Experimental Dermatology

A phase 2, randomised, double-blind, placebo controlled trial has been conducted in mild to moderate patchy alopecia areata (AA). This demonstrated significant and dose related improvements in hair regrowth with STS01, a controlled release, topical formulation of dithranol. Here we report the results of the Alopecia Areata Symptom Impact Scale (AASIS) that assesses the severity of symptoms, daily functioning and feelings. Similar to trials in severe AA, significant improvements in hair regrowth did not translate into significant health-related quality of life (HRQoL) improvements, even in patients with complete hair regrowth, although there was some treatment-related correlation between changes in AASIS scores from baseline and clinical assessment SALT scores. The use of current HRQoL methods or indeed new measures in development for future trials, will have considerable challenges: patients may not have a true baseline at entry, may develop coping mechanisms, and there may be a delay between physical and psychological improvement.

Pannexin (PANX) channels are present in skin and facilitate the movement of signalling molecules during cellular communication. PANX1 and PANX3 function in skin homeostasis and keratinocyte differentiation but were previously reduced in a small cohort of human cutaneous squamous cell carcinoma (cSCC) tumours compared to normal epidermis. In our study, we used SCC-13 cells, limited publicly available RNA-seq data and a larger cohort of cSCC patient-matched samples to analyze PANX1 and PANX3 expression and determine the association between their dysregulation and the malignant properties of cSCC. In a bioinformatics analysis, PANX1 transcripts were increased in cSCC and head and neck SCC tumours compared to normal tissues, but PANX3 mRNA showed no differences. However, in our own cohort, PANX3 transcripts were decreased in cSCC compared to patient-matched aged skin, whereas PANX1 was upregulated in cSCC. PANX1 localized to all regions within the cSCC tumour microenvironment and increased levels were associated with larger tumour dimensions. To investigate PANX1 function in SCC-13 cells, we deleted PANX1 via CRISPR/Cas9 and treated with PANX1 inhibitors which markedly reduced cell growth and migration. To assess PANX3 function in cutaneous carcinogenesis, we employed the DMBA/TPA model using our global Panx3 knockout (KO) mice, where 60% of wildtype and 100% of KO mice formed pre-cancerous papillomas. Average papilloma volumes at endpoint were significantly increased in KO mice and showed moderate evidence of increases in KO mice over time. Collectively, these findings suggest PANX1 and PANX3 dysregulation may have potential tumour promoting and suppressive effects for keratinocyte transformation, respectively. Key points summaryO_LIPannexin 1 and pannexin 3 are channel-forming proteins which are critical in the normal maintenance and function of keratinocytes in the skin but may become altered in cutaneous squamous cell carcinoma (cSCC) tumours. C_LIO_LIIn this study, we used a combination of culture models, mouse models and patient-derived tissues. We found pannexin 1 levels are increased in cSCC tumours and present in all tumour regions, functioning to promote cSCC cell growth and migration. C_LIO_LIConversely, pannexin 3 levels are decreased in cSCC tumours and this protein reduces the incidence and growth of pre-cancerous lesions. C_LIO_LITaken together, our data indicates that in cSCC these pannexin family members seem to have opposite effects, where pannexin 1 is pro-tumorigenic and pannexin 3 is anti-tumorigenic. C_LIO_LIThese results help us to better understand the mechanisms of malignant transformation of keratinocytes and offer a new potential therapeutic target for the treatment of advanced cSCC. C_LI

BackgroundCutaneous squamous cell carcinoma in situ (SCCIS) is a common nonmelanoma skin cancer with rising incidence and substantial treatment costs. While Mohs micrographic surgery remains the standard of care, cost, accessibility, and cosmetic concerns limit its use for some patients. Topical alternatives such as imiquimod and 5-fluorouracil are associated with variable efficacy and frequent adverse effects. ObjectiveTo evaluate the efficacy and tolerability of a 30% ascorbic acid (vitamin C) solution in 95% dimethyl sulfoxide (DMSO) for the treatment of biopsy-confirmed SCCIS. MethodsIn this open-label study, 17 patients with 27 histologically confirmed SCCIS lesions applied 30% ascorbic acid in DMSO topically twice daily for 12 weeks. Lesion size and histologic resolution were assessed by repeat biopsy at week 12. Primary outcome was complete resolution of SCCIS; secondary outcomes included lesion size reduction and adverse events. ResultsComplete histologic resolution occurred in 15 of 27 lesions (56%), while 44% of lesions showed >85% reduction in size. The mean reduction in lesion area was 71%. Only 2 lesions (7%) failed to respond. Most residual lesions demonstrated actinic atypia without carcinoma and were successfully treated with cryotherapy. No patients discontinued due to adverse effects. Ninety-four percent of participants (16/17) avoided surgical excision. ConclusionsTopical 30% ascorbic acid in DMSO demonstrated promising efficacy and excellent tolerability in the treatment of SCCIS, offering a potential noninvasive alternative to surgery. Larger, controlled trials are warranted.

