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Objective: Physical treatment modalities, such as ablative fractional laser (AFL), electrocautery, and cryotherapy, are extensively used in the field of dermatology. This study aimed to characterize the short-term innate and adaptive immune responses induced by AFL compared with heat- and cold-based procedures., Materials and Methods: Innate (CD11b + Ly6G + neutrophils) and adaptive (CD8 + CD3 + T cells) immune cell infiltration and histopathological changes were examined in murine skin on Days 1 and 7, following AFL, monopolar-electrocautery (RF), thermocautery, and cryotherapy. Interventions were standardized to reach the reticular dermis. Clinical skin reactions were photo-documented daily. As a comparator, the adaptive immune response was examined in murine basal cell carcinomas (BCC) on Day 7 after AFL exposure., Results: Baseline histopathology confirmed immediate deep dermal tissue impact by all procedures. Immune cell dynamics varied across treatments throughout the progression of clinical and histopathological responses. On Day 1, AFL and heat-based procedures triggered an innate immune response, characterized by CD11b + Ly6G + neutrophil cell infiltration that correlated with histopathological findings and immediate onset of clinical skin reactions. In addition, heat-based procedures led to an increase in overall dermal CD45 + cells (Day 1), which continued to rise for AFL and RF-electrocautery at Day 7 posttreatment. On the contrary, cryotherapy did not induce immediate (Day 1) innate immune responses, but instead a delayed increase in neutrophil and CD45 + cell infiltration (Day 7), which coincided with the late onset of clinical reaction. CD3 + T cells and CD8 + CD3 + T cells demonstrated a similar pattern, with an increase observed for heat-based procedures on Day 1 and a delayed increase for cryotherapy on Day 7. Distinctive for AFL-treated skin, the level of dermal CD3 + T cells increased over time, significant by Day 7, and AFL-treated mouse BCCs responded with increased CD8 + T cell infiltration at Day 7 posttreatment., Conclusion: Heat- and cold-based procedures developed distinct cutaneous immune responses, with cryotherapy resulting in a delayed response compared to immediate immune responses from heat-based procedures. The substantial T cell response induced by AFL in the skin and BCC tumors indicates a potential for AFL as an adjuvant in immunotherapeutic treatments of keratinocyte cancers., (© 2024 Wiley Periodicals LLC.)

Background: Since recurrences and new AKs commonly are observed after treatment long-term effects of field-directed therapies for AKs are crucial. Thus, we evaluated the 6- and 12-month efficacy and satisfaction of sequential topical 5-fluorouracil (5-FU) and daylight PDT (dPDT) with dPDT alone., Methods: In a randomized intra-individual study patients with multiple AKs in the face and scalp were treated with 4 % 5-fluorouracil cream twice daily for 7 days on one side of the scalp/face, followed by dPDT on both sides. Lesion clearance rate, lesion recurrence rate and number of new lesions were evaluated at 6- and 12-month after treatment., Results: 58/60 completed 6-month and 55/60 completed 12-month follow-up. Pre-treatment with topical 5-FU improved the long-term efficacy of dPDT, especially for moderately thick AKs, with a lesion clearance of 72 % at 12-month compared to 48 % after dPDT alone (p = 0.017). The recurrence rate at 12-month was 15 % for combination treatment and 20 % for dPDT alone (0.042). Most patients were highly satisfied with both treatments., Conclusions: Sequential treatment with short-term topical 5-FU followed by dPDT maintained a higher complete lesion clearance than dPDT alone at both 6- and 12-month follow-ups, with fewer new AKs developing after combination therapy., Competing Interests: Declaration of competing interest SRW has been a member of advisory board for Pierre Fabre and received travel grants from GME Medical for attending congresses. MH served as a consultant for Galderma and received honoraria for speaking. GF, FA, PB and UP declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Introduction & Objectives: Treatment with daylight photodynamic therapy (dPDT) of actinic keratosis (AK) is associated with local skin reactions (LSR), which may affect patients' quality of life and treatment acceptability. This study explores the potential of a prebiotic and panthenol-containing Dermocosmetic Cream (DC) to enhance tolerance and mitigate post-dPDT induced LSR in the treatment of AKs., Materials & Methods: This randomized controlled, intra-individual trial included 20 patients with ≥10 AKs in two symmetrical areas on their face or décolleté, treated with a single session of artificial dPDT. After treatment, the two areas were randomized to DC twice daily for 14 days or No-DC. Primary outcomes included clinical signs of LSR graded from 0=none to 3=severe, calculated as a composite score, and assessed on Days 2, 7, 14, and 30 post-treatment, along with AK clearance rate. Secondary outcomes encompassed objectively measured erythema, and clinical and objective skin photoaging assessment., Results: Topical application of DC following dPDT significantly improved post-treatment tolerance up to two weeks. By Day 2, DC-treated skin had milder LSR (median 3.0, IQR 2.0-4.8) compared to No-DC skin (median 4.0, IQR 3.0-5.0; p=0.011). This improvement continued on Day 7 (DC median 3.0, IQR 2.0-3.8 vs. No-DC median 4.5, IQR 3.0-5.8; p<0.001) and Day 14 (DC median 1.0, IQR 0.0-1.0 vs. No-DC median 1.0, IQR 1.0-2.0; p=0.004). Objective measurements showed milder erythema in DC-treated areas on Day 2 (p=0.045) and Day 7 (p=0.005). Crusting resolved more effectively in DC-treated areas by Day 7 (40% vs. 20%; p=0.039). No significant difference in complete lesion response rate was observed between DC and No-DC skin (p=0.850). By Day 30, clinical photoaging assessment demonstrated significant improvement in dyspigmentation (p=0.004) and skin texture (p<0.001) in both locations. Moreover, objective measurements revealed reduced dyspigmentation in both DC and No-DC treated skin (p≤0.001)., Conclusion: Application of a prebiotic and panthenol-containing multipurpose DC significantly enhanced tolerance from artificial dPDT and accelerated healing time up to 14 days after treatment. The use of DC cream did not affect the overall treatment efficacy of dPDT, indicating its potential to enhance patient comfort following dPDT., (Copyright © 2024. Published by Elsevier B.V.)

Treatment-resistant actinic keratosis (AK) is of concern in clinical practice, often requiring retreatment. Microvascular assessments might help differentiate treatment-resistant from treatment-responsive AKs, enabling targeted treatment. Using dynamic optical coherence tomography, AK vascularization was investigated following daylight photodynamic therapy, comparing treatment-resistant with cleared AKs. AKs on face/scalp were graded according to the Olsen Classification Scheme and scanned with dynamic optical coherence tomography pre-treatment, and 3- and 12-months post-treatment. Employing dynamic optical coherence tomography, total vessel length, mean vessel length, mean vessel diameter, vessel area density, and branchpoint density were quantified. Thirty-eight patients with 62 AKs were enrolled, including 37 AK I, 18 AK II, and 7 AK III. Treatment-resistant AKs displayed a trend toward intensified vascularization compared with cleared AK at baseline (AKs I, II), suggested by higher total vessel length (median 144.0, IQR 104.3-186.6) and vessel area density (median 27.7, IQR 18.4-34.2) than in cleared AK (median 120.9, IQR 86.9-143.0 and median 22.9, IQR 17.3-26.8). Additionally, vascularization in treatment-resistant AK I-II appeared disorganized, with trends toward shorter mean vessel length (median 151.0, IQR 138.5-167.5) and increased branchpoint density (median 3.2, IQR 2.3-3.8) compared with cleared AK (median 160.0, IQR 152.0-169.3 and median 2.6, IQR 2.2-3.0). These findings suggest that dynamic optical coherence tomography holds potential to identify treatment-resistant AKs.

