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Background: Advanced cutaneous squamous cell carcinoma (aCSCC) represents an area of unmet clinical need, with no standardized treatments until the recent approval of immune checkpoint inhibitors (ICIs). Objectives: The aim of the study was to describe clinical characteristics and therapeutic strategies of a real-life Italian cohort of aCSCC patients managed at the beginning of cemiplimab approval as compassionate use in Italy. Methods: A multicenter retrospective study was performed by 10 Italian centers in the period January 1, 2018–May 31, 2020. Patients aged ≥18 years and diagnosed with aCSCC (locally aCSCC and metastatic CSCC) were eligible for the study. Analysis of patients’ characteristics and treatment strategies was performed. Results: 239 patients were initially recruited in the study: 19 patients were excluded due to incomplete data collection, yielding a final cohort of 220 patients, of which 191 and 220 were included for patients’ clinical characteristics and therapeutic intervention analysis, respectively. Median age at the time of diagnosis was 81 years (range: 72–86); nodal metastases were detected in 64/220 (29%) patients, and distant metastatic spread was reported in 33/220 (15%) patients. Most of our patients referred chronic occupational and/or recreational sun exposure, experienced ≥1 sunburn during their lifetime, never wore hats or used photoprotective filters, and presented with signs of cumulative sun damage (solar lentigines and/or actinic keratosis). Majority of our cohort received at least one intervention directed to the primary tumor (n = 212, 96.3%); surgery and radiotherapy were the most common therapeutic choices. Immunotherapy was administered to a small number of patients as compassionate use, especially in the metastatic setting. Conclusions: Our study outlines the complex and heterogeneous clinical and therapeutic landscape of aCSCC patients at the beginning of ICI era, highlighting the need of a standardized care for this fragile and high-need patient population.

Background: The neutrophil/lymphocyte ratio (NLR) at baseline has been demonstrated to correlate with higher stages of disease and to be a prognostic factor in numerous cancers. However, its function as a prognostic factor for mycosis fungoides (MF) has not been yet clarified. Objective: Our work aimed to assess the association of the NLR with different stages of MF and to outline whether higher values of this marker are related to a more aggressive MF. Methods: We retrospectively calculated the NLRs in 302 MF patients at the moment of diagnosis. The NLR was obtained using the complete blood count values. Results: The median NLR among patients with early stage disease (low-grade IA-IB-IIA) was 1.88, while the median NLR for patients with high-grade MF (IIB-IIIA-IIIB) was 2.64. Statistical analysis showed positive associations of advanced MF stages with NLRs higher than 2.3. Conclusions: Our analysis demonstrates that the NLR represents a cheap and easily available parameter functioning as a marker for advanced MF. This might guide physicians in recognizing patients with advanced stages of disease requiring a strict follow-up or an early treatment.

The relationship between immune checkpoint status and disease outcome is a major focus of research in cutaneous T-cell lymphoma (CTCL), a disfiguring neoplastic dermatological disorder. Mycosis fungoides (MF) and Sézary syndrome (SS) are the two most common types of CTCL.The aim was to evaluate the immune checkpoint markers programmed death protein 1 (PD1), inducible T-cell co-stimulator (ICOS) and programmed death-ligand 1 (PD-L1) in skin biopsies from patients with CTCL relative to disease stage and overall survival.This consecutive case series enrolled 47 patients: 57% had stage IA-IIA disease and 43% had stage IIB-IVA2 disease (including seven with SS).PD1, PD-L1 and ICOS expression was seen in all biopsies. Notably, PD-L1 was predominantly expressed on histiocytes/macrophages, but focal expression on CTCL cells was seen. High expression of either ICOS or PD-L1 was associated with advanced-stage disease (P = 0·007 for both) and with the appearance of large-cell transformation (LCT), a histopathological feature associated with a poor prognosis (ICOS: P = 0·02; PD-L1: P = 0·002). PD1 expression was not significantly associated with disease stage (P = 0·12) or LCT (P = 0·49), but expression was high in SS biopsies. A high combined checkpoint marker score (PD1, PD-L1 and ICOS) was associated with advanced-stage disease (P = 0·001), LCT (P = 0·021) and lower overall survival (P = 0·014).These findings demonstrate the existence of a complex immunoregulatory microenvironment in CTCL and support the development of immunotherapies targeting ICOS and PD-L1 in advanced disease.

