British Journal of Dermatology

An online, cross-sectional survey was conducted to understand support for potential sunbed regulation strategies in the UK among 502 UK-based young adults (aged 18-24). Sunbed users showed strong support for sunbed regulation in the UK overall, particularly for staff supervision, mandatory health warnings, and business licensing, policies already implemented in some UK regions. Framing policies around public health protection rather than restricting personal freedom significantly enhanced support. These findings suggest a phased regulatory approach, starting with measures like stricter licensing and promotion of safer tanning alternatives that align with sunbed users sentiment, may build broader support for stronger regulation over time. This manuscript has been submitted to the British Journal of Dermatology and is currently under review.

With over 1.5 million new cases annually, skin cancers are the most commonly diagnosed group of cancers worldwide. Among these, melanoma and keratinocyte cancers (KC), comprising squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), are predominant. Retinol, a vitamin A derivative, is essential in the regulation of growth and differentiation of epidermal cells. Moreover, retinol exhibits antioxidant properties, protecting the skin against ultra-violet (UV) radiation induced oxidative damage. Existing research on the impact of retinol on melanoma, SCC and BCC development shows mixed results. Several dietary intake studies have suggested that higher retinol levels reduce skin cancer risk, however, others have failed to find this association. We used two-sample Mendelian randomization (MR) to explore if there is a causal relationship between retinol and the risk of developing melanoma, SCC or BCC. Genetically predicted circulating retinol levels were obtained from a genome wide association study (GWAS) meta-analysis of the INTERVAL (N=11,132) and METSIM (N=6,136) cohorts. Melanoma (30,134 cases and 375,188 controls), SCC (10,557 cases and 537,850 controls) and BCC (36,479 cases and 540,185 controls) risks were derived from published GWAS meta-analyses. We conducted two MR approaches. In the first MR we used a single SNP (rs10882283) that is associated with the levels of Retinol Binding Protein 4 (RBP4) as an instrument variable (IV) for circulating retinol levels. In the second MR we used all independent genetic variants that were strongly associated (P < 5 x 10-8) with retinol levels as IVs. Odds ratios (OR) for skin cancer were calculated for a one standard deviation (SD) increase in genetically predicted retinol levels. The single IV approach revealed that retinol levels were not significantly associated with risk of melanoma (OR = 1.04 [95% confidence interval 0.83, 1.31], P = 0.72), SCC (OR = 1.15[0.87, 1.51], P = 0.32) or BCC (OR = 1.06 [0.90, 1.23], P = 0.50). Similar null results were observed with the multiple IV approach for melanoma (OR = 1.03 [0.95, 1.11], P = 0.54), SCC (OR = 1.01 [0.91, 1.13], P = 0.83), and BCC (OR = 1.04 [0.96, 1.12], P = 0.38). In conclusion, we found no evidence that circulating retinol levels were causally associated with the development of melanoma, SCC and BCC.

The incidence of cutaneous malignancies is increasing worldwide, presenting an important public health burden. Cohort studies can provide high quality data on the epidemiology of these cancers, and are invaluable for deriving measures of disease burden used to inform prevention, diagnosis and treatment. We conducted a systematic review of the literature to summarise the characteristics of cohort studies that have published one or more papers describing the epidemiology of melanoma and/or keratinocyte cancers. Eligible studies were population-based cohort studies that have published findings on incidence or etiology of melanoma or keratinocyte cancer (including associations with phenotypic, environmental, and genetic factors). We excluded clinical cohorts focused on survivorship outcomes. We searched MEDLINE 1950 (U.S. National Library of Medicine, Bethesda, MD, USA), the ISI Science Citation Index (1990 to 31 July 2025) and the reference lists of retrieved articles, imposing no language restrictions. We identified 22 eligible cohort studies, 20 of which had published on melanoma, and 16 on keratinocyte cancer. Nine were conducted in the United States, eleven in Europe, and two in Australia. There was substantial variability in terms of cohort size, risk factor information recorded at baseline, and other data collected (e.g., health services, genetic). Only three studies were specifically designed to examine skin cancers as study endpoints, and only two cohorts pre-specified both melanoma and keratinocyte cancer endpoints. Our summary provides a resource for skin cancer researchers conducting investigations into the causes, burden and prevention of these important cancers.