Background: Severe keloids are difficult to treat. Corticosteroid injections with needles are painful and associated with frequent recurrences. Therefore, more effective, safe and patient-friendly alternative treatments are urgently needed., Objectives: To assess the efficacy, tolerability and patient satisfaction of intralesional bleomycin treatment using a needle-free electronic pneumatic jet injector (EPI) in severe keloids., Methods: Patients with severe keloids were included in this double-blind, randomized, placebo-controlled trial with split-lesion design. Three EPI treatments with bleomycin or saline were administered every 4 weeks in the intervention and control sides. Outcome measures were change in scar volume assessed by three-dimensional imaging, Patient and Observer Scar Assessment Scale (POSAS), skin perfusion with laser speckle contrast imaging (LSCI), spilled volume, procedure-related pain, adverse events and patient satisfaction., Results: Fourteen patients (nine female, five male) were included. The estimated mean keloid volume was significantly reduced by 20% after EPI-assisted bleomycin, compared with a slight increase of 3% in the control side (P < 0.01). The estimated mean POSAS patient and observer scores decreased by respectively 28% and 20% (P = 0.03 and P = 0.001). LSCI showed no significant change in perfusion. EPI treatment was preferred over previous needle injections in 85% of patients. The estimated mean spilled volume after EPI was around 50%, and numerical rating scale pain scores were moderate. Adverse events included bruising, hyperpigmentation and transient superficial necrosis., Conclusions: A course of three EPI-assisted bleomycin injections is efficacious and well tolerated in severe keloids. Moreover, EPI was preferred by most patients and may serve as a patient-friendly alternative treatment., Competing Interests: Conflicts of interest V.Z.B., K.M.Z., L.B., W.T.V., P.A., F.O., R.B., E.P.P., R.R. and M.B.A.vD. declare no conflicts of interest. M.H. declares no conflicts of interests related to this work and declares the following conflicts of interest outside of this work: Cherry Imaging (Equipment), Cynosure (Equipment), Galderma (lectures, teaching, research), GME Medical (equipment), LEO Pharma (research grant), L’Oréal/La Roche Posay (research grant, consulting), Lutronic (equipment), MiraDry (equipment), Procter & Gamble (consulting) and Venus Concept (research grant, equipment)., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Intralesional corticosteroid administration (ICA) is a first-line keloid treatment. However, it faces significant variability in current clinical and scientific practice, which hinders comparability of treatment results., Objectives: The aim of the study was to reach consensus on different aspects of ICA using hypodermic needles in keloids among an international group of dermatologists and plastic surgeons specialized in keloid treatment to provide consensus-based clinical treatment recommendations for all physicians treating keloids., Methods: The keloid expert panel of 12 dermatologists and 11 plastic surgeons rated 30 statements. Two online e-Delphi rounds were held, both with a response rate of 100%. Fifteen (65%) keloid experts participated in the final consensus meetings. Consensus was defined as ≥ 75% of the participants choosing agree or strongly agree on a 7-point Likert scale., Results: Consensus was reached on treatment goals, indication for ICA, triamcinolone acetonide (TAC) 40 mg/mL as the preferred corticosteroid administered at a maximum of 80 mg per month and at intervals of 4 weeks, minimizing pain during ICA, the use of 1 mL syringes and 25 or 27 Gauge needles, blanching as endpoint of successful infiltration, caution of not injecting subcutaneously, and the option of making multiple passes in very firm keloids prior to infiltration. Consensus could not be reached on TAC dosing, methods of prior local anesthesia, and location of injection., Conclusions: This e-Delphi study provides important clinical treatment recommendations on essential aspects of ICA in keloids. By implementing these recommendations, uniformity of ICA in keloid treatment will increase and better treatment results may be achieved., (© 2024. The Author(s).)

Skin barrier function (SBF) disorders are a class of pathologies that affect a significant portion of the world population. These disorders cause skin lesions with intense itch, impacting patients' physical and psychological well-being as well as their social functioning. It is in the interest of patients that their disorder be monitored closely while under treatment to evaluate the effectiveness of the ongoing therapy and any potential adverse reactions. Symptom-based assessment techniques are widely used by clinicians; however, they carry some limitations. Techniques to assess skin barrier impairment are critical for understanding the nature of the disease and for helping personalize treatment. This review recalls the anatomy of the skin barrier and describes an atomic-force microscopy approach to quantitatively monitor its disorders and their response to treatment. We review a panel of studies that show that this technique is highly relevant for SBF disorder research, and we aim to motivate its adoption into clinical settings., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The development of artificial intelligence (AI) is rapidly expanding, showing promise in the dermatological field. Skin checks are a resource-heavy challenge that could potentially benefit from AI-tool assistance, particularly if provided in widely available AI solutions. A novel smartphone application(app)-based AI system, "SCAI," was developed and trained to recognize spots in paired images of skin, pursuing identification of new skin lesions. This pilot study aimed to investigate the feasibility of the SCAI-app to identify simulated skin changes in vivo., Materials and Methods: The study was conducted in a controlled setting with healthy volunteers and standardized, simulated skin changes (test spots), consisting of customized 3-mm adhesive spots in three colors (black, brown, and red). Each volunteer had a total of eight test spots adhered to four areas on back and legs. The SCAI-app collected smartphone- and template-guided standardized images before and after test spot application, using its backend AI algorithms to identify changes between the paired images., Results: Twenty-four volunteers were included, amounting to a total of 192 test spots. Overall, the detection algorithms identified test spots with a sensitivity of 92.0% (CI: 88.1-95.9) and a specificity of 95.5% (CI: 95.0-96.0). The SCAI-app's positive predictive value was 38.0% (CI: 31.0-44.9), while the negative predictive value was 99.7% (CI: 99.0-100)., Conclusion: This pilot study showed that SCAI-app could detect simulated skin changes in a controlled in vivo setting. The app's feasibility in a clinical setting with real-life skin lesions remains to be investigated, where the challenge with false positives in particular needs to be addressed., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Recent studies have demonstrated that ablative fractional laser (AFL) can inhibit the hedgehog pathway, enhance immune infiltration and clear basal cell carcinomas (BCCs) in murine models. In this study, we applied RNA sequencing to further characterise the impact of AFL on the transcriptome of murine skin containing early-stage microscopic BCCs, contrasting it with the effects of topical application of the hedgehog inhibitor vismodegib. Our results showed that BCC induction in murine skin was primarily linked to gene upregulation (significantly upregulated genes: 277, significantly downregulated genes: 24). Characterisation of these genes with Ingenuity Pathway Analysis showed that tumour induction was associated with activation of BCC and Sonic Hedgehog signalling. Both AFL and vismodegib treatments reversed these changes, with vismodegib demonstrating superior performance by reversing most of the upregulated genes (AFL: 59/277; vismodegib: 180/277). Surprisingly, Ingenuity Pathway Analysis also revealed that both AFL and vismodegib treatments caused considerable immune cell infiltration. Based on gene set enrichment analysis and cell type deconvolution, AFL treatment resulted in the largest immune cell recruitment, which for both treatments primarily consisted of infiltrating neutrophils, macrophages and monocytes. In conclusion, the distinct effects observed in BCC skin following AFL and vismodegib treatment suggest key differences between the two interventions. Future applications of AFL or vismodegib treatments could leverage their individual effects, for example by combining the effect of AFL on the immune system with other topical treatments., (© 2024 The Author(s). Experimental Dermatology published by John Wiley & Sons Ltd.)

Line-field confocal optical coherence tomography (LC-OCT) is a new technology for skin cancer diagnostics. However, the interobserver agreement (IOA) of known image markers of keratinocyte carcinomas (KC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), as well as precursors, SCC in situ (CIS) and actinic keratosis (AK), remains unexplored. This study determined IOA on the presence or absence of 10 key LC-OCT image markers of KC and precursors, among evaluators new to LC-OCT with different levels of dermatologic imaging experience. Secondly, the frequency and association between reported image markers and lesion types, was determined. Six evaluators blinded to histopathologic diagnoses, assessed 75 LC-OCT images of KC (21 SCC; 21 BCC), CIS (12), and AK (21). For each image, evaluators independently reported the presence or absence of 10 predefined key image markers of KCs and precursors described in an LC-OCT literature review. Evaluators were stratified by experience-level as experienced (3) or novices (3) based on previous OCT and reflectance confocal microscopy usage. IOA was tested for all groups, using Conger's kappa coefficient (κ). The frequency of reported image marker and their association with lesion-types, were calculated as proportions and odds ratios (OR), respectively. Overall IOA was highest for the image markers lobules (κ = 0.68, 95% confidence interval (CI) 0.57;0.78) and clefting (κ = 0.63, CI 0.52;0.74), typically seen in BCC (94%;OR 143.2 and 158.7, respectively, p < 0.001), followed by severe dysplasia (κ = 0.42, CI 0.31;0.53), observed primarily in CIS (79%;OR 7.1, p < 0.001). The remaining seven image-markers had lower IOA (κ = 0.06-0.32) and were more evenly observed across lesion types. The lowest IOA was noted for a well-defined (κ = 0.07, CI 0;0.15) and interrupted dermal-epidermal junction (DEJ) (κ = 0.06, CI -0.002;0.13). IOA was higher for all image markers among experienced evaluators versus novices. This study shows varying IOA for 10 key image markers of KC and precursors in LC-OCT images among evaluators new to the technology. IOA was highest for the assessments of lobules, clefting, and severe dysplasia while lowest for the assessment of the DEJ integrity., (© 2024. The Author(s).)

