Pierre Fabre (United Kingdom)

INTRODUCTION: The ECCA grading scale (échelle d'évaluation clinique des cicatrices d'acné) is a tool designed to help dermatologists to assess the severity of acne scars and to standardize the discussions about the treatments of scars. METHODS: We developed an acne scar clinical grading scale called ECCA, which consists of 6 items designed to assess easily and quickly the severity of acne scars by a global score. The interobserver reliability of the ECCA grading was statistically validated. RESULTS: The statistical analysis showed the interinvestigator reliability of the ECCA grading scale among 7 dermatologists who used it on the same group of 10 acne patients. CONCLUSION: ECCA is a new tool which will now be available for dermatologists to use in their everyday practice and for clinical trials evaluating the efficacy of treatments on acne scars.

Milnacipran (Ixel) is a new antidepressant with essentially equal potency for inhibiting the reuptake of both serotonin and noradrenaline, with no affinity for any neurotransmitter receptor studied. A review of the studies comparing milnacipran, placebo and active comparator antidepressants provides clear-cut evidence of its efficacy in both severe and moderate depression in hospitalized and community settings. Meta-analyses of the original data of controlled trials involving 1032 patients, comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs), show that milnacipran provides antidepressant efficacy similar to that of imipramine and significantly superior to that of the SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of the tricyclic antidepressants (TCAs) with fewer cholinergic side-effects. The tolerability of milnacipran was comparable to that of the SSRIs, with a higher incidence of dysuria with milnacipran, and a higher frequency of nausea and anxiety with the SSRIs. Milnacipran is a new therapeutic option in depression, which offers a clinical efficacy in the range of the TCAs combined with a tolerability equivalent to that of the SSRIs.

OBJECTIVE: Self-assessment scores such as the Patient-Oriented Scoring of Atopic Dermatitis (PO-SCORAD) index being recommended by public health authorities for chronic disease management, we aimed at analysing correlations between PO-SCORAD and physician and patient assessment scores of atopic dermatitis (AD) severity and quality of life. METHODS: We perfomed an observational study conducted in 12 European countries in 4,222 atopic patients aged ≥1 month and prescribed Exomega® emollient cream. AD severity was measured by the SCORAD index, PO-SCORAD, Patient-Oriented Eczema Measure (POEM) and Self-Administered Eczema Area and Severity Index (SA-EASI) scales, and patient and family quality of life by the Dermatology Life Quality Index (DLQI) and Dermatitis Family Questionnaire Impact (DFQI) scales, respectively. Their correlations were analysed. RESULTS: PO-SCORAD was the only self-assessment score to be highly correlated with the SCORAD index and POEM (r ≥ 0.70). It was also the best correlated with the DLQI (r = 0.67) and DFQI (r = 0.56). After a 5-week treatment, SCORAD index and PO-SCORAD severity scores had decreased significantly by 60 and 56% (p < 0.0001), and quality of life had improved. CONCLUSION: PO-SCORAD is better correlated with quality of life scales than other self-assessment scores.

The aim of the present study was to assess the anti-inflammatory activity of two topically applied oatmeal extracts, i.e. Avena sativa and Avena Rhealba, using the sodium lauryl sulfate (SLS) irritation model. At baseline, test areas on the volar surface of the upper arms of 12 healthy individuals were pretreated with the two extracts and their vehicle (petrolatum ointment) under occlusion for 2 h, and one site was left untreated. Then a patch with a 1% SLS solution was applied to the test sites for 24 h. Irritation was determined at each period by measuring by chromametry and laser-Doppler. In a dose-ranging study with the Avena Rhealba extract alone, the 20 and 30% concentrations exerted a slight inhibition of the a* parameter increase and a marked reduction of the blood flow increase (p < 0.05, compared to vehicle). Then, the effects of the two extracts at the concentration of 20% were compared. All extracts displayed a statistically significant counteracting effect on both parameters (p < 0.05), but no statistically significant difference between treatment groups could be demonstrated. In conclusion, this study demonstrates the preventive effects of oatmeal extracts on skin irritation in the SLS model.

