Actinic keratosis: Current challenges and unanswered questions.

Actinic keratoses (AK) are common skin lesions associated with chronic exposure to sun. They are believed to be precursors of malignancy as they potentially may progress to invasive squamous cell carcinomas. The goal of current therapies is to reduce the number of AK and to prevent future cancer development. This review aims at providing an overview of the hallmarks of AK and skin field cancerization. We discuss epidemiology trends, risk factors and the state of the art and evidence of the current treatments. We review key figures of AK prevalence from different countries with regard to skin cancer risk and the associated economic burden of AK. We discuss the mutational status in AK lesions and the difficulties encountered by clinicians in evaluating AK visible and invisible lesions, referring to the concept of field cancerization. Based on a systematic literature review, we further evaluate the available treatment options. The presence of subclinical skin alterations in the periphery of visible AK lesions has gained a particular attention as those non-visible lesions are known to contain the same genetic changes as those found in the AK lesions themselves, prompting the concept of 'field cancerization'. Therefore, AK treatment guidelines now recognize the importance of treating the field in patients with AK. A recent systematic literature review and network meta-analysis showed that 5-FU interventions were associated with the best efficacy and a satisfactory acceptability profile compared with other field-directed therapies used in the treatment of AK. Although AK are considered quite common, they lack an accurate descriptive definition and conclusive epidemiologic data. Limited public awareness is a barrier to early and effective treatment, including prevention strategies. While different treatment options are available, there is still a limited understanding of long-term outcomes of treatment as measured by recurrence of cancer prevention.

Photoprotection: Current developments and controversies.

This review aimed at summarizing some of the key points that were discussed during the photoprotection session at the International Forum of Dermatology in 2022. This international conference was designed to address prominent topics of clinical dermatology in a holistic way, allowing to articulate multiple viewpoints. Therefore, this review does not claim to be exhaustive, but is instead intended to give an overview of recent developments and ongoing controversies in the field of photoprotection. Cumulative ultraviolet radiation (UVR) exposure is the major aetiological factor in the development of photoageing, photoimunosuppression and photocarcinogenesis. UVA (320-400 nm) penetrates into the dermis and damages DNA and other intracellular and acellular targets primarily by generating reactive oxygen species (ROS). It is the major contributor to photoageing, characterized by fine and coarse wrinkles, dyspigmentation and loss of elasticity. UVB (290-320 nm) is responsible for sunburns through direct damage to DNA by the formation of 6-4 cyclobutane pyrimidine dimers (CPDs) and pyrimidine 6-4 pyrimidone photoproducts. Both UVA and UVB exposure increase the risk of basal cell carcinoma, squamous cell carcinoma and melanoma. In recent years, visible light (VL; 400-700 nm) has also been implicated in the exacerbation of conditions aggravated by sun exposure such as hyperpigmentation and melasma. Photoprotection is a critical health strategy to reduce the deleterious effects of UVR and VL. Comprehensive photoprotection strategies include staying in the shade when outdoors, wearing photoprotective clothing including a wide-brimmed hat, and sunglasses, and the use of sunscreen. Due to the absorption of UV filters, the safety of sunscreens has been questioned. Newer sunscreens are becoming available with filters with absorption even beyond the UV spectrum, offering enhanced protection compared with older products. Prevention of photocarcinogenesis, sun-induced or sunlight-exacerbated hyperpigmentary conditions and drug-induced photosensitivity is an important reason for adopting comprehensive photoprotection strategies.

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.

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.

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.

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.

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.

Comparative efficacy of cemiplimab versus other systemic treatments for advanced cutaneous squamous cell carcinoma.

Aim: To estimate the comparative efficacy of cemiplimab, a programmed cell death protein 1 inhibitor, versus EGFR inhibitors, pembrolizumab and platinum-based chemotherapy in terms of overall survival (OS) and progression-free survival. Patients & methods: We performed an indirect treatment comparison of cemiplimab and other available systemic therapies for patients with advanced cutaneous squamous cell carcinoma. Results: Cemiplimab was associated with benefits in OS (hazard ratios range: 0.07-0.52) and progression-free survival (hazard ratios range: 0.30-0.67) versus EGFR inhibitors and pembrolizumab (data from KEYNOTE-629). Cemiplimab was more efficacious versus platinum-based chemotherapy in terms of OS. Conclusion: Cemiplimab may offer improvements in survival for advanced cutaneous squamous cell carcinoma patients compared with existing systemic therapies.

