BackgroundNon‐melanoma skin cancer (NMSC) and actinic keratosis (AK) are very common among fair‐skinned individuals. A disease continuum from AK to squamous cell carcinoma (SCC) has been frequently postulated. AK and NMSC may influence quality of life (QL) of patients, and it can be suspected that disease progression entails a QL reduction. The purpose of this study was to document QL in patients with NMSC and AK using the health‐outcome questionnaire EQ‐5D‐5L.MethodsThe study was designed as a non‐interventional, prospective, cross‐sectional study. Patients with AK, SCC, basal cell carcinoma (BCC) or multiple diagnoses were enrolled in this study in 29 dermatological centres across Germany. Patients were asked to complete the EQ‐5D‐5L (compromising EQ Index and EQ VAS), and the dermatologists provided diagnosis, disease history and treatment data.ResultsA total of 1184 patients were enrolled and diagnosed as follows: 73% AK, 49% BCC and 17% SCC. 66% had a single diagnosis, 28% two different diagnoses and 6% three different diagnoses. QL was strongly associated with patients’ diagnosis. Patients with a single AK diagnosis had significantly higher mean EQ VAS (78) than patients with BCC (74), SCC (72), and BCC plus SCC (69), P < 0.050. When the effects of disease progression were calculated, patients with AK plus SCC reported significantly less mean EQ VAS (71) than patients with a single AK diagnosis (78), P < 0.011.ConclusionsWhile rarely being imminently life‐threatening, NMSC and AK have an impact on QL as quantified by the EQ‐5D‐5L. This impact is associated with diagnosis (AK vs. NMSC) and clinical progression (AK vs. AK plus SCC). Both lead to a clear decline in QL. This shows that disease progression is perceived and judged as detrimental by patients and that AK and NMSC should be diligently treated to preserve and restore QL.

In spite of the 50% lower ALA content BF-200 ALA triggers significantly higher PpIX concentrations than the 20% ALA formulation, indicating that clinical efficacy with BF-200 ALA may be higher. Moreover, the ex vivo eyelid skin model may represent a useful tool to investigate drug permeation in human skin.

Photodynamic therapy is widely used in the treatment of superficial skin cancers. 5-Aminolevulinic acid (ALA) and its methylated form, methyl-ALA (MAL), are frequently used as precursors to photosensitizing substances. Nevertheless, the mechanism of the uptake of ALA and MAL in keratinocytes and of their skin penetration is still controversial. Since both compounds are not sufficiently lipophilic to penetrate through lipid membranes, they must employ specific uptake systems which may vary between different cell types. Here, we studied ALA and MAL uptake in keratinocyte cell lines originating from healthy cells (CCD 1106 KERTr cells) or keratinocyte tumors (A431 cells). ALA uptake resulted in faster protoporphyrin IX (PpIX) production than MAL uptake. A pharmacological characterization of the uptake systems revealed that PpIX formation was most efficiently reduced with GABA transporter (GAT) substrates. GABA, β-alanine, and (S)-SNAP-5114 reduced ALA uptake and, to a lesser extent, MAL uptake in the cell lines. The pharmacology of these compounds indicates that ALA and MAL are taken up by normal and pathological keratinocytes via GAT-3. Furthermore, the amino acids arginine, cysteine, and histidine also inhibited the uptake of ALA, and even more so MAL, suggestive of an additional involvement of amino acid transporters. To show that PpIX formation in vivo is restricted to the application site, which has been questioned for ALA in one other report, we applied clinically used ALA and MAL formulations to the skin of nude mice. Contrary to the results of these previous authors, the resulting PpIX fluorescence increased over time and was restricted to the application site for both preparations.

Background Mutations in kinetochore gene KNSTRN accelerate the development of cutaneous squamous cell carcinoma (SCC) and may correlate with different histological classifications of actinic keratosis (AKs). Objective To determine KNSTRN gene mutation frequency in healthy skin (HS), actinically damaged skin (ADS), in AKs with different histomorphological gradings and invasive SCCs. Methods All samples were histologically evaluated. AK lesions were additionally classified according to their upwards (AK I–III) and downwards (PRO I–III) directed growth pattern. Mutation analyses of all samples were performed using the Sanger method. Results With one exception, all detected mutations in KNSTRN gene showed an alanine‐to‐glutamate substitution at codon 40 (p.Ala40Glu). p.Ala40Glu mutation was found in 6.9% (2/29) of HS, in 16.1% (5/31) of ADS, in 18.3% (20/109) of AKs and in 30.0% (9/30) of invasive SCCs. Further stratification of AKs using the common AK classification of Röwert‐Huber revealed the p.Ala40Glu mutation in 14.7% (5/43), 13.3% (4/30) and 24.4% (11/45) (AK I, II and III). In contrast, the new PRO classification showed a distribution of 3.6% (1/28) in PRO I, 21.7% (13/60) in PRO II and 28.6% (6/21) in PRO III. Mutation frequency in HS showed significant differences compared to AKs classified as PRO III and invasive SCCs (P < 0.05). In contrast, there were no statistically significant differences between HS and AKs when classified according to Röwert‐Huber. Conclusions Recurrent somatic mutation p.Ala40Glu in KNSTRN gene is associated with basal proliferating AKs in accordance with invasive SCCs. This supports the impact of basal proliferative pattern in terms of progression.

Application of δ-aminolevulinic acid (ALA) or its methyl ester (MAL) onto cutaneous tumours increases intracellular Protoporphyrin IX (PpIX), serving as photosensitizer in photodynamic therapy (PDT). While PDT is highly effective as treatment of neoplastic skin lesions, it may induce severe pain in some patients. Here, we investigated ALA and MAL uptake and PpIX formation in sensory neurones as potential contributor to the pain. PpIX formation was induced in cultured sensory neurones from rat dorsal root ganglion by incubation with ALA or MAL. Using inhibitors of GABA transporters (GAT), a pharmacological profile of ALA and MAL uptake was assessed. GAT mRNA expression in the cultures was determined by RT-PCR. Cultured sensory neurones synthesised Protoporphyrin IX (PpIX) from extracellularly administered ALA and MAL. PpIX formation was dose- and time-dependent with considerably different kinetics for both compounds. While partial inhibition occurred using L-arginine, PpIX formation from both ALA and MAL could be fully blocked by the GABA-Transporter (GAT)-2/3 inhibitor (S)-SNAP 5114 with similar K (i) (ALA: 195 ± 6 μM; MAL: 129 ± 13 μM). GAT-1 and GAT-3 could be detected in sensory neurons using RT-PCR on mRNA level and using [³H]-GABA uptake on protein level. Cultured sensory neurones take up ALA and MAL and synthesize PpIX from both, enabling a direct impact of photodynamic therapy on cutaneous free nerve endings. The pharmacological profile of ALA and MAL uptake in our test system was very similar and suggests uptake via GABA and amino acid transporters.