Keratinocyte-derived skin cancers comprise basal cell carcinoma, squamous cell carcinoma, its precursor actinic keratosis, and Bowen's disease. Historically, this group of neoplasms has been subsumed under the term non-melanoma skin cancer. However, the term non-melanoma skin cancer can be misleading and lacks precision. Therefore, more precise and reasonable terminology, valuing the relevance of keratinocyte-derived cancer, appears pertinent to meet its clinical and scientific significance. A group of experienced dermato-oncologists initiated a consensus approach to promote the use of the term "keratinocyte cancer" instead of "non-melanoma skin cancer" when referring to carcinomas and their precursors that are derived from keratinocytes. The vote among members of the consensus group indicated unanimous agreement on the consistent use of the term "keratinocyte cancer" instead of "non-melanoma skin cancer". International delegates also voted in favour of the revised terminology. The more precise and, by means of etiopathogenesis, correct term "keratinocyte cancer" should be consistently used for malignancies originated from keratinocytes. This is expected to have a positive impact on patient-physician communication and gives better justice to this important group of keratinocyte-derived cancers.

Actinic keratosis (AK) classification relies on clinical characteristics limited to the skin's surface. Incorporating sub-surface evaluation may improve the link between clinical classification and the underlying pathology. We aimed to apply dynamic optical coherence tomography (D-OCT) to characterize microvessels in AK I-III and photodamaged (PD) skin, thereby exploring its utility in enhancing clinical and dermatoscopic AK evaluation. This explorative study assessed AK I-III and PD on face or scalp. AK were graded according to the Olsen scheme before assessment with dermatoscopy and D-OCT. On D-OCT, vessel shapes, -pattern and -direction were qualitatively evaluated at predefined depths, while density and diameter were quantified. D-OCT's ability to differentiate between AK grades was compared with dermatoscopy. Forty-seven patients with AK I-III (n = 207) and PD (n = 87) were included. Qualitative D-OCT evaluation revealed vascular differences between AK grades and PD, particularly at a depth of 300 μm. The arrangement of vessel shapes around follicles differentiated AK II from PD (OR = 4.75, p < 0.001). Vessel patterns varied among AK grades and PD, showing structured patterns in AK I and PD, non-specific in AK II (OR = 2.16,p = 0.03) and mottled in AK III (OR = 29.94, p < 0.001). Vessel direction changed in AK II-III, with central vessel accentuation and radiating vessels appearing most frequently in AK III. Quantified vessel density was higher in AK I-II than PD (p ≤ 0.025), whereas diameter remained constant. D-OCT combined with dermatoscopy enabled precise differentiation of AK III versus AK I (AUC = 0.908) and II (AUC = 0.833). The qualitative and quantitative evaluation of vessels on D-OCT consistently showed increased vascularization and vessel disorganization in AK lesions of higher grades., (© 2024 The Author(s). Experimental Dermatology published by John Wiley & Sons Ltd.)

Background: Photodynamic therapy (PDT) with topical δ-Aminolevulinic acid (ALA) has efficacy in treating basal cell carcinoma (BCC) but is limited by incomplete penetration of ALA into the deeper dermis. This prospective open-label pilot trial investigated the safety and efficacy of photosensitizer jet injection for PDT (JI-PDT) for BCC treatment. It was performed with 15 patients (n = 15) with histologically confirmed, untreated, low-risk nodular BCCs at a single institution., Methods: For the intervention, JI-PDT patients (n = 11) received two sessions of jet-injected ALA with PDT separated by four to 6 weeks. To further understand treatment technique, another group of patients (n = 4) received jet-injected ALA followed by tumor excision and fluorescence microscopy (JI-E). Treatment tolerability was assessed by local skin responses (LSR) score at five distinct time intervals. Fluorescence microscopy assessed protoporphyrin IX penetration depth and biodistribution within the tumor. At the primary endpoint, tumor clearance was evaluated via visual inspection, dermoscopy and reflectance confocal microscopy. Postinjection and postillumination pain levels, and patient satisfaction, were scored on a 0-10 scale., Results: Fifteen participants with mean age of 58.3, who were 15/15 White, non-Hispanic enrolled. The median composite LSR score immediately after JI-PDT was 5 (interquartile range [IQR] = 3) which decreased to 0.5 (IQR = 1) at primary endpoint (p < 0.01). Immunofluorescence of excised BCC tumors with jet-injected ALA showed photosensitizer penetration into papillary and reticular dermis. Of the 13 JI-PDT tumors, 11 had tumor clearance confirmed, 1 recurred, and 1 was lost to follow-up. 1/11 patients experienced a serious adverse event of cellulitis. 70% of patients had local scarring at 3 months. Patients reported an average pain level of 5.6 (standard deviation [SD] = 2.3) during jet injection and 3.7 (SD = 1.8) during light illumination., Conclusions: Jet injection of ALA for PDT treatment of nodular low-risk BCC is tolerable and feasible and may represent a novel modality to improve PDT., (© 2024 Wiley Periodicals LLC.)

This study investigates the incidence and clearance of cervical and anal high-risk human papillomavirus (hrHPV) infection in kidney transplant recipients (KTRs) compared to immunocompetent controls. During 2016-2017, we enrolled 125 female KTRs and 125 female controls. Liquid-based cervical and anal cytology samples collected at enrollment and follow-up were tested for human papillomavirus (HPV) DNA using the CLART HPV2 test. All participants answered a questionnaire on lifestyle and sexual behavior at both examinations. KTRs had an increased age-adjusted risk of incident cervical hrHPV infection compared to controls (hazard ratio [HR] = 3.6, 95% CI = 1.2-11.2). Probability of cervical hrHPV clearance at 18 months was lower among KTRs (8.3%) than controls (66.7%). There was no statistically significant difference in anal hrHPV incidence between KTRs and controls (HR = 0.9, 95% CI = 0.4-2.0). Clearance of anal hrHPV was similar between KTRs and controls at 18 months. During the total follow-up, a lower anal hrHPV clearance, although not statistically significant, was observed among KTRs (HR = 0.3, 95% CI = 0.06-1.2). KTRs had higher incidence of cervical hrHPV and lower probability of clearance, especially of cervical hrHPV infections, than controls. Our findings support that KTRs are at increased risk of HPV infection and point to the need for targeted HPV prevention strategies, such as cervical cancer screening., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Susanne K. Kjær has received a research grant outside this study through her affiliating institution from Merck. Jesper H. Bonde’s institution has received research funding or consumables at reduced prices or for free to support research from BD Diagnostics, GeneFirst, SelfScreen, Qiagen, Seegene, and Roche Diagnostics. Jesper H. Bonde has received honoraria for lectures from BD Diagnostics, MSD, and Hologic Ltd. Jesper H. Bonde is an appointed member of the National Danish Cervical Screening Committee by the Danish Health Authority. Linea Landgrebe Ring, Helle Kiellberg Larsen, Merete Hædersdal, Søren Schwartz Sørensen, Kirsten Frederiksen, and Louise Thirstrup Thomsen have no conflicts of interest to disclose., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Basal cell carcinoma (BCC), the most common keratinocyte cancer, presents a substantial public health challenge due to its high prevalence. Traditional diagnostic methods, which rely on visual examination and histopathological analysis, do not include metabolomic data. This exploratory study aims to molecularly characterize BCC and diagnose tumour tissue by applying matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and machine learning (ML). BCC tumour development was induced in a mouse model and tissue sections containing BCC (n = 12) were analysed. The study design involved three phases: (i) Model training, (ii) Model validation and (iii) Metabolomic analysis. The ML algorithm was trained on MS data extracted and labelled in accordance with histopathology. An overall classification accuracy of 99.0% was reached for the labelled data. Classification of unlabelled tissue areas aligned with the evaluation of a certified Mohs surgeon for 99.9% of the total tissue area, underscoring the model's high sensitivity and specificity in identifying BCC. Tentative metabolite identifications were assigned to 189 signals of importance for the recognition of BCC, each indicating a potential tumour marker of diagnostic value. These findings demonstrate the potential for MALDI-MSI coupled with ML to characterize the metabolomic profile of BCC and to diagnose tumour tissue with high sensitivity and specificity. Further studies are needed to explore the potential of implementing integrated MS and automated analyses in the clinical setting., (© 2024 The Author(s). Experimental Dermatology published by John Wiley & Sons Ltd.)

