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Keratinocyte carcinomas (KC) are the most common malignant human neoplasms. Although surgery and destructive approaches are first-line treatments, topical therapies are commonly used. Due to limited uptake of topical agents across the skin barrier, clearance rates are often sub-optimal. In pre-clinical investigations, ablative fractional laser (AFL)-assisted drug delivery has demonstrated improved uptake of topical drugs commonly used to treat KC. In 22 clinical trials, the effect of AFL-assisted treatments has been investigated for actinic keratosis (AK; n = 14), Bowen's disease (BD; n = 5), squamous cell carcinoma (n = 1), and basal cell carcinoma (n = 7). The most substantial evidence currently exists for AFL-assisted photodynamic therapy for the treatment of AK and BD. AFL improved 12-months follow-up clearance rates of photodynamic therapy from 45.0-51.0% to 78.5-84.8% for AK and from 50.0-55.3% to 87.0-87.5% for BD. AFL-assisted pharmacological therapy is a promising tool for optimizing topical treatments of KC and its precursor lesions. Future developments include AFL-assisted immune activation, changing drug administration route of systemic therapies, and utilizing drug chemo-combinations., Competing Interests: Declaration of Competing Interest AME has received a research grant from Leo iLab and equipment loan from PerfAction. UHO declares no conflicts of interest. MH has received research grants from Leo Pharma, Lutronic, Novoxel, Procter&Gamble and Sebacia, and received equipment or equipment loan from Cherry Imaging, Cynosure-Hologic, Lutronic, Novoxel and PerfAction. AMR has received research grants from Leo iLab, ASLMS, and the Skin Cancer Foundation, served as a consultant for Merz, Biofrontera, Dynamed, Canfield Scientific, Evolus, Quantia MD, Lam Therapeutics, Cutera, and Skinfix, sat on advisory board for Allergan Inc., received travel grants from Mavig and L'oreal, and received equipment loan from PerfAction., (Copyright © 2020. Published by Elsevier B.V.)

Background and Aim: Ingenol mebutate (IngMeb) is an effective treatment for actinic keratosis. In this study, we hypothesized that repeated treatments with IngMeb may prevent progression of UV-induced photodamage, and that concurrent application of a corticosteroid may reduce IngMeb-induced local skin responses (LSR)., Methods: Hairless mice (n = 60; 3 groups of 20 mice) were irradiated with solar simulated ultraviolet radiation (UVR) throughout the study. Five single treatments with IngMeb were given at 4-week intervals (Days 21, 49, 77, 105, and 133). Clobetasol propionate (CP) was applied once daily for 5 days prior to each IngMeb application, as well as 6 h and 1 day post treatment. One week after IngMeb treatment No. 1, 3, and 5 (Days 28, 84, and 140), biopsies from four mice in each group were collected for histological evaluation of UV-damage on a standardized UV-damage scale (0-12). LSR (0-24) were assessed once daily (Days 1-7) after each IngMeb treatment., Results: IngMeb prevented progression of photodamage in terms of keratosis grade, epidermal hypertrophy, dysplasia, and dermal actinic damage with a lower composite UV-damage score on day 140 (UVR 10.25 vs. UVR+IngMeb 6.00, p = 0.002) compared to UVR alone. IngMeb induced LSR, including erythema, flaking, crusting, bleeding, vesiculation, and ulceration. Concurrent CP increased LSR (max LSR Tx 1-5: UVR+IngMeb+CP 3.6-5.5 vs. UVR+IngMeb 2.6-4.3) and provided better prevention of photodamage compared to IngMeb alone (Day 140: UVR+IngMeb 6.00 vs. UVR+IngMeb+CP 3.00 p < 0.001)., Conclusion: Repeated field-directed treatments with IngMeb prevent progression of cutaneous photodamage in hairless mice, while CP cannot be used to alleviate IngMeb-induced LSR. The findings suggest that IngMeb may potentially serve as a prophylactic treatment for UV-induced tumors., Competing Interests: Leo Pharma A/S is the producer of the ingenol mebutate gel used in this study. AH, KS, and JRZ are employees at Pharma A/S, and AE, MH, and HCW have received research grants from Leo Pharma A/S. This does not alter adherence to PLOS ONE policies on sharing data and materials.

