Ontogeny of Skin Stem Cells and Molecular Underpinnings.

Skin stem cells (SCs) play a pivotal role in supporting tissue homeostasis. Several types of SCs are responsible for maintaining and regenerating skin tissue. These include bulge SCs and others residing in the interfollicular epidermis, infundibulum, isthmus, sebaceous glands, and sweat glands. The emergence of skin SCs commences during embryogenesis, where multipotent SCs arise from various precursor populations. These early events set the foundation for the diverse pool of SCs that will reside in the adult skin, ready to respond to tissue repair and regeneration demands. A network of molecular cues regulates skin SC behavior, balancing quiescence, self-renewal, and differentiation. The disruption of this delicate equilibrium can lead to SC exhaustion, impaired wound healing, and pathological conditions such as skin cancer. The present review explores the intricate mechanisms governing the development, activation, and differentiation of skin SCs, shedding light on the molecular signaling pathways that drive their fate decisions and skin homeostasis. Unraveling the complexities of these molecular drivers not only enhances our fundamental knowledge of skin biology but also holds promise for developing novel strategies to modulate skin SC fate for regenerative medicine applications, ultimately benefiting patients with skin disorders and injuries.

Skin Development and Disease: A Molecular Perspective.

Skin, the largest organ in the human body, is a crucial protective barrier that plays essential roles in thermoregulation, sensation, and immune defence. This complex organ undergoes intricate processes of development. Skin development initiates during the embryonic stage, orchestrated by molecular cues that control epidermal specification, commitment, stratification, terminal differentiation, and appendage growth. Key signalling pathways are integral in coordinating the development of the epidermis, hair follicles, and sweat glands. The complex interplay among these pathways is vital for the appropriate formation and functionality of the skin. Disruptions in multiple molecular pathways can give rise to a spectrum of skin diseases, from congenital skin disorders to cancers. By delving into the molecular mechanisms implicated in developmental processes, as well as in the pathogenesis of diseases, this narrative review aims to present a comprehensive understanding of these aspects. Such knowledge paves the way for developing innovative targeted therapies and personalised treatment approaches for various skin conditions.

Restoration of Skin Barrier Abnormalities with IL4/13 Inhibitors and Jak Inhibitors in Atopic Dermatitis: A Systematic Review.

Background and Objectives: Atopic dermatitis is a chronic inflammatory skin disorder with a significant burden on patients' quality of life. This systematic review aims to evaluate the restoration of skin barrier abnormalities with interleukin-4/interleukin-13 (IL-4/IL-13) inhibitors and Janus kinase (JAK) inhibitors in atopic dermatitis. Materials and Methods: A comprehensive review of the literature was conducted, focusing on studies that assess the use of IL-4/IL-13 inhibitors and JAK inhibitors for atopic dermatitis. We identified eligible studies by searching Medline via PubMed with a special focus on their effect on the restoration of the epidermal barrier. Included studies evaluated the transepidermal water loss (TEWL), the reduction in epidermal thickness (ET), the improvement in ceramide synthesis, and the increase in stratum corneum hydration (SCH) with IL-4/IL-13 inhibitors and JAK inhibitors. The quality of included studies was assessed using the ROBINS-I and the RoB 2.0 tool for assessing the risk of bias. Results: Ten of the included studies concern dupilumab, while two concern JAK inhibitors. Ten were observational studies and two were randomized controlled trials (RCTs). The total number of included participants was 378 concerning dupilumab and 38 concerning JAK inhibitors. Five studies did not include any comparison group, three included healthy volunteers, two were conducted versus placebo, and two compared dupilumab with other treatments. The follow-up period ranged between 29 days and 32 weeks. The results demonstrated a significant decrease in transepidermal water loss (TEWL) and an increase in SCH on eczematous lesions for patients with sustained response to dupilumab treatment and observed improvements in ET and filaggrin (FLG) staining, which further support the efficacy of JAK inhibitors in enhancing skin barrier function. Conclusions: This review underscores the efficacy of IL-4/IL-13 inhibitors in improving skin barrier function. However, the limited number of studies focusing on JAK inhibitors and the overall lack of RCTs highlight the need for further research to establish the definitive role of IL-4/IL-13 inhibitors and JAK inhibitors in the restoration of the skin barrier.