BackgroundDaily molecular rhythms modulate skin physiology. However, the effects of chronic sun exposure on these rhythms remain unstudied. ObjectivesThis study aimed to identify and compare rhythmic genes and pathways in photoprotected and chronically photoexposed human skin in vivo. MethodsTwenty healthy White women, aged 51-63, with moderate-severe photoageing of the dorsal forearm were recruited. Skin biopsies (3mm) were taken from photoprotected (upper buttock) and photoexposed (dorsal forearm) skin of each individual at noon, 6PM, midnight, and 6AM, across a 24-hour cycle. Skin biopsies were analysed by RNA sequencing. Cosinor analysis identified cycling genes along with their amplitudes and peak expression phases. Nested models were used to identify genes that were differentially rhythmic between the photoprotected and photoexposed sites. Phase set and gene set analyses identified pathways enriched among rhythmic transcripts or altered between the two sites. ResultsIn the photoprotected buttock skin, 1546 genes (12%) met the criteria for cycling. In photoexposed forearm skin, the number was reduced to 959 (8%). As a group, transcripts that cycled in both sites had overall higher amplitude in photoprotected skin (p < 2.2e-16). Peak expression times for these transcripts showed a pronounced bimodal distribution and were clustered in the early morning and mid-afternoon. Distributions of peak times were significantly different between photoexposed and photoprotected skin (p < 0.00025), with peak times advanced in photoexposed skin. We identified 480 genes with significantly different rhythmic properties between the skin sites. Genes involved in DNA repair, MYC targets, E2F and G2M checkpoint pathways were enriched among those that showed higher amplitude oscillations in photoprotected skin. Genes involved in epithelial mesenchymal transition and apical junction pathways showed higher amplitude oscillations in photoexposed skin. ConclusionsTemporal rhythms have a marked influence on skin molecular physiology and are altered in photoaged skin. Temporally advanced cycling patterns and a reduced number of rhythmic genes in photoexposed as compared to photoprotected skin suggest that chronic UV exposure may disrupt and/or reprogram circadian output rhythms to further alter skin physiology.

IntroductionHair disorders can have both physical and psychosocial effects significantly impacting patients quality of life. Well-designed patient-reported outcome measures (PROMs) are vital to determine meaningful patient-centered management. Currently available PROMs for individual hair disorders are available, however, making it difficult to use across diseases. This phase I protocol aims to create a clinically meaningful hair assessment across multiple hair disorders that evaluate the patients reported assessment of their disease, its symptoms, and impact on their quality of life, as well as defining characteristics of their desired outcome. Methods and analysisThis phase I study, we will use thematic analysis of qualitative semi-structured interviews. Participants aged 18 years and older, a sampling of patients diagnosed with alopecia areata, androgenic alopecia, lichen planopilaris, central centrifugal cicatricial alopecia, and sebopsoriasis will be invited to take part in qualitative interviews. Participants recruitment and interviews will continue iteratively until thematic saturation is reached, with a focus on interview quality and patient diversity in gender, race and ethnicity, age, and hair-related disorder. The open-ended interview questions will allow participants to reflect on their physical appearance, disease journey, and treatment goals, as well as define the associated physical symptoms and psychosocial impact. These predominant domains will be used to form the basis for a hair-related PROM that can be applied to a multitude of hair-related disorders. Ethics and disseminationThe Brigham and Womens Hospital Institutional Review Board (2022P001033) approved this study. Following the description of the study protocol, we obtained verbal consent from all the study participants. All personal information, interview responses, and medical records are confidential and are stored in an encrypted database. Findings from this study will be published in peer-reviewed journals and presented at dermatology conferences. This is an open access article with Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, that permits others to distribute, remix, and build upon the licensed work non-commercially, and require attribution to the original authors. See https://creativecommons.org/licenses/by-nc/4.0/ for details. Strengths and limitations of this studyO_LIRecruitment of participants with common scarring and non-scarring hair-related disorders will make it possible to establish patients perspectives on physical appearance, definitions of treatment success, physical signs and symptoms, psychological and social impact across multiple disease states involving hair, scalp, eyebrows, eyelashes, and beard. C_LIO_LIInclusion of patients from a wide range of demographics such as age, gender, race, and ethnicity will enable identification of domains common across these differing backgrounds. C_LIO_LIWe adhere to published guidelines for determining validity of scales. C_LIO_LIWe aim to use modern psychometric approach to ensure this study are clinically meaningful. C_LI