Background: Ingenol mebutate (IngMeb) is approved for treatment of actinic keratoses (AK) and may cause unpredictable local skin responses (LSR)., Objectives: We sought to investigate whether IngMeb-induced LSR, pain, and pruritus could be alleviated with a topical glucocorticoid and, further, to assess efficacy, cosmetic outcome, and patient satisfaction in patients with severe photodamage., Methods: In this blinded, randomized controlled clinical trial, patients with multiple AK and field cancerization of the face or scalp were treated in 2 areas with IngMeb (0.015%) daily for 3 days. After finalized IngMeb treatment, 1 area was randomized to receive topical clobetasol propionate (0.05%) twice daily for 4 days. Assessments included LSR (0-24; days 1, 4, 8, 15, 57), pain (0-10) and pruritus (0-3; days 1-15), AK clearance (days 15, 57), and cosmetic outcome (0-3; day 57)., Results: Clobetasol propionate application had no influence on LSR (P = .939), pain (P = .500), pruritus (P = .312), or AK cure rate (P = .991). Overall, IngMeb cleared 86% of all AK lesions, exerting a therapeutic effect on all AK severity grades; cure rates were 88%, 70%, and 60% for grade I, II, and III AK, respectively. Skin texture improved significantly in remedied areas (2.0 vs 1.0; P < .001); no hypopigmentation, hyperpigmentation, or scarring were observed., Limitations: These results do not provide safety and efficacy beyond 2 months of follow-up., Conclusion: Application of clobetasol propionate does not alleviate IngMeb-induced LSR after 3 days of IngMeb treatment., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: The incidence of actinic keratosis (AK) is increasing, and several treatment options are available. The aim of this study was to describe clinical characteristics and treatment patterns in patients with AK treated by Danish dermatologists., Methods: A multicenter, non-interventional, cross-sectional study was conducted. Three dermatology hospital departments and seven private dermatology clinics enrolled eligible AK patients consecutively during one week., Results: A total of 312 patients were included. Non-melanoma skin cancer (NMSC) was previously reported in 51.0% of patients and currently suspected in 9.4% of AK-affected anatomical regions. Lesions of AK were located primarily on the face (38.6%), scalp (12.8%), and hands (11.2%). Actinic keratosis commonly presented with multiple AK lesions (38.6%) and field cancerization (38.5%). The treatments used most frequently were cryotherapy (57.7%) and photodynamic therapy (PDT) with methyl aminolevulinate (17.1%) and imiquimod (11.2%). The likelihood of receiving cryotherapy was higher for men (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.10-2.47) and increased with age (2.2% per year, 0.4-4.0%). PDT represented the most frequently applied treatment for severe actinic damage and was more likely to be prescribed to women (OR 4.08, 95% CI 2.22-7.47) and young patients (OR 0.97 per year, 95% CI 0.95-0.99). The prevalence of severe actinic damage (17.3% versus 9.6%) and intake of immunosuppressive medication (29.0 versus 2.0) were higher among hospital patients compared with those treated in private practices (P < 0.0001)., Conclusions: The majority of AK patients in Danish dermatology clinics have a history of skin cancer, and NMSC is suspected in almost 10% of AK-affected regions. Cryotherapy is the most frequently used treatment overall, except in instances of severe actinic damage, in which PDT is the first-choice treatment., (© 2015 The International Society of Dermatology.)

Background: Actinic keratosis (AK) is a common skin condition that may progress to non-melanoma skin cancer (NMSC). The disease may influence Health Related Quality of Life (HRQoL), but studies of HRQoL in patients with AK are limited. The purpose of the study was to analyze HRQoL in patients with different severity levels of AK treated in dermatology specialist care using generic and disease-specific HRQoL instruments and to analyze their relationship., Methods: AK patients who visited dermatological clinics in Denmark were included in an observational, cross-sectional, study in a multi-center setting. Dermatologists assessed AK severity and patients completed: Actinic Keratosis Quality of Life Questionnaire (AKQoL), Dermatology Life Quality Index (DLQI), and EQ-5D-5 L including EQ-VAS. Differences between categorical subgroups were tested with Wilcoxon rank-sum test. The relationship between instruments was analyzed with the Spearman correlation test., Results: A total of 312 patients were included in the analyses. Patients reported impairment in the disease specific HRQoL instrument AKQoL (mean AKQoL 6.7, DLQI 2, EQ-5D-5 L 0.88, and EQ-VAS 79). HRQoL was least affected in patients with mild actinic disease, whereas patients with severe actinic damage suffered from further impaired HRQoL (mean AKQoL 10.1 and DLQI 4.6). Correlations between DLQI and AKQoL were moderate, whereas the correlations between DLQI and EQ-5D-5 L and between AKQoL and EQ-5D-5 L were weak., Conclusions: Patients with severe actinic damage showed more impairment in HRQoL than those with mild disease. Correlations between instruments suggest that they are complementary as they measure different aspects of HRQoL and are used for different purposes.

Background: Topical photodynamic therapy (PDT) for actinic keratoses (AK) is hampered by pain during illumination and inferior efficacy in organ-transplant recipients (OTR)., Objectives: We assessed ablative fractional laser (AFL)-assisted daylight photodynamic therapy (PDT) (AFL-dPDT) compared with daylight PDT (dPDT), conventional PDT (cPDT) and AFL alone (AFL) in field treatment of AK in OTR., Methods: In each patient, four areas in the same region were randomized to one treatment with AFL-dPDT, dPDT, cPDT and AFL. AFL was delivered with a 2940-nm AFL at 2·3 mJ per pulse, 1·15 W, two stacks, 50-μs pulse-duration, 2·4% density. In dPDT and AFL-dPDT, methyl aminolaevulinate (MAL) was applied for 2·5 h without occlusion during daylight exposure. For cPDT, MAL was occluded for 3 h followed by red-light (630 nm) irradiation at 37 J cm(-2). The primary end-point was complete response (CR) 3 months post-treatment., Results: Sixteen patients with 542 AK (grades I-III) in field-cancerized skin of the scalp, chest and extremities were treated during August and September 2012. After 3 months, CR (AK I-III) rates were 74% after AFL-dPDT, 46% after dPDT, 50% after cPDT and 5% after AFL (P < 0·001). CR rates in AFL-dPDT, dPDT and cPDT were also significantly different (P = 0·004). Median maximal pain scores differed significantly during AFL-dPDT (0), dPDT (0), AFL (0) and cPDT (5) (P < 0·001). Erythema and crusting were more intense following AFL-dPDT than dPDT and cPDT, but only transient hypopigmentation was observed., Conclusions: AFL-dPDT is a novel PDT modality that enhances CR with excellent tolerability compared with dPDT and cPDT in difficult-to-treat AK in OTR., (© 2014 British Association of Dermatologists.)