Operational classification of cutaneous squamous cell carcinomas based on unsupervised clustering of real cases by experts.

BACKGROUND: There is currently no staging system for cutaneous squamous cell carcinoma (cSCC) that is adapted to decision-making and universally used. Experts have unconscious ability to simplify the heterogeneity of clinical situations into a few relevant groups to drive their therapeutic decisions. Therefore, we have used unsupervised clustering of real cases by experts to generate an operational classification of cSCCs, an approach that was successful for basal cell carcinomas. OBJECTIVE: To generate a consensual and operational classification of cSCCs. METHOD: Unsupervised independent clustering of 248 cases of cSCCs considered difficult-to-treat. Eighteen international experts from different specialties classified these cases into what they considered homogeneous clusters useful for management, each with freedom regarding clustering criteria. Convergences and divergences between clustering were analysed using a similarity matrix, the K-mean approach and the average silhouette method. Mathematical modelling was used to look for the best consensual clustering. The operability of the derived classification was validated on 23 new practitioners. RESULTS: Despite the high heterogeneity of the clinical cases, a mathematical consensus was observed. It was best represented by a partition into five clusters, which appeared a posteriori to describe different clinical scenarios. Applicability of this classification was shown by a good concordance (94%) in the allocation of cases between the new practitioners and the 18 experts. An additional group of easy-to-treat cSCC was included, resulting in a six-group final classification: easy-to-treat/complex to treat due to tumour and/or patient characteristics/multiple/locally advanced/regional disease/visceral metastases. CONCLUSION: Given the methodology based on the convergence of unguided intuitive clustering of cases by experts, this new classification is relevant for clinical practice. It does not compete with staging systems, but they may complement each other, whether the objective is to select the best therapeutic approach in tumour boards or to design homogeneous groups for trials.

French national protocol for the management of congenital ichthyosis.

Congenital ichthyoses (CI) comprise a heterogeneous group of monogenic genetic skin diseases characterized by diffuse scaling, often associated with skin inflammation. Diagnosis of the individual form of ichthyosis is complex and is guided by clinical expertise. CI usually has a major impact on quality of life (QOL) and thus requires lifelong treatment. To date, there are no curative therapies, although various symptomatic treatment options exist. The present protocol for the management of CI has been drawn up in accordance with the recommendations published in 2012 by the French National Authority for Health, based on a literature review, with the help and validation of members of the French network for rare skin diseases (FIMARAD). It provides a summary of evidence and expert-based recommendations and is intended to help clinicians with the management of these rare and often complex diseases.

Effectiveness and safety of dupilumab in the treatment of atopic dermatitis in children (6-11 years): data from a French multicentre retrospective cohort in daily practice.

BACKGROUND: Dupilumab is the first biotherapy available for the treatment of moderate-to-severe childhood atopic dermatitis (AD). OBJECTIVE: The aim of this study was to evaluate the effectiveness and safety of dupilumab in daily practice. METHODS: Patients aged 6-11, who had received a first dose of dupilumab, were included in this multicentre retrospective cohort study. The primary endpoint was change in SCORAD after 3 months of treatment. Secondary endpoints were change in IGA score at 3 months, proportion of patients with SCORAD50 and SCORAD75, description of adverse events and proportion of children in our cohort who would be excluded from pivotal phase 3 clinical trial. RESULTS: Eighty patients were included. After 3 months of treatment, there was a significant decrease in SCORAD (mean: 21.8 ± 13.8 vs 53.9 ± 18.5; P < 0.0001) and IGA (1.3 ± 0.8 vs 3.5 ± 0.7; P < 0.0001). Conjunctivitis was observed in 11.3% (n = 9/80); three patients experienced dupilumab facial redness (DFR); 17.5% (n = 14/80) reported injection site reactions; 6.3% (n = 5/80) discontinued treatment. 61.2% (n = 49/80) children were ineligible in the phase 3 trial. LIMITATIONS: There is no control group. Because it was a real life study based on information from patient medical records in a French multicentre cohort, we cannot rule out the presence of reporting bias generated by the use of patient reported characteristics and missing information. CONCLUSION: These real-life data confirm the efficacy and safety of dupilumab in children with moderate to severe AD extended to dyshidrosis and atopic prurigo, but it also revealed a lower frequency of DFR and conjunctivitis. However, administration in injectable form may be a barrier in this age group.

Children with psoriasis and COVID-19: factors associated with an unfavourable COVID-19 course, and the impact of infection on disease progression (Chi-PsoCov registry).