BACKGROUND: Retinaldehyde (RAL), a key metabolite between vitamin A and retinoic acid, acts by modulating differentiation and proliferation of keratinocytes, which is of interest in acne lesions, mainly retentional lesions. Glycolic acid increases the exfoliation of corneocytes explaining its mild activity on retentional lesions. Thus, RAL and glycolic acid combined in the same product (Diacneal) have complementary activities which can be of interest for acne patients. The aim of this study was to evaluate the tolerance of Diacneal used by 1,709 acne patients in combination with their usual acne products except retinoids. RESULTS: This study demonstrated a very good tolerance of Diacneal when used with other acne treatments for 90 days. Complaints about side-effects were rare. Moreover, the significant decrease in both inflammatory and retentional lesions between day 0 and day 90 indicates that Diacneal could amplify the efficiency of other anti-acne products used at the same time by the patients. The subjective evaluation of the preparation's efficacy by investigators and patients was strongly favourable. CONCLUSION: These data show that a combination of RAL 0.1% and glycolic acid 6% may be used in association with other topical anti-acne treatments (benzoyl peroxide and topical antibiotics) with an excellent tolerance.

&lt;div data-canvas-width="597.5493333333335"&gt;Researchers in the area of collaborative networks are more and more aware of proposing collaborative approaches to address planning processes, due to the advantages associated when enterprises perform integrated planning models. Collaborative production-distribution planning, among the supply network actors, is considered a proper mechanism to support enterprises on dealing with uncertainties and dynamicity associated to the current markets. Enterprises, and especially SMEs, should be able to overcome the continuous changes of the market by increasing their agility. Carrying out collaborative planning allows enterprises to enhance their readiness and agility for facing the market turbulences. However, SMEs have limited access when incorporating optimization tools to deal with collaborative planning, reducing their ability to respond to the competition. The problem to solve is to provide SMEs affordable solutions to support collaborative planning. In this regard, new optimisation algorithms are required in order to improve the collaboration within the supply network partners. As part of the H2020 Cloud Collaborative Manufacturing Networks (C2NET) research project, this paper presents a study on integrated production and distribution plans. The main objective of the research is to identify gaps in current optimization models, proposed to address integrated planning, taking into account the requirements and needs of the industry. Thus, the needs of the companies belonging to the industrial pilots, defined in the C2NET project, are identified; analysing how these needs are covered by the optimization models proposed in the literature, to deal with the integrated production-distribution planning.&lt;/div&gt;

Background: The frequency of dermatological acts is increasing. These procedures often cause injuries and traumatic alterations in specific skin layers, slowing down wound healing. Patients and methods: An open observational study lasting 1 month was conducted on 2,363 patients who had undergone various dermatological procedures. This study was conducted in eight European countries and an Asian country during which the tolerance and efficacy of a cosmetic cream based on Rhealba oat plantlets' extract, l-ALA-l-GLU dipeptide, and hyaluronic acid were assessed on patients' wounds. Results: Efficacy was observed 5' after the first application, which leads to an immediate relief, confirmed by the overall efficacy judged by the doctors as good or very good in 96.8% of the cases. In Germany, the efficacy of the same cream was assessed on children suffering from first- or second-degree burns. In this dermatopediatric case, the aim was to support the regeneration process and prevent scarring by using a topical cream rather than a silicon bandage or corticosteroids. A positive effect on skin regeneration and prevention of scaring could already be observed after 4 weeks of application without any undesired complication. Conclusion: This clinical focus complements the previous meta-analysis by demonstrating that the tested cream containing Rhealba oat plantlets' extracts, l-ALA-l-GLU dipeptide, and hyaluronic acid could also be used with a great efficacy in children after thermal burns to prevent scaring.

