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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.)

Competing Interests: None disclosed.

Background: Patients with hypertrophic scars (HTS) risk reduced quality of life due to itching, pain, poor cosmesis, and restriction of movement. Despite good clinical efficacy, patients are often reluctant to undergo repeated needle injections due to pain or needle phobia., Objectives: To evaluate the applicability of needle-free pneumatic jet injection (PJI) and assess changes in hypertrophic scars following a single PJI treatment with 5-fluorouracil (5-FU) and triamcinolone acetonide (TAC)., Methods: Twenty patients completed this blinded, randomized, controlled, split-scar trial. The intervention side of the HTS received a one-time treatment with PJIs containing a mixture of TAC + 5-FU injected at 5 mm intervals (mean 7 PJI per HTS); the control side received no treatment. Assessments were made at baseline and 4 weeks posttreatment. Outcome measures included change in (1) Vancouver Scar Scale (VSS) total score and subscores, (2) scar volume and surface area assessed by three-dimensional imaging, (3) skin microarchitecture measured by optical-coherence tomography (OCT), (4) photo-assessed scar cosmesis (0-100), (5) patient-reported pain and satisfaction (0-10), and (6) depiction of drug biodistribution after PJI., Results: PJI with TAC + 5-FU significantly decreased both HTS height (-1 VSS; p = 0.01) and pliability (-1 VSS; p < 0.01) with a nonstatistically significant reduction of -1 in total VSS score (0 in control; p = 0.09). On 3D imaging, a 33% decrease in scar volume (p = 0.016) and a 37% decrease in surface area (p = 0.008) was observed. OCT indicated trends towards smoother scar surface (Ra 11.1-10.3; p = 0.61), normalized dermal microarchitecture (attenuation coefficient: 1.52-1.68; p = 0.44), and a reduction in blood flow between 9% and 17% (p = 0.50-0.79). Despite advances in VSS subscores and OCT, no improved photo-assessed cosmesis was found (-3.2 treatment vs. -1.4 control; p = 0.265). Patient-reported pain was low (2/10) and 90% of the patients that had previously received needle injections preferred PJI to needle injection. Depositions of TAC + FU were imaged reaching deep into the scar at levels corresponding to the reticular dermis., Conclusion: A single PJI injection containing 5-FU and TAC can significantly improve the height and pliability of HTS. PJI is favored by the patients and may serve as a complement to conventional needle injections, especially for patients with needle phobia., (© 2022 Wiley Periodicals LLC.)

Competing Interests: None disclosed.

Background: Extramammary Paget disease (EMPD) poses treatment challenges. Invasive and noninvasive treatment modalities exist with variable success reported. Reflectance confocal microscopy (RCM) is emerging as an adjuvant diagnostic tool., Objective: To evaluate the treatment of EMPD patients and the role of RCM., Methods: Prospective study. Demographic and tumor characteristics were recorded. Handheld-RCM was performed and correlated with histology. Treatment, clearance, pathology, and follow-up were all recorded., Results: Thirty-six EMPD lesions in 33 patients were included. Mean age was 71.7 years, and 23 were men. Mean number of surgical stages needed to clear margins was 1.9 (SD, 0.9; 1.0-3.0 stages), and mean margin needed to clear was 1.8 cm. Reflectance confocal microscopy correlated well with scouting punch biopsies (kappa, 0.93; p < .001). Disruption of the dermoepidermal junction was associated with invasive EMPD versus in situ (83.3% vs 25.9%) on histology (p = .01)., Limitations: Relatively small sample size., Conclusion: Extramammary Paget disease is challenging, and lesion demarcation is of the utmost importance. Using a staged surgical excision approach, the mean margins needed were 1.8 cm, less than previously reported. Nonsurgical modalities, including radiation therapy, imiquimod, or photodynamic therapy can be considered if surgery is not pursued. Reflectance confocal microscopy is a valuable noninvasive imaging modality for the management of EMPD., (Copyright © 2020 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