BackgroundThere are no widely accepted pediatric guidelines on who should undergo biopsy of the nail apparatus to screen for subungual melanoma (SUM). Reported cases of pre-adolescent children diagnosed with SUM presenting as melanonychia remain controversial. Further, observed age differences in the incidence of acral lentiginous melanoma are complicated by reported ethnic differences in adult prevalence and survival rates. MethodsWe conducted a retrospective chart review of Rady Childrens Hospital San Diego, a tertiary hospital system, with over 2 million patients in its electronic health records to identify patients diagnosed with melanonychia younger than 12 years and biopsies in these children, between January 1, 2010, and July 31, 2021. ResultsThere were 623,805 patients younger than 12 years of age seen in the outpatient setting. Average age was 7.2 years for melanonychia diagnosis, and 5.1 years for those biopsied. Nail apparatus biopsies were performed in 22 different individuals and involved the hand 17/22 (77%) and the foot 5/22 (23%). The presence of Hutchinsons sign was documented in 9/22 (41%) patients. Males were diagnosed with melanonychia and underwent biopsy more often than females. Many of the biopsies were performed in Hispanic/Latino 11/22 (50%) and Asian/Pacific Islander 3/22 (14%) patients. DiscussionRegardless of reported ethnicity, biopsy of nail apparatus is highly unlikely to uncover invasive ALM in children younger than 12 years. Prospective studies are needed to understand how incidence of melanonychia, age, gender, and ethnicity/race influence parental and clinicians perceptions of melanoma risk.

Chronic pruritus on non-lesional skin (CPNL) is a hallmark of chronic pruritus of undetermined origin (CPUO) and characterized by persistent pruritus without visible skin lesions. While atopic dermatitis (AD) is well known to involve epidermal barrier disruption, the pathophysiology of CPNL remains poorly understood. Our goal was to compare stratum corneum (SC) morphology and its role as a functional epidermal barrier, the severity of the symptoms, the relationship between persistent itch and primary skin and scratch lesions, and selected inflammatory markers in patients with CPNL, AD, and healthy controls. We assessed corneocyte morphology and corneodesmosome density in skin samples using atomic force microscopy (AFM) and fluorescence microscopy (FLM). Transepidermal water loss (TEWL) and tissue hemoglobin index (THI) were used to evaluate epidermal barrier integrity and skin blood perfusion. Symptom severity was assessed using the Worst and Average Itch-Numerical Rating Scale (NRS), Scratch Sign Score (SSS), and patient-reported sleep disturbance. AD patients demonstrated structural differences in the SC, including reduced corneocyte area, clustering of corneocytes, absence of intermediate filaments, and relocated corneodesmosomes, along with elevated TEWL, THI values and IgE serum levels. In contrast, patients with CPNL displayed corneocyte morphology and skin barrier parameters like healthy controls, despite reporting high itch intensity and frequent sleep disturbance in clinical interviews. These findings indicate that CPNL is not triggered by a disrupted epidermal barrier but may represent different mechanisms.

BackgroundCutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer and is associated with considerable morbidity. Population-based data analysis in Germany has largely focused on incidence and trends. ObjectivesTo assess incidence, anatomical site- and T-stage distribution, histological subtypes of cSCC in Germany, with a focus on sex- and age-group specific patterns and regional differences. MethodsA total of 213,935 first primary invasive cSCC cases diagnosed between 1986 and 2019 were analysed from four federal states of Germany with complete case ascertainment. Crude and age-standardized incidence rates (CIR, ASIR) were calculated, and subgroup analyses were performed by sex, anatomical site, histological subtype, and T-stage and region. ResultsCIR increased by over 500 % from 1986 to 2015, with a steeper rise in women. Incidence plateaued after 2015 in most states, except for a delayed increase in Saarland. The face (ICD-10 C44.3) was the most frequent tumor site showing equal incidence in males and females. T1 tumors predominated (88.6 %), although staging data were incomplete in 33.5 % of cases. Regional and sex-based differences were observed in both T-stage and histological subtype distribution. Spindle cell and non-keratinizing variants were associated with more advanced stages. Cancer registry data did not count more than one cSCC and carcinoma in situ such as Bowens disease or actinic keratosis, leading to systematic underestimation of disease burden. ConclusionscSCC incidence has risen substantially in Germany, with significant variation by sex, region, and tumor type. Improved registry protocols incorporating multiple primaries, clinical staging, and early in situ lesions are essential for accurate surveillance and healthcare planning. Plain Language SummaryHow common is squamous cell skin cancer in Germany and how does it behave? We looked at cutaneous squamous cell carcinoma (cSCC), a common skin cancer that starts in the flat cells on the skins surface. It is the second most common skin cancer and the second most common cancer, affecting tens of thousands of people in Germany each year. We found that the registration of new primary cSCC tumors increased more than fivefold between 1986 and 2015. However, incidence rates plateaued from 2015 to 2019. Tumors most often appeared on the face, but the distribution by site differed between men and women. Men developed cSCC at younger ages and more frequently than women. Approximately 90% of tumors were diagnosed at an early stage, but staging information was missing for about 34% of cases. cSCC develops on chronically sun-damaged skin, and patients often have more than one tumor. There are also early skin changes that require treatment. Because cancer registries count only one tumor per person and ignore these early lesions, the true burden of treating patients with chronic sun damage is underestimated. We concluded that cSCC has become more common in Germany, with clear differences by sex, age, and region. Improving cancer registries to record all tumors will provide a more accurate picture of stage and subtype distribution. Recognizing high-risk groups, will help guide prevention, screening, and earlier treatment strategies. What is already known about this topic?Cutaneous squamous cell carcinoma (cSCC) is the second most frequent malignancy overall as well as the second most frequent skin tumor. Epidemiological research has long focused on Basal Cell Carcinoma (BCC) and cSCC conclusively. Recent research has addressed major differences in their epidemiology, highlighting differnces in incidence rates across genders and age groups. The largest data set on squamous cell carcinoma analysed so far was 145.000 cases. What does this study add?This study provides conclusive results on incidence, localization, tumor stages and histologic types comparing men, women and age groups based on large scale data with over 200,000 primary tumors over a period of more than 30 years. What is the translational message?Identification of gender- and age-specific risk patterns in cSCC enables the formulation of targeted prevention strategies, screening recommendations, and earlier diagnosis and optimized management of high-risk populations. The burden of morbidity and tumors associated with chronic actinic damage remains underestimated in current literature and cancer statistics. Demographic changes are expected to increase the disease burden substantially, although the exact magnitude remains uncertain.