BackgroundChildhood cancer survivors (CCS) face elevated skin cancer risk, especially after radiotherapy or hematopoietic stem cell transplantation (HSCT). We evaluated the prevalence and predictors of sun protection, sunburn, and physician skin examination (PSE) among CCS in Switzerland. MethodsWe surveyed CCS diagnosed <21 years and surviving [&ge;]5 years after diagnosis about sun protection, sunburns during last summer, and PSE within the last year. We retrieved cancer-related data from the Swiss Childhood Cancer Registry and used multivariable logistic regression, stratified by age group, to identify predictors. ResultsWe included 1,048 children (5-15 years), 572 adolescents (16-19 years), and 1,959 adults ([&ge;]20 years). Regular sun protection was reported by 89% of children, 65% of adolescents, and 77% of adults, and sunburns by 23%, 49%, and 43%. PSE prevalence among those treated with radiotherapy was 21%, 18%, and 17%, and among HSCT recipients 36%, 28%, and 28%. Radiotherapy was unrelated to sun protection and PSE, but associated with fewer sunburns (OR=0.63-0.77). HSCT recipients were more likely to have attended a PSE (OR=2.06-3.75), but not radiotherapy recipients. Across age groups, survivors born more recently were less likely to protect from sun (OR range=0.94-0.97) and more likely to report sunburn (OR=1.04-1.14). ConclusionSurvivors protect insufficiently from sun and only few who are particularly at risk for skin cancer due to their treatment history attend PSEs as recommended by the Childrens Oncology Group. Healthcare practitioners should systematically integrate yearly PSE after radiotherapy or HSCT and encourage consistent sun protection, particularly among younger generations and adolescents.

ObjectiveTo examine how habitual ultraviolet (UV) exposure relates to cause-specific mortality and incidence, to quantify trade-offs between non-skin disease and skin cancer, and to explore potential circulating mediators. DesignA population-based prospective cohort study with epidemiological and proteomic mediation analyses. SettingUK Biobank, recruited from 22 assessment centres across England, Scotland, and Wales. Participants419 007 adults of White European ancestry with data on habitual UV exposure and follow-up for mortality and incident cardiovascular disease and cancer. A proteomic subcohort of 44 712 participants had plasma profiling. Main outcome measuresHabitual ultraviolet exposure was summarised using Sun-BEEM (Sun-Behavioural and Environmental Exposure Model), a multidimensional score integrating environmental and behavioural indicators, categorised as low, medium, or high. Primary outcomes were all-cause, cardiovascular, and cancer mortality and incidence, and associations with Sun-BEEM categories were estimated using multivariable Cox models. Two extensions were implemented: an epidemiological extension using parametric g-computation to estimate deaths under counterfactual low and high UV scenarios; and a biological extension using proteomic mediation analyses to identify circulating proteins potentially linking UV exposure to cardiovascular and cancer mortality. ResultsCompared with low Sun-BEEM, medium and high exposure were associated with lower all-cause mortality (hazard ratio 0.89, 95% confidence interval 0.87 to 0.91; and 0.84, 0.82 to 0.87), with similar inverse associations for cardiovascular and non-skin cancer mortality. Skin cancer mortality showed no clear dose-response relationship with UV exposure, although incident keratinocyte cancers increased across Sun-BEEM categories. Counterfactual modelling suggested that, if associations are causal, a uniformly high UV pattern would prevent many more cardiovascular and other cancer deaths than the additional melanoma and keratinocyte cancer deaths. Proteomic mediation analyses implicated UV-downregulated immunoregulatory, mucosal-barrier, and cardiorenal-neuroendocrine pathways. ConclusionsHigher habitual UV exposure, measured using a multidimensional score, was associated with lower cardiovascular and non-skin cancer mortality without clear increases in skin cancer mortality, supporting a more balanced view of sunlight and health. Summary boxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIPublic health advice in temperate countries mainly treats sunlight as a skin cancer hazard. C_LIO_LIFew studies have explicitly quantified the trade-off between the potential benefits of habitual ultraviolet exposure for major non-skin diseases and its harms for skin cancer. C_LIO_LIMechanistic research on how ultraviolet exposure affects health outcomes has focused largely on vitamin D, with only limited work on non-vitamin D pathways. C_LI What this study addsO_LIA multidimensional UV exposure score (Sun-BEEM), combining environmental and behavioural indicators, was associated with lower all-cause, cardiovascular, and non-skin cancer mortality, without clear increases in skin cancer mortality. C_LIO_LICounterfactual analyses suggested a net balance favouring cardiovascular and cancer mortality benefits over skin cancer harms; proteomics supported mainly non-vitamin D pathways. C_LI

