European consensus-based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes).

A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology, the European Dermatology Forum, the European Academy of Dermatology and Venereology, and the European Union of Medical Specialists was formed to develop European recommendations on AK diagnosis and treatment, based on current literature and expert consensus. This guideline addresses the epidemiology, diagnostics, risk stratification and treatments in immunocompetent as well as immunosuppressed patients. Actinic keratoses (AK) are potential precursors of cutaneous squamous cell carcinoma (cSCC) and display typical histopathologic and immunohistochemical features of this malignancy in an early stage. They can develop into cSSC in situ and become invasive in a low percentage of cases. AK is the most frequent neoplasia in white populations, frequently occurring within a cancerous field induced by ultraviolet radiation. Since it cannot be predicted, which lesion will progress to cSCC and when treatment is usually recommended. The diagnosis of AK and field cancerization is made by clinical examination. Dermatoscopy, confocal microscopy, optical coherence tomography or line-field confocal-OCT can help in the differential diagnosis of AK and other skin neoplasms. A biopsy is indicated in clinically and/or dermatoscopically suspicious and/or treatment-refractory lesions. The choice of treatment depends on patients' and lesion characteristics. For single non-hyperkeratotic lesions, the treatment can be started upon patient's request with destructive treatments or topical treatments. For multiple lesions, field cancerization treatment is advised with topical treatments and photodynamic therapy. Preventive measures such as sun protection, self-examination and repeated field cancerization treatments of previously affected skin areas in high-risk patients are advised.

Evaluating the Efficacy and Safety of 4% 5-Fluorouracil Cream in Patients with Actinic Keratosis: An Expert Opinion.

Actinic keratosis is a lesion that develops in sun-exposed areas of the skin and is considered to be a precancerous condition or an early in situ squamous cell carcinoma. Treatment of actinic keratosis is important for reducing skin cancer risk, with treatment choice based on patient-, lesion- and treatment-related considerations. Of the topical treatments used for field-directed therapy, those containing 5-fluorouracil are among the most effective and widely prescribed. The most recently developed topical 5-fluorouracil preparation (Tolak®; Pierre Fabre, France) contains 4% 5-fluorouracil in an aqueous cream. This narrative review discusses data on 4% 5-fluorouracil cream to treat actinic keratosis, and provides the authors' expert opinion on issues associated with it use. The effect of the cream has been evaluated in phase 2 and 3 trials of adult patients with actinic keratosis on the face, ears or scalp. These trials included patients with severe baseline disease, defined by high lesion counts and large-size treatment fields, which possibly affected the proportion of patients who were able to achieve complete clearance. Other efficacy parameters (e.g. percentage change in lesion count, ≥ 75% clearance of lesions or clinically significant changes in validated severity scales) should also be assessed to fully evaluate 4% 5-fluorouracil treatment efficacy in these patients. Nevertheless, 4% 5-fluorouracil is associated with high efficacy, a low level of recurrence and a satisfactory safety profile.

S3 guideline "actinic keratosis and cutaneous squamous cell carcinoma" - update 2023, part 2: epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

Actinic keratosis (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was updated and expanded by the topics cutaneous squamous cell carcinoma in situ (Bowen's disease) and actinic cheilitis. The guideline is aimed at dermatologists, general practitioners, ear nose and throat specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings, as well as other medical specialties, policy makers and insurance funds involved in the diagnosis and treatment of patients with AK and cSCC. A separate guideline exists for patients and their relatives. In this part, we will address aspects relating to epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

European consensus-based interdisciplinary guideline for diagnosis and treatment of basal cell carcinoma-update 2023.

Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multidisciplinary experts from European Association of Dermato-Oncology (EADO), European Dermatology Forum, European Society for Radiotherapy and Oncology (ESTRO), Union Européenne des Médecins Spécialistes, and the European Academy of Dermatology and Venereology developed updated recommendations on diagnosis and treatment of BCC. BCCs were categorised into 'easy-to-treat' (common) and 'difficult-to-treat' according to the new EADO clinical classification. Diagnosis is based on clinico-dermatoscopic features, although histopathological confirmation is mandatory in equivocal lesions. The first-line treatment of BCC is complete surgery. Micrographically controlled surgery shall be offered in high-risk and recurrent BCC, and BCC located on critical anatomical sites. Topical therapies and destructive approaches can be considered in patients with low-risk superficial BCC. Photodynamic therapy is an effective treatment for superficial and low-risk nodular BCCs. Management of 'difficult-to-treat' BCCs should be discussed by a multidisciplinary tumour board. Hedgehog inhibitors (HHIs), vismodegib or sonidegib, should be offered to patients with locally advanced and metastatic BCC. Immunotherapy with anti-PD1 antibodies (cemiplimab) is a second-line treatment in patients with a progression of disease, contraindication, or intolerance to HHI therapy. Radiotherapy represents a valid alternative in patients who are not candidates for or decline surgery, especially elderly patients. Electrochemotherapy may be offered when surgery or radiotherapy is contraindicated. In Gorlin patients, regular skin examinations are required to diagnose and treat BCCs at an early stage. Long-term follow-up is recommended in patients with high-risk BCC, multiple BCCs, and Gorlin syndrome.

Multi-omics approach to understand the impact of sun exposure on an in vitro skin ecosystem and evaluate a new broad-spectrum sunscreen.

A reconstructed human epidermal model (RHE) colonized with human microbiota and sebum was developed to reproduce the complexity of the skin ecosystem in vitro. The RHE model was exposed to simulated solar radiation (SSR) with or without SPF50+ sunscreen (with UVB, UVA, long-UVA, and visible light protection). Structural identification of discriminant metabolites was acquired by nuclear magnetic resonance and metabolomic fingerprints were identified using reverse phase-ultra high-performance liquid chromatography-high resolution mass spectrometry, followed by pathway enrichment analysis. Over 50 metabolites were significantly altered by SSR (p < 0.05, log2 values), showing high skin oxidative stress (glutathione and purine pathways, urea cycle) and altered skin microbiota (branched-chain amino acid cycle and tryptophan pathway). 16S and internal transcribed spacer rRNA sequencing showed the relative abundance of various bacteria and fungi altered by SSR. This study identified highly accurate metabolomic fingerprints and metagenomic modifications of sun-exposed skin to help elucidate the interactions between the skin and its microbiota. Application of SPF50+ sunscreen protected the skin ecosystem model from the deleterious effects of SSR and preserved the physiological interactions within the skin ecosystem. These innovative technologies could thus be used to evaluate the effectiveness of sunscreen.

Basal Proliferation and Acantholysis May Represent Histological High-Risk Factors for Progression into Invasive Squamous Cell Carcinoma: A Comparison Study in Solid Organ Transplant Recipients and Matched Immunocompetent Patients.

Histological risk factors of AKs cannot be directly determined. Recent studies indicate that AKs restricted to the lower third of the epidermis (AK I), with marked basal proliferation (PRO III) and acantholysis, are associated with an increased risk of progression to invasive squamous cell carcinoma (iSCC). To confirm the aforementioned histological risk factors, this study compared AKs from solid organ transplant recipients (sOTRs), known to carry an up to 250-fold higher risk for progression into iSCC, to a matched immunocompetent control group (ICG). In total, 111 AKs from 43 sOTRs showed more AKs (n = 54, 48.7%) graded as AK I compared to 35 AKs (31.5%) in the ICG (p = 0.009). In line with these findings, 89 AKs (80.2%) from sOTRs showed pronounced basal proliferation (PRO III) compared to 37 AKs (33.3%) in the ICG (p < 0.0001). Acantholysis was more frequent in sOTRs than the ICG (59.5% vs. 32.4%, p < 0.0001) and more frequently associated with advanced basal proliferation (p < 0.0001). In conclusion, this study showed that acantholytic AKs graded as AK I and PRO III are predominantly found in a population at high risk of iSCC. Thus, AKs with marked basal proliferation and acantholysis should be assumed to be histological high-risk factors for the progression into iSCC.