Deimination is a post-translational modification catalyzed by a family of enzymes named peptidylarginine deiminases (PADs). PADs transform arginine residues of protein substrates into citrulline. Deimination has been associated with numerous physiological and pathological processes. In human skin, three PADs are expressed (PAD1-3). While PAD3 is important for hair shape formation, the role of PAD1 is less clear. To decipher the main role(s) of PAD1 in epidermal differentiation, its expression was down-regulated using lentivirus-mediated shRNA interference in primary keratinocytes and in three-dimensional reconstructed human epidermis (RHE). Compared to normal RHEs, down-regulation of PAD1 caused a drastic reduction in deiminated proteins. Whereas proliferation of keratinocytes was not affected, their differentiation was disturbed at molecular, cellular and functional levels. The number of corneocyte layers was significantly reduced, expression of filaggrin and cornified cell envelope components, such as loricrin and transglutaminases, was down-regulated, epidermal permeability increased and trans-epidermal-electric resistance diminished drastically. Keratohyalin granule density decreased and nucleophagy in the granular layer was disturbed. These results demonstrate that PAD1 is the main regulator of protein deimination in RHE. Its deficiency alters epidermal homeostasis, affecting the differentiation of keratinocytes, especially the cornification process, a special kind of programmed cell death.

Resistance to androgen receptor (AR)-targeted therapies represents a major challenge in prostate cancer. A key mechanism of treatment resistance in patients who progress to castration-resistant prostate cancer (CRPC) is the generation of alternatively spliced AR variants (AR-V). Unlike full-length AR isoforms, AR-Vs are constitutively active and refractory to current receptor-targeting agents and hence drive tumor progression. Identifying regulators of AR-V synthesis may therefore provide new therapeutic opportunities in combination with conventional AR-targeting agents. Our understanding of AR transcript splicing, and the factors that control the synthesis of AR-Vs, remains limited. Although candidate-based approaches have identified a small number of AR-V splicing regulators, an unbiased analysis of splicing factors important for AR-V generation is required to fill an important knowledge gap and furnish the field with novel and tractable targets for prostate cancer treatment. To that end, we conducted a bespoke CRISPR screen to profile splicing factor requirements for AR-V synthesis. MFAP1 and CWC22 were shown to be required for the generation of AR-V mRNA transcripts, and their depletion resulted in reduced AR-V protein abundance and cell proliferation in several CRPC models. Global transcriptomic analysis of MFAP1-depleted cells revealed both AR-dependent and -independent transcriptional impacts, including genes associated with DNA damage response. As such, MFAP1 downregulation sensitized prostate cancer cells to ionizing radiation, suggesting that therapeutically targeting AR-V splicing could provide novel cellular vulnerabilities which can be exploited in CRPC. Implications: We have utilized a CRISPR screening approach to identify key regulators of pathogenic AR splicing in prostate cancer.

BACKGROUND AND OBJECTIVE: To assess an objective method evaluating the effects of a retinaldehyde-based cream (RA-cream) on solar lentigines; 29 women randomly applied RA-cream on lentigines of one hand and a control cream on the other, once daily for 3 months. METHODS: A specific method enabling a reliable visualisation of the lesions was proposed, using high-magnification colour-calibrated camera imaging. Assessment was performed using clinical evaluation by Physician Global Assessment score and image analysis. Luminance determination on the numeric images was performed either on the basis of 5 independent expert's consensus borders or probability map analysis via an algorithm automatically detecting the pigmented area. RESULTS: Both image analysis methods showed a similar lightening of ΔL* = 2 after a 3-month treatment by RA-cream, in agreement with single-blind clinical evaluation. CONCLUSION: High-magnification colour-calibrated camera imaging combined with probability map analysis is a fast and precise method to follow lentigo depigmentation.

Abstract. The analysis by proton-decoupled carbon-13 nuclear magnetic resonance spectroscopy of samples dissolved in solvents presenting strong multiple resonances can be facilitated by the suppression of these resonances by multisite presaturation. The advantage drawn from this operation is the elimination of the possible artifacts that arise from the solvent signals in non-optimized decoupling conditions. Solvent presaturation was implemented on glycerol, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, and 1,3-butanediol with at least 94 % on-resonance efficiency and a bandwidth of less than 50 Hz measured at 50 % signal intensity decrease. The experimental measurement of the signal suppression bandwidth leads to unexpected selectivity profiles for close-frequency resonances. Computer resolution of the Bloch equations during multisite presaturation provide an insight into the origin of the observed profile perturbations.