Photodynamic therapy (PDT) with topical aminolevulinic acid (ALA) can be effective for select basal cell carcinoma (BCC) lesions. However, the histological depth and subtype of tumors that respond to PDT remain uncertain. Here, we report a clinical trial of high-dose oral Vitamin D (VD), used as a PDT neoadjuvant for BCC. In this multi-institutional, intra-patient, randomized trial, 35 patients (9 with Gorlin Syndrome) received three PDT sessions (20% ALA; 417 nm blue light) preceded by oral VD, placebo, or no pretreatment. Tumors (122 BC) were monitored using 3D photography and computer-assisted volumetric analysis. Values for absolute volume (3DAbsVol) and average height (3DAvHt) were calculated and used to quantify tumor response kinetics. From histological sections, 3DAvHt was found to correlate with actual tumor depth, although 3DAvHt is only [~]10-20% of the latter. Importantly, 3DAvHt measurements revealed a distinct depth threshold that predicts PDT responsiveness. Of 122 tumors analyzed, 70% cleared after PDT; remaining tumors were micronodular or other aggressive histologic subtypes. To evaluate VDs effects upon treatment response kinetics after PDT, only 40% of original lesions were available for analysis. By stratifying remaining tumors by 3DAvHt, we found 65% of thin tumors to be VD-responsive, whereas only 28% of thick tumors responded to VD. Overall, PDT was effective for the majority of BCC lesions in our study. Tumors most likely to respond can be predicted histologically and by noninvasive 3D morphometry. For PDT-appropriate BCC lesions, neoadjuvant oral Vitamin D represents a safe and beneficial way to accelerate tumor resolution. CLINICAL TRANSLATION STATEMENTFor photodynamic therapy (PDT) of basal cell carcinoma (BCC), a clinical challenge is deciding which tumors to treat since the penetration depth of visible light into the skin is limited. In this clinical trial, noninvasive 3D photography and computer analysis were used to determine the height and volume of BCC tumors and to correlate these calculated parameters with tumor clearance after PDT, with or without the use of oral vitamin D3 (VD) as a neoadjuvant. Two very practical findings emerged. First, tumor height (3DAvHt) was found to correlate with BCC tumor depth and to predict therapeutic response; tumors below a height threshold of 0.13 mm ([~]1.5 - 2 mm histological depth) were highly likely to respond. Second, adding VD as a neoadjuvant prior to PDT of appropriate BCC tumors (superficial and thin nodular subtypes) is a safe and effective way to boost PDT efficacy.

Melanoma develops as the result of complex interactions between sun exposure and genetic factors. Data on the relationship between sunlight and melanoma from prospective studies are scant, and the combination of ultraviolet exposure data collected before melanoma diagnosis and genetic information is rarer still. We aimed to quantify the association between ambient and personal UV exposure in relation to risk of incident melanoma (invasive; invasive+in situ) in a large population-based prospective study of men and women (n=38,833) residing in a high ambient UV setting, and to examine potential gene-environment interactions. During a median follow-up time of 4.4 years, 782 (1.5%) participants developed cutaneous melanoma (316 invasive, 466 in situ). Country of birth, age at migration and sunburns during all periods of life were significantly associated with melanoma risk. Histories of keratinocyte cancer and of other actinic lesions were both strongly associated with melanoma risk. An interaction with polygenic risk is possible; among people at low risk, markers of cumulative sun exposure were associated with melanoma. In contrast, among people at high polygenic risk, markers of high-level early life ambient exposure were associated with melanoma. Polygenic risk scores can assist in identifying individuals for whom sunlight exposure is most relevant.