Clinical, dermatoscopic, histological and molecular predictive factors of distant melanoma metastasis: A systematic review and meta-analysis.

BACKGROUND: Melanoma metastasis to distant sites is associated with diminished survival rates and poor prognosis. Except of Breslow thickness and ulceration that are currently used in melanoma staging, the investigation of additional clinicopathological, dermatoscopic and molecular factors that could predict tumors with aggressive biologic behavior is of paramount importance. METHODS: A literature search was conducted in PubMed, Scopus, Cochrane databases and gray literature until November 2023. Observational studies (including cohorts and case-control studies) were included and clinical and histopathological factors of primary cutaneous melanomas, along with dermatoscopic and molecular predictors of distant metastasis (DM) and distant metastasis-free survival (DMFS) were assessed. Random - effect models were preferred, the results were presented as Hazard Ratios (HRs) with 95 %Confidence Intervals (CIs) and the I2 index quantified heterogeneity. Subgroup analysis according to AJCC stage and sensitivity analysis were also conducted. RESULTS: One hundred forty-three and 101 studies were included in the qualitive and quantitative synthesis, respectively. Regarding clinical factors, males, compared to females, and head and neck location, compared to trunk, demonstrated higher risk for DM [n=36, HR 1.49, 95%CI 1.36 - 1.63, I2 33% and n=21, HR 1.24, 95 %CI 1.01 - 1.52, I2 62 %]. Both factors had similar effects on DMFS. Breslow thickness and ulceration were significant predictors or DM. Additional factors that posed an increased risk for DM were nodular (n=15, HR 2.51, 95 %CI 1.83 - 3.43, I2 56 %) and lentigo maligna subtypes (n=12, HR 1.87, 95 %CI 1.27 - 2.75, I2 0 %), compared to superficial spreading subtype, lymphovascular invasion (n=9, HR 2.05, 95 %CI 1.18 - 3.58, I2 78 %), SLN positivity and BRAF+ mutational status. In contrast, regression was a negative predictor of DM (n=15, HR 0.59, 95 %CI 0.44 - 0.79, I2 68 %). Two studies focused on dermatoscopic factors and found that low pigmentation and the presence of blue-white veil might predict DM development. The results of subgroup analysis for stage I-II patients were essentially similar and sensitivity analysis did not reveal significant alterations, despite the moderate or high heterogeneity in some categories. CONCLUSIONS: Clinical and histological characteristics of the tumor along with dermatoscopic features and molecular parameters hold significant prognostic information and could be incorporated into models to predict melanomas with high metastatic potential.

Interleukin antagonists for atopic dermatitis: a new era of therapy.

INTRODUCTION: Over the last decade, increasing understanding of the immunopathogenesis of atopic dermatitis (AD) enabled the recognition of multiple therapeutic targets and subsequently the development of novel, highly effective systemic treatments, including interleukin (IL)-antagonists. To date, the IL-4Ra-inhibitor dupilumab and the IL-13 inhibitor tralokinumab have gained regulatory approval in Europe for the treatment of moderate-to-severe AD, while more than 70 new therapeutics are currently in development. AREAS COVERED: In this review, we address the role of ILs in the pathogenesis of AD and provide an overview of the novel and investigational IL-antagonists, as regards their efficacy and safety on moderate-to-severe AD. EXPERT OPINION: Current data have established IL-4 and IL-13 inhibitors as effective and safe for the treatment of moderate-to-severe AD, as regards the rapid control of flares as well as the long-term remission of the disease. Data regarding the efficacy and safety of other IL-inhibitors, including those targeting IL-31, IL-22, IL-33, IL-36 and IL-18, are accumulating. There is still an unmet need for real-world-evidence studies and head-to-head studies for both currently available and future agents in AD treatment. Establishing predictive biomarkers of treatment response in a disorder of such considerable heterogenicity might help physicians pursue a patient-tailored therapeutic response.

