Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation of OBFC1.

The 10q24.33 locus is known to be associated with susceptibility to cutaneous malignant melanoma (CMM), but the mechanisms underlying this association have been not extensively investigated. We carried out an integrative genomic analysis of 10q24.33 using epigenomic annotations and in vitro reporter gene assays to identify regulatory variants. We found two putative functional single nucleotide polymorphisms (SNPs) in an enhancer and in the promoter of OBFC1, respectively, in neural crest and CMM cells, one, rs2995264, altering enhancer activity. The minor allele G of rs2995264 correlated with lower OBFC1 expression in 470 CMM tumors and was confirmed to increase the CMM risk in a cohort of 484 CMM cases and 1801 controls of Italian origin. Hi-C and chromosome conformation capture (3C) experiments showed the interaction between the enhancer-SNP region and the promoter of OBFC1 and an isogenic model characterized by CRISPR-Cas9 deletion of the enhancer-SNP region confirmed the potential regulatory effect of rs2995264 on OBFC1 transcription. Moreover, the presence of G-rs2995264 risk allele reduced the binding affinity of the transcription factor MEOX2. Biologic investigations showed significant cell viability upon depletion of OBFC1, specifically in CMM cells that were homozygous for the protective allele. Clinically, high levels of OBFC1 expression associated with histologically favorable CMM tumors. Finally, preliminary results suggested the potential effect of decreased OBFC1 expression on telomerase activity in tumorigenic conditions. Our results support the hypothesis that reduced expression of OBFC1 gene through functional heritable DNA variation can contribute to malignant transformation of normal melanocytes.

Viral reactivation following COVID-19 vaccination: a review of the current literature.

Currently, four vaccines for COVID-19 have been licensed by the European Medicines Agency: two viral vector-based vaccines and two mRNA-based vaccines. Since their approval, several cutaneous reactions related to vaccination have been reported in the literature. Among these, viral reactivations are one of the most frequent. The aim of this article was to investigate the current literature regarding viral reactivations following COVID-19 vaccination, focusing attention on pityriasis rosea (PR), herpes zoster and herpes simplex. A comprehensive literature search using various databases was performed and we included metanalyses, reviews, letters to the editor, real-life studies, case series and reports. A total of 48 articles involving 2067 patients were selected. Of these, 32, 6 and 17 articles reported varicella zoster virus (VZV) reactivation (1758 patients), herpes simplex virus (HSV) (238 patients) onset and PR (71 patients), respectively (some articles discussed more than one of these three reactivations). Possible pathogenetic mechanisms underlying viral reactivation are still not understood. Also, the possible correlations between vaccination and viral reactivation should be clarified. Certainly, vaccination should not be discouraged.

Short-, mid- and long-term efficacy of dupilumab in moderate to severe atopic dermatitis: a real life multicenter Italian study on 2576 patients.

BACKGROUND: The efficacy and safety of dupilumab in atopic dermatitis (AD) have been defined in clinical trials but limited real-world evidence on long term treatment outcomes are currently available to inform clinical decisions. OBJECTIVES: to describe long-term effectiveness and safety of dupilumab up to 48 months in patients with moderate-to-severe AD. METHODS: a multicenter, retrospective, dynamic cohort study was conducted to assess long term effectiveness and safety of dupilumab in patients with moderate to severe AD in a real-world setting. Predictors of minimal disease activity (MDA) optimal treatment target criteria (defined as the simultaneous achievement of EASI90, itch NRS score ≤1, sleep NRS score ≤1 and DLQI ≤1) were investigated. RESULTS: 2576 patients were enrolled from June 2018 to July 2022. MDA optimal treatment target criteria were achieved by 506 (21.91%), 769 (40.63%), 628 (50.36%), 330 (55.37%) and 58 (54.72%) of those that reached 4, 12, 24, 36 and 48 months of follow-up, respectively. Logistic regression revealed a negative effect on MDA achievement for conjunctivitis and food allergy at all timepoints. Adverse events (AE) were mild and were observed in 373 (15.78%), 166 (7.02%), 83 (6.43%), 27 (4.50%) and 5 (4.55%) of those that reached 4, 12, 24, 36 and 48 months of follow-up. Conjunctivitis was the most frequently reported AE during the available follow-up. AE led to treatment discontinuation in <1% of patients during the evaluated time periods. CONCLUSION: High long-term effectiveness and safety of dupilumab were confirmed in this dynamic cohort of patients with moderate to severe AD, regardless of clinical phenotype and course at baseline. Further research will be needed to investigate the effect of Th2 comorbidities and disease duration on the response to dupilumab and other newer therapeutics for AD.