Severity of Local Skin Reactions with 4% 5-Fluorouracil Plus Emollient versus 4% 5-Fluorouracil Alone in Patients with Actinic Keratosis: A Single-Blind Randomised Trial.

INTRODUCTION: Topical 5-fluorouracil (5-FU)-containing treatments are effective for actinic keratosis (AK); however, they frequently lead to transient local skin reactions (LSRs), which often result in treatment non-adherence. METHODS: The aim of this international, phase IV clinical trial was to investigate whether addition of an emollient to topical 4% 5-FU would reduce the frequency and severity of LSRs over 4 weeks of treatment (intervention group) compared with 4% 5-FU alone (control group) in patients with AK. The primary objective was to assess the severity of LSRs (i.e. erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration) at week 4 of treatment (or before, in case of a major local reaction). Key secondary objectives were LSR total scores at weeks 2 and 8, the scores of individual LSR items at each visit, and the proportions of patients with 100% and ≥ 75% AK lesion clearance at week 8. RESULTS: In total, 141 patients were included in the efficacy analysis (71 in the intervention group and 70 in the control group). There were no statistically or clinically significant differences between the treatment groups in terms of LSR total score at week 4 (overall and by subgroups defined by the number of lesions and patient age at baseline), scores of individual LSR items at any time point, and AK lesion clearance rates at week 8. LSR scores with topical 4% 5-FU alone were lower than expected. Skin reactions were the most common treatment-emergent adverse events in both groups, leading to treatment discontinuation in nine patients (12.3%) in the intervention group and seven (9.9%) in the control group. No new safety signals were observed with the addition of an emollient to 4% 5-FU. CONCLUSIONS: Daily emollient applications during the 4-week treatment course did not impact the safety and efficacy profile of 4% 5-FU.

Merkel Cell Carcinoma: An Update and Review.

Merkel cell carcinoma (MCC) is a rare, very aggressive skin cancer with a high mortality rate and a high tendency of metastatic spread [...].

Epidemiology of Merkel Cell Polyomavirus Infection and Merkel Cell Carcinoma.

Merkel cell polyomavirus (MCPyV) is a ubiquitous virus replicating in human dermal fibroblasts. MCPyV DNA can be detected on healthy skin in 67−90% of various body sites, and intact virions are regularly shed from the skin. Infection occurs early in life, and seropositivity increases from 37 to 42% in 1- to 6-year-olds to 92% in adults. Merkel cell carcinoma (MCC) is a rare but very aggressive neuroendocrine tumor of the skin. It develops mainly on sun-exposed areas as a fast-growing, reddish nodule. Two MCC entities exist: about 80% of MCC are MCPyV-associated. Tumorigenesis is driven by viral integration into the host genome and MCPyV oncogene expression. In MCPyV-negative MCC, UV radiation causes extensive DNA damage leading to the deregulation of the cell cycle. In recent decades, MCC incidence rates have increased worldwide, e.g., in the United States, from 0.15 in 1986 to 0.7/100,000 in 2016. Risk factors for the development of MCC include male sex, older age (>75 years), fair skin, intense UV exposure, and immunosuppression. Projections suggest that due to aging populations, an increase in immunosuppressed patients, and enhanced UV exposure, MCC incidence rates will continue to rise. Early diagnosis and prompt treatment are crucial to reducing high MCC morbidity and mortality.

The Role of Hormones in Hidradenitis Suppurativa: A Systematic Review.