Palmoplantar pustulosis (PPP) and dyshidrotic eczema (DE) are chronic vesiculopustular dermatoses with overlapping clinical presentations but distinct underlying biology. Although comparative transcriptomic and proteomic analyses between PPP and DE have been reported, they remain limited in number and scope, with no comprehensive understanding of their distinct molecular signatures. Moreover, their molecular mechanisms remain unclear, and currently available therapeutic options are limited. To clarify disease-specific epidermal programs underlying vesicle formation, we conducted Visium HD spatial transcriptomic analysis of FFPE lesional skin samples obtained from patients with PPP and DE, followed by immunohistochemical validation against normal palmoplantar skin controls. Spatial clustering identified a keratinocyte subpopulation adjacent to vesicles that exhibited distinct transcriptional programs in the two diseases. In PPP, vesicle-associated keratinocytes demonstrated marked downregulation of aquaporin-3 (AQP3) and E-cadherin, together with strong, spatially localized activation of JAK-STAT3 signaling. Conversely, DE exhibited diffuse AQP3 expression and more homogeneous activation of JAK-STAT3 signaling throughout the epidermis. These results indicate that, although PPP and DE share inflammatory pathways, they differ substantially in their spatial molecular architecture. Reduced AQP3 expression and localized STAT3 activation may contribute to vesicle formation in PPP, supporting our previous hypothesis that implicates intraepidermal sweat leakage as a pathogenic mechanism in PPP. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/723901v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@19c7591org.highwire.dtl.DTLVardef@eab29aorg.highwire.dtl.DTLVardef@73c2e2org.highwire.dtl.DTLVardef@1ffc02f_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundSkin disease affects 4.7-4.9 billion individuals globally; however, little is known about access to dermatological care. MethodsWe conducted a multinational, cross-sectional survey of dermatological care across 194 WHO member states and three additional geographic areas in 2024-2025. Primary outcomes included dermatologist density per 100,000 population and number of dermatologists globally. Secondary outcomes included training programme density, workforce distribution, perceived access to care, and health system characteristics. Descriptive statistics and nonparametric tests compared outcomes across World Bank Income (WBI) levels and WHO regions. FindingsResponses were obtained from 158 countries. Mean dermatologist density was 2.66 per 100,000, ranging from 0.37 in low-income (LICs) to 5.05 in high-income countries (HICs). There are estimated 175,633 dermatologists globally (95% CI: 173,598-177,668). Forty-two percent of countries reported inadequate or extremely poor access to dermatological care. There was significant variation (p < 0.001) in access to all types of subspecialty care (paediatric, surgical, dermatopathology) across WBI levels, with consistently worse access in lower-income countries. Dermatologists are primarily based in urban centres (79%). Twenty-one percent of countries lack dermatology training programs, with training varying by WBI level (p < 0.001). Non-dermatologist healthcare workers bear a substantial responsibility for management of skin disease. InterpretationSignificant global disparities exist in access to dermatological care, particularly in lower resource settings. Achieving skin health equity will require global commitment to expanding/funding training programmes, incentivizing decentralization of dermatology practice, and optimizing alternative care delivery including upskilling front-line healthcare workers. FundingInternational League of Dermatological Societies and LOreal Dermatological Beauty.

IntroductionTo improve dermatological care in underserved rural regions, the "Teledermatology in Styria" project launched on January 1st, 2020. This project digitally connected general practitioners (GP) with dermatologists (DERM), funded by Styrian Health Fund and supported by a partnership between Styrian Medical Association, Austrian Health Insurance Fund Styria, Universities Department of Dermatology, and e-derm-consult GesmbH. MethodologyThe project allows GPs to submit clinical and dermoscopic images of patient skin conditions, with relevant clinical information, via a "store-and-forward" teledermatology service to DERM, who responds with diagnosis and treatment recommendations. After five years, the collected data was analyzed, and acceptance among patients and doctors was assessed using questionnaires. ResultsOf 5119 cases, 19% required no therapy, while 61% were managed by their GPs following teledermatological consultation. Referrals included 12% for routine dermatological appointments, 3% for urgent appointments, and 2% for hospital visits. The case spectrum covered all dermato-venereological conditions, with neoplasms accounting for only 34%. Patient satisfaction exceeded 95%, based on 692 returned questionnaires. ConclusionOnly 17% of patients required additional specialist dermatological examination after teledermatology. The notably faster diagnosis and the surprisingly high level of patient satisfaction highlight the benefits of teledermatological consultations.

Vitiligo is an autoimmune skin disease that is characterized by the progressive destruction of melanocytes by autoreactive CD8+ T cells. Melanocyte destruction in active vitiligo is mediated by CD8+ T cells but why white patches in stable disease persist is poorly understood. The interaction between immune cells, melanocytes, and keratinocytes in situ in human skin has been difficult to study due to the lack of proper tools. Here, we combine non-invasive multiphoton microscopy (MPM) imaging and single-cell RNA sequencing (scRNA-seq) to identify distinct subpopulations of keratinocytes in lesional skin of stable vitiligo patients. We show that these keratinocytes are enriched in lesional vitiligo skin and differ in metabolism, an observation corroborated by both MPM and scRNA-seq. Systematic investigation of cell-cell communication show that CXCL is the prominent signaling change in this small population of keratinocytes, which secrete CXCL9 and CXCL10 to create local inflammatory cytokine loops with T cells to drive stable vitiligo persistence. Pseudotemporal dynamics analyses predict an alternative keratinocyte differentiation trajectory that generates this new population of keratinocytes in vitiligo skin. In summary, we couple advanced imaging with transcriptomics and bioinformatics to discover cellcell communication networks and keratinocyte cell states that perpetuate inflammation and prevent repigmentation. One Sentence SummaryCommunication between keratinocytes, immune cells, and melanocytes maintain depigmented patches in stable vitiligo.