Insights into Early Systemic Treatment in Atopic Dermatitis: Scientific Facts and Practical Considerations.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized clinically by pruritus, and pathophysiologically by immune dysregulation, and compromised skin barrier function. While topical therapies are currently the cornerstone of AD management, especially in mild disease, recent advancements in systemic treatments and a deeper understanding of similar skin diseases, such as psoriasis, have highlighted the importance of early intervention. In this commentary, we explore the potential benefits of early systemic intervention in AD, with pruritus determining such a decision. Building on this concept, we assume that, through the timely systemic treatment that targets the immune dysregulation present in AD, the progression of the disease could be modified, improving overall patient outcomes. Early systemic intervention may minimize systemic inflammation, halting the "atopic march" and disrupting the "itch-scratch" cycle. Managing pruritus at its root could prevent secondary complications and reduce the psychosocial burden of the disease. This paradigm shift fosters a collaborative healthcare approach that empowers patients with long-term disease control strategies. In conclusion, the safety and efficacy of novel systemic treatments offer a compelling scenario for early intervention in atopic dermatitis care.

Photodynamic Therapy for Field Cancerization in the Skin: Where Do We Stand?

INTRODUCTION: Photodynamic therapy (PDT) with a photosensitizer is available for the treatment of multiple actinic keratoses (AKs) in a restricted skin area or, as it is established, for the field-cancerized skin. OBJECTIVES: Our review aims to present the up-to-date literature on skin field cancerization using PDT employing different topical photosensitizers, modified light delivery protocols and combination treatments to obtain excellent efficacy and safety in everyday clinical practice. METHODS: We sought PubMed, MEDLINE, Scopus, OVID, Embase, Science Direct, Cochrane Library, Research Gate and Google Scholar for [(aminolevulinic acid OR aminolevulinate) AND photodynamic therapy] with (field-directed OR field cancerization, (actinic keratosis), and (efficacy OR effectiveness OR pain OR tolerability) for studies published until February 2023. RESULTS: Advantages of PDT compared to the other field treatments, including imiquimod, 5-fluorouracil, ingenol mebutate gel and diclofenac, reported better cosmetic outcomes and greater patient satisfaction. On the other hand, some drawbacks of field PDT include pain and treatment duration. Alternate illumination methods have also been investigated, including daylight as a light source. Pretreating the affected area may enhance photosensitizer absorption leading to better therapeutic results, while combinational treatments have also been tested. Patients prefer daylight PDT to traditional light sources since it is more well-tolerated and equally effective. Even as a preventive treatment, field PDT yields promising outcomes, especially for high-risk individuals, including organ transplant recipients. CONCLUSIONS: This review provides a thorough display of the field of PDT on cancerized skin, which will facilitate physicians in applying PDT more efficiently and intuitively.

Dermatoscopic shiny white structures in benign cutaneous tumours.

The dermatoscopic characteristics of shiny white structures (SWS) in malignant skin tumours are well described, but data on benign skin neoplasms are scarce. To evaluate dermatoscopic features of SWS in common benign tumours, we reviewed our database for histopathologically confirmed cases. The dermatoscopic images were evaluated for the presence of any type of SWS. Those images with SWS were further analyzed for their quantity, distribution and shape. Of 2420 evaluated benign tumours, 357 (14.8%) displayed SWS. The highest frequencies were observed in pyogenic granuloma (62/100, 62.0%), angioma (63/113, 55.8%) and adnexal tumours (42/84, 50.0%). The lowest frequency was found in common nevi (16/1032, 1.6%) and solar lentigo (0%). The presence of SWS was not associated with sex or anatomic location. SWS were usually diffuse and multiple. SWS may be present in a broad spectrum of benign tumours. Therefore, they should not be considered as de-facto indicators of malignancy.