BACKGROUND: The COVID-19 pandemic has raised questions regarding the management of chronic skin diseases, especially in patients on systemic treatments. Data concerning the use of biologics in adults with psoriasis are reassuring, but data specific to children are missing. Moreover, COVID-19 could impact the course of psoriasis in children. OBJECTIVES: The aim of this study was therefore to assess the impact of COVID-19 on the psoriasis of children, and the severity of the infection in relation to systemic treatments. METHODS: We set up an international registry of paediatric psoriasis patients. Children were included if they were under 18 years of age, had a history of psoriasis, or developed it within 1 month of COVID-19 and had COVID-19 with or without symptoms. RESULTS: One hundred and twenty episodes of COVID-19 in 117 children (mean age: 12.4 years) were reported. The main clinical form of psoriasis was plaque type (69.4%). Most children were without systemic treatment (54.2%); 33 (28.3%) were on biologic therapies, and 24 (20%) on non-biologic systemic drugs. COVID-19 was confirmed in 106 children (88.3%) and 3 children had two COVID-19 infections each. COVID-19 was symptomatic for 75 children (62.5%) with a mean duration of 6.5 days, significantly longer for children on non-biologic systemic treatments (P = 0.02) and without systemic treatment (P = 0.006) when compared with children on biologics. The six children who required hospitalization were more frequently under non-biologic systemic treatment when compared with the other children (P = 0.01), and particularly under methotrexate (P = 0.03). After COVID-19, the psoriasis worsened in 17 cases (15.2%). Nine children (8%) developed a psoriasis in the month following COVID-19, mainly a guttate form (P = 0.01). DISCUSSION: Biologics appear to be safe with no increased risk of severe form of COVID-19 in children with psoriasis. COVID-19 was responsible for the development of psoriasis or the worsening of a known psoriasis for some children.

Leg ulcers in childhood: A multicenter study in France.

BACKGROUND: Leg ulcers in adults are a major public health concern. Their incidence increases with age and many causes have been identified, predominantly associated with vascular diseases. Leg ulcers in children and teenagers are less frequent. The aim of our study was to identify the causes of leg ulcers in children and teenagers, and to evaluate their management. METHODS: This retrospective multicenter study was conducted by members of the Angio-dermatology Group of the French Society of Dermatology and of the French Society of Pediatric Dermatology. Data from children and teenagers (< 18 years), seen between 2008 and 2020 in 12 French hospitals for chronic leg ulcer (disease course>4 weeks), were included. RESULTS: We included 27 patients, aged from 2.3 to 17.0 years. The most frequent causes of leg ulcer were: general diseases (n=9: pyoderma gangrenosum, dermatomyositis, interferonopathy, sickle cell disease, prolidase deficiency, scleroderma, Ehlers-Danlos syndrome), vasculopathies (n=8: hemangioma, capillary malformation, arteriovenous malformation), trauma (n=4: bedsores, pressure ulcers under plaster cast), infectious diseases (n=4: pyoderma, tuberculosis, Buruli ulcer) and neuropathies (n=2). Comorbidities (59.3%) and chronic treatments (18.5%) identified as risk factors for delayed healing were frequent. The average time to healing was 9.1 months. DISCUSSION: Leg ulcers are less frequent in children and teenagers than in adults and their causes differ from those in adults. Comorbidities associated with delayed healing must be identified and managed. Children and teenagers tend to heal faster than adults, but a multidisciplinary management approach is necessary.

Characteristics of children and adolescents with atopic dermatitis who attended therapeutic patient education.

BACKGROUND: Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease. Therapeutic patient education (TPE) has been demonstrated to be effective in AD in reducing disease severity and improving coping and quality of life. OBJECTIVES: To describe the sociodemographic and clinical characteristics of children and adolescents with AD who had attended TPE sessions, as well as the characteristics of their parents, and compare them with those who did not attend TPE. METHODS: Parents of children with AD aged 6-17 years old were recruited from a representative sample of the French population contacted by e-mail. Sociodemographic data and clinical information were collected in patients and parents. Clinical severity was assessed by parents using a proxy version of the Patient-Oriented Eczema Measure (POEM). Attendance to TPE sessions was assessed by the following question 'did your child or one or both parents attended TPE for AD?'. Also, the number of sessions was recorded. Determinants of TPE attendance were evaluated by univariable and multivariable analyses. RESULTS: Data were collected on 1063 parents and children with AD. A total of 131 (12.3%) children and/or parents attended TPE sessions. Most of them attended 2-5 TPE sessions. In that group, there were 85 boys (64.9%), and severity evaluated by POEM was mild in 29.8%, moderate in 52.7% and severe in 17.6% of patients. In the multivariable model, attending TPE sessions was significantly associated with sex of the child (boy vs. girl), consultation with a dermatologist or a paediatrician, high clinical severity and presence of AD in parents. CONCLUSIONS: Despite recommendations, the use of TPE in children with AD is still low in France. There is a need for implementing such programmes in the management of the disease, in particular when the disease is severe.