Skin cancer is the most common malignancy worldwide, comprising three major types: melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). A critical goal in advancing our understanding of skin cancer is to identify the shared and distinct biological mechanisms that drive the risk profiles for each skin cancer type. In this study, we integrated tissue-specific chromatin conformation and expression quantitative trait loci data (spatial eQTL) to construct gene regulatory networks (GRNs) for melanocytes, sun-exposed skin, not sun-exposed skin, and blood. These GRNs, which capture spatially regulated gene expressions, were used as instrumental variables along with GWAS summary statistics for melanoma, BCC and SCC, to infer causal relationships between specific gene expression changes and each type of skin cancer. These Mendelian randomization analyses identified 82, 62, and 125 causal genes for melanoma, BCC, and SCC, respectively, with many of these genes not evident from the GWAS data alone. Our analyses revealed distinct mechanisms for each skin cancer type: telomere maintenance and nevus pathways in melanoma, inherited immune traits in BCC, and p53 dysfunction in SCC. Notably, apoptosis and pigmentation emerged as shared biological processes across skin cancers. These findings provide new insights into the genetic drivers of three distinct skin cancers, highlighting new gene targets which can be used to increase diagnostic precision, as well as potential therapeutic targets.

Non-melanoma skin cancer is the most common human malignancy and is primarily caused by exposure to ultraviolet (UV) radiation. The earliest detectable precursor of UV-mediated skin cancer is the growth of cell groups harboring clonal mutation (CM) in clinically normal appearing skin. Systematic evaluation of CMs is crucial to understand early photo-carcinogenesis. Previous studies confirmed the presence of CMs in sun-exposed skin. However, the relationship between UV-exposure and the accumulation of CMs, and the correlation of CMs with skin cancer risk remain poorly understood. To elucidate the exact molecular and clinical effects of long-term UV-exposure on skin, we performed targeted ultra-deep sequencing in 450 individual-matched sun-exposed (SE) and non-sun-exposed (NE) epidermal punch biopsies obtained from clinically normal skin from 13 donors. A total of 638 CMs were identified, including 298 UV-signature mutations (USMs). The numbers of USMs per sample were three times higher in the SE samples and were associated with significantly higher variant allele frequencies (VAFs), compared with the NE samples. We identified genomic regions in TP53, NOTCH1 and GRM3 where mutation burden was significantly associated with UV-exposure. Six mutations were almost exclusively present in SE epidermis and accounted for 42% of the overall difference between SE and NE mutation burden. We defined Cumulative Relative Clonal Area (CRCA), a single metric of UV-damage calculated by the overall relative percentage of the sampled skin area affected by CMs. The CRCA was dramatically elevated by a median of 11.2 fold in SE compared to NE samples. In an extended cohort of SE normal skin samples from patients with a high- or low-burden of cutaneous squamous cell carcinoma (cSCC), the SE samples in high-cSCC patients contained significantly more USMs than SE samples in low-cSCC patients, with the difference mostly conferred by mutations from low-frequency clones (defined by VAF≤1%) but not expanded clones (VAF&gt;1%). Our studies of differential mutational features in normal skin between paired SE/NE body sites and high/low-cSCC patients provide novel insights into the carcinogenic effect of UV exposure, and suggest CMs might be used to develop novel biomarkers for predicting cancer risk.Significance statement In UV radiation exposed skin, mutations fuel clonal cell growth. We established a sequencing-based method to objectively assess the mutational differences between sun-exposed (SE) and non-sun-exposed (NE) areas of normal human skin. Striking differences, in both the numbers of mutations and variant allele frequencies, were found between SE and NE areas. Furthermore, we identified specific genomic regions where mutation burden is significantly associated with UV-exposure status. These findings revealed previously unknown mutational patterns associated with UV-exposure, providing important insights into UV radiation’s early carcinogenic effects. Additionally, in an extended cohort, we identified preliminary association between normal skin mutation burden and cancer risk. These findings pave the road for future development of quantitative measurement of subclinical UV damage and skin cancer risk.Competing Interest StatementThe authors have declared no competing interest.Common AbbreviationsUVUltravioletCMClonogenic mutationNMSCNonmelanoma skin cancerSESun-exposedNENon-sun-exposedUSMUV-signature mutationNUSMNon-UV-signature mutationCRCACumulative Relative Clonal AreacSCCCutaneous squamous cell carcinomaAKActinic keratosisSNVSingle nucleotide variant Indels – Insertions/deletionsDNVDinucleotide variantCSNVCluster of single nucleotide variantMACMulti-Nucleotide Variant Annotation CorrectorVAFVariant allele frequencyView Full Text