Topical 5-aminolevulinic acid (ALA)-photodynamic therapy (PDT) for lichen sclerosus of face: case report and literature review.

Lichen sclerosus (LS) is a chronic inflammatory dermatosis typical of the genital region, with rare involvement of extragenital areas and particularly the face. LS therapeutic management is challenging, and common therapies including topical and systemic corticosteroids, topical calcineurin inhibitors, surgery are often ineffective. Herein, we present a case of LS occurred in a 36-year-old girl with facial involvement resistant to therapy with systemic corticosteroids and topical tacrolimus. Considering the involvement of a sensitive area, the young age of the patient, and the consistent clinical experience in using photodynamic therapy for the treatment of facial skin disease, we started a treatment with topical 5-aminolevulinic acid (ALA)-photodynamic therapy (PDT) with a dosage of 37 J/cm2 once a month. We compared our case with eight other facial LS patients from the literature and treated differently.

Unaddressed Challenges in the Treatment of Cutaneous Melanoma?

Background and Objectives: While the management of noninvasive cutaneous melanoma (CM) is typically limited to a secondary excision to reduce recurrence risk and periodic follow-up, treating patients with advanced melanoma presents ongoing challenges. Materials and Methods: This review provides a comprehensive examination of both established and emerging pharmacologic strategies for advanced CM management, offering an up-to-date insight into the current therapeutic milieu. The dynamic landscape of advanced CM treatment is explored, highlighting the efficacy of immune checkpoint inhibitors and targeted therapies, either in monotherapy or combination regimens. Additionally, ongoing investigations into novel treatment modalities are thoroughly discussed, reflecting the evolving nature of melanoma management. Results: The therapeutic landscape for melanoma management is undergoing significant transformation. Although various treatment modalities exist, there remains a critical need for novel therapies, particularly for certain stages of melanoma or cases resistant to current options. Conclusions: Consequently, further studies are warranted to identify new treatment avenues and optimize the utilization of existing drugs.

Clinical Characteristics of an Italian Patient Population with Advanced BCC and Real-Life Evaluation of Hedgehog Pathway Inhibitor Safety and Effectiveness.

BACKGROUND: Advanced basal cell carcinoma (aBCC) represents a complex and clinically heterogeneous group of lesions for which curative surgery and/or radiotherapy is unlikely. Systemic therapy with hedgehog pathway inhibitors (HHIs) changed the treatment landscape for this complex patient population. OBJECTIVES: The aims of the present study are to describe the clinical characteristics of a real-life Italian cohort diagnosed with aBCC and to investigate effectiveness and safety of HHI. METHODS: A multicenter observational study was performed by twelve Italian centers in the period January 1, 2016 - October 15, 2022. Patients aged ≥18 years and diagnosed with aBCC (locally advanced [laBCC] and metastatic BCC [mBCC]) were eligible for the study. Methods for investigating tumor response to HHI included clinical and dermatoscopic evaluation, radiological imaging, and histopathology. For HHI safety assessment, therapy-related adverse events (AEs) were reported and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: We enrolled 178 patients under treatment with HHI: 126 (70.8%) and 52 patients (29.2%) received sonidegib and vismodegib, respectively. Comprehensive data on HHI effectiveness and disease outcome were available for 132 (74.1%) of 178 patients: 129 patients had a diagnosis of laBCC (n = 84, sonidegib; n = 45, vismodegib) and 3 patients of mBCC (n = 2, vismodegib; n = 1, sonidegib, off-label). Objective response rate was 76.7% (95% confidence interval [CI]: 82.3-68.7) and 33.3% (95% CI: 88.2-1.7) for laBCC (complete response [CR]: 43/129; PR: 56/129) and mBCC (CR: 0/3; PR: 1/3), respectively. High-risk aBCC histopathological subtypes and occurrence of >2 therapy-related AEs were significantly associated with nonresponse to HHI therapy ([OR: 2.61; 95% CI: 1.09-6.05; p: 0.03] and [OR: 2.74; 95% CI: 1.03-7.9; p: 0.04]), respectively. Majority of our cohort (54.5%) developed at least 1 therapy-related AE, most of which were mild-moderate in severity. CONCLUSIONS: Our results demonstrate the effectiveness and safety profile of HHI and confirm the reproducibility of pivotal trial results in real-life clinical setting.