Actinic keratosis (AK) is an intraepithelial condition characterized by the development of scaly, erythematous lesions after repeated exposure to ultraviolet radiation. Significant immunosuppression is a risk factor for the development of AK and subsequent lesion progression to squamous cell carcinoma. Immunocompromised patients (ICPs), particularly organ transplant recipients, often have more advanced or complex AK presentations and an increased risk of skin carcinomas versus non-ICPs with AK, making lesions more difficult to treat and resulting in worse treatment outcomes. The recent "Personalising Actinic Keratosis Treatment" (PAKT) consensus reported that delivering patient-centric care may play a role in supporting better clinical outcomes and patient satisfaction with treatments for chronic dermatologic conditions such as AK, which require repeated cycles of treatment. Additionally, currently published guidance and recommendations were considered by the PAKT panel to be overly broad for managing ICPs with their unique and complex needs. Therefore, the "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) panel was established to build upon general recommendations from the PAKT consensus. The panel identified current gaps in guidance for AK care in ICPs, offered practical care approaches based on typical ICP scenarios, and highlighted the need to adapt AK management to optimize care and improve treatment outcomes in ICPs. In particular, dermatologists should establish collaborative and transparent relationships with patients' multidisciplinary teams to enhance overall care for patients' comorbidities: given their increased risk of progression to malignancy, earlier assessments/interventions and frequent follow-ups are vital.The panel also developed a novel "triage" tool outlining effective treatment follow-up and disease surveillance plans tailored to patients' risk profiles, guided by current clinical presentation and relevant medical history. Additionally, we present the panel's expert opinion on three fictional ICP scenarios to explain their decision-making process for assessing and managing typical ICPs that they may encounter in clinical practice., (© 2024. The Author(s).)

Clinical grading of actinic keratosis (AK) is based on skin surface features, while subclinical alterations are not taken into consideration. Dynamic optical coherence tomography (D-OCT) enables quantification of the skin´s vasculature, potentially helpful to improve the link between clinical and subclinical features. We aimed to compare microvascular characteristics across AK grades using D-OCT with automated vascular analysis. This explorative study examined AK and photodamaged skin (PD) on the face or scalp. AKs were clinically graded according to the Olsen Classification scheme before D-OCT assessment. Using an open-source software tool, the OCT angiographic analyzer (OCTAVA), we quantified vascular network features, including total and mean vessel length, mean vessel diameter, vessel area density (VAD), branchpoint density (BD), and mean tortuosity from enface maximum intensity projection images. Additionally, we performed subregional analyses on selected scans to overcome challenges associated with imaging through hyperkeratosis (each lesion group; n = 18). Our study included 45 patients with a total of 205 AKs; 93 grade I lesions, 65 grade II, 47 grade III and 89 areas with PD skin. We found that all AK grades were more extensively vascularized relative to PD, as shown by greater total vessel length and VAD (p ≤ 0.009). Moreover, AKs displayed a disorganized vascular network, with higher BD in AK I-II (p < 0.001), and mean tortuosity in AK II-III (p ≤ 0.001) than in PD. Vascularization also increased with AK grade, showing significantly greater total vessel length in AK III than AK I (p = 0.029). Microvascular quantification of AK unveiled subclinical, quantitative differences among AK grades I-III and PD skin. D-OCT-based microvascular assessment may serve as a supplement to clinical AK grading, potentially raising perspectives to improve management strategies., (© 2024. The Author(s).)

Botulinum toxin A (BTX) and microwave thermolysis (MWT) are standard axillary hyperhidrosis treatments, but comparison of their subclinical effects is lacking. Line-field confocal optical coherence tomography (LC-OCT) is a promising non-invasive imaging tool for visualizing tissue-interactions. This study aimed to describe subclinical effects of BTX and MWT for axillary hyperhidrosis with LC-OCT-imaging compared to histology. This study derived from an intra-individual, randomized, controlled trial, treating axillary hyperhidrosis with BTX versus MWT. Subclinical effects based on LC-OCT images from baseline and 6-month follow-up (n = 8 patients) were evaluated and compared to corresponding histological samples. At baseline, LC-OCT visualized eccrine pores at the skin surface and ducts in the upper dermis (500 μm), but not deeper-lying sweat glands. Histology identified entire sweat glands. Six months post-treatment, LC-OCT revealed no detectable morphology changes in any BTX-treated axillae (100%), while recognizing obstructed eccrine pores and atrophy of eccrine ducts in most MWT-treated axillae (75%). Histology corroborated LC-OCT findings, while also showing substantial changes to entire sweat glands. LC-OCT enabled visualization of subclinical alterations of superficial eccrine ducts after MWT and unchanged morphology after BTX. LC-OCT is a promising tool for non-invasive assessment of treatment-specific tissue-interactions that can be complementary to histology., (© 2024 The Author(s). Experimental Dermatology published by John Wiley & Sons Ltd.)

Cutaneous squamous cell carcinoma (SCC) is an increasingly prevalent global health concern. Current diagnostic and surgical methods are reliable, but they require considerable resources and do not provide metabolomic insight. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) enables detailed, spatially resolved metabolomic analysis of tissue samples. Integrated with machine learning, MALDI-MSI could yield detailed information pertaining to the metabolic alterations characteristic for SCC. These insights have the potential to enhance SCC diagnosis and therapy, improving patient outcomes while tackling the growing disease burden. This study employs MALDI-MSI data, labelled according to histology, to train a supervised machine learning model (logistic regression) for the recognition and delineation of SCC. The model, based on data acquired from discrete tumor sections (n = 25) from a mouse model of SCC, achieved a predictive accuracy of 92.3% during cross-validation on the labelled data. A pathologist unacquainted with the dataset and tasked with evaluating the predictive power of the model in the unlabelled regions, agreed with the model prediction for over 99% of the tissue areas. These findings highlight the potential value of integrating MALDI-MSI with machine learning to characterize and delineate SCC, suggesting a promising direction for the advancement of mass spectrometry techniques in the clinical diagnosis of SCC and related keratinocyte carcinomas., (© 2024. The Author(s).)

In electrochemotherapy, permeabilization of the cell membrane by electric pulses increases the anti-tumour effect of chemotherapeutics. In calcium electroporation, chemotherapy is replaced by calcium chloride with obvious benefits. This study explores the effect and underlying mechanisms of calcium electroporation on basal cell carcinomas using either high- or low-frequency electroporation. Low-risk primary basal cell carcinomas were treated in local anaesthesia with intratumoral calcium chloride followed by electroporation with high (167 kHz) or low (5 kHz) frequencies. Non-complete responders were retreated after 3 months. The primary endpoint was tumour response 3 months after last calcium electroporation. Plasma membrane calcium ATPase was examined in various cell lines as plasma membrane calcium ATPase levels have been associated with calcium electroporation efficacy. Twenty-two out of 25 included patients complete the study and 7 of these (32%) achieved complete response at 3 months with no difference in efficacy between high- and low-frequency pulses. High-frequency calcium electroporation was significantly less painful (p=0.03). Plasma membrane calcium ATPase was increased 16-32-fold in basal cell carcinoma cell lines compared with 4 other cancer cell lines. Calcium electroporation for low-risk basal cell carcinomas does not fulfil the requirements of a new dermatological basal cell carcinoma treatment but may be useful as adjuvant treatment to surgery in more advanced basal cell carcinomas. The elevated PMCA levels in basal cell carcinomas may contribute to low efficacy.