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 Objectives: Many cutaneous drug-delivery techniques rely on passive diffusion to deliver topical compounds to the skin. When attempting to deliver drugs to thicker lesions, such as skin tumors, modalities that do not rely on diffusion may serve as a better drug-delivery method. In this histological study, we aim to investigate the cutaneous delivery patterns of an electronic pneumatic needle-free injection device., Study Design/materials and Methods: Needle-free-injection was investigated in 24 ex vivo porcine skin samples and one basal cell carcinoma (BCC) tissue sample. A needle-free injection device with a nozzle size of 200 μm delivered 80 μl compound ink (0.1 cc black ink: 5.0 cc saline) at low (30%/3.1 bar; n = 6 porcine skin; n = 1 BCC tissue), medium (50%/3.9 bar; n = 6 porcine skin), high (65%/4.6 bar; n = 6 porcine skin), and stacked (30 + 50%/3.1 + 3.9 bar; n = 6 porcine skin) pressures. Depth, width, and depth of maximum width of ink deposition were evaluated on histological slides., Results: Depositions with small ink-lined vacuoles were seen intra-dermally in all samples, including the BCC tissue. Deposition depth was similar at low and medium pressures (924 vs. 994 μm; P = 0.873) but increased significantly with high pressure (1,564 μm; P = 0.010). When injections were stacked (3.1 + 3.9 bar), the depth remained similar to that of a single injection (931 μm; P = 1.000). The width of the deposition stayed comparable for low, medium, and high pressures when a single needle-free injection was performed (30% = 2,394 μm; 50% = 2,226 μm; and 65% = 2,757 μm; P = 0.09), but increased significantly with stacking (2,979 μm; P = 0.037). The depth of maximal width was superficially located in the papillary dermis at low and medium pressures (321 and 305 μm; P = 0.748) but shifted to the deeper reticular dermis with high pressure (950 μm; P = 0.004) and with stacking (734 μm; P = 0.004)., Conclusions: In conclusion, with an electronically controlled, pneumatic needle-free injector, depth and width of a cutaneous deposition can be influenced by pressure and stacking, respectively. The pneumatic needle-free injection can potentially serve as a viable drug-delivery technique for cutaneous pathologies where dermal deposition is essential. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

Fractional laser-assisted drug delivery (LADD) is increasingly finding its way into clinical practice as a new means to enhance topical drug uptake and improve treatment of cutaneous disorders. To date, LADD has been used for a wide range of conditions, including photodamaged skin, neoplastic lesions, scars, cutaneous infections, and vitiligo as well as for topical anesthetic and aesthetic procedures. Substantiated by randomized controlled clinical trials, strong evidence is available for LADD's usefulness for photodynamic therapy (PDT), for which improved efficacy using laser-assisted photosensitizer treatment is established for actinic keratosis compared with conventional PDT. Over time, the modality has undergone increasing refinement and offers the potential advantages of reduced treatment durations, shortened incubation times, and the replacement of cumbersome, patient-dependent treatment regimens with quick, in-office procedures. Notwithstanding, LADD is still a new enhancement technique, and risks of both local and systemic adverse events are insufficiently explored. With conscientious development, however, LADD promises to improve existing regimens and make new pharmacological treatments a reality for a wide range of cutaneous disorders., (©2017 Frontline Medical Communications.)

Non-melanoma skin cancer is the most frequently occurring cancer in Caucasians today. Incidence rates in Europe have increased steadily since the 1960s and more than tripled over the last 50 years. Despite primary preventative efforts, incidences of non-melanoma skin cancer continue to rise and development of effective chemopreventative strategies is needed. In 2013, ingenol mebutate was approved in Denmark as a new topical drug for field-directed treatment for actinic keratoses. Ingenol mebutate has a dual mechanism of action, causing initial cell death, followed by an immune activation. The treatment induces an acute inflammation, manifesting as local skin responses, often accompanied by pain and pruritus. The severity of local skin responses for a given patient is unpredictable, and some individuals may develop insufferable inflammation. The overall aim of the thesis was to investigate if ingenol mebutate could be used as a chemopreventive agent to prevent development of non-melanoma skin cancer with minimal side effects. Specific aims included: Determine if ingenol mebutate can prevent progression of histological photodamage and squamous cell carcinoma (murine). Determine if ingenol mebutate can reverse clinical actinic damage in patients with multiple actinic keratoses and fieldcancerized skin (clinical). Determine if a topical glucocorticoid (clobetasol propionate) can reduce ingenol mebutate-induced local skin responses, pain, and pruritus without compromising the treatment efficacy (murine clinical). In two in vivo murine studies, ingenol mebutate's effect on photodamage and squamous cell carcinoma formation was investigated. Mice were irradiated with solar simulated ultraviolet radiation. During the first 20 weeks, 5 single applications with ingenol mebutate were given at four-week intervals with and without concurrent application of clobetasol propionate. Prophylactic treatments with ingenol mebutate prevented progression of histological photodamage of all investigated characteristics, including keratosis grade, epidermal hypertrophy, dysplasia, and dermal actinic damage. In addition, tumor formation was postponed by 3 weeks. In the clinical trial, patients with multiple actinic keratoses and field-cancerized skin were treated with ingenol mebutate, according to label, with and without sequential application of clobetasol propionate. Ingenol mebutate treatments were found to clear overall 86% of all actinic keratoses, exerting a therapeutic effect on all severity grades; cure rates were 88%, 70%, and 60% for Grade I, II, and III actinic keratoses, respectively. Ingenol mebutate treatments generated erythema, flaking, crusting, vesiculation, swelling/bleeding, and ulceration. Concurrent application of clobetasol propionate increased local skin responses in murine skin, likely due to an enhanced penetration of ingenol mebutate that resulted in a greater therapeutic effect compared to ingenol mebutate alone. In patients with actinic keratoses, sequential application of ingenol mebutate and clobetasol propionate did not reduce local skin responses, pain, or pruritus, nor did it affect treatment efficacy compared to ingenol mebutate alone. In conclusion, the thesis highlights ingenol mebutate's potential as a prophylactic remedy for non-melanoma skin cancer with promise to support primary preventative efforts in reducing non-melanoma skin cancer incidence., (Articles published in the Danish Medical Journal are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Background and Objective: Intense pulsed light (IPL) is a mainstream treatment for hair removal. Side effects after IPL are known, but risk factors remain to be investigated. The objective of this study was to assess the contribution of skin pigmentation, fluence level, and ultraviolet radiation (UVR) on IPL-induced side effects., Methods: The study was a blinded, randomized intra-individual controlled trial including 16 healthy subjects with Fitzpatrick Skin Types (FST) II-V. Three test areas were each divided into four sites, randomized to a single IPL exposure of 22, 34, 46 J/cm 2 or triple stacking of 46 J/cm 2 . Areas were subsequently randomized to no UVR or single solar-simulated UVR exposure of 3 Standard Erythema Dose at 30 minutes or 24 hours after IPL. Each area had a corresponding control, resulting in 15 treatment sites. Follow-up visits were scheduled up to 4 weeks after IPL. Outcome measures were: (i) blinded clinical skin reactions; (ii) objectively measured erythema and pigmentation; (iii) pain measured by visual analog scale (VAS); (iv) histology (H&E, Fontana-Masson); and (v) mRNA-expression of p53., Results: Fifteen subjects with FST II-IV completed the protocol. IPL induced a wide range of skin reactions, including erythema (87% of subjects), purpura (27%), blisters (20%), edema (13%), crusting (13%), hyper- (60%), and hypopigmentation (20%). Darker skin pigmentation and increasing IPL fluence were determinants for IPL-induced side effects (P ≤ 0.002), while a single exposure of UVR did not exacerbate side effects (P ≥ 0.180). Clinical findings were confirmed objectively by reflectance spectrometry and qualitatively by histological changes in skin architecture, inflammatory infiltration, and pigmentation. Marker of cellular DNA damage, that is, p53, did not increase after IPL (P ≥ 0.24)., Conclusions: Skin pigmentation and IPL fluence are major determinants of side effects after IPL exposure, while a single exposure to three SED of UVR at 30 minutes or 24 hours after IPL, does not amplify such side effects. Lasers Surg. Med. 49:88-96, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background and Objectives: Pulsed dye laser (PDL) represents the gold-standard treatment for port wine stains (PWS). However, approximately 20% of patients are poor responders and yield unsatisfactory end-results. The Alexandrite (Alex) laser may be a therapeutic alternative