Hidradenitis Suppurativa and JAK Inhibitors: A Review of the Published Literature.

Background: Hidradenitis suppurativa (HS), also known as acne inversa or Verneuil's disease, is a chronic, inflammatory, recurrent, and debilitating skin disease of the hair follicles characterized by inflammatory, painful, deep-rooted lesions in the areas of the body characterized by the presence of the apocrine glands. Unfortunately, huge unmet needs still remain for its treatment. Objective: The purpose of our review was collecting all cases, case series, trials, and ongoing studies available in the literature on the use of this class of drugs for HS. Materials and Methods: The investigated manuscripts included trials, reviews, letters to the editor, real-life studies, case series, and reports. Manuscripts were identified, screened, and extracted for the relevant data following the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. Results: We selected 56 articles of which 25 met the selection criteria for our review. Among the JAK inhibitors to date, there is only one published clinical trial in the literature (Janus kinase 1 inhibitor INCB054707), a real-life study with 15 patients up to week 24 in which upadacitinib was used and a case series where tofacitinib was successfully used. Conversely, there are several ongoing clinical trials. Conclusions: Results to date in the literature show promising levels of efficacy and the safety of JAK inhibitors in HS. Several clinical trials are underway from which it will be very important to compare the available data. There are still too few studies conducted with a low sample size, so it remains critical to investigate this issue further in the future with a real-life study involving a large sample of patients in order to provide safe and viable therapeutic alternatives for HS.

Reflectance confocal microscopy for Kaposi's sarcoma treatment monitoring after intralesional vincristine chemotherapy.

Kaposi's sarcoma (KS) is a multifocal systemic disease, originating from endothelial cells mainly affecting elderly men. Intralesional chemotherapy with vinblastine or vincristine is an effective and well-tolerated treatment in patients presenting single nodules on the skin. Despite reflectance confocal microscopy represents a useful diagnostic method for many dermatological diseases, to date, there are few data regarding the use of RCM in mucocutaneous KS. Objective of this study was to evaluate the use of RCM for therapeutic follow-up in KS patients treated with intralesional vincristine. An observational retrospective study involving patients with a histological diagnosis of classic KS was conducted. All patients were treated with intralesional vincristine; reflectance confocal microscopy images were taken for each patient at baseline (T0) and 1 month after vincristine injection. Four male patients with a median age of 76.8 years were included in the study and four nodules (one for each patient) were evaluated with RCM examination before and after vincristine injections. At 1 month from intralesional vincristine treatment, therapeutic response was confirmed at RCM examination; a reduction of inflammatory cell at the stratum spinosum level in all evaluated lesions was observed; at papillary dermis levels, black luminal structures were decreased in diameter and superficial linear canalicular structures were not represented. Aggregates of inflammatory cells and of hemosiderin deposition, at the dermal level, were reduced in number. Reflectance confocal microscopy showed to be a promising method to evaluate vincristine therapeutic response in patients with KS; further studies evaluating RCM use in KS patients in order to monitor treatment efficacy are still required.

A 24-weeks real-world experience of dupilumab in adolescents with moderate-to-severe atopic dermatitis.