Objective: This systematic review and meta-analysis aims to investigate the prevalence of cervical high-risk human papillomavirus (hrHPV) among kidney transplant recipients (KTRs) and, furthermore to compare it to that in immunocompetent controls., Methods: A systematic literature search was conducted in PubMed, EMBASE, and Cochrane Library databases from January 2000 to February 2023, to identify studies investigating the prevalence of cervical hrHPV in KTRs. Pooled cervical hrHPV prevalences, odds ratios (ORs) comparing KTRs to controls and corresponding confidence intervals (CIs) were estimated using random effects logistic regression models. Heterogeneity between studies was assessed through the I 2 statistic, and the significance was evaluated by the Cochrane's Q test., Results: Altogether, 16 studies covering >1200 KTRs were included. The prevalence of cervical hrHPV in KTRs was 27.7% (95% CI 21.3-35.1) with substantial interstudy heterogeneity. Stratification indicated a higher prevalence in recent years (2019-2023) and in Asia (39% (95% CI 11.2-61.4)). The prevalence of HPV16 and HPV18 in KTRs was 8.0% (95% CI 3.9-15.9) and 1.7% (95% CI 0.8-3.7), respectively. Comparing hrHPV prevalence in KTRs and controls based on six studies including >500 KTRs and 1000 controls, the OR for hrHPV was 2.0 (95% CI 1.1-3.6)., Conclusions: This meta-analysis establishes an increased cervical hrHPV prevalence in KTRs compared to controls. The increased risk may be associated with immunosuppressive therapy post-transplantation. Further research is needed to explore the potential benefits of HPV vaccination, including potential revaccination strategies in KTRs., Competing Interests: Declaration of competing interest No conflict of interest was reported by the other authors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Exposure to ultraviolet radiation (UVR) leads to skin DNA damage, specifically in the form of cyclobutane pyrimidine dimers, with thymidine dimers being the most common. Quantifying these dimers can indicate the extent of DNA damage resulting from UVR exposure. Here, a new liquid chromatography-mass spectrometry (LC-MS) method was used to quantify thymidine dimers in the urine after a temporary increase in real-life UVR exposure. Healthy Danish volunteers (n = 27) experienced increased UVR exposure during a winter vacation. Individual exposure, assessed via personally worn electronic UVR dosimeters, revealed a mean exposure level of 32.9 standard erythema doses (SEDs) during the last week of vacation. Morning urine thymidine dimer concentrations were markedly elevated both 1 and 2 days post-vacation, and individual thymidine dimer levels correlated with UVR exposure during the last week of the vacation. The strongest correlation with erythema-weighted personal UVR exposure (Power model, r 2  = 0.64, p < 0.001) was observed when both morning urine samples were combined to measure 48-h thymidine dimer excretion, whereas 24-h excretion based on a single sample provided a weaker correlation (Power model, r 2  = 0.55, p < 0.001). Sex, age, and skin phototype had no significant effect on these correlations. For the first time, urinary thymidine dimer excretion was quantified by LC-MS to evaluate the effect of a temporary increase in personal UVR exposure in a real-life setting. The high sensitivity to elevated UVR exposure and correlation between urinary excretion and measured SED suggest that this approach may be used to quantify DNA damage and repair and to evaluate photoprevention strategies., (© 2024. The Author(s).)

Raman spectroscopy provides non-destructive, label-free quantitative studies of chemical compositions at the microscale as used on NASA's Perseverance rover on Mars. Such capabilities come at the cost of high requirements for instrumentation. Here we present a centimeter-scale miniaturization of a Raman spectrometer using cheap non-stabilized laser diodes, densely packed optics, and non-cooled small sensors. The performance is comparable with expensive bulky research-grade Raman systems. It has excellent sensitivity, low power consumption, perfect wavenumber, intensity calibration, and 7 cm -1 resolution within the 400-4000 cm -1 range using a built-in reference. High performance and versatility are demonstrated in use cases including quantification of methanol in beverages, in-vivo Raman measurements of human skin, fermentation monitoring, chemical Raman mapping at sub-micrometer resolution, quantitative SERS mapping of the anti-cancer drug methotrexate and in-vitro bacteria identification. We foresee that the miniaturization will allow realization of super-compact Raman spectrometers for integration in smartphones and medical devices, democratizing Raman technology., (© 2024. The Author(s).)

Non-invasive diagnostics like line-field confocal optical coherence tomography (LC-OCT) are being implemented in dermato-oncology. However, unification of terminology in LC-OCT is lacking. By reviewing the LC-OCT literature in the field of dermato-oncology, this study aimed to develop a unified terminological glossary integrated with traditional histopathology. A PRISMA-guided literature-search was conducted for English-language publications on LC-OCT of actinic keratosis (AK), keratinocyte carcinoma (KC), and malignant melanoma (MM). Study characteristics and terminology were compiled. To harmonize LC-OCT terminology and integrate with histopathology, synonymous terms for image features of AK, KC, and MM were merged by two authors, organized by skin layer and lesion-type. A subset of key LC-OCT image-markers with histopathological correlates that in combination were typical of AK, squamous cell carcinoma in situ (SCCis), invasive squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and MM in traditional histopathology, were selected from the glossary by an experienced dermatopathologist. Seventeen observational studies of AK (7 studies), KC (13 studies), MM (7 studies) utilizing LC-OCT were included, with 117 terms describing either AK, KC, or MM. These were merged to produce 45 merged-terms (61.5% reduction); 5 assigned to the stratum corneum (SC), 23 to the viable epidermis, 2 to dermo-epidermal junction (DEJ) and 15 to the dermis. For each lesion, mandatory key image-markers were a well-defined DEJ and presence of mild/moderate but not severe epidermal dysplasia for AK, severe epidermal dysplasia and well-defined DEJ for SCCis, interrupted DEJ and/or dermal broad infiltrative strands for invasive SCC, dermal lobules connected and/or unconnected to the epidermis for BCC, as well as single atypical melanocytes and/or nest of atypical melanocytes in the epidermis or dermis for MM. This review compiles evidence on LC-OCT in dermato-oncology, providing a harmonized histopathology-integrated terminology and key image-markers for each lesion. Further evaluation is required to determine the clinical value of these findings., (© 2024 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Background: Daylight photodynamic therapy (dPDT) and topical 5-fluorouracil (5-FU) are each effective treatments for thin grade I actinic keratosis (AKs), but less so for thicker grade II-III AKs. Prolonged topical treatment regimens can be associated with severe skin reactions and low compliance. This study compares the efficacy of sequential 4 % 5-FU and dPDT with dPDT monotherapy for multiple actinic keratoses., Methods: Sixty patients with a total of 1547 AKs (grade I: 1278; grade II: 246; grade III: 23) were treated in two symmetrical areas (mean size 75 cm 2 ) of the face or scalp, which were randomized to (i) 4% 5-FU creme twice daily for 7 days before a single dPDT procedure and (ii) dPDT monotherapy. Daylight exposure was either outdoor or indoor daylight., Results: Twelve weeks after treatment 87 % of all AKs cleared after 5-FU+dPDT compared to 74 % after dPDT alone (p<0.0001). For grade II AKs, the lesion response rate increased from 55 % with dPDT monotherapy to 79 % after 5-FU+dPDT (p<0.0056). Moderate/severe erythema was seen in 88 % 5-FU+dPDT areas compared to 41 % of dPDT areas two days after dPDT. Twelve weeks after treatment 75 % of the patients were very satisfied with both treatments., Conclusions: Sequential 5-FU and dPDT was more effective than dPDT monotherapy in the treatment of AKs, especially for grade II AKs. Local skin reactions were more pronounced after combination treatment, but no patients discontinued the treatment. The combination of 5-FU and dPDT is an effective treatment of large treatment areas with high compliance and satisfaction., Competing Interests: Declaration of competing interest SRW has been a member of advisory board for Pierre Fabre and received travel grants from GME Medical for attending congresses. MH served as a consultant for Galderma and received honoraria for speaking. GF, FA, PB and UP declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Hybrid trials are a new trend in dermatological research that leverage mobile health technologies to decentralize a subset of clinical trial elements and thereby reduce the number of in-clinic visits. In a Phase I/IIa randomized controlled hybrid trial, the safety and efficacy of an anti-proliferative and anti-inflammatory drug inhibiting cytosolic phospholipase A2 (AVX001) was tested using 1%, 3% or vehicle gel in 60 patients with actinic keratosis (AK) and assessed in-clinic as well as remotely. Over the course of 12 weeks, patients were assessed in-clinic at baseline, end of treatment (EOT) and end of study (EOS), as well as 9 times remotely on a weekly to biweekly basis. Safety outcomes comprising local skin reactions (LSR; 0-5), adverse events (AE) and cosmesis, were graded in-clinic and remotely using patient-obtained smartphone photographs (PSPs) and questionnaires; efficacy was assessed in-clinic based on clinically visible clearance of AK target area of >50%. A total of 55 participants (91.7%) completed the treatment course. The average submission rate of PSPs was high (≥85%), of which 93% were of sufficient quality. No serious AE were reported and only two experienced temporary LSR >2 (scale 0-4) and cosmesis remained stable throughout the study. Based on the mild AE and LSR profile, daily application of AVX001 gel for 1 month appears safe, tolerable, and cosmetically acceptable for use in patients with AK. At EOT, AVX001 achieved a subtle treatment response with clearance of AK target area of >50% in 18% of patients. Remote and in-clinic assessments of LSRs were in high agreement, suggesting that the use of mobile health technologies in early-phase hybrid studies of AK does not compromise patient safety., (© 2024 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