Acute acral eruptions in children during the COVID-19 pandemic: Characteristics of 103 children and their family clusters.

BACKGROUND: A marked increase in frequency of acute acral eruptions (AAE) was observed in children during the COVID-19 pandemic in the spring period. OBJECTIVES: In this observational multicenter study, based on children with AAE, we aimed to assess the proportion of household members possibly infected by SARS-CoV-2. METHODS: We collected data from all children observed with AAE, prospectively from April 7, 2020 to June 22, 2020, and retrospectively since February 28, 2020. The primary outcome was the household infection rate, defined as the proportion of family clusters having at least one member with COVID-19 infection other than the child with AAE ("index child"). The definition of a case was based on characteristic clinical signs and a positive PCR or serology. RESULTS: The study included 103 children in 10 French departments and in Quebec. The median age was 13 years and the interquartile range [8-15], with a female-to-male ratio of 1/1.15. In children with AAE, all PCR tests were negative (n=18), and serology was positive in 2/14 (14.3%) cases. We found no significant anomalies in the lab results. A total of 66 of the 103 families (64.1%) of included children had at least one other infected member apart from the index child. The total number of household members was 292, of whom 119 (40.8%) were considered possibly infected by SARS-CoV-2. No index children or households exhibited severe COVID-19. DISCUSSION: Among the 103 households included, 64.1% had at least one infected member. Neither children with AAE nor their households showed severe COVID-19.

[Five years' experience of cosmetic camouflage of disfiguring skin disorders: Patient satisfaction]. / Cinq ans d'expérience d'un atelier de maquillage médical correcteur des dermatoses affichantes : évaluation par la satisfaction des patients.

INTRODUCTION: Living with disfiguring disorders can impair the emotional well-being and relationships of patients as well as their social and professional life. Since 2010, courses in medical cosmetic correction for disfiguring diseases have been conducted at the dermatology department of the Timone University Hospital in Marseille and they form part of an educational program. The aim of this study was to assess the satisfaction of patients taking part in this program. PATIENTS AND METHODS: This is a retrospective study of 55 patients taking part in make-up sessions from January 2010 to December 2014 and subsequently completing a questionnaire. RESULTS: The median patient age was 46 years with most being women (n=49, 89 %). They presented pigmentary disorders (54.5 %), inflammatory diseases (27.3 %) and scars (18.2 %). 75 % of patients stated that they had improved their knowledge and 82 % remarked that the technique was personalized to their needs. The technique was considered as easy by 62 % and reproducible by 87 % of patients. 55 % of patients considered that cosmetic camouflage improved their quality of life and 56 % stated that it helped them accept the gaze of others. CONCLUSION: In our study skin camouflage appears easy to use and meets patient expectations.

Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients.

BACKGROUND: Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification. OBJECTIVES: To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations. METHODS: We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined. CONCLUSIONS: A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.

Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation.

BACKGROUND: Data on dermatological manifestations of Noonan syndrome (NS) remain heterogeneous and are based on limited dermatological expertise. OBJECTIVES: To describe the dermatological manifestations of NS, compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11 mutations. METHODS: We performed a large 4-year, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Overall, 129 patients with NS were enrolled, including 65 patients with PTPN11-NS, 34 patients with PTPN11-NS with multiple lentigines (NSML), and 30 patients with NS who had a mutation other than PTPN11. Easy bruising was the most frequent dermatological finding in PTPN11-NS, present in 53·8% of patients. Multiple lentigines and café-au-lait macules (n ≥ 3) were present in 94% and 80% of cases of NSML linked to specific mutations of PTPN11, respectively. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P = 0·001), including keratosis pilaris (P = 0·005), ulerythema ophryogenes (P = 0·0001) and palmar and/or plantar hyperkeratosis (P = 0·06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P = 0·035) and scarce or absent eyelashes (P = 0·06, trend association) than those with PTPN11 mutations. CONCLUSIONS: The cutaneous phenotype of NS with a PTPN11 mutation is generally mild and nonspecific, whereas the absence of a PTPN11 mutation is associated with a high frequency of keratinization disorders and hair abnormalities.