Objective: Q-switched laser is considered a gold standard treatment for Nevus of Ota (NO). We report how few laser sessions in long intervals of time may achieve satisfying outcomes reducing the ra...

Simple Summary Transformed mycosis fungoides (LCT-MF) is a histopathological marker of poor prognosis and associated with worse survival. We compared miRNA and mRNA expression profiles of LCT-MF with classic MF and found a distinct miRNA regulatory network modulated immunosuppressive tumor microenvironment in LCT-MF. Our findings provide novel insights and therapeutic targets for LCT-MF. Abstract Large cell transformation of mycosis fungoides (LCT-MF) occurs in 20–50% of advanced MF and is generally associated with poor response and dismal prognosis. Although different mechanisms have been proposed to explain the pathogenesis, little is known about the role of microRNAs (miRs) in transcriptional regulation of LCT-MF. Here, we investigated the miR and mRNA expression profile in lesional skin samples of patients with LCT-MF and non-LCT MF using RNA-seq analysis. We found miR-146a and miR-21 to be significantly upregulated, and miR-708 the most significantly downregulated miR in LCT-MF. Integration of miR and mRNA expression profiles revealed the miR-regulated networks in LCT-MF. Ingenuity pathway analysis (IPA) demonstrated the involvement of genes for ICOS-ICOSL, PD1-PDL1, NF-κB, E2F transcription, and molecular mechanisms of cancer signaling pathways. Quantitative real time (qRT)-PCR results of target genes were consistent with the RNA-seq data. We further identified the immunosuppressive tumor microenvironment (TME) in LCT-MF. Moreover, our data indicated that miR-146a, -21 and -708 are associated with the immunosuppressive TME in LCT-MF. Collectively, our results suggest that the key LCT-MF associated miRs and their regulated networks may provide insights into its pathogenesis and identify promising targets for novel therapeutic strategies.

International audience; Human malignant melanoma shows a high rate of mortality after metastasization, and its incidence is continuously rising worldwide. Several studies have suggested that MCAM/MUC18/CD146 plays an important role in the progression of this malignant disease. MCAM/MUC18/CD146 is a typical single-spanning transmembrane glycoprotein, existing as two membrane isoforms, long and short, and an additional soluble form, sCD146. We previously documented that molecular MCAM/MUC18/CD146 expression is strongly associated with disease progression. Recently, we showed that MCAM/MUC18/CD146 and ABCB5 can serve as melanoma-specific-targets in the selection of highly primitive circulating melanoma cells, and constitute putative proteins associated with disease spreading progression. Here, we analyzed CD146 molecular expression at onset or at disease recurrence in an enlarged melanoma case series. For some patients, we also performed the time courses of molecular monitoring. Moreover, we explored the role of soluble CD146 in different cohorts of melanoma patients at onset or disease progression, rather than in clinical remission, undergoing immune therapy or free from any clinical treatment. We showed that MCAM/MUC18/CD146 can be considered as: (1) a membrane antigen suitable for identification and enrichment in melanoma liquid biopsy; (2) a highly effective molecular “warning” marker for minimal residual disease monitoring; and (3) a soluble protein index of inflammation and putative response to therapeutic treatments.

Background The neutrophil/lymphocyte ratio (NLR) and red blood cell distribution width (RDW) at diagnosis have been shown to correlate with advanced disease and to be prognostic factors in many tumors. However, their role as a prognostic factor for cutaneous squamous cell carcinoma (cSCC) has not yet been studied. Objective Therefore, the aim of our study was to evaluate the correlation of NLR and RDW with stages of disease in patients with cSCC in order to define whether or not higher values of these two markers correlate with a more aggressive disease. Methods We retrospectively analyzed the NLR and RDW in a total of 51 newly diagnosed cSCC patients. NLR and RDW were calculated using data obtained from the complete blood count (CBC). Results Median NLR among patients with the non-advanced disease (in situ and stage I) was 2.2, whereas median NLR for patients with advanced disease was 4.87. Median RDW among patients with early stage disease was 13.7%, while median RDW in patients with advanced disease was 15.81%. Statistical analysis showed positive associations of advanced cSCC stages with NLR or RDW higher than 3.07 or 14.5%, respectively. Conclusions Therefore, our analysis demonstrated how both NLR and RDW represent cheap and easily available factors that could be used as markers for advanced cSCC. They could help to identify patients with advanced stages disease that requires a strict follow-up.

Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common types of cutaneous lymphoma, accounting for approximately 60% of cutaneous T-cell lymphomas. Diagnosis requires correlation of clinical, histologic, and molecular features. A multitude of factors have been linked to the aetiopathogenesis, however, none have been definitively proven. Erythrodermic MF (E-MF) and SS share overlapping clinical features, such as erythroderma, but are differentiated on the degree of malignant blood involvement. While related, they are considered to be two distinct entities originating from different memory T cell subsets. Differential expression of PD-1 and KIR3DL2 may represent a tool for distinguishing MF and SS, as well as a means of monitoring treatment response. Treatment of E-MF/SS is guided by disease burden, patients’ ages and comorbidities, and effect on quality of life. Current treatment options include biologic, targeted, immunologic, and investigational therapies that can provide long term response with minimal side effects. Currently, allogeneic stem cell transplantation is the only potential curative treatment.

Background Antibiotics are recognized as first-line treatments for hidradenitis suppurativa (HS), but the data on their efficacy are limited. Objective Evaluate the efficacy of oral clindamycin versus that of clindamycin plus rifampicin in patients with HS. Methods A total of 60 patients with mild-to-moderate-severe HS who were classified according to their International Hidradenitis Suppurativa Severity Score System (IHS4) and Hurley scores, were subdivided into 2 groups of 30 patients each (group A, the members of which received clindamycin plus rifampicin, and group B, the members of which were treated with clindamycin alone) and retrospectively studied. The main objective was to evaluate and compare the clinical and ultrasound responses between the groups after 8 weeks of treatment according to the Hidradenitis Suppurativa Clinical Response measure. Results After the treatment, 17 of 30 patients in group A and 19 of 30 in group B met the primary outcome. Both groups showed a similar improvement of IHS4 score, whereas the Dermatology Life Quality Index and pain Visual Analogue Scale scores improved more in group B. In particular, the reductions in nodule and abscess counts were similar between the 2 groups, whereas the number of draining tunnels decreased more in group B. The factors significantly associated with Hidradenitis Suppurativa Clinical Response score were age, body mass index, IHS4 score, and absence of axillary involvement. Disease-free survival was similar between the 2 groups. Limitations The study was not randomized or placebo-controlled. Conclusion Clindamycin may be a useful treatment alternative to antibiotic combination regardless of HS clinical stage.

Background: Basal cell carcinoma is one of the most common types of non-melanoma skin cancers, which can be locally destructive despite low-rate metastasis. Surgery is the treatment of choice, but it lacks of efficacy on advanced cases. Hedgehog pathway inhibitors are a class of drugs providing a new therapeutic option for patients affected by advanced disease. Besides systemic therapy, such as vismodegib and sonidegib, also topical inhibitors have been developed. Patidegib is able to decrease tumor burden, reducing the adverse effects induced by systemic targeted therapies. Methods: We performed comprehensive research to summarize the use of patidegib in advanced and recurrent aggressive basal cell carcinomas. Only English language human studies were included in the search. Results: Seven trials reported the application of patidegib. Both topical and systemic patidegib demonstrated safety, tolerability, and efficacy in naïve patients with stage II and III basal cell carcinomas, while stage IV disease and not-naïve patients did not show any benefit. Conclusion: Unlike systemic Hedgehog pathway inhibitors, patidegib 2% gel is not associated with systemic adverse effects and allows a better patient management. Considering the multidisciplinary management of neoplasia, in the era of precision medicine, it is mandatory to confide in pharmacogenomics to obtain personalized combined or sequential therapies.