(1) Background: Skin cancer is the most common cancer in transplant recipients. Timely and regular screening may reduce advanced disease. The study aimed to determine referral rates to screening, the incidence, and risk factors of skin cancer in a Danish liver transplant recipient cohort. (2) Methods: All first-time liver transplant recipients, >18 years old, attending outpatient care between January 2018 and December 2021 were included. The referral rates and incidence of skin cancer/preneoplastic lesions were calculated. Risk factors were assessed using Cox regression analyses. (3) Results: Of the 246 included recipients, 219 (89.0%) were referred to screening, and 102 skin cancer/preneoplastic lesions were diagnosed in 32 (15.6%) recipients. The IR of any skin cancer/preneoplastic lesion was 103.2 per 1000 person-years. BCC was the most frequent skin cancer followed by SCC, IR: 51.3 vs. 27.1 per 1000 person-years, respectively. No cases of MM were observed. The IR of actinic keratosis and Bowen's Disease were 48.1 vs. 13.2 per 1000 person-years, respectively. Time since transplantation was independently associated with skin cancer/preneoplastic lesions, HR (95%CI) 2.81 (1.64-4.80). (4) Conclusions: The study determined the incidence and risk factors of skin cancer/preneoplastic lesions in liver transplant recipients enrolled in a screening program, while demonstrating a high screening referral rate.

Objectives: Ablative fractional laser (AFL) treatment is a well-established method for reducing signs of skin photoaging. However, the biological mechanisms underlying AFL-induced healing responses and skin rejuvenation remain largely unknown. It is known that macrophages play an important role in orchestrating healing, normalization, and remodeling processes in skin. Macrophage phenotypes are characterized by inflammatory markers, including arginase-1 (Arg1), major histocompatibility class II molecules (MHC II), and CD206. This study aims to explore AFL's effect on macrophage phenotype by evaluating changes in inflammatory markers and the potential concurrent accumulation of Arg1 in the skin., Methods: Mice (n = 9) received a single AFL treatment on the left side of the back skin (100 mJ/microbeam, 5% density) while the right side of the back remained untreated as control. Treated and untreated skin from each mouse were collected Day 5 posttreatment for flow cytometry and histology analysis. Flow cytometry evaluated the immune infiltration of macrophages and the expression of macrophage inflammatory markers (Arg1, MHC II, and CD206). In addition, Arg1 presence in the skin was evaluated through antibody staining of histology samples and quantification was performed using QuPath image analysis software., Results: Following AFL, the number of macrophages increased 11-fold (p = 0.0053). Phenotype analysis of AFL-treated skin revealed an increase in the percentage of macrophages positive for Arg1 (p < 0.0001) and a decrease in the percentage of macrophages positive for MHC II (p < 0.0001) compared to untreated skin. No significant differences were observed in percentage of CD206-positive macrophages (p = 0.8952). Visualization of AFL-treated skin demonstrated a distinct pattern of Arg1 accumulation that correlated with the microscopic treatment zones (MTZ). Quantification of the percentage of Arg1-positive area in epidermis and dermis showed a significant increase from 3.5% ± 1.2% to 5.2% ± 1.7 (p = 0.0232) and an increase from 2.2% ± 1.2% to 9.6% ± 3.3 (p < 0.0001) in whole skin samples., Conclusion: AFL treatment polarizes macrophages toward a wound healing phenotype and induces Arg1 accumulation in the MTZ. We propose that the polarized wound healing macrophages are a major source for the increased Arg1 levels observed in the skin following treatment., (© 2024 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.)

Background: Systemically delivered hedgehog inhibitors including vismodegib and sonidegib are widely used to treat basal cell carcinomas (BCCs). Ablative fractional laser (AFL)-assisted topical delivery of vismodegib has been demonstrated in preclinical studies. The aim of this explorative clinical study was to evaluate intratumoral vismodegib concentrations and effect on hedgehog pathway gene expression following AFL-assisted topical vismodegib delivery to BCCs., Methods: In an open-label clinical trial, 16 nodular BCCs (in n = 9 patients) received one application of CO 2 -AFL (40 mJ/microbeam, 10% density) followed by topical vismodegib emulsion. After 3-4 days, vismodegib concentrations in tumor biopsies (n = 15) and plasma were analyzed and compared with samples from patients receiving oral treatment (n = 3). GLI1, GLI2, PTCH1, and PTCH2 expression was determined by quantitative polymerase chain reaction (n = 7) and GLI1 additionally by in situ hybridization (n = 3)., Results: Following AFL-assisted topical administration, vismodegib was detected in 14/15 BCCs and reached a median concentration of 6.2 µmol/L, which compared to concentrations in BCC tissue from patients receiving oral vismodegib (9.5 µmol/L, n = 3, p = 0.8588). Topical vismodegib reduced intratumoral GLI1 expression by 51%, GLI2 by 55%, PTCH1 and PTCH2 each by 73% (p ≤ 0.0304) regardless of vismodegib concentrations (p ≥ 0.3164). In situ hybridization demonstrated that GLI1 expression was restricted to tumor tissue and downregulated in response to vismodegib exposure., Conclusion: A single AFL-assisted topical application of vismodegib resulted in clinically relevant intratumoral drug concentrations and significant reductions in hedgehog pathway gene expressions., (© 2024 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.)

Squamous cell carcinoma represents the second most common type of keratinocyte carcinoma with ultraviolet radiation (UVR) making up the primary risk factor. Oral photoprotection aims to reduce incidence rates through oral intake of photoprotective compounds. Recently, drug repurposing has gained traction as an interesting source of chemoprevention. Because of their reported photoprotective properties, we investigated the potential of bucillamine, carvedilol, metformin, and phenformin as photoprotective compounds following oral intake in UVR-exposed hairless mice. Tumour development was observed in all groups in response to UVR, with only the positive control (Nicotinamide) demonstrating a reduction in tumour incidence (23.8%). No change in tumour development was observed in the four repurposed drug groups compared to the UV control group, whereas nicotinamide significantly reduced carcinogenesis (P = 0.00012). Metformin treatment significantly reduced UVR-induced erythema (P = 0.012), bucillamine and phenformin increased dorsal pigmentation (P = 0.0013, and P = 0.0005), but no other photoprotective effect was observed across the repurposed groups. This study demonstrates that oral supplementation with bucillamine, carvedilol, metformin, or phenformin does not affect UVR-induced carcinogenesis in hairless mice., (© 2024. The Author(s).)