High ROS Production by Celecoxib and Enhanced Sensitivity for Death Ligand-Induced Apoptosis in Cutaneous SCC Cell Lines.

Incidence of cutaneous squamous cell carcinoma (cSCC) and actinic keratosis has increased worldwide, and non-steroidal anti-inflammatory drugs as celecoxib are considered for treatment. We show here strong anti-proliferative effects of celecoxib in four cSCC cell lines, while apoptosis and cell viability largely remained unaffected. Impeded apoptosis was overcome in combinations with agonistic CD95 antibody or TNF-related apoptosis-inducing ligand (TRAIL), resulting in up to 60% apoptosis and almost complete loss of cell viability. Proapoptotic caspase cascades were activated, and apoptosis was suppressed by caspase inhibition. TRAIL receptor (DR5) and proapoptotic Bcl-2 proteins (Puma and Bad) were upregulated, while anti-apoptotic factors (survivin, XIAP, cFLIP, Mcl-1, and Bcl-w) were downregulated. Strongly elevated levels of reactive oxygen species (ROS) turned out as particularly characteristic for celecoxib, appearing already after 2 h. ROS production alone was not sufficient for apoptosis induction but may play a critical role in sensitizing cancer cells for apoptosis and therapy. Thus, the full therapeutic potential of celecoxib may be better used in combinations with death ligands. Furthermore, the immune response against cSCC/AK may be improved by celecoxib, and combinations with checkpoint inhibitors, recently approved for the treatment of cSCC, may be considered.

[Psychiatric comorbidities in hidradenitis suppurativa/acne inversa]. / Psychiatrische Komorbidität bei Hidradenitis suppurativa/Acne inversa.

BACKGROUND: The findings of most studies suggest that depression and anxiety disorders are the most common psychiatric comorbidities in patients with hidradenitis suppurativa/acne inversa (HS/AI). METHODS: In a prospective study, 51 patients with HS/AI were further examined for psychiatric comorbidity using a standardized interview and questionnaires. RESULTS: In psychiatric examination, 29.4% of HS/AI patients had additional mental symptoms, mainly manifested as depressive disorder. The HS/AI patients were rather young and female, and they showed a high incidence of nicotine and alcohol use, and a positive family history of paternal alcohol dependence. In addition, HS/AI patients experienced more severe psychosocial impairments in the form of lack of partnership and lower school attainment. CONCLUSIONS: Acne inversa is a severe chronic inflammatory skin disease that, like other inflammatory dermatoses, is associated with mental comorbidity and psychosocial impairments. Since especially young patients are affected, a psychiatric-psychotherapeutic cotreatment should be considered already at an early stage.

Actinic keratosis: where do we stand and where is the future going to take us?

Introduction: Actinic keratosis (AK) is a chronic disease which is mainly located across areas of sun-exposed skin. Clinical and subclinical lesions coexist across a large area resulting in a field cancerization. As these lesions have the potential to transform into invasive squamous cell carcinoma (iSCC), treatment is crucial. With global prevalence increasing, AK is expected to be the most common in situ carcinoma of the skin.Areas covered: In this article, we cover the established algorithm of treating AK and give an insight into the drugs under development. There are six compounds under development covering different treatment angles, from Sinecatechin a Polyphenon E which targets the link between HPV infection and development of AK, over Tirbanibulin which targets the SRC proto-oncogene and fast proliferating cells, to Tuvatexib a small-molecule dual VDAC/HK2 modulator that has shown that it can compete with the established therapies.Expert opinion: These new treatment options are moving us further toward a more individually tailored treatment for each patient considering his abilities, the size and location of his lesions but also the genetic bases as well as individual risk of transforming into a iSCC and possibly other factors contributing to each patients individual AK lesions.

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma - short version, part 1: diagnosis, interventions for actinic keratoses, care structures and quality-of-care indicators.

Actinic keratoses (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 developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guideline is aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AK and cSCC. The guideline is also aimed at affected patients, their relatives, policy makers and insurance funds. In the first part, we will address aspects relating to diagnosis, interventions for AK, care structures and quality-of-care indicators.

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma (cSCC) - short version, part 2: epidemiology, surgical and systemic treatment of cSCC, follow-up, prevention and occupational disease.