BACKGROUND: Fragile skin is a poorly understood skin condition, particularly in the general adult population. There are currently limited epidemiological data on the prevalence of fragile skin in adults. The objectives of this study were to assess the prevalence of perceived fragile skin across different skin types in representative samples of the general adult populations in Mexico and Russia, and to identify skin characteristics associated with perceived fragile skin. METHODS: Two identical cross-sectional surveys, using a short online self-administered questionnaire, were conducted on samples of recruited individuals that were representative of the general Mexican and Russian populations. Participants responded to questions about fragile skin, with the main question being "In your opinion, do you have fragile skin (ie, skin less resistant and reacting quickly to external aggressions)?". The survey also covered questions relating to skin appearance, skin symptoms, skin disease, dermatological procedures, and living environment and climate. RESULTS: Overall, 1,210 individuals in Mexico (N=606) and Russia (N=604) completed the online survey. Fragile skin was perceived in 50.0% and 45.9% of participants in Mexico and Russia, respectively. The principal skin appearance characteristics reported by individuals with perceived fragile skin were thin, easily wrinkled, and transparent; the main skin symptoms were dryness, redness, and/or itching (≥50% of individuals in Mexico), and dryness, tightness, and/or redness (>60% of individuals in Russia). Individuals with perceived fragile skin had experienced skin disease and/or undergone a dermatological procedure in the past 12 months, and they reported being exposed to stress (>80% of individuals in both surveys). CONCLUSION: A substantial proportion of the general adult population of Mexico and Russia perceived that they had fragile skin, regardless of their skin type; fragile skin was perceived more frequently in women. These findings should assist dermatologists to extend their understanding and management of individuals with perceived fragile skin.

Aims: With recent European Union marketing authorization, tabelecleucel is the first off-the-shelf, allogeneic Epstein-Barr virus (EBV)-specific T-cell immunotherapy approved for the treatment of relapsed/ refractory EBV-positive post-transplant lymphoproliferative disease (EBV PTLD).In the absence of a control arm, real-world evidence can provide a comparative benchmark for single-arm studies in ultrarare populations.This study assessed the treatment effect of tabelecleucel in the single-arm phase 3 ALLELE study (NCT03394365) versus a treatment group from a multinational, multicenter retrospective chart review study (RS002) of patients with EBV PTLD.Methods: In ALLELE, patients had disease relapsed/refractory to rituximab chemotherapy and received tabelecleucel 2x10 6 cells/kg on days 1, 8, and 15 in 35-day cycles.Patients in RS002 had disease relapsed/refractory to rituximab chemotherapy and received next line of systemic therapy between January 2000 and December 2018.Propensity score-based standardized mortality/morbidity ratio weighting was used to achieve balance between treatment and comparator arms.Kaplan-Meier estimators and Cox regression models were used to compare overall survival (OS) in the re-weighted sample.Results: 30 patients (n 14 hematopoietic cell transplant [HCT], n 16 solid organ transplant [SOT]) from ALLELE (data cutoff: November 2021) and 84 patients (n 36 HCT, n 48 SOT) from RS002 (data lock: January 2021) were included.Median time from diagnosis to first tabelecleucel dose (ALLELE) or start date of next line of systemic therapy (RS002) was 3.6 months.Tabelecleucel was associated with a substantial OS benefit compared with current treatment, with an unadjusted HR of 0.47 (95% confidence interval [CI] 0.25-0.88)and adjusted HR of 0.37 (95% CI 0.20-0.71)when using the start date of the next line of therapy as the index date.Sensitivity analyses yielded consistent results.Conclusions: In this study of real-world data, tabelecleucel was associated with an OS benefit among patients with R/R EBV PTLD for whom there is high unmet need.

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Abstract. The analysis by proton-decoupled carbon-13 nuclear magnetic resonance spectroscopy of samples dissolved in solvents presenting strong multiple resonances can be facilitated by the suppression of these resonances by multi–site presaturation. The advantage drawn from this operation is the elimination of the possible artifacts that arise from the solvent signals in non–optimized decoupling conditions. Solvent presaturation was implemented on glycerol, 1,2–propanediol, 1,3–propanediol, 1,2–butanediol, 1,3–butanediol with at least 94 % on–resonance efficiency and a bandwidth of less 5 than 50 Hz measured at 50 % signal intensity decrease. The experimental measurement of the signal suppression bandwidth leads to unexpected selectivity profiles for frequency close resonances. Computer resolution of the Bloch equations during multi–site presaturation provide an insight into the origin of the observed profile perturbations.