This study aimed to investigate the impact of ablative fractional laser (AFL) on hedgehog pathway gene expression in murine microscopic basal cell carcinomas (BCCs) and compare these results to the effect of topical treatment with vismodegib, an FDA-approved hedgehog inhibitor. In 25 mice, 1 cm 2 skin test sites (n = 44) containing microscopic BCCs were exposed to one of three interventions: a single CO 2 AFL treatment (1 pulse, 40 mJ/microbeam, wavelength 10.6 μm, 5% density, pulse rate 250 Hz, n = 12), eight topical vismodegib treatments (3.8 mg/mL, n = 8), or combination of AFL and vismodegib treatments (n = 9). Untreated controls were included for comparison (n = 15). After 4 days, skin samples were analyzed for hedgehog gene expression (Gli1, Gli2, and Ptch1) by qPCR and vismodegib concentrations by liquid chromatography mass spectrometry (data analyzed with two-tailed t-tests and linear regression). A single treatment with AFL monotherapy significantly reduced hedgehog gene expression compared to untreated controls (Gli1 72.4% reduction, p = 0.003; Gli2 55.2%, p = 0.010; Ptch1 70.9%, p < 0.001). Vismodegib treatment also reduced hedgehog gene expression (Gli1 91.6%; Gli2 83.3%; Ptch1 83.0%), significantly surpassing AFL monotherapy for two out of three genes (Gli1, p = 0.017; Gli2, p = 0.007; Ptch1, p = 0.15). AFL and vismodegib combination mirrored the effects of vismodegib monotherapy (Gli1, p = 0.424; Gli2, p = 0.289; Ptch1, p = 0.593), possibly due to comparable cutaneous vismodegib concentrations (mean ± SD, vismodegib monotherapy 850 ± 475 µmol/L; combination 1036 ± 824 µmol/L; p = 0.573). In conclusion, a single AFL treatment significantly reduced hedgehog gene expression in murine BCCs mimicking the effects of eight topical applications of vismodegib. Further studies are needed to assess whether AFL can be utilized for BCC treatment, either as monotherapy or in combination with other drugs., (© 2024. The Author(s).)

PD-1 checkpoint inhibitors are used as systemic immunotherapy for locally advanced and metastatic cutaneous squamous cell carcinoma (SCC); however, improved treatment efficacy is urgently needed. In this study, we aimed to investigate the effect of combining systemic anti-PD-1 treatment with adjuvant ablative fractional laser (AFL) in a spontaneous SCC mouse model. Tumours induced by ultraviolet radiation in the strain C3.Cg-Hr hr /TifBomTac were divided into four groups: anti-PD-1-antibody+AFL (n = 33), AFL alone (n = 22) anti-PD-1-antibody alone (n = 31) and untreated controls (n = 46). AFL was given at Day 0 (100 mJ/mb, 5% density), while anti-PD-1-antibody (ip, 200 μg) at Days 0, 2, 4, 6 and 8. Response to treatment was evaluated by tumour growth, survival time and by dividing response to treatment into complete responders (clinically cleared tumours), partial responders (reduced tumour growth rate compared to untreated controls) and non-responders (no decrease in tumour growth rate compared to untreated controls). The strongest tumour response was observed following the combination of systemic anti-PD-1 treatment combined with laser exposure, resulting in the highest percentage of complete responders (24%) compared with untreated controls (0%, p < 0.01), AFL monotherapy (13%, p > 0.05) and anti-PD-1-antibody monotherapy (3%, p > 0.05). Moreover, all three treatment interventions demonstrated significantly reduced tumour growth rates compared with untreated controls (p < 0.01), and the mice had significantly longer survival times (p < 0.01). In conclusion, the combination treatment revealed an improved treatment effect that significantly enhanced the complete tumour clearance not observed with the monotherapies, indicating a possible additive effect of anti-PD-1 with adjuvant AFL in treatment of SCC., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Botulinum toxin A (BTX) and microwave thermolysis (MWT) represent 2 treatment modalities for axillary hyperhidrosis with different procedural and efficacy profiles., Objective: To compare long-term outcomes following BTX vs MWT treatment of axillary hyperhidrosis., Methods: A prospective, randomized, within-patient, controlled trial, treating axillary hyperhidrosis with contralateral BTX and MWT. Objective sweat measurement and patient-reported outcome measures for sweat and odor were collected at baseline, 6-month and 1-year follow-up (6M/1YFU). Hair reduction and patient treatment preference was also assessed., Results: Sweat reduction was significant (all P <.01) for both interventions throughout the study. Objectively, sweat reduction was equal at 1-year FU (Δ P =.4282), but greater for BTX than MWT at 6-month FU (Δ P =.0053). Subjective sweat assessment presented comparable efficacy (6MFU: Δ P =.4142, 1YFU: Δ P =.1025). Odor reduction was significant (all P <.01) following both interventions, whereas only sustaining for MWT (6MFU: Δ P =.6826, 1YFU: Δ P =.0098). Long-term, hair reduction was visible after MWT, but not BTX (Δ P ≤.0001), and MWT was preferred by the majority of patients (76%)., Limitations: The intrinsic challenges in efficacy assessment., Conclusion: This study exhibited BTX and MWT with similar sweat reduction, but distinguishable odor and hair reduction at 1-year FU. These findings support individualized treatment approaches for axillary hyperhidrosis based on patient-specific symptoms and preferences., Competing Interests: Dr Haedersdal has received speaker honorarium for microwave thermolysis symposium. Drs Grove, Togsverd-Bo, and Zachariae have no conflicts of interest to declare., (© 2024 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

Introduction: Ultraviolet radiation (UVR) is the primary risk factor for keratinocyte carcinomas. Oral supplementation with nicotinamide (NAM) is reported to reduce the formation of new keratinocyte carcinomas. NAM's photoprotection is mediated by enhanced DNA repair. We wanted to explore whether NAM in combination with antiproliferative (metformin [Met]) or antioxidant (phloroglucinol [PG]) compounds could potentially enhance its photoprotective effects., Methods: Hairless mice (C3.Cg-Hrhr/TifBomTac) were treated orally with either a standard dose of NAM monotherapy (NAM-mono; 600 mg/kg) or NAM (400 mg/kg) combined with Met (200 mg/kg) (NAM-Met) or PG (75 mg/kg) (NAM-PG). Mice were irradiated with 3.5 standard erythema doses of UVR three times per week to induce tumour development. Photoprotective effects were based on (i) tumour onset of the first three tumours, (ii) skin photodamage, and (iii) DNA damage (cyclobutane pyrimidine dimers [CPDs] and pyrimidine-pyrimidone (6-4) photoproducts [6-4PPs])., Results: All mice treated with NAM demonstrated a delay in tumour onset and reduced tumour burden compared to the UV control group (NAM, NAM-Met, NAM-PG vs. UV control: p ≤ 0.015). NAM-mono and NAM-PG increased time until all three tumours with no difference between them, indicating a similar degree of photoprotection. NAM-mono had no effect on DNA damage compared to the UV control group (p &gt; 0.05), whereas NAM-PG reduced 6-4PP lesions (p &lt; 0.01) but not CPDs (p &gt; 0.05) compared to NAM-mono. NAM-Met delayed the onset of the third tumour compared to the UV control but demonstrated a quicker onset compared to NAM-mono, suggesting inferior photoprotection compared to nicotinamide monotherapy., Conclusion: NAM-PG was as effective in delaying UVR-induced tumour onset as NAM-mono. The reduction in 6-4PP lesions may indicate that the mechanism of NAM-PG is better suited for photoprotection than NAM-mono. NAM-mono was superior to NAM-Met, indicating a dose dependency of NAM's photoprotection. These results highlight the potential for combining photoprotective compounds to enhance photoprotection., (© 2024 S. Karger AG, Basel.)

Objectives: Non-invasive imaging with line-field confocal optical coherence tomography (LC-OCT) can support the diagnosis of squamous cell carcinoma (SCC) through visualization of morphological characteristics specific to skin cancer. We aimed to visualize prominent morphological characteristics of SCC using LC-OCT in a well-established murine SCC model., Materials and Methods: Nine hairless mice were exposed to ultraviolet radiation three times weekly for 9 months to induce SCC development. Visible SCC tumors (n = 9) were imaged with LC-OCT and the presence of 10 well-described morphological characteristics of SCC were evaluated in the scans by two physicians with adjudication by a third., Results: Overall, murine morphological characteristics resembled corresponding features previously reported in human SCCs. Interrupted dermal-epidermal junction occurred in 100% of tumors. In epidermis, the most frequently observed characteristics were severe epidermal dysplasia (100%) and tumor budding (89%). Common dermal characteristics included broad strands (100%) and collagen alterations (78%)., Conclusion: LC-OCT imaging can be used to non-invasively visualize morphological characteristics specific to SCC in an in vivo preclinical model., (© 2023 Wiley Periodicals LLC.)

