Efficacy and safety of tirbanibulin 1% ointment in actinic keratoses: Data from two phase-III trials and the real-life clinical practice presented at the European Academy of Dermatology and Venereology Congress 2022.

BACKGROUND: The 31st European Academy of Dermatology and Venereology (EADV) Congress took place between 7th and 10th of September 2022 in Milan, Italy. OBJECTIVES: We report presented clinical data on the efficacy/effectiveness, safety and tolerability of tirbanibulin 1% ointment that has recently been licensed for actinic keratosis (AK) of the face or scalp in adults. METHODS: Summary of presentations given at the EADV Congress. RESULTS: Prof. Pellacani presented two post hoc analyses from two phase-III trials with AK patients (NCT03285477 [N = 351] and NCT03285490 [N = 351]): A descriptive analysis of medical history, concomitant medications, and safety results confirming a favourable profile for tirbanibulin showing that number of baseline AK lesions was not correlated to severity of local skin reactions. The latter analysis showed that cases of tirbanibulin application site pain or pruritus were few, and most were found to be mild. Prof. Kunstfeld reported six real-life clinical cases in Austria showing good tirbanibulin effectiveness, safety and tolerability for the treatment of new or recurring AK lesions. Results demonstrated that after 2- to 4-month follow-up, tirbanibulin was well tolerated and effective in AK patients. Presentations by Dr. Patel confirmed good outcomes and tolerability of tirbanibulin in Olsen grade 1-2 AK (N = 12) and porokeratosis patients (N = 4) treated once daily for 5 consecutive days in the United Kingdom. Furthermore, real-world experience in solid organ transplant recipients (N = 2) demonstrated effectiveness of tirbanibulin in skin field cancerization treatment. A symposium sponsored by Almirall was conducted during the congress in which Dr. Hadshiew and Dr. Lear brought together their clinical experience in Germany and the United Kingdom respectively. Interesting clinical cases of 5 consecutive days of tirbanibulin treatment compared to other treatments were discussed with attendees, as well as current treatment needs of AK patients. CONCLUSIONS: This article provides an overview of presentations and symposium discussions, summarizing key phase-III results and real-life clinical experience with tirbanibulin shared by dermatologists across Europe.

Dermo-cosmetic spray containing Rhealba oat plantlets and Uncaria tomentosa extract in patients with mild-to-moderate cutaneous pain.

BACKGROUND: Chronic cutaneous pain has a substantial negative impact on quality of life (QoL). Dermo-cosmetics can support therapies for treatment of chronic skin diseases, providing symptomatic relief from chronic cutaneous pain and improved QoL. OBJECTIVES: To assess the global tolerance and efficacy of a dermo-cosmetic spray containing Rhealba® Oat Plantlet and Uncaria tomentosa extracts in reducing cutaneous pain when used as a monotherapy or in association with drug or dermo-cosmetic treatments in patients with an underlying skin pathology. METHODS: Patients aged ≥1 month with a cutaneous pain level ≥3 and an underlying skin pathology were provided with the spray to use up to six times daily for 6-8 weeks. Immediate effect on cutaneous pain and patient satisfaction were assessed after the first application. Global efficacy and tolerance, reduction in symptoms, improvement in QoL, pain reduction and patient overall satisfaction were assessed after 6-8 weeks. RESULTS: Immediately after the first application, significant reductions in cutaneous pain were observed across all age groups (P < 0.0001), with 94% of patients reporting a reduction in pain. After 6-8 weeks, global tolerance was rated 'very good' or 'good' for 97% of patients, and the spray was efficacious in 95% of patients. Patient satisfaction with the efficacy of the spray was 95%. QoL scores improved in 86% and 94% of patients aged ≥12 and <12 years, respectively. Findings were similar across underlying pathology and therapy types (monotherapy or in association with another therapy). CONCLUSIONS: The spray was well-tolerated and efficacious in providing symptom relief in patients with mild-to-moderate cutaneous pain, irrespective of the underlying pathology or therapy type.

Low-dose 5-fluorouracil in combination with salicylic acid for the treatment of actinic keratoses on the hands and/or forearms - results of a non-interventional study.