Effect of a novel "emollient plus" formulation on mild-to-severe atopic dermatitis and other dry skin-related diseases as monotherapy or adjunctive therapy: an observational study on efficacy, tolerance and quality of life in adult patients.

BACKGROUND: Atopic dermatitis (AD), psoriasis and senile xerosis comprise common chronic and relapsing inflammatory skin disorders with clinical symptoms such as lichenification, pruritus and inflammatory lesions that affect the quality of life of patients. OBJECTIVES: In this study, we aimed to evaluate the efficacy of a novel "emollient plus" formulation (Lipikar baume AP+M), containing non-living lysates of non-pathogenic Vitreoscilla Filiformis bacteria from LaRoche-Posay Thermal Spring water, in improving quality of life, alleviating skin pain, and managing symptoms of mild-to-severe AD or skin disorders associated with dryness or severe xerosis in adults. MATERIALS & METHODS: The study included 1,399 adult patients, who participated in a two-month observational study over two visits, conducted at dermatologists' practices. Visits included clinical assessment of skin disease before and after administration of the product as well as completion of the 10-question Dermatology Life Quality Index. Questionnaires were used to evaluate efficacy, safety, satisfaction and tolerance of the product both by the dermatologists and patients, as well as assess quality of life of patients. RESULTS: Statistically significant improvement (p<0.001) by at least one grade was observed by more than 90% based on patients' evaluation of efficacy regarding intensity of the skin disease, skin dryness, surface affected by inflammatory lesions, pruritus, quality of sleep, daily discomfort, dryness and desquamation. Quality of life after two months improved by 82.6%. CONCLUSION: This study demonstrated significant reduction in symptoms of mild-to-severe skin dryness after application of the "emollient plus" formulation over two months, either alone or as adjunctive therapy.

Metformin in Hidradenitis Suppurativa: Is It Worth Pursuing Further?

Hidradenitis suppurativa (HS) often coexists with obesity, metabolic syndrome, diabetes mellitus, or impaired glucose tolerance and insulin resistance and polycystic ovarian syndrome. Metformin is a medication used for the treatment of diabetes, acting in multiple ways. There is evidence that it decreases inflammatory cytokines, some of which are implicated in the pathogenesis of HS (TNF-α, IL-17). We performed a systematic review of data regarding the efficacy and safety of metformin for the treatment of HS. Four electronic databases (MEDLINE, ScienceDirect, Cochrane Library, and ClinicalTrials.gov), as well as the abstracts compendia of major dermatologic congresses, were searched. A total of 133 patients received metformin for HS across 6 studies, 117 of whom received it as monotherapy. The great majority of participants were female, in their thirties and overweight or obese, with one study including only children. The efficacy tools employed varied widely. Four studies (106 patients) documented improvement, 1 documented treatment failure, and 1 had mixed results. Only mild and transient side effects were noted. Metformin has been tried in few HS patients with acceptable efficacy in a fair number of them. As it is generally well tolerated and reasonably priced, carefully designed clinical trials comparing it with placebo are worth performing.

Sebaceous Neoplasms.

Sebaceous neoplasms describe a group of tumors with sebaceous differentiation commonly seen in lesions located primarily in the face and neck. The majority of these lesions are benign, while malignant neoplasms with sebaceous differentiation are uncommon. Sebaceous tumors present a strong association with the Muir-Torre Syndrome. Patients suspected with this syndrome should undergo neoplasm excision, followed by histopathologic and additional immunohistochemistry and genetics examinations. Clinical and dermoscopic features of the sebaceous neoplasms, as well as management procedures collected from the literature analysis regarding sebaceous carcinoma, sebaceoma/sebaceous adenoma, and sebaceous hyperplasia are described in the current review. A special note is made for describing the Muir-Torre Syndrome in patients presenting multiple sebaceous tumors.

The Role of Tight Junctions in Atopic Dermatitis: A Systematic Review.