for selected PWS subgroups, but optimal laser parameters are not known. The aim of this study was to assess clinical PWS clearance and safety of Alex laser at a range of pulse durations., Materials and Methods: Sixteen individuals (14 previously PDL-treated) with deep red (n = 4), purple macular (n = 5) and purple hypertrophic (n = 7) PWS were included. Four side-by-side test areas were marked within each lesion. Three test areas were randomized to Alex laser at pulse durations of 3, 5, or 10 ms (8 mm spot, DCD 60/40), while the fourth was untreated. The lowest effective fluence to create purpura within the entire test spot was titrated and applied to intervention areas. Standardized clinical photographs were taken prior to, immediately after laser exposure and at 6-8 weeks follow up. Clinical PWS clearance and laser-related side effects were assessed using clinical photos., Results: Alex laser at 3, 5, and 10 ms pulse durations demonstrated significant clearance compared to untreated controls (P < 0.001). Three milli second pulse duration exhibited improved clearance versus 5 ms (P = 0.016) and 10 ms (P = 0.004), while no difference between five and 10 ms was shown (P = 0.063). Though not significant, good responders (>50% clearance) were more likely to have purple hypertrophic PWS (5/7) compared to purple macular (2/5) and deep red lesions (1/4). Eight laser-exposed test areas (17%) developed hypopigmented atrophic scarring. Side effects tended to be more frequently observed with 5 ms (n = 4) and 10 ms (n = 3) versus 3 ms pulse duration (n = 1). Correspondingly, 3 ms was associated with a superior (n = 6) or comparable (n = 10) overall cosmetic appearance for all individuals., Conclusion: Alex laser at 3 ms pulse duration offers superior clinical clearance and safety compared to 5 and 10 ms, and seems best suited for purple hypertrophic PWS. Treatment should be restricted to experienced personnel due to a particularly narrow therapeutic window. Lasers Surg. Med. 49:97-103, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background and Aim: The incidence of squamous cell carcinomas (SCC) is increasing, and effective chemopreventative strategies are needed. We hypothesized that repeated treatments with ingenol mebutate (IngMeb) would postpone development of SCC in hairless mice, and that application of a corticosteroid would reduce IngMeb-induced local skin responses (LSRs) without affecting tumor postponement., Methods: Hairless mice (n=150; 6 groups á 25 mice) were irradiated with solar simulated ultraviolet radiation (UVR) until SCC developed. During UV-irradiation and before tumor development, five single treatments (Tx) with IngMeb were given at four-week intervals (days 21, 49, 77, 105, 133). Clobetasol propionate (CP) was applied once daily for 5days prior to IngMeb, as well as 6h and 1day post treatment. Tumor formation was evaluated weekly for 52weeks. LSR (scale 0-24) were assessed at baseline, 1h, 6h, 1-, 2-, 3-, 4-, 5-, 6-, and 7days after each IngMeb treatment., Results: IngMeb significantly delayed tumor development compared to UVR alone (UVR day 168 vs. UVR+IngMeb day 189; p=0.025). LSR included erythema, flaking, crusting, bleeding, vesiculation, and ulceration. The composite LSR-scores were of moderate intensity in non-UV irradiated skin (max LSR IngMeb Tx 1-5: 1.5-2.5) and more pronounced in photodamaged skin (max LSR Tx 5; IngMeb 1.5 vs. UVR+IngMeb 1.8; p<0.001). LSR intensity correlated with tumor development by means of greater composite LSR-score resulted in longer tumor-free survival (r(2)=0.257, p<0.001). Contrary to our hypothesis, concurrent CP increased LSR (max LSR Tx 1-5: UVR+CP+IngMeb 3.2-4.9 vs. UVR+IngMeb 1.3-2.2, p<0.001) and postponed tumor development compared to IngMeb alone (UVR+CP+IngMeb day 217 vs. UVR+IngMeb day 189, p<0.001)., Conclusion: Repeated field-directed treatments with IngMeb delay development of UV-induced SCC in hairless mice, and increased IngMeb induced LSRs correlated with improved clinical outcomes. The findings highlight the potential of IngMeb as a prophylactic remedy for SCC in humans., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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 and Objective: Ablative fractional laser (AFXL) facilitates delivery of topical methotrexate (MTX). This study investigates impact of laser-channel depth on topical MTX-delivery., Materials and Methods: MTX (1% [w/v]) diffused for 21 hours through AFXL-exposed porcine skin in in vitro Franz Cells (n = 120). A 2,940 nm AFXL generated microscopic ablation zones (MAZs) into epidermis (11 