BACKGROUND: As an in situ carcinoma, actinic keratoses should be treated early. Previous studies on the efficacy of a low-dose 0.5% 5-fluorouracil solution in combination with 10% salicylic acid (low-dose 5-FU/SA) are mostly related to lesions appearing on the head and face. In contrast, actinic keratoses (AK) lesions of the upper extremities are considered to be difficult to treat. OBJECTIVE: The efficacy of low-dose 5-FU/SA in the treatment of actinic keratoses on the hands and/or forearms was studied for the first time in this non-interventional study (NIS) under practical conditions in a large patient population. In addition to the clinical course during therapy and a follow-up period, the length of application and adherence were documented. METHODS: As part of this NIS, 649 patients with AK were treated at 207 centres with low-dose 5-FU/SA. The data of the study were recorded at baseline, optionally during an intermediate examination, at the end of therapy and during a final assessment. RESULTS: The average number of AK lesions decreased during the entire observation period by 92%. Side-effects were documented only rarely in the form of local skin reactions (2%). The attending physicians assessed the efficacy, tolerability and safety of the therapy as being predominantly very good or good (in each case ≥90%). CONCLUSION: AK lesions on the hands and/or forearms were effectively treated with low-dose 5-FU/SA under routine conditions in dermatological practice and the treatment was well tolerated.

Polymorphous light eruption (PLE) and a new potent antioxidant and UVA-protective formulation as prophylaxis.

BACKGROUND: Polymorphous light eruption (PLE) is the most common photodermatosis. While its etiology still remains elusive, pathogenesis seems to involve UVA-induced oxidative stress and subsequent deregulation of antioxidative immune responses. Only few and often ineffective prophylactic and therapeutic measures exist to date. METHODS: In our randomized, double-blind, placebo-controlled clinical study, we compared the efficacy of a new topical formulation, consisting of 0.25%alpha-glucosylrutin (AGR) (a natural, modified flavonoid), 1% tocopheryl acetate (vitamin E) and a broad-spectrum, highly UVA-protective sunscreen (SPF 15) in a hydrodispersion gel vehicle, to a sunscreen-only gel and vehicle. Thirty patients with a history of PLE were pretreated with either the above formulation, a similar preparation (with the same concentration for vitamin E and AGR, but a different UV filter system), placebo or a SPF 15 sunscreen-only gel, 30 min prior to daily photoprovocation with UVA irradiations of 60-100 J/cm(2) to 5 x 5 cm(2) areas on the upper arms. RESULTS: After 4 days, results revealed a statistically highly significant difference (P<0.001) between the antioxidant containing formulations and placebo, and sunscreen-only formulation, respectively, in experimentally eliciting PLE. While only one patient developed clinical signs of PLE with accompanying itch in the area treated with the new antioxidant UV-protective gel formulation, 62.1% of the placebo-treated areas and 41.3% of the sunscreen-only treated areas showed mild to moderate signs of PLE. CONCLUSION: Combining a potent antioxidant with a broad-spectrum, highly UVA-protective sunscreen is far more effective in preventing PLE than sunscreen alone or placebo and should thus be employed as the prophylaxis of choice for PLE.

[Photoprotective mechanisms of human skin. Modulation by oligonucleotides]. / Photoprotektive Mechanismen in menschlicher Haut. Modulation durch Oligonukleotide.

There are at least two classic photoprotective DNA damage responses that can be elicited by UV exposure: induction of melanogenesis (tanning) and enhancement of DNA repair. Both mechanisms are mediated, at least in part, by the tumor-suppressor protein and transcription factor p53. Both of these responses can be induced in vitro as well as in vivo by small DNA fragments of specific sequences, without prior induction of actual DNA damage. The topical application of such fragments onto human skin might enhance photoprotection in human skin, as typically elicited by gradual sun exposure. The induction of photoprotection by this means, however, would not bear the mutagenic and carcinogenic risk of exposure to natural sunlight.

Stimulation of melanogenesis by DNA oligonucleotides: effect of size, sequence and 5' phosphorylation.