Vitiligo is an acquired pigmentary disorder of the skin and mucus membranes. Previous study has demonstrated that autologous cultured epithelial grafts (ACEG) is an effective treatment for stable vitiligo. However, extraction of full-thickness skin might result in scar formation at donor site, which have hindered the wider application of this technology, especially for patients requiring large-area transplantation. Hair follicle as a source of keratinocyte and melanocyte, could be potential source of cells for preparation of autologous cultured sheet. Through culture system optimization, we have demonstrated maintenance of undifferentiated hair follicle-derived cells in feeder-independent culture system. After expansion, the hair follicle cells were directed to differentiate into a multi-layered, epidermis-like sheet. Cell identity, viability, purity, genomic stability, and antiseptic testing for hair follicle-derived epithelial sheet (HFES) were evaluated to ensure its safety. Immunofluorescence staining showed that basal keratinocytes were the main cell type of the autologous HFES. Optimization of culture conditions leads to increased melanocyte proliferation and functionality. Transcriptomic analysis confirmed upregulation of melanosome maturation genes. The proportions of cells are also similar to composition of cells under physiological conditions. Transplantation of HFES to depigmented areas in patients with stable vitiligo results in skin repigmentation. This technology provides a novel therapeutic option for vitiligo management.

Cutaneous Squamous Cell Carcinoma (cSCC) represents about 20% of all non-melanoma skin cancers. Whilst generally low risk to patients, metastases are associated with a poor prognosis. cSCC incidence is increasing, owing to an ageing population, greater exposure to UV radiation, and more patients receiving immunosuppressive treatments associated with organ transplants. Therefore, there is interest in identifying new biomarkers that may be to track progression of the disease and to exploit as therapeutic vulnerabilities. We show dynamic changes in AKT expression in precursor lesions and in SCC tumour tissue, with initial loss of AKT activity followed by progressive and widespread increase in AKT activity in SCC. Phosphoproteomic analysis and kinase substrate enrichment analysis on a panel of isogenic cSCC cell lines representing different stages of the disease from premalignancy to metastasis revealed several up-regulated kinases and AKT-targets. From this analysis we chose DNA dependent protein kinase (DNA-PK), a key kinase upstream of AKT phoshorlyation, and N-Myc downstream-regulated gene 2 (NDRG2) a downstream AKT phosphorylation target, to investigate in further detail. Both proteins were up-regulated and mis-expressed in a panel of SCC tissue from different patients. We therefore explored the potential of inhibiting DNA-PK and NDRG2 as cSCC treatments. Treatment with the iron chelator Dp44mT decreased levels of phosphorylated NDRG2 and led to significant losses to viability and reduced migration in our cSCC cell lines, while DNA-PK inhibition promoted the differentiation of premalignant and early-stage SCC cell lines. Our results suggest that NDRG2 and DNA-PK may be viable targets in cSCC treatment, with effectiveness at different stages of SCC progression.