BACKGROUND: Tight junctions are transmembrane proteins that regulate the permeability of water, solutes including ions, and water-soluble molecules. The objective of this systematic review is to focus on the current knowledge regarding the role of tight junctions in atopic dermatitis and the possible impact on their therapeutic potential. METHODS: A literature search was performed in PubMed, Google Scholar, and Cochrane library between 2009 and 2022. After evaluation of the literature and taking into consideration their content, 55 articles were finally included. RESULTS: TJs' role in atopic dermatitis extends from a microscopic scale to having macroscopic effects, such as increased susceptibility to pathogens and infections and worsening of atopic dermatitis features. Impaired TJ barrier function and skin permeability in AD lesions is correlated with cldn-1 levels. Th2 inflammation inhibits the expression of cldn-1 and cldn-23. Scratching has also been reported to decrease cldn-1 expression. Dysfunctional TJs' interaction with Langerhans cells could increase allergen penetration. Susceptibility to cutaneous infections in AD patients could also be affected by TJ cohesion. CONCLUSIONS: Dysfunction of TJs and their components, especially claudins, have a significant role in the pathogenesis and vicious circle of inflammation in AD. Discovering more basic science data regarding TJ functionality may be the key for the use of specific/targeted therapies in order to improve epidermal barrier function in AD.

Atopic Dermatitis and Water: Is There an Optimum Water Intake Level for Improving Atopic Skin?

Water is a vital nutrient with innumerable functions for every living cell. The functions of human skin include protection against dehydration of the body. Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease that presents with dry skin, erythematous and eczematous lesions, and lichenification. This paper discusses the question of whether extra water intake in children with AD affects skin hydration and the skin barrier function. Among the methods used to treat dry skin, topical leave-on products are the first-line treatment, intended to improve hydration and the skin barrier function. The effectiveness of adequate water intake as a measure to treat dry skin is still under debate. Normal skin hydration increases with dietary water intake, particularly in those with prior lower water consumption. Skin dryness in AD is instrumental to the itch and inflammation cycle, contributing to barrier impairment and aggravating disease severity and flares. Certain emollients provide significant hydration to AD skin, with relief of dryness and reduction in barrier impairment, disease severity, and flares. Further investigations are needed to evaluate the optimum water intake levels in children with AD, as important questions remain unanswered, namely, does oral hydration provide relief of skin dryness and reduce barrier impairment, disease severity, and flares; is there any additional benefit from using mineral or thermal spring water; or is there a need to specifically study the fluid/water intake in children with AD and food allergy (FA) restrictions?

Real-Life Data on the Management of Incompletely Excised Basal Cell Carcinoma.

BACKGROUND: The histopathologic presence of basal cell carcinoma (BCC) cells at one or more margins of the specimen after surgical excision is considered suggestive of incomplete tumor clearance. The management of incompletely excised BCC might vary in different clinical scenarios from re-excision to application of other treatments or even watchful waiting. OBJECTIVE: The aims of the study were to report the real-life management of incompletely excised BCC in a tertiary referral center and compare the recurrence rates according to the selected management modality. METHODS: A retrospective study was conducted at a tertiary Dermatology Center in Northern Greece. Our electronic database was scanned over a 5-year period to retrieve all BCCs with available histopathologic assay reporting at least one involved margin (lateral or deep). The included patients were divided into 3 groups according to the selected management after incomplete excision: group 1 included those who underwent immediate re-excision (n = 26), group 2 those who were followed up without any additional therapy (n = 40), and group 3 those who were treated with adjuvant/complementary non-surgical treatment (n = 18). Finally, we recorded the presence or absence of residual tumor in the new histopathologic report of those tumors that were selected to be re-excised (group 1). The primary outcome was the appearance of clinical tumor recurrence. RESULTS: Of 1,689 BCCs recorded in our database, 84 met the inclusion criteria and were included in the analysis. Re-excision had been selected in 26 of 84 patients (group 1), watchful waiting in 40 (group 2), and non-surgical treatments in 18 (group 3). The histopathologic reports of the 26 tumors of group 1 that were re-excised revealed residual tumor in 14 (53.8%) cases. Overall, a clinical recurrence occurred in 14 of 84 patients (16.7%) after a mean follow-up of 17 months. The median time to recurrence was 14 months. Of 40 patients without any treatment, recurrence developed in 10 (25%), while only 2 of 18 patients treated with non-surgical treatments recurred (11.1%). CONCLUSIONS: Our study suggests that positive histopathologic margins after BCC excision result in a clinical recurrence only in a proportion of patients. This percentage is higher when no further treatment is applied and lower when the area is re-excised or treated with imiquimod alone or combined with cryotherapy.