Photosensitivity induced by drugs is a widely experienced problem, concerning both molecule design and clinical practice. Indeed, photo-induced cutaneous eruptions represent one of the most common drug adverse events and are frequently an important issue to consider in the therapeutic management of patients. Phototoxicity and photoallergy are the two different pathogenic mechanisms involved in photosensitization. Related cutaneous manifestations are heterogeneous, depending on the culprit drug and subject susceptibility. Here we report an updated review of the literature with respect to pathogenic mechanisms of photosensitivity, clinical manifestations, patient management, and prediction and evaluation of drug-induced photosensitivity. We present and discuss principal groups of photosensitizing drugs (antimicrobials, nonsteroidal anti-inflammatory drugs, anti-hypertensives, anti-arrhythmics, cholesterol, and glycemia-lowering agents, psychotropic drugs, chemotherapeutics, etc.) and their main damage mechanisms according to recent evidence. The link between the drug and the cutaneous manifestation is not always clear; more investigations would be helpful to better predict drug photosensitizing potential, prevent and manage cutaneous adverse events and find the most appropriate alternative therapeutic strategy.

Mastocytosis is a rare disease characterised by expansion and collection of clonal mast cells in various organs including the skin, bone marrow, spleen, lymph nodes and gastrointestinal tract. The prevalence of mastocytosis has been estimated to be one in 10 000, while the estimated incidence is one per 100 000 people per year. Cutaneous mastocytosis is classified into (i) maculopapular cutaneous mastocytosis, also known as urticaria pigmentosa; (ii) diffuse cutaneous mastocytosis; and (iii) mastocytoma of the skin. In adults, cutaneous lesions are usually associated with indolent systemic mastocytosis and have a chronic evolution. Paediatric patients, on the contrary, have often cutaneous manifestations without systemic involvement and usually experience a spontaneous regression. Diagnosis of cutaneous mastocytosis may be challenging due to the rarity of the disease and the overlap of cutaneous manifestations. This short review describes pathogenesis and clinical aspects of cutaneous mastocytosis with a focus on diagnosis and currently available therapies.

The role of heavy metals in carcinogenetic process has been widely established; however, information on the most common environmental metals that serve as major risk factors for actinic keratosis (AK)/non-melanoma skin cancer (NMSC) are still lacking. The aim of this study was to evaluate levels of the most common environmental heavy metals in hair of patients with AK/NMSC as compared to healthy controls.Thirty-one patients diagnosed with AK/NMSC and 34 healthy controls were enrolled. Patients were interviewed for heavy metals exposure and underwent hair analysis for detection of arsenic (As), cadmium (Cd), chromium (Cr), nickel (Ni) and lead (Pb). Continuous variables were analyzed using Wilcoxon Non-Parametric Rank Test and proportions were compared by Fisher's Exact Test. Statistical significance was determined by P0.05.In our cohort we observed 48.4% patients had AKs, 16.1% basal cell carcinoma (BCC), 9.7% squamous cell carcinoma (SCC) and 25.9% of patients presented with a combination of these lesions. There were significantly elevated levels of As and Cr in AK-NMSC group as compared to controls.We identified a strong positive correlation between As and Cr concentration and AK/NMSC adding new clues to the scenery of NMSC risk factors that should be taken under consideration in exposed populations.

Background: The role of heavy metals in carcinogenetic process has been widely established however, information on the most common environmental metals that serve as major risk factors for actinic keratosis (AK)/non-melanoma skin cancer (NMSC) are still lacking. We aim to evaluate levels of the most common environmental heavy metals in hair of patients with AK/NMSC as compared to healthy controls. Methods: 31 patients diagnosed with AK/NMSC and 34 healthy controls were enrolled. Patients were interviewed for heavy metals exposure and underwent hair analysis for detection of arsenic (As), cadmium (Cd), chromium (Cr), nickel (Ni) and lead (Pb). Continuous variables were analyzed using Wilcoxon non-parametric rank test and proportions were compared by Fisher exact test. Statistical significance was determined by p