INTRODUCTION: Asian subjects are particularly prone to skin sensitivity. We developed a facial cream and balm containing 4-t-butylcyclohexanol to provide skin comfort and a soothing effect for sensitive skin. OBJECTIVES: Assess the dermatological and ophthalmological tolerance and efficacy in improving skin sensitivity of face cream and balm under normal conditions of use by a population known to be particularly prone to this problem. METHODS: In a monocentric non-randomized open trial, the cream or balm was applied twice daily to the face, neck, and eye contour of 33 stinger subjects with hypersensitive skin (22-63 years old). Assessments included dermatological and ophthalmological physical and functional signs on Day 1 (D1), D8, and D22, and cosmetic acceptability, cutaneous sensitivity according to a stinging test and the sensitive scale, and the soothing efficacy according to a questionnaire on D22. RESULTS: The cream and balm were very well tolerated. Immediately after application, subjects reported a reduction in the skin's hypersensitivity (93.9% of subjects for the cream and 81.8% for the balm), skin redness (90.9% of subjects for the cream and 87.9% for the balm), sensations of tightness (93.9% for the cream and 97.0% for the balm), and discomfort sensations (93.9% for the cream and 87.9% for the balm). After 21 days, the application of the cream and balm decreased the stinging scores by 65% and 41%, respectively, with 94% and 77% of subjects showing an improvement, respectively. The sensitivity scale questionnaire indicated that the cream and balm significantly and profoundly decreased all negative signs, for example, irritability, stinging, general discomfort, redness, and dryness on D22 compared to D1. On D22, all 15 parameters recorded were improved by 89%-100% by the cream and by 74%-100% by the balm. The majority (90.9% and 96.8% of subjects using the cream and balm, respectively) of the subjects noticed positive changes in their skin condition after using the product for 21 days. CONCLUSIONS: The cream and balm were very well-tolerated. This study demonstrated that both products controlled and markedly reduced skin hypersensitivity in Asian subjects, with an immediate and lasting skin soothing and repairing effect over 21 days.

OBJECTIVE: The BEACON CRC randomised controlled trial (NCT02928224) in BRAF-mutant metastatic colorectal cancer (mCRC) patients showed improved overall survival for the combination treatment of encorafenib (BRAF inhibitor) with cetuximab (EGFR inhibitor) compared with cetuximab with chemotherapy (FOLFIRI (folinic acid, fluorouracil and irinotecan) or irinotecan). We aimed to evaluate the cost-effectiveness of encorafenib with cetuximab in adult patients with BRAF-mutant mCRC after prior systemic therapy, from the perspective of the French healthcare system. DESIGN: A partitioned survival analysis model was developed to assess the cost-effectiveness of encorafenib with cetuximab using data from BEACON CRC (encorafenib with cetuximab and cetuximab with FOLFIRI or irinotecan). For two further comparator treatments (FOLFIRI alone and bevacizumab with FOLFIRI), a systemic literature review identified appropriate clinical trial data for indirect comparison. Piecewise modelling extrapolation was used to fulfil a lifetime horizon in the model. A discount rate of 2.5% was used. Treatment-emergent adverse events ≥grade 3 with an incidence of ≥2% were included, as well as relative dose intensity and utility values. OUTCOME MEASURES: The effectiveness outcomes of the model were expressed in terms of incremental life years gained and incremental quality-adjusted life years (QALY) gained. The cost-effectiveness of encorafenib with cetuximab was assessed using the incremental cost-effectiveness ratio (ICER). Results were presented probabilistically to account for parametric uncertainty. Deterministic and scenario analyses were conducted. RESULTS: The ICER for encorafenib with cetuximab versus cetuximab with FOLFIRI or irinotecan, FOLFIRI alone and bevacizumab with FOLFIRI was €69 823/QALY, €70 421/QALY and €72 336/QALY, respectively. Encorafenib with cetuximab was considered cost-effective compared with the three comparators at a willingness to pay threshold of €90 000/QALY, with probabilities of being cost-effective of 89.8%, 98.2% and 86.4%, respectively. CONCLUSIONS: This analysis showed encorafenib with cetuximab to be a cost-effective treatment in mCRC patients with a BRAF V600E mutation.