It has been shown that the small DNA fragment thymidine dinucleotide, (pTpT) induces photoprotective responses in cultured cells and intact skin. These responses include increased melanogenesis, enhanced DNA repair, and induction of TNF-alpha, and are accomplished, at least in part, through the induction and activation of the p53 tumor suppressor and transcription factor. Here it is reported that other, but not all, larger oligonucleotides induce the pigmentation response even more efficiently than pTpT. A 9 base oligonucleotide (p9mer) stimulated pigmentation in Cloudman S91 murine melanoma cells to 6-times the level of control cells while a 5 base oligonucleotide (p5mer#1) was inactive. In addition, the p9mer increased p21 mRNA levels and inhibited cell proliferation to a greater degree than did pTpT, consistent with the presumptive mechanism of action involving p53. Smaller, truncated versions of the p9mer also stimulated pigmentation, although to a lesser extent than did the p9mer. The ability of these oligonucleotides to stimulate pigmentation was highly dependent on the presence of a 5' phosphate group on the molecule, which was shown by confocal microscopy and fluorescent activated cell sorter (FACS) analysis to greatly facilitate the uptake of these oligonucleotides into the cells. Although the melanogenic activity of the oligonucleotides was directly related to increased length and 5' phosphorylation, nucleotide sequence is also critical because a p20mer was efficiently internalized yet was a poor inducer of pigmentation.

New roles for glial cell line-derived neurotrophic factor and neurturin: involvement in hair cycle control.

Glial cell line-derived neurotrophic factor (GDNF), neurturin (NTN), and their receptors, GDNF family receptor alpha-1 (GFRalpha-1) and GDNF family receptor alpha-2 (GFRalpha-2), are critically important for kidney and nervous system development. However, their role in skin biology, specifically in hair growth control, is as yet unknown. We have studied expression and function of GDNF, neurturin, GFRalpha-1, and GFRalpha-2 in murine skin during the cyclic transformation of the hair follicle (HF) from its resting state (telogen) to active growth (anagen) and then through regression (catagen) back to telogen. GDNF protein and GFRalpha-1 messenger RNA are prominently expressed in telogen skin, which lacks NTN and GFRalpha-2 transcripts. Early anagen development is accompanied by a significant decline in the skin content of GDNF protein and GFRalpha-1 transcripts. During the anagen-catagen transition, GDNF, GFRalpha-1, NTN, and GFRalpha-2 transcripts reach maximal levels. Compared with wild-type controls, GFRalpha-1 (+/-) and GFRalpha-2 (-/-) knockout mice show a significantly accelerated catagen development. Furthermore, GDNF or NTN administration significantly retards HF regression in organ-cultured mouse skin. This suggests important, previously unrecognized roles for GDNF/GFRalpha-1 and NTN/GFRalpha-2 signaling in skin biology, specifically in the control of apoptosis-driven HF involution, and raises the possibility that GFRalpha-1/GFRalpha-2 agonists/antagonists might become exploitable for the treatment of hair growth disorders that are related to abnormalities in catagen development.

Skin aging and photoaging: the role of DNA damage and repair.

Both genetic (intrinsic) and environmental (extrinsic) factors contribute to the phenotypic changes in cutaneous aging. However, only recently have the underlying molecular mechanisms involved in these changes been elucidated. DNA damage to both genomic and mitochondrial DNA and subsequent DNA repair contribute greatly to age-associated skin changes and carcinogenesis. Better understanding of these intricate, interwoven mechanisms involved in DNA damage and repair might help to develop new strategies in preventing and treating changes of intrinsic skin aging and photoaging, improving skin appearance and reducing the risk of skin cancer.

Age-associated decreases in human DNA repair capacity: Implications for the skin.

Multiple pathways are involved in accurate synthesis and distribution of DNA during replication, repair and maintenance of genomic integrity. An increased error rate, abovethe spontaneous mutation baseline, has been implicated in carcinogenesis and aging. Moreover, cytogenetic abnormalities are increased in Down's, Edwards', Patau's, and Klinefelter's syndromes with increasing maternal age, and in Marfan's and Apert's syndromes with paternal age. In response to DNA damage, multiple overlapping systems of DNA repair have evolved, preferentially repairing the transcribed strand within transcriptionally-active regions of the genome. These include direct reversal of dimers and specific adducts and pathways for base excision, nucleotide excision, and mismatch repair. A consensus has emerged that some DNA repair capacities decline with organism age, contradictory reports notwithstanding. As is the case for inborn defects in humans, knockout mice lacking components of nucleotide excision repair or DNA-damage checkpoint arrest have increased frequencies of skin and internal cancers, whereas mice overexpressing DNA repair genes have fewer spontaneous cancers. Oxidative stress and resultant free radicals can damage genomic and mitochondrial DNA; damage increases with age but decreases with caloric restriction. We review recent studies of long-lived C. elegans mutants which appear to involve metabolic attenuation, the role of telomere shortening and telomerase in cellular senescence, and the genetic bases of progeroid syndromes in humans. Finally, we discuss roles of extrinsic and intrinsic factors in skin aging, and their association with DNA damage, emphasizing preventive and protective measures and prospects for intervention by modulating DNA repair pathways in the skin.