Basal cell carcinoma (BCC) is the most common skin cancer in humans. Pigmented basal cell carcinoma (pBCC) is a rare variant of BCC. Vismodegib, was the first drug to be approved for the treatment of locally advanced (laBCCs) or metastatic basal cell carcinoma. The aim of this study was to evaluate the efficacy of Vismodegib in patients with pBCCs. We retrospectively analyzed patients receiving Vismodegib as treatment for laBCCs presenting also various pBCCs. After 6 months of treatment, we performed excisional biopsies of pBCCs, that apparently at clinical and dermoscopic assessment did not respond to therapy. A total of nine patients were assessed. After 6 months of treatment, locally advanced target BCCs showed complete remission in four out of nine patients (44.4%), four patients (44.4%) were considered in partial remission and one patient (11%) showed no response to treatment. On the contrary, all the pBCCs showed both clinically and dermoscopically resistance to treatment. Therefore, clinically persistent pBCCs were surgically removed in three patients. Histology showed a complete elimination of the neoplastic cells together with features of previous regression. Our findings indicate that the efficacy of Vismodegib is higher than that documented by clinical or even dermatoscopic observation alone.

En coup de sabre morphea is a clinical variant of morphea, presenting as a linear depressed, atrophic area in the paramedian forehead or the frontoparietal scalp, resembling a stroke from a sword. It affects the skin and subcutaneous connective tissues, with possible extension to the underlying musculature, cartilage, and bone and variable association with neurologic symptoms. A 50-year-old woman presented to our clinic for evaluation of an atrophic lesion on her forehead and scalp appearing 1 year before, progressively extending over time. An alopecic atrophic area involving the skin and subcutaneous tissues of her right forehead and scalp arranged in a linear fashion with an “en coup de sabre” appearance was observed in relation with hair loss in the affected area. Reflectance confocal microscopy showed marked hyperreflective areas with severe eccrine gland atrophy. All sebaceous glands had disappeared, with sporadic follicular persistence reduction. Histopathological examination of a punch biopsy specimen taken from a central parietal alopecic area was consistent with a diagnosis of morphea. To our knowledge, this is the first report regarding the use of reflectance confocal microscopy as an ancillary diagnostic technique in linear localized morphea of the scalp and face. This noninvasive technique may represent a useful tool in distinguishing between early stages of the disease, with prevalence of inflammatory lymphocytic infiltrate, and late stages characterized by more prominent sclerosis with mild or absent signs of inflammation.

Primary cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ LPDs) are the second most common cutaneous lymphomas after mycosis fungoides and Sezary syndrome. They include primary cutaneous anaplastic large cell lymphoma (pcALCL), lymphomatoid papulosis (LyP), and borderline lesions. The purpose of this literature review is to consolidate the available evidence on the primary cutaneous CD30+ LPD in order to define the tools for correct diagnosis and appropriate treatment. The current body of knowledge regarding the clinical features, histopathologic changes, recently described genetic alterations, and therapeutic options will be covered in this comprehensive review. Primary cutaneous CD30+ LPD represent rare cutaneous lymphomas that have significant histologic overlap within the defined group as well as with other neoplastic and reactive entities. The importance of differentiating these entities is crucial, as each one has a different clinical course and prognosis.

We present the third reported case of a primary cutaneous marginal zone lymphoma (PCMZL) treated with doxycycline in a pediatric patient with negative serology for Borrelia burgdorferi. A 14-year-old boy presented with multiple asymptomatic erythematous papules and nodules on his extremities and trunk which biopsy confirmed to be PCMZL. He was started on doxycycline and experienced a near-complete response. Given the favorable side effect profile of doxycycline and the indolent nature of PCMZL, we believe doxycycline is a possible therapy for PCMZL pediatric patients who have widely disseminated cutaneous disease.