The effect of menopausal hormone therapy on the risk of melanoma and keratinocyte skin cancer: A systematic review and meta-analysis of observational studies.

BACKGROUND: Whether menopausal hormone therapy (MHT) increases the risk of skin cancer is controversial. AIM: To systematically review and meta-analyze evidence regarding the association of MHT with the risk of melanoma and keratinocyte cancer (KC). MATERIAL AND METHODS: A comprehensive literature search was conducted of the PubMed, Scopus and Cochrane databases, through to 30 October 2021. Skin neoplasms were divided into melanoma and KC. In the latter category, both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) were considered. The results are presented as hazard ratios (HR) with 95 % confidence intervals (CI). The I2 index was used to assess heterogeneity. Subgroup analysis and sensitivity analysis were also conducted in order to explore potential differences among studies. RESULTS: Twenty-seven studies were included in the qualitative and 23 in the quantitative analysis, with a total of 2,612,712 menopausal women (25,126 with skin cancer; 20,150 with melanoma). MHT was associated with an increased risk of melanoma (HR 1.11; 95 % CI 1.05-1.19; I2 45%). With regard to MHT type, both estrogen monotherapy (HR 1.22, 95 % CI 1.16-1.29; I2 0%) and estrogen in combination with progestogen (HR 1.11, 95 % CI 1.05-1.18, I2 26%) significantly increased that risk. Regarding melanoma subtype, superficial spreading melanoma (SSM) and lentigo maligna melanoma (LMM) were the only histologic subtypes associated with MHT use. MHT was also associated with an increased risk of KC (HR 1.17, 95 % CI 1.04-1.31, I2 83%), specifically BCC (HR 1.22, 95 % CI 1.12-1.32; I2 29%). Longer duration (>5 years) of MHT, current use and estrogen monotherapy were associated with an increased KC risk compared with no use. CONCLUSION: The use of MHT by postmenopausal women was associated with an increased risk of melanoma and KC. This risk was higher for current MHT users and those treated for over 5 years.

Quality-of-Life Endpoints in Women of Childbearing Age with Hidradenitis Suppurativa: A Tertiary-Care-Centre-Based Study.

Background: Hidradenitis suppurativa (HS) principally affects women of childbearing age, who face gender-specific challenges and have lower life-quality than men. HS also seems to impact desire for procreation. Objective: To investigate various quality-of-life endpoints in women of childbearing age with HS. Study design: A cross-sectional questionnaire-based study was performed at a university dermatology department. Eighteen yes/no and one open-ended questions explored impact of HS on social life, sexual life, family planning, working life and healthcare-backed support. A sensitivity analysis was performed for women under 25, who are significantly less likely to be married/in a permanent relationship in Greece, as this could act as a confounding factor regarding family planning. Results: Ninety-six women were included. Most women (80.8%) carry a stigma because of HS, which also affects their choice of clothes and social relationships. Sexual impairment affects 73.1% of women. One third of women wants less or no children because of HS, 67.7% worry about its impact on pregnancy, birth, and the postpartum, and 84.6% worry about the impact of HS treatment on fertility and their babies' health. Almost 43% fear losing their job because of HS, 34.4% are discriminated against at work and 33.3% state HS has hindered their career. Most women are not adequately informed about their disease or available support groups/material and 41.7% have not received good enough care through pregnancy/postpartum. Conclusions: Life-quality endpoints should be meticulously screened in women. Multidisciplinary-led treatment should be offered during pregnancy and the postpartum.