mJ/channel, MAZ-E), superficial-dermis (26 mJ/channel, MAZ-DS), and mid-dermis (256 mJ/channel, MAZ-DM). High performance liquid chromatography (HPLC) was used to quantify MTX deposition in full-thickness skin, biodistribution profiles at specific skin levels, and transdermal permeation. Fluorescence microscopy was used to visualize UVC-activated MTX-fluorescence (254 nm) and semi-quantify MTX distribution in skin., Results: AFXL increased topical MTX-delivery (P < 0.001). Without laser exposure, MTX-concentration in full-thickness skin was 0.07 mg/cm(2) , increasing sixfold (MAZ-E), ninefold (MAZ-DS), and 11-fold (MAZ-DM) after AFXL (P < 0.001). Deeper MAZs increased MTX-concentrations in all skin layers (P < 0.038) and favored maximum accumulation in deeper skin layers (MAZ-E: 1.85 mg/cm(3) at 500 μm skin-level vs., Maz-Dm: 3.75 mg/cm(3) at 800 μm, P = 0.002). Ratio of skin deposition versus transdermal permeation remained constant, regardless of MAZ depth (P = 0.172). Fluorescence intensities confirmed MTX biodistribution through coagulation zones and into surrounding skin, regardless of thickness of coagulation zones (6-47 μm, P ≥ 0.438)., Conclusion: AFXL greatly increases topical MTX-delivery. Deeper MAZs deliver higher MTX-concentrations than superficial MAZs, which indicates that laser channel depth may be important for topical delivery of hydrophilic molecules. Lasers Surg. Med. 48:519-529, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background and Objectives: Pretreatment of skin with ablative fractional laser enhances accumulation of topical provided photosensitizer, but essential information is lacking on the interaction between laser channel densities and pharmacokinetics. Hence our objectives were to investigate how protoporphyrin accumulation was affected by laser densities, incubation time and drug concentration., Methods: We conducted the study on the back of healthy male volunteers (n=11). Test areas were pretreated with 2940nm ablative fractional Er:YAG laser, 11.2mJ per laser channel using densities of 1, 2, 5, 10 and 15% (AFL 1-15%). Control areas received pretreatment with curettage or no pretreatment. Methyl aminolevulinate (MAL) was applied under occlusion in concentrations of 0, 80 and 160mg/g. MAL-induced protoporphyrin fluorescence was quantified with a handheld photometer after 0, 30, 60, 120 and 180min incubation. The individual fluorescence intensity reached from the highest density (15%) and longest MAL 160mg/g incubation time (180min) was selected as reference (100%) for other interventional measurements., Results: A low laser density of 1% markedly enhanced fluorescence intensities from 34% to 75% (no pretreatment vs. AFL 1%, MAL 160mg/g, 180min; p<0.001). Furthermore, fluorescence intensities increased substantially by enhancing densities up to 5% (p≤0.0195). Accumulation of protoporphyrins was accelerated by laser exposure. Thus, laser exposure of 5% density and a median incubation time of 80min MAL (range 46-133min) induced fluorescence levels similar to curettage and 180min incubation. Furthermore, MAL 80 and 160mg/g induced similar fluorescence intensities in skin exposed to laser densities of 1, 2 and 5% (p>0.0537, 30-180min)., Conclusion: MAL-induced protoporphyrin accumulation is augmented by enhancing AFL densities up to 5%. Further, this model indicates that incubation time as well as drug concentration of MAL may be reduced with laser pretreatment., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Ablative fractional lasers enhance uptake of topical therapeutics and the concept of fractional laser-assisted drug delivery has now been taken into clinical practice., Objectives: We systematically reviewed preclinical data and clinical evidence for fractional lasers to enhance drug uptake and improve clinical efficacy., Methods: We searched PubMed and Embase databases; 34 articles met the inclusion criteria. Studies were categorized into experimental preclinical studies and clinical trials, the latter graded according to level of evidence., Results: All preclinical trials (n = 16) documented enhanced topical drug uptake into skin after ablative fractional laser treatment. Clinical evidence encompassed 18 studies, of which 9 were randomized controlled trials and 2 were controlled trials, examining neoplastic lesions, photodamaged skin, scars, onychomycosis, and topical anesthetics. The highest level of evidence was reached for actinic keratoses treated with methylaminolevulinate for photodynamic therapy (level IB, 5 randomized controlled trials), substantiating superior and long-lasting efficacy versus conventional photodynamic therapy. No adverse events were reported, but ablative fractional laser-assisted drug delivery implies risks of systemic drug absorption, especially when performed over large skin areas., Conclusions: Fractional laser-assisted drug delivery is beneficial in enhancing preclinical and clinical outcomes for certain skin conditions., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