We present the results on retrospective analysis about the efficacy of Certolizumab pegol (CZP), an antitumor necrosis factor-alpha agent, as monotherapy on skin psoriasis (PsO) in patients affect both by psoriatic arthritis (PsA) and mild-severe PsO. To date, the CZP is authorized for the treatment of PsA, PsO beyond that rheumatoid arthritis, axial spondyloarthritis/ankylosing spondylitis, and Crohn's. Assessments included an evaluation of the Psoriasis Area and Severity Index (PASI). Twelve patients (9M and 3F mean age 57.8 ± 8 years) were enrolled in our study. Nine patients had been previously treated with others biologic agents, three patients were naive. Clinical and laboratory evaluations including PASI, erythrosedimentation rate, and C-reactive protein were performed at baseline (BL), at Week 12 (W12), Week 24 (W24), and Week 52 (W52) of treatment. Although the combination between methotrexate and CZP is allowed, we included, in our study, patients treated only with CZP. In such a way as to be as specific as possible, topical corticosteroids, vitamin D derivatives, retinoid creams, anthralin derivatives as well as p-UVA or UV-B have been forbidden to enrolled patients. With the same purpose, all the patients used the identical moisturizing cream two times a day. Mean PASI score decreased from 18 (BL) to 0 (W52) as follows: 18 at BL, 4 at W12, 0 at W24, and 0 at W52. Severe adverse events were not reported. Safety evaluations were performed every 3 months: liver and renal functions were monitored in all patients during the treatment, and no patient presented abnormal values. To the best of our knowledge, this is the first report that highlights the efficacy of CZP as monotherapy in psoriasis with mild to severe cutaneous involvement. Although to date the drug is authorized only for PsA, our results demonstrate that CZP is safe and effective on both cutaneous and joint components representing, therefore, an effective option in the treatment of cutaneous symptoms of PsO. Limitations of our study are presented by the relatively short observation time (W52) and by numeric small study group. Long-term data with a larger number of enrolled patients are necessary in order to confirm our preliminary observations.

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting areas with a high density of apocrine glands and characterized by subcutaneous nodules that may evolve into fistulas with pus secretion. Methods: The aim of this review is to investigate all current knowledge on cytokine regulation in the pathogenesis of HS. A systematic literature research using the words “cytokine”, “interleukin”, “pathway”, and “hidradenitis suppurativa” was performed in PubMed/Medline and Scopus/Embase databases. A search of the clinicaltrials.gov website for interventional recruiting and completed trials including the term “hidradenitis suppurativa” was also performed up to August 2020. We will discuss the pathogenetic role of various cytokines in HS and potential therapeutic targets for this debilitating disease. Results: The pathophysiology underlying this complex condition has not been clearly defined. An upregulation of various cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-17, IL-23, and other molecules seems to be related to this inflammatory condition. Various cells, such as lymphocytes T Helper 1 and 17 and keratinocytes seem to be involved in the genesis of this condition. Conclusions: Several future studies and clinical trials are necessary in order to have new knowledge about HS and to properly treat this complex condition.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that impairs patients’ quality of life. Various psychiatric or psychological conditions have been associated with HS, however, no data are available on alexithymia, a psychological construct characterized by the inability to express, describe, and recognize feelings. To assess the presence of alexithymia in HS patients. Demographic and clinical data from patients with HS were collected. Alexithymiawas assessed using the Toronto Alexithymia Scale (TAS)-20 questionnaire to define non-alexithymic subjects (scoring 20-50), borderline (possible) alexithymia subjects (scoring 51-60), and alexithymic subjects (scoring≥61). The alexithymic personality trait is identified based on TAS-20 score≥51. This multicentre study included 86 HS patients, 100 obese individuals, and 85 healthy control subjects. The mean TAS-20 score was significantly higher in the HS patient cohort (55.37 ±13.42) than in the control group (40.96±10.47) (p

Background/Aims: The association between hidradenitis suppurativa (HS) and multiple comorbidities has been widely investigated but data about the coexistence of Down syndrome (DS) are scarce. We sought to evaluate the prevalence of DS among a population of HS patients and assess their clinical features. Methods: We collected demographic and clinical data of patients affected with HS referred to three Italian outpatient dermatology clinics. Results: A total of 257 HS patients were enrolled, 62% females and 38% males (mean age [±SD]: 23.3 ± 10.7 years); 9 of the 257 patients (3.5%), 7 females and 2 males, had concomitant HS and DS. The patients with DS and HS had a significantly earlier age of onset (mean age: 14.3 ± 3.6 vs. 23.4 ± 12.31 years; p = 0.029), a significantly younger age at diagnosis (mean age: 21.1 ± 11.1 vs. 31.8 ± 13.5 years; p = 0.015), and were significantly younger (mean age: 23.3 ± 10.7 vs. 34.6 ± 13.07 years; p = 0.005). No significant differences about other clinical data were found between the two groups. Conclusion: The prevalence of DS in HS patients corresponds to a not negligible 3.5% of cases, who experienced an onset of HS at a younger age compared to patients with HS only.