Effects of topically applied antioxidants in experimentally provoked polymorphous light eruption.

BACKGROUND: Polymorphous light eruption (PLE) is the most common photodermatosis, with a prevalence of 10-20% in Western European countries and in the USA. Only few preventive measures for PLE exist, while its etiology and pathogenesis are still elusive. Recent theories on pathogenesis discuss the possible influence of oxidative stress. OBJECTIVE: The presented randomized, placebo-controlled, double-blind study examines for the first time the protective effect of 3 different topically applied antioxidative preparations in experimentally photo-induced PLE. METHOD: 30 patients with a history of PLE underwent photoprovocation after having had applied 3 different formulations with antioxidants and one formulation with the vehicle only to the extensor surface of their upper arms, representing the individual site of predilection, twice daily for 1 week prior to and during the consecutive week of photoprovocation. The antioxidants used were combinations of different concentrations of alpha-glycosylrutin, ferulic acid and tocopheryl acetate. RESULTS: Evaluation after the 4th photoprovocation revealed that the development and severity of PLE and concomitant pruritus were significantly reduced by the application of distinct combinations of antioxidants. CONCLUSION: The results offer a new insight into possible pathomechanisms of PLE and suggest a new approach for preventive and therapeutic measures.

[Blood group antigen expression in papillary carcinoma of the thyroid gland. An immunohistochemical and clinical study of expression of Lewis, ABO and related antigens]. / Blutgruppenantigenexpression in papillären Karzinomen der Schilddrüse. Eine immunhistochemische und klinische Studie über das Vorkommen von Lewis-, ABO- und verwandten Antigenen.

Nine monoclonal antibodies, lectin from Ulex europaeus and neuraminidase enzyme were employed to demonstrate the occurrence of type 1 and type 2 blood group antigens in 104 cases of papillary carcinoma of the thyroid. The reagents applied, recognize the following blood group related antigens: CA-50 (sialylated type 1 precursor), CA-19-9 (sialylated Le(a)), Le(a), Le(b), A, B, H, Le(x), sialylated Le(x), and Le(y). Immunohistochemical studies revealed that papillary carcinoma of the thyroid, in contrast to histologically normal thyroid tissue, is characterised by a progressive expression of blood group antigens. Most tumours (84%) reacted with C-50 antibody, whereas only a minority of the tissues demonstrated the CA-19-9 antigen (38%). Type 2 structures Le(x) (47%) and Le(y) (13%) were found less often than their corresponding type 1 isomers Le(a) (71%) and Le(b) (62%). Desialylation with neuraminidase increased the Le(a) and Le(x) staining intensity in 27 and 44 case, respectively. Of the A, B, H antigens the A determinants encountered most frequently (24%). Comparative examinations of sequential sections of the same tumour revealed coexpression of type 1 antigens in the same areas. In carcinomas showing type 1 and type 2 antigen reactivity, a complementary distribution of the structures in different tumour areas was often demonstrated. Some tumours presented combined type 1 and type 2 antigen expression in the same cells, however, in distinct areas within the cell. A follow-up examination was carried out in 68 of the 104 cases. The observation time ranged from 12 to 217 months. Thirteen patients suffered from recurrence, of which 7 died. While lymphatic metastases occurred in 39 tumours, distant metastases were detected in 6 patients. Most of the recurrences were found in patients with tumour classification pT4 (n = 19), whereas none of the pT1 carcinomas (n = 20) showed recurrence. The clinical results were compared to the blood group antigen expression results. There was no correlation between antigen expression and differentiation degree of the tumour. The pT4 tumours showed a significant higher expression of the CA-50, CA-19-9, Le(a) and Sialyl Le(x) structures. Carcinomas expressing the Le(y) antigen were associated with a significant higher level of metastasizing capacity. The Le(y), H type 1 and H type 2 antigens occurred more frequently in recurrent tumours (n = 14). In contrast, none of the patients whose carcinomas expressed the A-antigens (n = 14) suffered from a recurrence or hematogenous metastasis. Multiple stepwise regression analysis was carried out to check the importance of each staining and clinical factor. In this analysis, "distant metastasis' was the most important parameter, whereas the staining results were of minor statistical importance.