Objectives: The impact of skin hydration on patterns of thermal injury produced by ablative fractional lasers (AFLs) is insufficiently examined under standardized conditions. Using skin with three different hydration levels, this study assessed the effect of hydration status on microchannel dimensions generated by a fractional CO 2 laser., Methods: A hydration model (hyperhydrated-, dehydrated- and control) was established in ex vivo porcine skin, validated by changes in surface conductance and sample mass. After, samples underwent AFL exposure using a CO 2 laser (10,600 nm) at two examined pulse energies (10 and 30 mJ/mb, fixed 10% density, six repetitions per group). Histological assessment of distinct microchannels (n = 60) determined three standardized endpoints in H&E sections: (1) depth of microthermal treatment zones (MTZs), (2) depth of microscopic ablation zones (MAZs), and (3) coagulation zone (CZ) thickness. As a supplemental in vivo assessment, the same laser settings were applied to hyperhydrated- (7-h occlusion) and normohydrated forearm skin (no pretreatment) of a human volunteer. Blinded measurement of MAZ depth (n = 30) was performed using noninvasive optical coherence tomography (OCT)., Results: Modest differences in microchannel dimensions were shown between hyperhydrated, dehydrated and control skin at both high and low pulse energy. Compared to controls, hyperhydration led to median reductions in MTZ and MAZ depth ranging from 5% to 8% (control vs. hyperhydrated at 30 mJ/mb; 848 vs. 797 µm (p < 0.003) (MAZ); 928 vs. 856 µm (p < 0.003) (MTZ)), while 14%-16% reductions were shown in dehydrated skin (control vs. dehydrated at 30 mJ/mb; MAZ: 848 vs. 727 µm (p < 0.003); MTZ: 928 vs. 782 µm (p < 0.003)). The impact of skin hydration on CZ thickness was in contrast limited. Corresponding with ex vivo findings, hyperhydration was similarly associated with lower ablative depth in vivo skin. Thus, median MAZ depth in hydrated skin was 10% and 14% lower than in control areas at 10 and 30 mJ/mb pulse energy, respectively (10 mJ: 210 vs. 180 µm (p < 0.001); 30 mJ: 335 vs. 300 µm (p < 0.001))., Conclusion: Skin hydration status can exert a minimal impact on patterns of microthermal injury produced by fractional CO 2 lasers, although the clinical implication in the context of laser therapy requires further study., (© 2023 Wiley Periodicals LLC.)

Background: Patient recruitment is a major cause of delays in randomized controlled trials (RCT). Online recruitment is evolving into an alternative to conventional in-clinic recruitment for RCT. The objective of this study was to test the effectiveness of online patient recruitment for an RCT on actinic keratosis (AK)., Methods: In this proof-of-concept study, adults with AK were recruited for a Phase I/IIa RCT (NCT05164393) via social media using targeted advertising Interested users were directed to a landing page to learn about the study, respond to questionnaires, and upload self-obtained smartphone pictures of potential AK. Facebook Analytics was used to track the number of advertisement views, individual users exposed to the advertisement, and advertisement clicks. Following eligibility-review by remote dermatologists, candidates were contacted for an in-clinic visit. A review of pertinent RCTs on AK (2012-2022) was conducted to compare recruitment metrics., Results: The online campaign served 886,670 views, reached 309,000 users, and generated 27,814 clicks. A total of 556 users underwent eligibility review, leading to 140 pre-evaluated potential study subjects. The RCT's enrollment target of 60 patients (68.8 ± 7.1 years, 43.3 % female) was reached in 53 days after screening 90 participants in-clinic, corresponding to a screen failure rate of 33.3 %. The total cost of this online recruitment campaign was 14,285 USD i.e. 238 USD per randomized patient. Compared to the existing literature (44 RCTs), our online approach resulted in 9 times more time-efficient recruitment per site., Conclusion: Using targeted advertisements, 60 patients with AK were recruited for a single-center Phase I/IIa RCT in 53 days. Social media appears to be an efficient platform for online recruitment of patients with low-grade AK for RCT., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. JRZ is a paid consultant to Coegin Pharma AB; OB, SH, and CAPL are employees at S&Me; IM is a paid consultant to S&Me; MH has received a research grant from S&Me., (© 2023 The Authors.)

Competing Interests: Conflicts of interest: J.R.Z. is a paid consultant to Coegin Pharma AB; A.C.M. is an employee of Studies&Me A/S; I.M. is a paid consultant to Studies&Me A/S; J.R.Z. and A.D.A. are previous employees of Studies&Me A/S; M.H. has received a research grant from Studies&Me A/S.

Ultraviolet radiation is the primary risk factor for keratinocyte carcinoma. Because of increasing incidence rates, new methods of photoprotection must be explored. Oral supplementation with photoprotective compounds presents a promising alternative. Phytochemical compounds like hesperidin methyl chalcone, phloroglucinol, and syringic acid are particularly of interest because of their antioxidant properties. Our primary outcome was to evaluate the effects of oral phytochemicals on photocarcinogenesis with time until tumour onset as the primary endpoint. A total of 125 hairless C3.Cg-Hr hr /TifBom Tac mice were randomised to receive tap water supplemented with either 100 mg/kg hesperidin methyl chalcone, phloroglucinol, or syringic acid, 600 mg/kg nicotinamide as a positive control, or no supplementation. The mice were irradiated with 3.5 standard erythema doses thrice weekly to induce photocarcinogenesis. Supplementation with the phytochemicals phloroglucinol and syringic acid and nicotinamide delayed tumour onset from a median of 140 days to 151 (p = 0.036), 157 days (p = 0.02), and 178 (p = 2.7·10 -5 ), respectively. Phloroglucinol and nicotinamide supplementation reduced tumour number. Nicotinamide increased UV-induced pigmentation and reduced oedema formation, while phloroglucinol supplementation reduced epidermal thickness. These results indicate that oral supplementation with phloroglucinol and syringic acid protects against photocarcinogenesis in hairless mice, but not to the same extent as nicotinamide., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Photodynamic therapy (PDT) is approved for treatment of actinic keratoses (AKs) and field-cancerisation. Pretreatment with pharmacological compounds holds potential to improve PDT efficacy, through direct interaction with PpIX formation or through an independent response, both of which may improve PDT treatment., Objective: To present the currently available clinical evidence of pharmacological pretreatments prior to PDT and to associate potential clinical benefits with the pharmacological mechanisms of action of the individual compounds., Methods: A comprehensive search on the Embase, MEDLINE, and Web of Science databases was performed., Results: In total, 16 studies investigated 6 pretreatment compounds: 5-fluorouracil (5-FU), diclofenac, retinoids, salicylic acid, urea, and vitamin D. Two of these, 5-FU and vitamin D, robustly increased the efficacy of PDT across multiple studies, illustrated by mean increases in clearance rates of 21.88% and 12.4%, respectively. Regarding their mechanisms, 5-FU and vitamin D both increased PpIX accumulation, while 5-FU also induced a separate anticarcinogenic response. Pretreatment with diclofenac for four weeks improved the clearance rate in one study (24.9%), administration of retinoids had a significant effect in one of two studies (16.25%), while salicylic acid and urea did not lead to improved PDT efficacy. Diclofenac and retinoids demonstrated independent cytotoxic responses, whereas salicylic acid and urea acted as penetration enhancers to increase PpIX formation., Conclusion: 5-FU and vitamin D are well-tested, promising candidates for pharmacological pretreatment prior to PDT. Both compounds affect the haem biosynthesis, providing a target for potential pretreatment candidates., Key Words: Photodynamic Therapy, Actinic Keratosis,Pre-tretment,Review,enhancement., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)