Hidradenitis suppurativa (HS) is a chronic inflammatory disease manifesting in inverse body regions. In a systematic review, the role of hormones in HS will be presented to better understand the pathomechanisms of HS. The review is based on the PRISMA criteria. Systematic research was carried out using keywords. Subsequently, the data were analyzed based on the clinical response and other relevant information. The main focus of our systematic review was on HS manifestation, exacerbation, sex hormones, antiandrogen therapy, thyroid function, polycystic ovary syndrome, insulin resistance, and adipokines. In HS, there appears to be a dysregulated adipokine release that is shifted towards pro-inflammatory adipokines. Insulin resistance is significantly more common in HS than in healthy patients regardless of BMI, age, and gender. Insulin resistance in HS patients leads to further cardiovascular disease. The mechanism of insulin resistance and role of adipokines should be investigated in future studies to better provide the pathomechanisms of HS. The role of androgens seems to be important in a certain subgroup of female patients. Anti-androgenic therapy can be useful and helpful in some patients. However, further studies are needed to better understand the hormonal relationship in HS.

Tirbanibulin for Actinic Keratosis: Insights into the Mechanism of Action.

Actinic keratosis (AK) is a common pre-neoplastic skin lesion constituted by uncontrolled proliferation of atypical keratinocytes that may evolve to squamous cell carcinoma. With global prevalence increasing, AK is expected to be the most common carcinoma of the skin. Tirbanibulin is a reversible tubulin polymerization inhibitor with potent anti-proliferative and anti-tumoral effects. In-vivo and in-vitro studies have shown that tirbanibulin significantly inhibits cell proliferation, tumor growth and downregulates Src signaling with no overt toxicity. Early phase and Phase III trials have shown high lesion clearance, compliance, and few side effects of once daily tirbanibulin treatment. This review discusses tirbanibulin anti-cancer activity, focusing on tubulin polymerization and Src signaling inhibitory effects, highlighting relevant literature and novel preclinical results from the ATNXUS-KX01-001 study. Furthermore, we address the relevant findings obtained in recent clinical trials to evaluate the safety, efficacy, pharmacokinetics, clearance efficacy, and side effects of the 1% tirbanibulin ointment applied once daily. In summary, we highlight preclinical and clinical evidence on the use of tirbanibulin as an effective and safe treatment option for AK.

Einflussfaktoren auf oberflächliche und tiefe Beinvenenthrombosen nach Schaumverödung von Krampfadern.

HINTERGRUND: Bei einer Schaumsklerosierungstherapie von Varizen können als Nebenwirkungen sowohl tiefe (TVT) als auch oberflächliche Beinvenenthrombosen (OVT) auftreten. Noch weitgehend unklar sind die Risikofaktoren, welche die Entstehung einer OVT oder TVT nach Schaumsklerosierung begünstigen. Das Ziel dieser retrospektiven Analyse war, anhand eines größeren Kollektivs von Patienten mit thromboembolischen Komplikationen sowohl patienten- als auch eingriffsbezogene Risikofaktoren für thromboembolische Komplikationen durch eine Schaumsklerosierung herauszuarbeiten. PATIENTEN UND METHODIK: Insgesamt wurden 170 Patienten untersucht, die eine Schaumsklerosierung erhielten. Vor dem Stichtag 17. März 2020 wurden die letzten 85 Patienten mit thromboembolischen Komplikationen als Studiengruppe A und die letzten 85 Patienten ohne thromboembolische Komplikationen als Kontrollgruppe B nach Sklerosierung mit aufgeschäumtem Sklerosierungsmittel erfasst und verglichen. ERGEBNISSE: Patienten mit thromboembolischen Komplikationen hatten häufiger eine Thrombophilie (11/85 vs. 3/85). Die mittleren BMI-Werte waren in Gruppe A (25,9 ± 5,1) signifikant niedriger als in Gruppe B (28,0 ± 7,2) (P = 0,034). Thromboembolische Komplikationen zeigen sich nach Schaumsklerosierung eher am Unterschenkel (61/105) als am Oberschenkel (1/13) (P < 0,001) dabei häufiger nach dorsaler als nach ventraler Schaumsklerosierung (39 von 47 vs. 5 von 40, P < 0,001). Von den 39 thromboembolischen Komplikationen am dorsalen Unterschenkel waren 23 Muskelvenenthrombosen. SCHLUSSFOLGERUNG: Das Risiko für Muskelvenenthrombosen nach Schaumsklerosierung ist vor allem bei schlanken Patienten, welche am dorsalen Unterschenkel sklerosiert werden, erhöht.

