Christina S. Haak

Fractional laser-assisted delivery of methyl aminolevulinate: Impact of laser channel depth and incubation time†

Pretreatment of skin with ablative fractional lasers (AFXL) enhances the uptake of topical photosensitizers used in photodynamic therapy (PDT). Distribution of photosensitizer into skin layers may depend on depth of laser channels and incubation time. This study evaluates whether depth of intradermal laser channels and incubation time may affect AFXL‐assisted delivery of methyl aminolevulinate (MAL).

Fractional CO2 laser resurfacing for atrophic acne scars: A randomized controlled trial with blinded response evaluation

The treatment of acne scars with fractional CO2 lasers is gaining increasing impact, but has so far not been compared side‐by‐side to untreated control skin.

The impact of treatment density and molecular weight for fractional laser-assisted drug delivery.

Ablative fractional lasers (AFXL) facilitate uptake of topically applied drugs by creating narrow open micro-channels into the skin, but there is limited information on optimal laser settings for delivery of specific molecules. The objective of this study was to investigate the impact of laser treatment density (% of skin occupied by channels) and molecular weight (MW) for fractional CO(2) laser-assisted drug delivery. AFXL substantially increased intra- and transcutaneous delivery of polyethylene glycols (PEGs) in a MW range from 240 to 4300 Da (Nuclear Magnetic Resonance, p<0.01). Increasing laser density from 1 to 20% resulted in augmented intra- and transdermal delivery (p<0.01), but densities higher than 1% resulted in reduced delivery per channel. Mass spectrometry indicated that larger molecules have greater intracutaneous retention than transcutaneous penetration. At 5% density, median delivery of PEGs with mean MW of 400, 1000, 2050 and 3350 Da were respectively 0.87, 0.31, 0.23 and 0.15 mg intracutaneously and 0.72, 0.20. 0.08 and 0.03 mg transcutaneously, giving a 5.8- and 24.0-fold higher intra- and transcutaneous delivery of PEG400 than PEG3350 (p<0.01). This study substantiates that fractional CO(2) laser treatment allows uptake of small and large molecules into and through human skin, and that laser density can be varied to optimize intracutaneous or transcutaneous delivery.

Fractional laser-mediated photodynamic therapy of high-risk basal cell carcinomas – a randomized clinical trial

Photodynamic therapy (PDT) is approved for selected nodular basal cell carcinomas (nBCC) but efficacy is reduced for large and thick tumours. Ablative fractional lasers (AFXL) facilitate uptake of methyl aminolaevulinate (MAL) and may thus improve PDT outcome.

Fractional ablative erbium YAG laser: Histological characterization of relationships between laser settings and micropore dimensions

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.

Ablative fractional laser enhances MAL-induced PpIX accumulation: Impact of laser channel density, incubation time and drug concentration.

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.

Laser-induced thermal coagulation enhances skin uptake of topically applied compounds: LASER-INDUCED UPTAKE OF TOPICALLY APPLIED PEGs

Ablative fractional laser (AFL) generates microchannels in skin surrounded by a zone of thermally altered tissue, termed the coagulation zone (CZ). The thickness of CZ varies according to applied wavelength and laser settings. It is well‐known that AFL channels facilitate uptake of topically applied compounds, but the importance of CZ is unknown.

Lesion dimensions following ablative fractional laser treatment in non-melanoma skin cancer and premalignant lesions

Non-melanoma skin cancer (NMSC), which comprises basal cell carcinomas (BCC) and squamous cell carcinomas (SCC), is the most common human cancer with an estimated incidence of more than one million new cancers per year alone in the USA [1–5]. SCC may be preceded by precursor lesions such as actinic keratoses (AK) and SCC in situ (Bowen’s disease), whereas BCCs are regarded as invasive tumours from the beginning. The incidence of the premalignant lesions is even higher with a reported prevalence of AK at 15.4% in men over 40 years of age in a UK population [5]. Ablative fractional laser (AFXL) resurfacing has over the past 5 years gained increasing popularity due to its clinical efficacy and short healing times compared to conventional ablative laser treatment [6]. AFXL creates microscopic vertical channels in the skin, surrounded by undamaged viable tissue. These vertical laser channels, socalled microscopic ablation zones (MAZ), are surrounded by a microscopic treatment zone, which consists of a thin necrotic layer and a coagulated tissue zone [7]. Fractional ablative lasers are available as CO2 lasers (10,600 nm), erbium yttrium aluminium garnet lasers (Er:YAG, 2,940 nm) and yttrium scandium gallium garnet lasers (YSGG, 2,790 nm), all of which have a high absorption in the target chromophore, water, and thus target intraand extracellular water-rich components such as keratinocytes and vessels [6]. AFXL resurfacing is currently used in the treatment of photodamaged skin, wrinkles, and acne and burn scars, but so far not for malignant or premalignant lesions, which is the case for conventional ablative lasers [9–13]. The immediate tissue damage after AFXL and the dimensions of the laser-ablated channels can be characterized histologically [9, 15]. MAZ dimensions have previously been investigated in animal models [14] and normal skin [15–17], whereas no data to our knowledge are available on MAZ dimensions from NMSC and dysplastic lesions. As premalignant and malignant lesions differ histologically from normal skin in several aspects including content of cell types, tumour load, vascularization, and collagen and water content, AFXL may induce different ablation patterns in dysplastic skin and normal skin. Recently, AFXL-assisted drug delivery has been introduced as a novel treatment concept to intensify the biodistribution of topical pharmaceuticals [18]. In vivo studies in pigs have shown that AFXL enhances deep tissue penetration and photoactivation of topically applied methyl aminolevulinate, which is a photosensitizer used for photodynamic therapy (PDT) [18, 19]. PDT is based on photosensitizer uptake by tumour tissue followed by illumination with visible light, which in the presence of oxygen forms cytotoxic oxygen species, causing apoptosis and necrosis of tumour tissue. PDT is approved for the treatment of BCC and premalignant lesions with high cure rates of 90% being reported for superficial malignant lesions, but less effective cure rates of 70–80% for thicker lesions [20]. The inferior treatment outcome in thick lesions K. Togsverd-Bo (*) : C. S. Haak :M. Haedersdal Department of Dermatology, Bispebjerg Hospital, University of Copenhagen, Bispebjerg Bakke 23, 2400 Copenhagen, NV, Denmark e-mail: ktogsverdbo@dadlnet.dk

Topical corticosteroid has no influence on inflammation or efficacy after ingenol mebutate treatment of grade I to III actinic keratoses (AK): A randomized clinical trial.

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.

Office-based transurethral devascularisation of low grade non-invasive urothelial cancer using diode laser. A feasibility study

Frequent recurrence of non‐muscle invasive bladder tumours (NMIBC) requiring transurethral resection of bladder tumour (TUR‐BT) and lifelong monitoring makes the lifetime cost per patient the highest of all cancers. A new method is proposed for the removal of low grade NMIBCs in an office‐based setting, without the need for sedation and pain control and where the patient can leave immediately after treatment.