Sebaceous gland (SG) secretions are pivotal to skin and eye health. At the SG-epidermis confluence is an overlooked epidermal collar we named the follicular epidermis (FE). Here, we show that the FE is similar among different SG types and contains unique Axin2+ stem cells in a niche at its basal FE-perpendicular flexure (FE-PF). Lineage tracing and ablation assays demonstrate Axin2+ cells as integral for FE homeostasis. Wnt-secretion arrest experiments resulted in FE-obstruction via hyperproliferation and inhibited differentiation inferring FE-PF Axin2+ cells are Wnt-producers maintaining FE-patency. Upon constitutive Axin2+ cell Wnt signalling, FE-PF-specific cell proliferation with early-stage signs of malignancy formed alongside a keratin-plugging FE-obstruction type. While keratin-based obstructions are recognized, inhibited differentiation obstructions are not, which suggests a one-size-fits-all therapeutic approach is not optimal. We offer a molecular identification toolkit to aid anti-obstruction advances in dermatology/ophthalmology and highlight the FE-PF as a skin tumorigenic site. SummaryThis work characterises a novel site in the skin, its stem cells and niche, a site prone to cancer. Obstructions can occur at this site by two mechanisms, one of which is novel, bringing into question current therapy and prompting a rethink of disease in dermatology and ophthalmology to account for this novel site. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=133 HEIGHT=200 SRC="FIGDIR/small/554243v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@19ebe94org.highwire.dtl.DTLVardef@f1ef95org.highwire.dtl.DTLVardef@1a846aaorg.highwire.dtl.DTLVardef@b75322_HPS_FORMAT_FIGEXP M_FIG C_FIG

Acne vulgaris is one of the most prevalent inflammatory skin diseases worldwide, yet the molecular events initiating comedogenesis remain poorly understood. The comedone switch hypothesis proposes that acne originates from an imbalance in lineage commitment within the junctional zone of the pilosebaceous unit, promoting infundibular differentiation at the expense of sebaceous gland maintenance. However, direct evidence from human acne tissue at single-cell resolution has been lacking. Here, we integrated single-cell transcriptomic datasets from healthy skin, non-lesional skin of acne patients, and lesional acne tissue to reconstruct the earliest stages of comedogenesis. We identified a previously uncharacterized cell population in non-lesional skin with transcriptomic features consistent with a microcomedone and mapped this population across independent datasets to reconstruct the transcriptional comedone architecture. Comedonal remodeling was characterized by enhanced keratinization and inflammatory programs. Quantitative analyses supported a shift from sebaceous toward infundibular cell fate, providing first data-driven evidence for the comedone switch hypothesis in human acne. Beyond the pilosebaceous unit, we identified broader epithelial alterations, including loss of POSTN and ERRFI1 expression in basal interfollicular epidermal keratinocytes. Together, these findings provide a cell-resolved framework for human comedogenesis and identify candidate mechanisms linking genetic susceptibility, environmental triggers, and lineage imbalance within the upper hair follicle.

BackgroundPyoderma gangrenosum (PG) is a rare neutrophilic ulcerative dermatosis with no FDA-approved therapies and limited validated outcome measures. Investigators Global Assessments (IGAs) are widely used in dermatology but often lack objective criteria, robust validation, and comparability across studies. There remains a critical need for a PG-specific, standardized, and validated severity instrument. MethodsWe developed and conducted initial validation of the Investigator Global Assessment for Pyoderma Gangrenosum (IGAPg(C)), a novel PG-specific IGA. An international multistakeholder panel guided development, with a core team designing the instrument based on prior research identifying key objective clinical features of PG severity. The IGAPg(C) incorporates ulcer depth, drainage, discoloration, and undermining, with ulcer location and extent used to resolve indeterminate cases. Standardized rater training materials were created. Construct validity was assessed in 36 patients evaluated by an expert PG clinician, with correlations to Patient Global Assessment (PGA), Skindex-Mini, and numeric rating scales (NRS) for 24-hour and 7-day pain. Inter-rater reliability was evaluated in a subset of 26 patients assessed independently by five raters using a two-way random-effects intraclass correlation coefficient (ICC [2,1]) within a linear mixed-effects model. ResultIGAPg(C) scores demonstrated strong correlation with PGA when assessed by an expert PG dermatologist (Pearsons r = 0.73) and when averaged across all raters (r = 0.69). Moderate correlations were observed with Skindex-Mini (r = 0.49), 24-hour pain NRS (r = 0.48), and 7-day pain NRS (r = 0.52), consistent with differing constructs measured. Inter-rater reliability was high (ICC = 0.76). Raters reported the instrument to be comprehensive, comprehensible, and efficient to administer. Reliability and construct validity metrics are summarized in Table 1. O_TBL View this table: org.highwire.dtl.DTLVardef@ff22edorg.highwire.dtl.DTLVardef@4e33aaorg.highwire.dtl.DTLVardef@21f9c0org.highwire.dtl.DTLVardef@93d13forg.highwire.dtl.DTLVardef@8e96fc_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable 1.C_FLOATNO O_TABLECAPTIONConstruct validity and inter-rater reliability of the IGAPg morphological tool. Correlations between IGAPg scores and patient-reported outcomes (PGA, Skindex-Mini, and average pain) demonstrate moderate-to-strong construct validity. Values are shown for all raters, Rater 1 alone, and Raters 2-5. Inter-item PRO correlations confirm internal consistency. Pearson correlations between Rater 1 and Raters 2-5 are reported with shared patient counts and p-values (p < 0.05 was considered significant). ICC(2,1) indicated good inter-rater reliability with most score variability attributable to differences between patients with minimal variability due to rater differences and a moderate residual component. Inter-item patient reported outcomes correlations confirm difference in measured constructs. C_TABLECAPTION C_TBL ConclusionsDespite limitations including modest sample size and rater homogeneity, the IGAPg(C) demonstrated strong construct validity and high inter-rater reliability. Designed for dermatologists and trainees familiar with PG morphology, the IGAPg(C) represents a promising PG-specific outcome measure for clinical research and therapeutic trials. Future work will focus on refining training materials and expanding validation with structured patient-investigator engagement.