Dupilumab is a monoclonal antibody approved for the treatment of moderate-to-severe atopic dermatitis (AD) in patients aged ≥12 years. Large, double-blind, randomized, placebo-controlled trials showed its efficacy and safety in adolescents. However, real-life data are few. The aim of this monocentric retrospective observational study (December 2020-November 2021) was to assess the effectiveness and safety of dupilumab in AD adolescents treated for at least 24 weeks. For each patient demographic features, clinical data and adverse events (AEs) were collected. Eczema Area and Severity Index (EASI), Numerical Rating Scale (NRS) for pruritus (P-NRS) and for sleep disturbances (S-NRS), and Children Dermatology Life Quality Index (cDLQI) were assessed at baseline, week (W)4, W16, and W24. Twenty-seven patients (18 males; 15.23 ± 3.54 years) were enrolled. Dupilumab was administered subcutaneously at dosage of 600 mg induction dose, followed by 300 mg every 2 weeks in 14 (51.85%) patients with a weight ≥60 kg, while 13 (48.15%) patients with a weight <60 kg were treated with dupilumab 200 mg every 2 weeks after a loading dose of 400 mg. The mean EASI score at baseline was 26.96 ± 4.93 and significantly reduced to 3.74 ± 3.47 at W16 (<0.001), and to 3.4 ± 5.04 at W24 (p < 0.001). P-NRS (9.14 ± 0.94 at baseline vs. 2.33 ± 4.93 at W16 [p < 0.001], and 1.45 ± 2.35 at W24 [p < 0.001]), S-NRS (7.88 ± 1.64 at baseline vs. 0.92 ± 1.35 at W16 [p < 0.001], and 1.66 ± 2.84 at W24 [p < 0.0001]) and cDLQI (26.62 ± 4.45 vs. 2.18 ± 3.51 at baseline vs. 2.18 ± 3.51 at W16 [p < 0.001], and 3.4 ± 5.02 at W24 [p < 0.001]) showed a statistically significative improvement as well. Injection-site reaction (5/27; 18.52%), conjunctivitis (2/27; 7.41%), and asthenia (2/27; 7.41%) were the main AEs collected. This study seems to confirm the efficacy and safety of dupilumab in adolescents with moderate-to-severe AD also in real-life setting.

The Treatment of Advanced Melanoma: Therapeutic Update.

Cutaneous melanoma is the main cause of death for skin cancer. The majority of patients with a diagnosis of melanoma have localized disease, which can be successfully treated with surgical treatment. However, the surgical approach is not curative for advanced melanoma (AM). Indeed, the management of AM is still challenging, since melanoma is the solid tumor with the highest number of mutations and cancer cells have the capacity to evade the immune system. In the past, the treatment of AM relied on chemotherapeutic agents, without showing efficacy data. Recent knowledge on melanoma pathogenesis as well as the introduction of immunotherapies, targeted therapies vaccines, small molecules, and combination therapies has revolutionized AM management, showing promising results in terms of effectiveness and safety. The aim of this review is to assess and to discuss the role of emerging therapies for AM management in order to obtain a complete overview of the currently available treatment options and future perspectives.

Dupilumab effectiveness for the treatment of patients with concomitant atopic dermatitis and chronic rhinosinusitis with nasal polyposis.

Dupilumab is a fully human monoclonal antibody targeting interleukin (IL) 4 and IL13 pathways. We performed a retrospective observational study to evaluate the efficacy of dupilumab for the treatment of adult patients referred to our department, from January 2019 to May 2021, with a diagnosis of moderate to severe atopic dermatitis (AD) and concomitant chronic rhinosinusitis with nasal polyps (CRSwNP), with a clinical indication for dupilumab treatment. Skin disease activity was assessed using EASI, Numerical Rating Scale (NRS) for pruritus (P-NRS) and sleep (S-NRS), and Dermatology Life Quality Index (DLQI). The CRSwNP activity was evaluated using 22-item Sino-Nasal Outcome Test (SNOT-22), endoscopic nasal polyp score (ENPS), nasal congestion or obstruction score (scale 0-3), loss-of-smell score (scale 0-3), and rhinosinusitis disease severity (visual analog scale 0-10 cm). A significant improvement of all the score values was recorded assessing patients at baseline, week (W)16, and W24. In particular, concerning the CRSwNP, a reduction of ENPS score (baseline: 4.9 ± 1.85; W16: 2.49 ± 1.42, p < 0.01; W24: 1.68 ± 1.25, p < 0.01) and SNOT-22 (baseline: 35.9 ± 19.11; W16: 12.85 ± 6.31, p < 0.01; W24: 10.71 ± 7.29, p < 0.01) was observed. Furthermore, dupilumab is a labeled drug for the treatment of both AD and CRSwNP. The use of a single drug to obtain the improvement up to the near remission of AD and CRSwNP increases not only patient's compliance with the treatment, but also the benefits in terms of health cost related to these chronic diseases.