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 and Objective: Ablative fractional laser (AFXL) is rapidly evolving as one of the foremost techniques for cutaneous drug delivery. While AFXL has effectively improved topical drug-induced clearance rates of actinic keratosis, treatment of basal cell carcinomas (BCCs) has been challenging, potentially due to insufficient drug uptake in deeper skin layers. This study sought to investigate a standardized method to actively fill laser-generated channels by altering pressure, vacuum, and pressure (PVP), enquiring its effect on (i) relative filling of individual laser channels; (ii) cutaneous deposition and delivery kinetics; (iii) biodistribution and diffusion pattern, estimated by mathematical simulation., Methods: Franz diffusion chambers (FCs) were used to evaluate the PVP-technique, comparing passive (AFXL) and active (AFXL + PVP) channel filling. A fractional CO2-laser generated superficial (225 µm;17.5 mJ/channel) and deep (1200 µm; 130.5 mJ/channel) channels, and PVP was delivered as a 3-minutes cycle of 1 minute pressure (+1.0 atm), 1 minute vacuum (-1.0 atm), and 1 minute pressure (+1.0 atm). Filling of laser channels was visualized with a colored biomarker liquid (n = 12 FCs, n = 588 channels). Nuclear magnetic resonance quantified intracutaneous deposition of topically applied polyethylene glycol (PEG400) over time (10 minutes, 1 hour, and 4 hours), investigated with (n = 36 FCs) and without (n = 30 FCs) PVP-filling. Two-dimensional mathematical simulation was used to simulate intradermal biodistribution and diffusion at a depth of 1,000 µm., Results: Active filling with application of PVP increased the number of filled laser channels. At a depth of 1,000 µm, filling increased from 44% (AFXL) to 94% with one PVP cycle (AFXL + PVP; P < 0.01). Active filling greatly enhanced intracutaneous deposition of PEG400, resulting in a rapid delivery six-folding uptake at 10 minutes (AFXL 54 µg/ml vs. AFXL + PVP 303 µg/ml, P < 0.01). AFXL alone generated an inhomogeneous uptake of PEG400, which greatly improved with active filling, resulting in a uniform uptake within the entire tissue., Conclusion: Active filling with PVP secures filling of laser channels and induces a deeper, greater, more rapid delivery than conventional AFXL. This delivery technique has promise to improve treatment efficacy for medical treatments of dermally invasive lesions, such as BCCs., (© 2015 Wiley Periodicals, Inc.)

The prevailing advice is to avoid sun exposure after intense pulsed light (IPL) hair removal. However, no systematic evaluation of ultraviolet radiation (UVR) after IPL hair removal exits. Therefore, we investigated the occurrence of side effects in subjects receiving solar-simulated UVR after a low-fluence IPL treatment with a home-use device. Sixteen subjects with Fitzpatrick skin types (FST) II-V were enrolled. Three constitutive buttock blocks (4.4 × 6.4 cm) were each subdivided into four sites, randomized to one IPL exposure of 0, 7, 8, or 10 J/cm2 (spectral output 530-1100 nm). Blocks were randomized to no UVR or three standard erythema doses (SEDs) UVR either 30 min or 24 h after IPL. Follow-up visits were 48 h, 1 week, and 4 weeks after IPL. Outcome measures were (i) clinical skin reactions, (ii) reflectance measurements of erythema and pigmentation, and (iii) pain. Subjects with FST II-IV experienced no skin reactions up to 4 weeks after IPL, neither erythema, edema, blisters, crusting, textual, nor pigment changes. Reflectance confirmed no change in erythema and pigmentation (p ≥ 0.090). UVR exposure induced erythema and increased pigmentation. The combination of IPL and UVR induced skin reactions not different to responses from UVR (IPL-UVR vs. UVR, p ≥ 0.164). Pain was generally low (median 1, range 0-4) and correlated positively with fluence and pigmentation (Spearman's rho ≥ 0.394, p < 0.001). One subject with FST V experienced perifollicular hyperpigmentation after IPL and slightly more intense when exposed to UVR. A single UVR exposure of three SEDs either shortly or 1 day after low-fluence IPL causes no amplification of skin responses in constitutive skin of individuals with FST II-IV.