Age-specific characteristics of neutrophilic dermatoses and neutrophilic diseases in children.

BACKGROUND: Our suggested 'modern' concepts of 'neutrophilic dermatoses' (ND) and 'neutrophilic disease' were based on observations in adult patients and have not been studied in paediatric patients. Only a minority of ND occurs in children, and little is known about age-specific characteristics. OBJECTIVES: To describe age-specific characteristics of ND in children and to study whether our suggested 'modern' classification of ND may be applied to children. METHODS: We conducted a retrospective multicentre study in a French cohort of 27 paediatric patients diagnosed with pyoderma gangrenosum (PG) or Sweet's syndrome (SS). RESULTS: Demographics and distribution of typical/atypical forms were similar in patients diagnosed with PG and SS. Atypical ND were more frequent in infants (90%), when compared to young children (60%) and adolescents (33%). Neutrophilic disease was observed in 17/27 patients and was most frequent in infants. Neutrophilic disease of the upper respiratory tract, as well as cardiac neutrophilic disease, was only observed in infants, whereas other locations were similarly found in infants, young children and adolescents. In infants and young children, ND were associated with a large spectrum of general diseases, whereas in adolescents associations were limited to inflammatory bowel disease and Behçet's disease. CONCLUSIONS: Our study describes the concept of ND in paediatric patients and shows that they have some characteristics different from ND occurring in adults. ND occurring in infants can be associated with a large spectrum of general diseases. Occurrence of neutrophilic disease is frequent in children. Thus, ND occurring in young paediatric patients should incite clinicians to schedule complementary explorations in order to search for involvement of other organs and to rule out monogenetic autoinflammatory syndromes.

Biological treatments for paediatric psoriasis : a retrospective observational study on biological drug survival in daily practice in childhood psoriasis.

BACKGROUND: Three biotherapies - etanercept, adalimumab and ustekinumab - are licensed in childhood psoriasis. The few data available on their efficacy and tolerance are mainly derived from industry trials. However, biological drug survival impacts long-term performance in real-life settings. OBJECTIVE: The objective of this study was to evaluate the survival rates of biological therapies in children with psoriasis in real-life conditions. Secondary objectives were to evaluate the factors associated with the choice of the biological therapy and to report severe adverse events. MATERIALS AND METHODS: This study was an observational retrospective study. Data were extracted from the clinical records of 134 children. Kaplan-Meier estimates were used to analyse drug survival overall and in subgroups of plaque psoriasis, bio-naïve and non-naïve patients. RESULTS: We analysed 184 treatment courses: 70 with etanercept, 68 with adalimumab and 46 with ustekinumab. Factors associated with the choice of first-line biological agent were age at initiation (younger for adalimumab, P < 0.0001), age at onset of psoriasis (younger for adalimumab and etanercept, P = 0.03) and baseline Psoriasis Assessment Severity Index and Physician global assessment (both higher for adalimumab, P < 0.001). Drug survival rates were higher for ustekinumab than for adalimumab and etanercept (P < 0.0001) for all treatment and all psoriasis types, plaque-type psoriasis (P = 0.0003), patients naïve for biological agents (P = 0.0007) and non-naïve patients (P = 0.007). We reported eight serious adverse events (SAEs): severe infections (n = 3), significant weight gain (n = 2), psoriasis flare (n = 1) and malaise (n = 1). Biological therapy was discontinued in three children (one with psoriasis flare and two with weight gain). Only the two cases of weight gain resulted in an unfavourable outcome. CONCLUSIONS: Our real-life comparative study found that ustekinumab had the best drug survival outcome. The profile of SAEs in children was comparable to that in adults. These results will assist dermatologists in the decision-making process when choosing treatment options for children with psoriasis in daily practice.

[Clinical and evolutionary characteristics of a child with aquagenic keratoderma: A retrospective study of 12 patients]. / Caractéristiques cliniques et évolutives de la kératodermie aquagénique de l'enfant : étude rétrospective de 12 cas.