Actinic keratoses (AKs) 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 guidelines for actinic keratosis and cutaneous squamous cell carcinoma were developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guidelines are aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AKs and cSCC. The guidelines are also aimed at affected patients, their relatives, policy makers and insurance funds. In the second part, we will address aspects relating to epidemiology, etiology, surgical and systemic treatment of cSCC, follow-up and disease prevention, and discuss AKs and cSCC in the context of occupational disease regulations.

Dicer Sequencing, Whole Genome Methylation Profiling, mRNA and smallRNA Sequencing Analysis in Basal Cell Carcinoma.

BACKGROUND/AIMS: Perturbations in the expression of microRNAs (miRNAs) and their maturing machinery components such as Dicer have been previously described for basal cell carcinoma (BCC). However, the mutational status of Dicer in BCC is unclear. Further, the sclerodermiform subtype of BCC (sBCC) has not been previously investigated regarding its methylation profile or its smallRNA expression profile via RNA sequencing. We conducted this study to investigate the mutational status of Dicer in BCC. METHODS: Dicer sequencing was performed on the Illumina MiSeq System in a total of 16 BCC samples (8 nodular BCCs, 8 sBCCs) and mapped against the human reference genome (i.e., hg19). Dicer sequencing was performed in all 16 BCC samples. We performed whole genome methylation profiling with Infinium MethylationEPIC BeadChips as well as mRNA and smallRNA sequencing in 5 sBCCs with the Illumina NextSeq500 next-generation sequencing system. RESULTS: Compared to the wildtype Dicer sequence, we found 5 to 7 variants per sBCC sample including insertion, deletion, and multiple nucleotide variants. Global methylation profiles were highly similar between groups. mRNA sequencing revealed S100A9, KRT14, KRT10, S100A8, S100A7, COX1, KRT1, COX3, and smallRNA sequencing analysis miR-21, miR-99a, miR26-a-2, let-7f, let-7g, let-7i, miR-100, and miR-205 were the most strongly expressed in sBCCs. CONCLUSION: We identified a variety of Dicer mutations that could play a role in aberrant miRNA expression in BCC. The noted RNA sequences should be further evaluated in functional studies to explore their potential pathogenetic role in sBCC.

Diclofenac Sodium 3% in Hyaluronic Acid 2.5% Gel Significantly Diminishes the Actinic Keratosis Area and Severity Index.

BACKGROUND/AIMS: Actinic keratosis area and severity index (AKASI) is a new assessment tool to quantify the severity of actinic damage on the head. Thus far, it has not been evaluated in monitoring the efficacy of field-directed topical treatments in actinic keratosis (AK) in routine clinical practice. Thus, the aim of this study was to determine treatment outcomes by using AKASI 3 months after the initiation of topical application of diclofenac sodium 3% in hyaluronic acid 2.5% gel (DFS) in patients with AKs on the head. METHODS: We performed a retrospective analysis of patients with AKs who had AKASI scores prior to and after treatment with DFS. RESULTS: Of the 24 patients included, 20 (83.3%) showed an improvement in AKASI, 2 (8.3%) a stable AKASI, and 2 (8.3%) a worsening of AKASI after a median (interquartile range) follow-up period of 91.5 days (89.8-104.3). The median AKASI reduction was 31.4% (16.7-59.1). The Wilcoxon test showed significant differences (p = 0.0008) between baseline and posttreatment AKASI values. CONCLUSIONS: AKASI is an easy-to-use quantitative tool for assessing the treatment outcome of field-directed therapies. Field-directed therapies of AK should no longer be monitored by assessments based on lesion counts alone.

Nonmelanoma skin cancer - from actinic keratosis to cutaneous squamous cell carcinoma.

Actinic keratoses (AKs) are defined as intraepithelial proliferation of atypical keratinocytes. Given their potential for progression to invasive squamous cell carcinoma, they may eventually evolve into a life-threatening disease. In recent decades, there has been a significant increase in the incidence of AKs, primarily due to changes in recreational activities and demographic trends in industrialized countries. As it is currently impossible to predict if and when a given AK might progress to invasive carcinoma, rigorous treatment of field cancerization is a key component in preventing potential progression. In addition to a broad armamentarium of procedures as well as pharmaceutical treatment options, primary prevention through diligent UV protection likewise plays a crucial role. New clinical, histomorphological, or molecular classifications are needed to be able to reliably stratify patients based on their individual risk. Especially in light of socio-economic aspects, such a step might prevent over- and undertreatment of an ever-growing patient population and help develop treatment concepts based on individual patient needs.