In vitro models of scarring and fibrosis are essential to improve our understanding of disease mechanisms and ultimately develop much-needed effective therapeutic strategies. This is particularly true for keloids, the example of pathological scarring exploited in this study, as there is no animal model. Our emerging appreciation of fibroblast heterogeneity from single cell RNA sequencing (scRNA-seq) information leaves a knowledge gap about what is represented in typical fibroblast cultures. Specifically, it is important to know whether quantitative differences in fibroblast subtypes observed in pathological tissues are represented and/or whether disease-associated molecular alterations of subtypes are maintained. This study performed scRNA-seq on patient-matched keloid and normal adjacent dermis immediately following surgical removal, which was compared to sc- and bulk-RNA-seq on primary dermal fibroblast cultures from the same samples after 4+ passages. Freshly dissociated tissue showed anticipated differences in cell proportions in keloid versus normal skin; however, comparably for both tissue types, there was an assimilation of fibroblast subtypes after culture. Cultured cells clustered conspicuously from the original populations, with evidence of only minor heterogeneity persisting. Cells displayed, to varying degrees, elements of each of the original subset signatures, with FAP+/SFRP2+ mesenchymal features the strongest. Pseudo-bulk analysis of mesenchymal subpopulations ex vivo showed cell-intrinsic keloid versus normal skin transcriptional differences consistent with current disease understanding; however, only a subset of these persisted in vitro. Cell-cell communication analysis provides potential strategies to maintain specific cell populations and their in vivo phenotypes. As an example, we report that culture with ascorbic acid (stimulating cell-derived extracellular matrix) enriched the mesenchymal signature. The data presented herein provide resources supporting greater understanding of, and strategies to refine, essential human fibroblast culture models.

BackgroundHypertrophic scars can cause pain, movement restrictions, and reduction of quality of life. Despite numerous options to tackle hypertrophic scarring, efficient therapies are still scarce, and cellular mechanisms are not well understood. Secreted factors from peripheral blood mononuclear cells (PBMCsec) were previously described for their beneficial effects in tissue regeneration. Here, we investigated the effects of PBMCsec on skin scarring in mouse models and human scar explant cultures at single cell resolution (scRNAseq). MethodsMouse wounds and scars were treated with PBMCsec either intradermally or topically. Human mature scars were treated with PBMCsec ex vivo in explant cultures. All experimental settings were analyzed by single cell RNA sequencing (scRNAseq). A variety of bioinformatics approaches were used to decipher gene regulation in the scRNAseq data sets. Components of the extracellular matrix (ECM) were investigated in situ by immunofluorescence. The effect of PBMCsec on myofibroblast differentiation and elastin expression was investigated by stimulating human primary fibroblasts with TGF{beta}. FindingsTopical and intradermal application of PBMCsec regulated the expression of a variety of genes involved in pro-fibrotic processes and tissue remodeling. Our bioinformatics approach identified elastin as a common linchpin of antifibrotic action in both, the mouse and human experimental setting. In vitro, we found that PBMCsec prevents TGF{beta}-mediated myofibroblast-differentiation and attenuates abundant elastin expression through non-canonical signaling inhibition. Furthermore, TGF{beta}-induced breakdown of elastic fibers was strongly inhibited by addition of PBMCsec. InterpretationTogether, we showed anti-fibrotic effect of PBMCsec on cutaneous scars in mouse and human experimental settings, suggesting PBMCsec as a novel therapeutic option to treat skin scarring. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSParacrine factors secreted from irradiated peripheral mononuclear cells (PBMCsec) show strong tissue regenerative properties in a variety of organs and are shown to enhance cutaneous wound healing. Whether PBMCsec shows anti-fibrotic properties on scar formation has not been investigated so far. Added value of this studyIn the present study, we were able to demonstrate that PBMCsec improves quality of developing and mature scars in mouse and human scar tissue. We found that PBMCsec is able to attenuate the expression of various genes, promoting scar formation and inhibit TGF{beta}-induced myofibroblast differentiation. Elastin and TXNIP were identified as a common linchpin of its anti-fibrotic action. Implications of all the available evidenceUsing in vivo, ex vivo, and in vitro models and analyses on a single-cell level, our study paves the way for clinical studies evaluating the use of PBMCsec for the treatment of human cutaneous scars.

Although there are many possible ways to treat skin cancer, most skin cancers are effectively treated by complete excision followed by standard histologic evaluation to ensure clear margins. The bread loaf technique describes a common method of processing specimens in which multiple slices of tissue are taken perpendicular to the major axis of an excision and submitted for microscopic analysis. Although sections may only be approximately four microns thick (0.000004 meters), this method is associated with high cure rates for basal cell and squamous cell carcinoma. Some authors have stated that this technique assesses less than 1% of the margins. We critically reviewed this assumption. While we confirm that the bread loaf technique often directly visualizes 1% or less of the peripheral and deep margins when considering only the width of sections compared to the entire length of an excisional specimen of the excision, much useful additional information is gained as soon as clear sections are identified towards the tips of a typical excisional specimen. For tumors that tend to grow in a nodular or spherical arrangement such as nodular basal cell carcinoma or squamous cell carcinoma of keratoacanthomatous type, we show that a variable but significant portion of the margin may be considered sampled by proxy when slice faces are clear. We highlight the importance of understanding the principles involved in tissue sectioning in order to allow clinicians to make informed decisions on behalf of patients.

