had for objective to study the modifications of the PIV with the ageing. In old mice, without peripheral neuropathy, the PIV was reduced because of a decrease of the endothelium-dependent vasodilatation and the endothelium factors of the vasodilatation were redistributed with a contribution of Endothelium-Derived Hyperpolarizing Factor because of a decrease of the nitric oxide and the prostacyclin. In old subjects (60-75 years), the PIV was altered in comparison with young subjects (20-35 years) because of a decrease of the endothelium-dependent vasodilatation and a sensory fibres and/or neuromediators alteration. In the presence of a peripheral neuropathy, the PIV was abolished. These modifications of the cutaneous microcirculation with the ageing would lead to an early occurrence of ischemia related to an increased risk for pressure ulcers and the understanding of PIV modifications allow to glimpse of news perceptives of prevention and treatment of pressure ulcers in elderlyLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Triplet combination of durvalumab, tremelimumab, and paclitaxel in biliary tract carcinomas: Safety run-in results of the randomized IMMUNOBIL PRODIGE 57 phase II trial

International audienc

Atezolizumab plus modified docetaxel, cisplatin, and fluorouracil as first-line treatment for advanced anal cancer (SCARCE C17-02 PRODIGE 60): a randomised, non-comparative, phase 2 study.

peer reviewed[en] BACKGROUND: The modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen has shown efficacy and safety as first-line treatment for advanced squamous cell carcinoma of the anus, making it a standard regimen. Inhibitors of programmed cell death protein 1 and its ligand, such as pembrolizumab, nivolumab, retifanlimab, avelumab, and atezolizumab, have shown some antitumour activity as monotherapy in advanced squamous cell carcinoma of the anus that is refractory to chemotherapy. This phase 2 study evaluated the combination of mDCF and atezolizumab as first-line treatment in advanced squamous cell carcinoma of the anus. METHODS: In this randomised, open-label, non-comparative, phase 2 study, participants from 21 centres (academic, private, and community hospitals and cancer research centres) across France with chemo-naive, metastatic, or unresectable locally advanced recurrent squamous cell carcinoma of the anus, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly allocated (2:1) to receive either atezolizumab (800 mg intravenously every 2 weeks up to 1 year) plus mDCF (eight cycles of 40 mg per m2 docetaxel and 40 mg per m2 cisplatin on day 1 and 1200 mg per m2 per day of fluorouracil for 2 days, every 2 weeks intravenously; group A) or mDCF alone (group B). Randomisation was done centrally using a minimisation technique and was stratified by age (<65 years vs ≥65 years) and disease status. The primary endpoint was investigator-assessed 12-month progression-free survival in the modified intention-to-treat population in group A (35% for the null hypothesis and 50% for the alternative hypothesis). This trial is registered with ClinicalTrials.gov, NCT03519295, and is closed to new participants. FINDINGS: 97 evaluable participants (64 in group A and 33 in group B) were enrolled between July 3, 2018, and Aug 19, 2020. The median follow-up was 26·5 months (95% CI 24·8-28·4). The median age of participants was 64·1 years (IQR 56·2-71·6), and 71 (73%) were female. 12-month progression-free survival was 45% (90% CI 35-55) in group A and 43% (29-58) in group B. In participants with a PD-L1 combined positive score of 5 or greater, 12-month progression-free survival was 70% (95% CI 47-100) in group A and 40% (19-85) in group B (interaction p=0·051) Both groups showed high compliance. Adverse events of grade 3 or higher were observed in 39 (61%) participants in group A and 14 (42%) in group B. The most common grade 3-4 adverse events were neutropenia (nine [14%] participants in group A vs five [15%] in group B), anaemia (nine [14%] vs one [3%]), fatigue (three [5%] vs four [12%]), and diarrhoea (seven [11%] vs one [3%]). Serious adverse events occurred in 16 (25%) participants in group A and four (12%) in group B, and these were mDCF-related in seven (11%) participants in group A and four (12%) in group B. Atezolizumab-related serious adverse events occurred in nine (14%) participants in group A, including grade 2 infusion-related reaction in three (5%), grade 3 infection in two (3%), and grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and a grade 4 platelet count decrease each in one participant (2%). There were no treatment-related deaths. INTERPRETATION: Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies. FUNDING: GERCOR, Roche

Stankiewicz-Isidor syndrome: expanding the clinical and molecular phenotype

Purpose: Haploinsufficiency of PSMD12 has been reported in individuals with neurodevelopmental phenotypes, including developmental delay/intellectual disability (DD/ID), facial dysmorphism, and congenital malformations, defined as Stankiewicz-Isidor syndrome (STISS). Investigations showed that pathogenic variants in PSMD12 perturb intracellular protein homeostasis. Our objective was to further explore the clinical and molecular phenotypic spectrum of STISS. Methods: We report 24 additional unrelated patients with STISS with various truncating single nucleotide variants or copy-number variant deletions involving PSMD12. We explore disease etiology by assessing patient cells and CRISPR/Cas9-engineered cell clones for various cellular pathways and inflammatory status. Results: The expressivity of most clinical features in STISS is highly variable. In addition to previously reported DD/ID, speech delay, cardiac and renal anomalies, we also confirmed preaxial hand abnormalities as a feature of this syndrome. Of note, 2 patients also showed chilblains resembling signs observed in interferonopathy. Remarkably, our data show that STISS patient cells exhibit a profound remodeling of the mTORC1 and mitophagy pathways with an induction of type I interferon-stimulated genes. Conclusion: We refine the phenotype of STISS and show that it can be clinically recognizable and biochemically diagnosed by a type I interferon gene signature