Topically applied ingenol mebutate (IngMeb) is approved for field-treatment of actinic keratosis and is currently being investigated for treatment of non-melanoma skin cancer (NMSC). Ablative fractional lasers (AFXLs) generate microscopic ablation zones (MAZs) in the skin, which may help induce a deep penetration needed for effective treatment of NMSC. Using Franz diffusion cells, uptake and bio-distribution were investigated over 21 h in intact (n = 9) and AFXL-exposed porcine skin (n = 58). A 2940-nm fractional Er:YAG laser generated intraepidermal (11.2 mJ/MAZ; 66 μm deep, 177 μm wide) and intradermal (128 mJ/MAZ; 570 μm deep, 262 wide) MAZ's with 16, 97, and 195 MAZs/cm(2). Surface ablation densities corresponded to 0.5, 2.5, and 5 % for intraepidermal MAZs, and corresponded to 1, 5, and 10.5 % for intradermal MAZs. Liquid-chromatography-mass-spectrometry quantified deposition of IngMeb in stratum corneum, epidermis, dermis, and receiver chamber. In intact skin, IngMeb readily penetrated to the epidermal layer (1,314 ng, 41 % of the applied IngMeb), while dermal deposition was limited (508 ng, 16 %). In AFXL-exposed skin, a profound dermal deposition of IngMeb was achieved, while less accumulated in SC and epidermis. Uptake depended entirely on laser density; increasing coverage from 0 % to 0.5 %, 1 %, 2.5 %, 5 %, and 10.5 % enhanced dermal uptake 1.6-, 2.1-, 3.1-, 3.4-, and 3.9-fold, respectively (p < 0.0001). Channel depth did not influence drug uptake; at 5 % density, dermal deposition with intraepidermal and intradermal MAZs was analogous (1801 vs. 1744; p = 0.447). In conclusion, IngMeb readily distributes to superficial layers of intact skin, whereas dermal uptake is limited. Independent of channel depth, AFXL enhances dermal drug deposition, providing for customized topical delivery and potential use of IngMeb for treatment of NMSC.

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.)

Background and Objectives: Treatment of a variety of skin disorders with ablative fractional lasers (AFXL) is driving the development of portable AFXLs. This study measures micropore dimensions produced by a small 2,940 nm AFXL using a variety of stacked pulses, and determines a model correlating laser parameters with tissue effects., Materials and Methods: Ex vivo pig skin was exposed to a miniaturized 2,940 nm AFXL, spot size 225 µm, density 5%, power levels 1.15-2.22 W, pulse durations 50-225 microseconds, pulse repetition rates 100-500 Hz, and 2, 20, or 50 stacked pulses, resulting in pulse energies of 2.3-12.8 mJ/microbeam and total energy levels of 4.6-640 mJ/microchannel. Histological endpoints were ablation depth (AD), coagulation zone (CZ) and ablation width (AW). Data were logarithmically transformed if required prior to linear regression analyses. Results for histological endpoints were combined in a mathematical model., Results: In 138 sections from 91 biopsies, AD ranged from 16 to a maximum of 1,348 µm and increased linearly with the logarithm of total energy delivered by stacked pulses, but also depended on variations in power, pulse duration, pulse repetition rate, and pulse energy (r(2)  = 0.54-0.85, P < 0.0001). Microchannels deeper than 500 µm were created only by the highest pulse energy of 12.8 mJ/microbeam. Pulse stacking increased AD, and enlarged CZ and AW. CZ varied from 0 to 205 µm and increased linearly with total energy (r(2)  = 0.56-0.75, P < 0.0001). AW ranged from 106 to 422 µm and increased linearly with the logarithm of number of stacked pulses (r(2)  = 0.53-0.61, P < 0.001). The mathematical model estimated micropores of specific ADs with an associated range of CZs and AWs, for example, 300 µm ADs were associated with CZs from 27 to 73 µm and AWs from 190 to 347 µm., Conclusions: Pulse stacking with a small, low power 2,940 nm AFXL created reproducible shallow to deep micropores, and influenced micropore configuration. Mathematical modeling established relations between laser settings and micropore dimensions, which assists in choosing laser settings for desired tissue effects., (© 2014 Wiley Periodicals, Inc.)