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.

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.

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.

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

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

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.

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

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.

Hidradenitis suppurativa (HS) is a chronic, debilitating, inflammatory skin disorder. Medications have been reported in association with cases of new-onset HS or exacerbation of existing disease; however, the extent of this risk is unclear. We queried the FDA adverse event reporting system (FAERS) from 2003-2023 to identify drug-specific reporting signals for HS. We stratified reports by whether HS was listed as an indication (Drug-Worsened, DW) or not (Drug-Induced, DI) to distinguish disease flares from de novo disease. Primary suspect drugs with > 3 HS reports were included. Disproportionality was quantified using reporting odds ratio (ROR) with Wald 95% confidence intervals (CI). Time-to-onset was also evaluated. We identified 5,529 HS reports: 3,725 DW and 1,804 DI. Females comprised 63% (mean age 41) and the US was the top reporting country (81.8% DW; 53.66% DI). In the DI group, statistically significant signals were observed for immunomodulators also used to treat HS including adalimumab (n=506, ROR= 12.6 [11.3-14.0]) infliximab (n=108, ROR=8.2 [6.7-10.0]), and secukinumab (n=79, ROR=6.6 [5.2-8.2]), consistent with paradoxical reactions. Median time-to-onset was 22 days for secukinumab, compared to 312 and 319 days for adalimumab and infliximab. Signals were also identified for isotretinoin (n=28, ROR= 6.2 [4.2-8.9]), and for antineoplastic agents including cytarabine (n=25, ROR= 24.7 [16.6-36.6]) and omacetaxine (n=8; ROR= 7416 [CI 2923-18816]), which may reflect reported eccrine hidradenitis. In the DW group, adalimumab (n=2967), secukinumab (n=67), and infliximab (n=57) predominated but displayed lower RORs (0.72-1.4), likely reflecting indication bias. While mechanisms of drug-associated HS require further clarification, our findings demonstrate significant associations and highlight the importance of dermatologic monitoring when initiating certain agents.

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.

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.

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.

IntroductionWe are conducting a multicenter study to identify classifiers predictive of disease-specific survival in patients with primary melanomas. Here we delineate the unique aspects, challenges, and best practices for optimizing a study of generally small-sized pigmented tumor samples including primary melanomas of at least 1.05mm from AJTCC TNM stage IIA-IIID patients. This ongoing study will target 1,000 melanomas within the international InterMEL consortium. We also evaluated tissue-derived predictors of extracted nucleic acids quality and success in downstream testing. MethodsFollowing a pre-established protocol, participating centers ship formalin-fixed paraffin embedded (FFPE) tissue sections to Memorial Sloan Kettering Cancer Center for the centralized handling, dermatopathology review and histology-guided coextraction of RNA and DNA. Samples are distributed for evaluation of somatic mutations using next gen sequencing (NGS) with the MSK-IMPACT assay, methylation-profiling (array), and miRNA expression (Nanostring nCounter). ResultsSufficient material was obtained for screening of miRNA expression in 683/685 (99%) eligible melanomas, methylation in 467 (68%), and somatic mutations in 560 (82%). In 446/685 (65%) cases, aliquots of RNA/DNA were sufficient for testing with all three platforms. Among samples evaluated by the time of this analysis, the mean NGS coverage was 249x, 59 (18.6%) samples had coverage below 100x, and 41/414 (10%) failed methylation QC due to low intensity probes or insufficient Meta-Mixed Interquartile (BMIQ)- and single sample (ss)- Noob normalizations. Six of 683 RNAs (1%) failed Nanostring QC due to the low proportion of probes above the minimum threshold. Age of the FFPE tissue blocks (p<0.001) and time elapsed from sectioning to co-extraction (p=0.002) were associated with methylation screening failures. Melanin reduced the ability to amplify fragments of 200bp or greater (absent/lightly pigmented vs heavily pigmented, p<0.003). Conversely, heavily pigmented tumors rendered greater amounts of RNA (p<0.001), and of RNA above 200 nucleotides (p<0.001). ConclusionOur experience with many archival tissues demonstrates that with careful management of tissue processing and quality control it is possible to conduct multi-omic studies in a complex multi-institutional setting for investigations involving minute quantities of FFPE tumors, as in studies of early-stage melanoma.

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.

The negative health consequences of acute ultraviolet (UV) exposure are evident, with reports of 30,000 emergency room visits annually to treat the effects of sunburn in the United States alone. Acute effects of sunburn include erythema, edema, and severe pain, and chronic overexposure to UV radiation can lead to skin cancer. While the pain associated with the acute effects of sunburn may be relieved by current interventions, existing post-sunburn treatments are not capable of reversing the cumulative and long-term pathological effects of UV exposure, an unmet clinical need. Here we show that activation of the vascular endothelial growth factor (VEGF) pathway is a direct and immediate consequence of acute UV exposure, and activation of VEGF signaling is necessary for the initiating the acute pathological effects of sunburn. In UV-exposed human subjects, VEGF signaling is activated within hours. Topical delivery of VEGF pathway inhibitors, targeted against the ligand VEGF-A (gold nanoparticles conjugated with anti-VEGF antibodies) and small molecule antagonists of VEGF receptor signaling, prevent the development of erythema and edema in UV-exposed mice. Collectively, these findings suggest targeting VEGF signaling may reduce the subsequent inflammation and pathology associated with UV-induced skin damage, which reveals a new post-exposure therapeutic window to potentially inhibit the known detrimental effects of UV on human skin.