Inhibition of Cell Proliferation and Cell Viability by Sinecatechins in Cutaneous SCC Cells Is Related to an Imbalance of ROS and Loss of Mitochondrial Membrane Potential.

The term sinecatechins designates an extract containing a high percentage of catechins obtained from green tea, which is commercially registered as Veregen or Polyphenon E (PE) and may be considered for treatment of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis (AK). As shown here, treatment of four cSCC cell lines with 200 µg/mL of PE resulted in strong, dose-dependent decrease in cell proliferation (20-30%) as well as strongly decreased cell viability (4-21% of controls, 48 h). Effects correlated with loss of mitochondrial membrane potential, whereas early apoptosis was less pronounced. At the protein level, some activation of caspase-3 and enhanced expression of the CDK inhibitor p21 were found. Loss of MMP and induced cell death were, however, largely independent of caspases and of the proapoptotic Bcl-2 proteins Bax and Bak, suggesting that sinecatechins induce also non-apoptotic, alternative cell death pathways, in addition to apoptosis. Reactive oxygen species (ROS) were downregulated in response to PE at 4 h, followed by an increase at 24 h. The contributory role of initially reduced ROS was supported by the antioxidant N-acetyl cysteine, which in combination with PE further enhanced the negative effects on cell viability. Thus, sinecatechins inhibited cell proliferation and viability of cSCC cells, which could suggest the use of PE for AK treatment. The mechanisms appear as linked to an imbalance of ROS levels.

Factors influencing superficial and deep vein thrombosis after foam sclerotherapy in varicose veins.

BACKGROUND: Side effects of foam sclerotherapy for varicose veins can include both deep (DVT) and superficial leg vein thrombosis (SVT). The risk factors that favor the development of SVT or DVT after foam sclerotherapy are still largely unclear. The aim of our retrospective analysis was to use a larger group of patients with thromboembolic complications to identify both patient-related and procedure-related risk factors for thromboembolic complications from foam sclerotherapy. PATIENTS AND METHODS: A total of 170 patients who received foam sclerotherapy were examined. With reference to a cut-off date, March 17th, 2020, the 85 most recent patients with thromboembolic complications (study group A) were included and compared to the most recent 85 patients without thromboembolic complications (control group B), after sclerotherapy with foamed sclerosant. RESULTS: Patients with a thromboembolic complication were more likely to have thrombophilia (11/85 vs. 3/85). The mean BMI values in group A (25.9 ± 5.1) were significantly lower than in group B (28.0 ± 7.2) (P = 0.034). Thromboembolic complications were more likely to appear after foam sclerotherapy on the lower leg (61/105) than on the thigh (1/13) (P < 0.001), particularly after dorsal than after ventral foam sclerotherapy (39 of 47 vs. 5 of 40, P < 0.001). Of the 39 thromboembolic complications on the dorsal lower leg, 23 were muscle vein thromboses. CONCLUSION: The risk of muscle vein thrombosis after foam sclerotherapy is especially increased in slender patients with sclerosed, dorsal lower legs.

The Overall Number of Actinic Keratosis Lesions Is Not Predictable by the Number of Visible Lesions: Consequences for Field-Directed Therapies.

Actinic keratoses are keratotic lesions occurring on skin areas extensively damaged by sunlight. Using data from a previously published Phase III randomized, controlled clinical trial in patients with at least 5 actinic keratoses, we explored the potential link between the number of visible actinic keratosis lesions before any treatment and the total number of lesions of the field cancerization as revealed by 5-fluorouracil cream. Our analysis suggests that the baseline number of visible actinic keratoses is a poor indicator of the real number of lesions in the field of cancerization, reinforcing the need to explain the field cancerization concept to patients. (Curr Ther Res Clin Exp. 2022; 82:XXX-XXX) © 2022 Elsevier HS Journals, Inc.