BackgroundA significant relationship exists between perceived stress and the exacerbation and perpetuation of chronic pruritic dermatoses. Despite this, there is a notable absence of validated tools to specifically measure pruritus-associated stress. ObjectiveTo develop and pilot the Pruritus-Associated Stress Scale (PASS), a patient-reported outcome measure (PROM) for assessing pruritus-associated stress. Patients and MethodsPatients with chronic prurigo (CPG), atopic dermatitis (AD), and chronic pruritus on non-lesional skin (CPNL) were recruited at a German university centre. They were interviewed on pruritus-associated stress, and perceived stress using the PSS-10 and PSQ-30 questionnaires, to compile the first PASS version in accordance with the guidelines for PROM development. Subsequently, a second patient cohort was interviewed to refine the items of the PASS instrument based on impact analysis, interitem and item-total correlation, and internal consistency reliability. ResultsOf 55 patients (15 with AD, 20 with CPG, and 20 with CPNL; 61.8% female; mean age 61.0 {+/-} 15.4 years), who participated in the item selection phase, 94.5% reported pruritus-associated stress in the previous two weeks. The preliminary PASS demonstrated excellent internal consistency (Cronbachs alpha = 0.91). The twelve items that showed strong impact scores addressed nervousness, therapeutic strategies for managing pruritus-associated stress, fatigue, and urges to scratch more frequently or intensely due to pruritus. ConclusionsThis pilot study yielded a preliminary PASS, identified poorly performing items, and collected information for further refinement. As a next step, retaining the full item pool, an exploratory factor analysis will be conducted in a larger sample. SIGNIFICANCEThis study addresses a critical gap in dermatological research by developing and piloting the first questionnaire specifically designed to assess pruritus-associated stress in patients with chronic pruritus of diverse aetiologies.

A handheld microwave device (Swift(R), Emblation Limited) has been licenced and available for clinical use since 2016 in the fields of podiatry and dermatology and has been extensively used in treating cutaneous warts. As part of post marketing surveillance by the manufacturer, an online 79-item survey was distributed to podiatry clinics in the United Kingdom with a Swift(R) device. A total of 126 clinics responded (59.6%). 6998 adults (<65 years) underwent wart treatment with microwave (81.9% plantar warts; 18.1% common, non-plantar warts). The median efficacy rate was reported as 79.2% (65.9 - 87.5%) and 82.3% (71.4 - 100%) respectively. In older adults (over 65 years) efficacy rates were similar for both sites: plantar (73.2%, 50-90%, n=1232) and non-plantar (80.0%, 42.1-100%, n=276). A median of three treatments was required to bring about resolution. Sub-group analysis of the data revealed good clearance rates in patients with diabetes (79.6%), but less in immunocompromised individuals (61.3%) and those with autoimmune disease (58.6%). Overall, mean user satisfaction was rated as "very satisfied" on a 10-point scale (n=93 practices). A small number of adverse events were reported including blistering, superficial ulceration and poor healing were reported (n=7). Despite the limitations of a post-marketing questionnaire survey, these data provide good evidence of the safety and efficacy for Swift(R) microwave treatment of cutaneous warts. What is already known about this topic?O_LIMicrowave treatment has shown to be effective in the treatment of cutaneous warts. C_LI What does the study add?O_LIThis survey of clinics using SWIFT microwave treatments reports on the effectiveness and safety of the device in the treatment of 8506 adult patients with common and plantar warts. C_LIO_LIResponding user clinics reporting efficacy with good clearance rates and low levels of adverse events demonstrating microwave is a safe and effective treatment for plantar and common warts. C_LI