BackgroundIn the Melanoma Genomics Managing Your Risk Study, access to personal genomic risk testing led to improvements in some melanoma prevention and early detection behaviors. PurposeWe aimed to examine the hypothesized psychosocial mediators of the effects observed in the trial. MethodsAustralians of European ancestry without melanoma and aged 18-69 years were recruited via the national Medicare database and randomized to receive personal genomic risk information or usual care (N=1,025). Questionnaires were administered at baseline, 1-month post-intervention, and 12-months post-baseline to assess self-reported prevention and early detection behaviors and psychosocial measures. To identify potential mediators, we first evaluated the interventions effect on psychosocial measures and the associations between psychosocial measures and behavioral outcomes. We then estimated the natural indirect effects (NIEs) and their 95% confidence intervals (CIs) to quantify the effects mediated by potential mediators identified. ResultsAmong participants with high traditional melanoma risk, the interventions effect on increased sun protection at 1-month was partially mediated by changes in perceived importance [NIE mean difference (95% CI): 0.02 (0.00, 0.04)] and perceived effectiveness [0.01 (0.00, 0.03)] of sun protection strategies. Among women, the interventions effect on increased whole-body skin examinations at 1-month was partially mediated by perceived capability to engage in skin examinations [NIE odds ratio (95% CI): 1.08 (1.00, 1.29)] and perceived control over detecting a future melanoma [1.13 (1.03, 1.32)]. ConclusionsThe effectiveness of precision prevention and early detection interventions may be enhanced by targeting key psychosocial mediators through tailored communication of personal melanoma risk.

Background There are no licensed treatments for patients with mild to moderate patchy alopecia areata (AA). Objectives To evaluate the efficacy, safety and dose response of STS01, a novel nanoparticle controlled release, topical formulation of dithranol/Prosilic. Methods In a phase 2, double blind study, adult patients with mild to moderate AA (guideline 10% to 50% of scalp hair loss) were randomly assigned to STS01 at doses of 0.25%, 0.5%, 1%, 2% or placebo, daily for 6 months. The primary endpoints included the proportion of patients achieving a >=30% improvement in Severity of Alopecia Tool (SALT) score, and percentage change from baseline in SALT score. This minimum level of improvement is generally accepted as an indicator of the population likely to progress to complete regrowth Results A total of 155 patients were randomized and treated (placebo, n=32; STS01 groups, n=30 to 31). STS01 1% met the primary efficacy endpoint of >=30% SALT score improvement compared to placebo: 75.9% (95% CI, 60.3 to 91.4%) vs 36.7% (95% CI, 19.4 to 53.9%) at 6 months; p=0.0037. The least squares (LS) mean percentage change in SALT score from baseline to end of treatment showed a clear dose response relationship; STS01 0.5% was the minimally effective dose and 2% the maximum tolerated dose, and there was a statistically significant improvement in the STS01 1% group (minus 55.0% vs +0.6% with placebo; p<0.01). Significant improvements (p<0.05) in LS mean percentage changes from baseline in SALT scores were demonstrated in the STS01 1% group at 2 months (-28.6% vs 12.8%), 4 months (-57.2% vs 1.5%), and 6 months (minus 67.0% vs 0.6%). Clinical Global Impression improvement was reported in 72.0% of patients with STS01 1% vs 41.7% with placebo (p<0.05). The most commonly reported treatment emergent adverse events were skin irritation reactions, but were mostly mild (STS01: 56.7% to 71.0%; placebo: 21.9%) or moderate (STS01:13.3% to 35.5%; placebo: 0%) and manageable by reduced frequency of application. There were 15 skin-related discontinuations with STS01 (12.2%) and 2 (6.3%) with placebo. Conclusions STS01 demonstrated a clear dose response, with STS01 1% dose optimally more effective than placebo for hair regrowth with minimal tolerance concerns in mild to moderate patchy AA. Skin irritation reactions were generally manageable and there were no new safety signals. Further characterisation of the STS01 1% dose is planned in a phase 3 study. Chief Investigator AGM reports fees from Soterios Ltd. Chief Statistician DMF is an employee of Soterios Ltd. All other authors were Principal Investigators in the trial and their clinics were reimbursed for the work involved. Most also had sponsorship in the form of consultancies, investigational roles or lecturing roles on behalf of other Dermatological pharmaceutical companies