Community Knowledge About the Use, Reuse, Disinfection and Disposal of Masks and Filtering Facepiece Respirators: Results of a Study Conducted in a Dermatology Clinic at the University of Naples in Italy.

In Italy, as well as in almost all countries, the use of masks in public with several other measures has been an important health measure during the ongoing COVID-19 pandemic. The correct use of masks is essential, as a wrong use and disposal may increase the rate of contagious. Herein, we report a descriptive study evaluating the knowledge and use, reuse and disposal of masks in community settings. An anonymous questionnaire called MaSK (Mask uSe and Knowledge) questionnaire was developed and offered to patients referring at our dermatologic outpatient clinic. A total of 2562 full complete patients' questionnaires were considered for the study. Our results showed that awareness and information campaigns aimed at the general population are urgently needed in order to implement a correct use of masks and limit as much as possible the infection rate.

Neural crest-derived tumor neuroblastoma and melanoma share 1p13.2 as susceptibility locus that shows a long-range interaction with the SLC16A1 gene.

Neuroblastoma (NB) and malignant cutaneous melanoma (CMM) are neural crest cells (NCC)-derived tumors and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association studies (GWAS). We took a three-staged approach to conduct cross-disease meta-analysis of GWAS for NB and CMM (2101 NB cases and 4202 controls; 12 874 CMM cases and 23 203 controls) to identify shared loci. Findings were replicated in 1403 NB cases and 1403 controls of European ancestry and in 636 NB, 508 CMM cases and 2066 controls of Italian origin. We found a cross-association at locus 1p13.2 (rs2153977, odds ratio = 0.91, P = 5.36 × 10-8). We also detected a suggestive (P < 10-7) NB-CMM cross-association at 2q37.1 with opposite effect on cancer risk. Pathway analysis of 110 NB-CMM risk loci with P < 10-4 demonstrated enrichment of biological processes such as cell migration, cell cycle, metabolism and immune response, which are essential of human NCC development, underlying both tumors. In vitro and in silico analyses indicated that the rs2153977-T protective allele, located in an NB and CMM enhancer, decreased expression of SLC16A1 via long-range loop formation and altered a T-box protein binding site. Upon depletion of SLC16A1, we observed a decrease of cellular proliferation and invasion in both NB and CMM cell lines, suggesting its role as oncogene. This is the largest study to date examining pleiotropy across two NC cell-derived tumors identifying 1p13.2 as common susceptibility locus for NB and CMM risk. We demonstrate that combining genome-wide association studies results across cancers with same origins can identify new loci common to neuroblastoma and melanoma arising from tissues which originate from neural crest cells. Our results also show 1p13.2 confer risk to neuroblastoma and melanoma by regulating SLC16A1.

Cutaneous melanoma associated with naevi prevalence: A 15-year cross-sectional retrospective study.