Oxidative stress is associated to the massive generation of reactive oxygen species inducing fast oxidative reactions in chain. To overcome this problem, reasonable supplementations of antioxidants are widely practiced, mostly based on empirical protocols. An electrochemical process is proposed to choose the best molecules association inducing the greatest antioxidant capacity, by coupling homogeneous or heterogeneous catalytic reactions involving antioxidants with an electrochemical step. Cyclic voltammetry and constant potential electrolysis experiments were used to highlight regeneration reactions induced by specific associations of hydrophilic and lipophilic antioxidants in homogeneous medium or at liquid/liquid interface. Results showed that N-Acetyl-L-Cysteine (NAC) was effectively regenerated by both ascorbic acid (AA) and ascorbyl glucoside (AA-2G) but not by ascorbyl phosphate magnesium (AA-2P). The antioxidant properties of alpha-tocopherol also increased to 40% when associated with AA. The process was successfully applied for the first time to the study of simple emulsions. Formulations involving NAC and AA-2G presented the highest synergic effect, the antioxidant capacity being amplified by more than 35%. On the other hand no catalytic mechanism was observed when introducing three antioxidants in the cream because it induced too low reaction kinetics. This electrochemical process can thus be exploited as a tool for the optimisation of “anti-aging” dermocosmetic formulations.

Abstract Doubts surrounding the potential adverse effects of antimicrobial preservatives have modified the demand of consumers, who increasingly insist on the production of low-level and even preservative-free cosmetics. Protection of the product against microbial contamination is therefore focused on the packaging. This has prompted the emergence of a highly diverse array of so-called “protective”, “overprotective”, and “barrier” packaging. However, these designations are not normalized and the choice of the right packaging adapted to each cosmetic product is still essentially empirical, hazardous, and time consuming. The Cosmetic Valleys cluster has launched a commission to define a complete and experimentally-validated method to classify the level of protection of cosmetic packaging against microbial contamination. As reported herein, this required the development a specific bacteriostatic medium that can be used for seven days and an in vitro procedure that reproduces in-use contamination and consumer practices. Based on tests performed on over 800 packages of different origin and performance characteristics, we propose a classification, divided into six grades, to differentiate the protective efficiency of cosmetic packaging. This work can be considered as a first step towards a regulatory text.

ABSTRACT Background Colorectal cancer (CRC) is a major health burden globally and in China, where 3%–5% of cases involve the BRAF V600E mutation, which is associated with aggressive disease and therefore a poor prognosis. Although the combination of encorafenib and cetuximab has demonstrated improved survival in BRAF V600E mutant metastatic CRC (mCRC), such treatments remain unavailable as chemotherapy‐free options in China. Methods The NAUTICAL CRC, a Phase II study in Chinese patients with BRAF V600E mutant metastatic CRC, includes a Safety Lead‐In (SLI) phase for tolerability assessment and a randomized phase comparing encorafenib/cetuximab vs. irinotecan‐based regimens, potentially bridging the treatment gap and evaluating safety, efficacy, and Quality of Life (QoL) outcomes in this Chinese population. Results No dose‐limiting toxicity was identified in the SLI phase ( N = 10). In the Randomized phase ( N = 97), the Doublet arm demonstrated superior progression‐free survival (PFS) of 4.2 months vs. 2.5 months in the Control arm (hazard ratio [HR]: 0.37, p = 0.0004) and longer overall survival (OS) of 11.6 months vs. 8.2 months (HR: 0.55). Treatment‐related adverse events were common but more severe in the Control arm. QoL measures consistently favored the Doublet arm, showing improved health status and reduced deterioration risk. Conclusions This NAUTICAL CRC Phase II study showed that the combination of encorafenib and cetuximab offers significant clinical benefits, improving PFS and OS, while providing manageable safety and important QoL advantages, making it a valuable treatment option for Chinese patients with previously treated BRAF V600E mutant mCRC. Trial Registration Clinical study registration number: NCT05004350