IntroductionSolid organ transplant recipients (SOTRs) are at much higher risk of developing squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), compared to the general population. Previous studies have derived genetics-based predictors (polygenic risk scores, PRS) of SCC and BCC risk in SOTRs by assuming that genetic risk variants act in the same way in the general population as in SOTRs, but this assumption has not been fully tested. ObjectiveTo investigate whether known genetic risk variants for SCC and BCC have different effect sizes in SOTRs versus in non-transplantees, and if a re-weighted PRS would improve risk prediction. MethodsWe conducted genome-wide association studies for SCC and BCC separately in the non-transplant general population and in SOTRs, and compared the risks associated with selected common genetic variants for KC risk in SOTR vs non-transplant individuals from the UK Biobank. For regions with an increased log odds ratio in SOTRs, PRSs including these weights were validated in the QSkin study, and applied to the Australian STAR SOTR cohort. ResultsEffect sizes for functional variants in MC1R (rs1805007), ASIP (rs6059655), and IRF4 (rs12203592) were much more strongly associated with the risk of KC in SOTRs than in non-transplantees. The proportional increase in the effect sizes ranged from 1.9-fold for rs6059655 and BCC risk (SOTRs log (OR)=0.49, 95%CI=0.00-0.98 vs log (OR)=0.26, 95%CI=0.24-0.30 in non-transplantees) to as high as 4.8-fold for rs1805007 and SCC risk (SOTR log (OR)=0.88, 95% CI=0.41-1.35 vs log (OR)=0.18, 95% CI=0.12-0.24 in non-transplantees). PRS with SOTR derived weights for these SNPs showed improved SCC/BCC risk stratification in the STAR Cohort, with the optimised PRS reclassifying 19% of SCC cases vs 8% using the standard PRS, and 18% of BCC cases vs 12% using the standard PRS. ConclusionEffect sizes for SCC and BCC risk for genetic variants in the MC1R, ASIP and IRF4 genes are elevated in SOTRs, and correctly weighting these variants improves risk stratification based on polygenic risk.

Prurigo nodularis (PN) is an intensely pruritic, chronic inflammatory skin disease that disproportionately affects black patients. However, the pathogenesis of PN is poorly understood. We performed single-cell transcriptomic profiling, ligand receptor analysis and cell trajectory analysis of 28,695 lesional and non-lesional PN skin cells to uncover disease-identifying cell compositions and genetic characteristics. We uncovered a dysregulated role for fibroblasts (FBs) and myofibroblasts as a key pathogenic element in PN, which were significantly increased in PN lesional skin. We defined seven unique subclusters of FBs in PN skin and observed a shift of PN lesional FBs towards a cancer-associated fibroblast (CAF)-like phenotype, with WNT5A+ CAFs increased in the skin of PN patients and similarly so in squamous cell carcinoma (SCC). A multi-center PN cohort study subsequently revealed an increased risk of SCC as well as additional CAF-associated malignancies in PN patients, including breast and colorectal cancers. Systemic fibroproliferative diseases were also upregulated in PN patients, including renal sclerosis and idiopathic pulmonary fibrosis. Ligand receptor analyses demonstrated increased FB1-derived WNT5A and periostin interactions with neuronal receptors MCAM and ITGAV, suggesting a fibroblast-neuronal axis in PN. Type I IFN responses in immune cells and increased angiogenesis/permeability in endothelial cells were also observed. As compared to atopic dermatitis (AD) and psoriasis (PSO) patients, increased mesenchymal dysregulation is unique to PN with an intermediate Th2/Th17 phenotype between atopic dermatitis and psoriasis. These findings identify a pathogenic role for CAFs in PN, including a novel targetable WNT5A+ fibroblast subpopulation and CAF-associated malignancies in PN patients.