Urolithin A is a gut microbiome derived postbiotic that has been shown to stimulate mitophagy, and improve muscle and mitochondrial health when administered orally to humans. In three separate randomized trials, we have now investigated the effect of topical administration of Urolithin A on skin aging features and on UVB-mediated photodamaged skin. Post-menopausal women with evidence of skin aging such as > Grade 3 wrinkle formation were included in a split-face/arm study design in the first trial (aging study 1; n=48), followed by a second larger trial (aging study 2; n=108) in middle-aged men and women focusing on wrinkle reduction. Healthy participants were included in the placebo-controlled, randomized UVB-induced trial (photo-damage trial; n=22). Participants were randomized to receive topical supplementation with either 0.5% Urolithin A cream or placebo for 8-weeks in a low-dose arm or 1% Urolithin A cream or placebo in the high-dose arm in the aging study 1. In the aging study 2 participants were randomized to receive 1% UA in a day-cream, a night cream and a serum, that were compared to the untreated site. For the photo-damage trial, topical patches containing either 0.5% or 1% UA or placebo cream were applied for 24-hours following UVB irradiation. The primary outcome in the aging study 1 was an impact on biological pathways linked to skin aging in skin biopsies, and an impact on skin barrier function after 8-weeks. Key secondary endpoints were a change in facial wrinkle appearance (crows feet area). The aging study 2 focused on wrinkle reduction as a primary outcome. In the UVB-mediated photo-damage study, the primary read-out was the change in erythema after application. Molecular analyses were conducted on skin biopsies and using ex-vivo systems to investigate the mechanism of action mediating skin protective effects of Urolithin A. In the aging study 1, Urolithin A at 1% significantly up-regulated collagen synthesis pathways in human skin biopsies and led to a decrease in wrinkle depth on facial wrinkles. The lower dose had no significant impact. There was no change on skin barrier function with both doses suggesting maintenance of a healthy skin barrier function. In aging study 2, topical application of Urolithin A at the 1% dose in different formulations (day-cream, night cream and serum) led to significant wrinkle reduction compared to the untreated side, confirming the previous findings. Skin hydration was improved significantly as well. In the third trial, investigating impact on photodamaged skin, Urolithin A application led to a significant decrease in UV-induced erythema ([~]14%) compared to the untreated area, while placebo and lower dose UA creams showed no benefits. Urolithin A topical administration was safe and well-tolerated in all studies. UA also inhibited collagen degrading and pro-inflammatory pathways and up-regulated gene expression of biomarkers linked to induction of mitophagy and autophagy in human skin cells. Taken together, these clinical studies support the topical use of Urolithin A to manage and prolong skin health longevity by acting at the cellular level, supporting collagen structure, reducing wrinkle appearance and protecting against photoaging. The studies are registered in clinicaltrials.gov as: NCT05300984; NCT05473832; NCT05300542

Patients prone to psoriasis suffer after a breakdown of the epidermal barrier and develop poorly healing lesions with abnormal proliferation of keratinocytes. Strong inflammatory reactions with genotoxicity (short telomeres) suggest impaired immune defences with DNA damage repair response (DDR) in patients with psoriasis. Recent evidence indicates the existence of crosstalk mechanisms linking the DDR machinery and hormonal signalling pathways that cooperate to influence both progressions of many diseases and responses to treatment. The aim of this study was to clarify whether steroid biosynthesis and genomic stability markers are altered in parallel during the formation of psoriatic skin. Understanding between the interaction of the steroid pathway and DNA damage response is crucial to addressing underlying fundamental issues and managing resulting epidermal barrier disruption in psoriasis. Twenty patients with psoriasis and fifteen healthy volunteers were included in this study. Transcription levels of estrogen (ESR1, ESR2), androgen (AR), glucocorticoid/mineralocorticoid receptors (NR3C1, NR3C2), HSD11B1/HSD11B2 genes, and DNA damage sensors (SMC1A, TREX1, TREX2, SSBP3, RAD1, RAD18, EXO1, POLH, HUS1) were determined by Real-Time-PCR in blood and skin samples (Lesional, non-lesional) from psoriasis and control groups. ResultsWe found that ESR1, ESR2, HSD11B1, NR3C1, NR3C2, POLH, and SMC1A transcripts were significantly decreased and AR, TREX1, RAD1, and SSBP3 transcripts were increased dramatically in the lesional skin compared to skin samples of controls. As a result, we found that the regulation of the steroidogenic pathway was disrupted in the lesional tissue of psoriasis patients and that a sufficient glucocorticoid and mineralocorticoid response did not form and the estrogen/androgen balance was altered in favour of androgens. We suggest that an increased androgen response in the presence of DDR increases the risk of developing psoriasis. Although this situation may be the cause or the consequence of a disruption of the epidermal barrier, our data suggest developing new therapeutic strategies.

Backgroundfollowing a first cutaneous squamous cell carcinoma (CSCC), one-third of patients develop new primaries, escalating their risk of metastasis and poor outcomes. However, current follow-up strategies are not risk-stratified, representing a critical gap in patient management. Objectiveto develop and validate a prognostic model to quantify individualized absolute risk of a first metachronous CSCC after an index tumor, accurately accounting for the high competing risk of mortality in this typically elderly population. Methodswe conducted a nationwide, population-based cohort study of 11,737 patients with a first histologically confirmed CSCC (Netherlands Cancer Registry, 2007-2008) with up to 10 years of follow-up. Data on subsequent tumors was retrieved via linkage to the Automated National Pathological Anatomy Archive (Palga). A Fine-Gray competing-risk model was developed using routinely available clinical and pathological predictors (age, sex, hematologic malignancy, basal cell carcinoma (BCC) and actinic keratosis (AK) history, presence of synchronous CSCC, primary tumor location, and differentiation). Model performance was assessed 10-fold cross-validation, quantifying discrimination (time-dependent C-index) and calibration. Resultsduring follow-up, 3,288 (28%) developed a first metachronous CSCC. The model identified key predictors: markers of cumulative UV-exposure (included AK history, [&ge;]5 prior BCCs), and immunosuppression (chronic lymphocytic leukaemia/small lymphocytic leukaemia). Male sex, presence of synchronous CSCC at baseline were also associated with higher risk. While discrimination was modest (cross-validated 5-year C-index: 0.64), the model demonstrated excellent calibration. Conclusionsthis competing-risk model provides individualized, well-calibrated absolute risk estimates for a first metachronous CSCC. Based on routinely available clinical features, it offers insight into how established predictors shape risk in this high-susceptibility population. External validation and the identification of novel predictors are necessary to further refine the model and support personalized dermatologic care.