INTRODUCTION: Aquagenic keratoderma (AK) is a rare condition characterized by wrinkled and edematous appearance of the skin of the hands occurring within minutes of immersion in water. Other than in a setting of cystic fibrosis, AK has rarely been reported in children, with only 13 clinical cases on record. Many clinicians are unfamiliar with AK and have fears relating to the association with cystic fibrosis The aim of this study is to describe the characteristics and to discuss management of the disease. METHODS: Retrospective, multicentre study, including children aged under 16 years presenting AK. RESULTS: 12 children were included. KA started at a mean age of 9.25 years (range: 20 months to 15 years). Clinical appearance and mode of onset were classical, with the palms being more severely affected than the soles. Pruritus or pain were reported in six cases. The median impact on daily life was 1.5/10. Some of the children underwent investigations: two had a negative sweat test, three had molecular analysis of the gene CFTR: one was negative and two had a heterozygote mutation. The course of the disease was variable: eight stabilizations, two exacerbations, one cure and one improvement. DISCUSSION: This is the first series on childhood KA. Clinical characteristics were similar to those seen in adults. Impact was moderate and the disease course was variable. Systematic medical check-up for cystic fibrosis does not appear warranted in children since to date, cystic fibrosis has not been diagnosed in any patients presenting AK alone. CONCLUSION: AK is rare in children and should not cause erroneous concern, and improvement can occur.

[Treatment of wrinkles of the upper lip by emulsified fat or "Nanofat": Biological and clinical study about 4 cases]. / Traitement des ridules de la lèvre supérieure par graisse émulsifiée ou « Nanofat ¼ : étude biologique et clinique à propos de 4 cas.

OBJECTIVE: Emulsified fat injection showed its interest in aesthetic facial surgery. The adipose tissue harvested is mechanically emulsified and filtered. The suspension obtained is injected into the dermis through small diameter needles (27 to 30 gauges). The objective of our study was to evaluate the biological composition of emulsified fat and its clinical effectiveness in the treatment of peri-oral wrinkles in 4 patients aged 50 to 59 years. MATERIAL AND METHOD: Each patient received an intradermal injection of emulsified fat in the peri-oral wrinkles prepared from abdominal fat under local anesthesia. The cell viability, stromal vascular fraction (FVS) composition in emulsified fat and the adipocyte differentiation capacity of mesenchymal stem cells (MSC) were studied. The clinical results were evaluated by standardized photographs, 3D microphotography, confocal microscopy, and self-evaluation of patient satisfaction over a period of 4 months. RESULTS: The biological study of the emulsified fat found a lysis of all the adipocytes. The mean number of FVS cells was 126,330±2758 cells by cc of emulsified fat with preserved cell viability (85.1±6.84 %) and a good proportion of regeneratives cells (18.77±6.2 %). The clinical study found a tendency to decrease the volume of wrinkles on standardized photography and 3D microphotography no significative. Patients were satisfied with treatment with an average score of 7±1.15/10 to 4 months. CONCLUSION: Intradermal injection of emulsified fat seems to be an interesting treatment of face wrinkles. Our study has shown its safety, but additional studies seems necessary to confirm its clinical efficacy.

Genomic signatures of adaptation to wine biological ageing conditions in biofilm-forming flor yeasts.

The molecular and evolutionary processes underlying fungal domestication remain largely unknown despite the importance of fungi to bioindustry and for comparative adaptation genomics in eukaryotes. Wine fermentation and biological ageing are performed by strains of S. cerevisiae with, respectively, pelagic fermentative growth on glucose and biofilm aerobic growth utilizing ethanol. Here, we use environmental samples of wine and flor yeasts to investigate the genomic basis of yeast adaptation to contrasted anthropogenic environments. Phylogenetic inference and population structure analysis based on single nucleotide polymorphisms revealed a group of flor yeasts separated from wine yeasts. A combination of methods revealed several highly differentiated regions between wine and flor yeasts, and analyses using codon-substitution models for detecting molecular adaptation identified sites under positive selection in the high-affinity transporter gene ZRT1. The cross-population composite likelihood ratio revealed selective sweeps at three regions, including in the hexose transporter gene HXT7, the yapsin gene YPS6 and the membrane protein coding gene MTS27. Our analyses also revealed that the biological ageing environment has led to the accumulation of numerous mutations in proteins from several networks, including Flo11 regulation and divalent metal transport. Together, our findings suggest that the tuning of FLO11 expression and zinc transport networks are a distinctive feature of the genetic changes underlying the domestication of flor yeasts. Our study highlights the multiplicity of genomic changes underlying yeast adaptation to man-made habitats and reveals that flor/wine yeast lineage can serve as a useful model for studying the genomics of adaptive divergence.