BACKGROUND/OBJECTIVES: Melanoma may develop de novo or naevus associated (NAM). The exact prevalence and features of NAM are not fully elucidated. METHODS: A 15-year cross-sectional retrospective study was performed of all melanoma cases diagnosed and treated at the skin cancer centre of the University of Naples Federico II from September 2003 to August 2018. Data collected included patient's age, gender, melanoma anatomic site, Breslow thickness, and histolopathology including melanoma-associated lesion characteristics. RESULTS: A total of 1986 melanomas were included in the study. Based on histolopathogical examination, NAM represented 8.4% (n = 167) with de novo melanoma representing the great majority of the melanomas (91.6%). NAM was significantly more common in younger age compared to de novo melamoma (mean age 48 ± 14.9 vs 54.3 ± 15.9 years, P < 0.001), and more frequently involved the trunk (62.3% vs 51.8% P = 0.01). Mean Breslow thickness was significantly higher in de novo melanoma  compared to NAM (0.97 ± 1.48 mm vs 0.83 ± 0.95, P < 0.001). However, in situ melanoma was more commonly observed in de novo melanoma (n = 640, 35.2%) rather than NAM (n = 41, 24.5%; P < 0.01) whereas invasive melanoma represented 75.5% (n = 126) of NAM and 64.8% (n = 1179) of de novo melanoma, P < 0.01. CONCLUSIONS: NAM represent a small percentage of melanomas (8.4%) compared to de novo melanoma. NAM appeared to be significantly more common in younger age and more frequently involved the trunk, being associated with an overall better prognosis, due to a lower mean Breslow thickness respect to de novo melanoma.

Dermoscopic patterns of intradermal naevi.

BACKGROUND: Intradermal naevi represent a benign histopathological variant of common melanocytic naevi. Studies describing dermoscopic criteria of dermal naevi are very limited. OBJECTIVES: To identify dermoscopic features of dermal naevi in order to facilitate differential diagnosis from malignant lesions. METHODS: A 15-year retrospective study was performed to evaluate the dermoscopic characteristics of 202 dermal naevi, histopathologically diagnosed through the analysis of digital dermoscopic images performed with polarised light dermoscopy. For each lesion, vascular pattern, pigment pattern and other dermoscopic clues were evaluated. RESULTS: 147 Unna naevi and 55 Miescher naevi were included in the study. Brown pigment (37.1%) was the pigment pattern most frequently observed in both Unna and Miescher naevi, followed by cobblestone pattern (30.6%) in Unna naevi and white areas (23.6%) and dotted/globule pattern (20%) in Miescher naevi. As regards the vascular patterns, the polymorphic one was the most frequently observed (34.6%). The combination between comma-shaped and arborising vessels was the most common among all naevi. CONCLUSIONS: Our study describes the dermoscopic features of dermal naevi that may help to differentiate them from malignant lesions such as basal cell carcinoma, amelanotic melanoma and Spitz naevi.

Hailey-Hailey disease successfully treated with vitamin D oral supplementation.

Hailey-Hailey disease (HHD) also known as familial benign chronic pemphigus is a rare autosomal dominant genodermatosis. HHD treatment is often not satisfactory and hence, various modalities of treatment have been tried. We describe the case of a 37-year-old woman with a 2 years history of macerated erythematous plaques along with erosions, fissures, and crusts located on axillae and submammary areas, successfully treated with only oral supplementation of vitamin D (800 I.U./die) for 3 months. We reported this case to suggest that oral vitamin D may be enumerated in the various treatments proposed for HHD so far due to its rapid efficacy on skin lesions and symptoms.

Management of clinical and subclinical actinic keratoses with histological and immunohistochemical assessments by confocal microscopy.

Reflectance confocal microscopy has been used to monitor treatment efficacy in non-melanoma skin cancer, but few studies have compared different therapies using the same confocal criteria. We compare a single score designed in previous study to evaluate confocal, histological, and immunohistochemical results obtained before and after two treatments of actinic keratosis (AK) and in field cancerisation area. Thirty volunteer male patients, aged >50-year old, with at least three clinically visible AKs on the bald scalp, were included in this study: 15 patients were submitted to 3% diclofenac therapy and 15 to 5% fluorouracil therapy. Confocal imaging was performed on a 5 × 5 cm skin area. In five patients of each group we performed cutaneous biopsies. Scaling, upper nucleated cells, and inflammatory cells showed a higher percentage reduction in field cancerisation, especially in diclofenac treatment group, while in AK inflammatory cells showed a greater percentage reduction in 5-fluorouracil treatment group. Both therapies are efficacious, but their effectiveness is different on the single parameters of the confocal, histology, immunohistochemically.