BackgroundThere is growing evidence that individuals with different skin phototypes require tailored approaches to achieve optimal photoprotection. Individuals with darker skin phototypes are more prone to UVA1- and visible light-induced pigmentation, whereas lighter phototypes are more susceptible to shorter wavelengths such as UVB and UVA2. Thus, skin phototype is an important determinant of sunscreen efficacy. In the present study we have asked if ethnicity - independent of phototype - is another factor affecting sunscreen efficacy. Objectives(i) To determine the overall photoprotective effects of two sunscreen formulations against UVA1, visible light (VL), and combined visible light plus UVA1, and (ii) to compare the photoprotective efficacy of both products between Han Chinese and Caucasian participants. MethodsForty healthy volunteers (N=20 Han Chinese; N=20 Caucasian), matched for phototype, constitutive pigmentation, gender, and age, were exposed to VL, UVA1, and combined VL plus UVA1 to induce pigmentation responses following standardized irradiation protocols. Skin responses across treated and untreated sites were analysed using linear mixed-effects models. ResultsAcross all participants, both sunscreen formulations provided significant protection against VL, UVA1, and combined VL plus UVA1. Notably, photoprotective efficacy against UVA1-induced immediate (IPD) and persistent pigment darkening (PPD) differed significantly between ethnic groups, with one formulation showing stronger protection in Han Chinese. ConclusionThis study indicates that ethnicity could influence sunscreen efficacy. Thus, sunscreens should not only be tailored to different phototypes, but also consider ethnic background.

BackgroundPost-menopausal women undergo significant dermatological changes, including thinning skin and reduced sebaceous gland activity, alongside increased incidence of dermatological diseases and hair loss. These changes reshape the skins ecological niche, influencing the skin mycobiome composition and behavior. Malassezia, a lipid-dependent human pathobiont and dominant fungal resident of skin, has been implicated in several dermatological disorders. We hypothesize that shifts in Malassezia populations contribute to post-menopausal skin disorders through altered host-microbe interactions. ResultsShotgun metagenomics of facial and scalp skin from 345 Asian women were stratified by menopausal stage (pre- [N=171], peri- [N=36], and post-menopausal [N=138]) and revealed the presence of seven out of the seventeen recognized Malassezia species: M. globosa, M. restricta, M. arunalokei, M. furfur, M. dermatis, M. japonica, and M. sympodialis. Detection frequencies of several species varied markedly across menopausal groups. Notably, M. globosa was detected 20% more frequently on the scalp of post- versus pre-menopausal women. Reduced sebum concentration on post-menopausal womens skin correlated with increased M. globosa abundance. In vitro co-culture of keratinocytes with Malassezia spp. showed cells tolerated fungal loads up to 104.5 CFU/cm{superscript 2}, but severe cytotoxicity was observed at [&ge;]105.5 CFU/cm{superscript 2}. M. globosa elicited the highest cytotoxicity towards keratinocytes. All Malassezia spp. tested invaded keratinocytes and triggered strong pro-inflammatory responses. Notably, IL-1, IL-1{beta}, IL-6, IL-8, IL-21, TNF-, GM-CSF, G-CSF, and MMP1 were significantly overproduced. Transcriptomics of keratinocytes exposed to toxic fungal loads revealed a gene expression profile characteristic of hyperproliferative and undifferentiated cells, alongside elevated expression of NLRP3, a key inflammasome sensor involved in pyroptosis. ConclusionsMenopause is associated with distinct shifts in Malassezia spp. prevalence and abundance. Reduced skin lipids and thickness may increase fungal burden relative to host cells, promoting inflammation and barrier dysfunction. Malassezias ability to invade keratinocytes suggests a mechanism for immune evasion and induction of chronic inflammation. Furthermore, keratinocytes exposed to high fungal loads exhibited a transcriptomic profile indicative of hyperproliferation and impaired differentiation, resembling patterns observed in psoriasis, seborrheic dermatitis, and other inflammatory skin conditions. Our co-culture model provides mechanistic insight into Malassezia-driven skin inflammation and offers a platform to develop targeted therapies for post-menopausal skin disorders.