Cutaneous mastocytosis: A dermatological perspective.

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.

Efficacy of Vismodegib in pigmented basal cell carcinoma: Appearances are deceiving.

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.

High-Risk Recurrence Basal Cell Carcinoma: Focus on Hedgehog Pathway Inhibitors and Review of the Literature.

Basal cell carcinoma is the most common skin tumour, with the majority of the cases occurring on the head and neck district, where cosmetic and functional results are crucial. It can be locally destructive if not diagnosed early and treated appropriately. Surgery is the treatment of choice for most lesions, but aggressive, recurrent, or unresectable tumours can be challenging to manage. Advanced basal cell carcinoma includes high recurrence risk subtypes, in which standard therapies demonstrate lack of efficacy. This led to a need for investigating more deeply the pathogenesis of the disease and to the discovery of the implication of the hedgehog pathway. The development of systemic inhibitors of this pathway provides new treatment options for patients with advanced disease, resulting in survival improvement. Food and Drug Administration, before, and European Medicines Agency later approved 2 Hedgehog pathway inhibitors for the treatment of advanced basal cell carcinomas, vismodegib and sonidegib. Here, we present a review of the current English language literature trying to analyze differences in the 2 drugs as a head-to-head comparison between them has not already been documented in a randomized controlled clinical trial. Although vismodegib and sonidegib showed similar efficacy and safety profiles, in an indirect comparison scenario, sonidegib has shown slightly better outcomes in locally advanced basal cell carcinoma than vismodegib. They present different molecular structures, as they bind different residues on their targets and develop resistance for different mutations. In a future scenario, clinical trials comparing the 2 drugs are needed, as well as expanding data on discontinuation of therapy and/or consequential administration of them, with the aim to improve our clinical practise.

Efficacy and safety of Vismodegib treatment in patients with advanced basal cell carcinoma and multiple comorbidities.

Basal cell carcinoma (BCC) is the most common malignancy in Caucasians, and its incidence is increasing. Most BCCs are treated surgically, nevertheless surgery is not an effective treatment for locally advanced or metastatic BCC. Alterations in hedgehog signaling pathway, a key regulator of cell growth and differentiation during development, are implicated in the pathogenesis of basal-cell carcinoma. Vismodegib is a small-molecule inhibitor of smoothened (SMO), a key component of the hedgehog (Hh) signaling pathway, administered in BCC patients, especially when surgery and radiotherapy treatments have failed. We report a series of eight elderly patients treated with vismodegib for advanced BCC and affected by concomitant multiple comorbidities. The efficacy and tolerability of vismodegib in patients with single and/or multiple comorbidities has been poorly studied. In our observation an overall high safety and tolerability has been observed over the course of treatment, with side effects of grade I and II and no changes in vital parameters, electrocardiography and echocardiogram. Vismodegib has been shown to be a safe and well tolerated treatment option for elderly patients affected by multiple comorbidities and advanced BCC.

Developmental factor IRF6 exhibits tumor suppressor activity in squamous cell carcinomas.

The transcription factor interferon regulatory factor 6 (IRF6) regulates craniofacial development and epidermal proliferation. We recently showed that IRF6 is a component of a regulatory feedback loop that controls the proliferative potential of epidermal cells. IRF6 is transcriptionally activated by p63 and induces its proteasome-mediated down-regulation, thereby limiting keratinocyte proliferative potential. We hypothesized that IRF6 may also be involved in skin carcinogenesis. Hence, we analyzed IRF6 expression in a large series of squamous cell carcinomas (SCCs) and found a strong down-regulation of IRF6 that correlated with tumor invasive and differentiation status. IRF6 down-regulation in SCC cell lines and primary tumors correlates with methylation on a CpG dinucleotide island located in its promoter region. To identify the molecular mechanisms regulating IRF6 potential tumor suppressive activity, we performed a genome-wide analysis by combining ChIP sequencing for IRF6 binding sites and gene expression profiling in primary human keratinocytes after siRNA-mediated IRF6 depletion. We observed dysregulation of cell cycle-related genes and genes involved in differentiation, cell adhesion, and cell-cell contact. Many of these genes were direct IRF6 targets. We also performed in vitro invasion assays showing that IRF6 down-regulation promotes invasive behavior and that reintroduction of IRF6 into SCC cells strongly inhibits cell growth. These results indicate a function for IRF6 in suppression of tumorigenesis in stratified epithelia.

Detection of adalimumab and anti-adalimumab levels by ELISA: clinical considerations.

Psoriasis (Ps) is a common and stigmatizing chronic inflammatory skin disease that may cause other chronic inflammatory conditions with overlapping pathology, such as rheumatoid arthritis (RA). Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a pivotal role in chronic inflammatory and autoimmune diseases such as uveitis, multiple sclerosis, systemic lupus, arthritis, Ps, and Crohn's disease. The TNF superfamily and receptors represent active targets for drug development. Anti-TNF biological therapies, such as infliximab, adalimumab (ADL), and etanercept, are effective in treating RA, spondyloarthritis, Ps, and inflammatory bowel diseases, but long-term treatment can induce anti-drug antibody (ADA) formation associated with lower drug levels and clinical nonresponse. An investigation of the relationship between serum ADL/anti-adalimumab antibody (AAA) concentration, and clinical response in moderate to severe Ps, confirmed an association between ADL and AAA levels and response. Although the detection of ADAs can be used to determine the cause of nonresponse and aid therapy decisions, the contrary observation of long-term responders with low drug levels and detectable ADA suggests that another mechanism is also involved.

Baseline neutrophil/lymphocyte ratio (NLR) and red blood cell distribution width (RDW) correlate with advanced stages in cutaneous squamous cell carcinoma.

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.

Minimal Residual Disease in Melanoma:molecular characterization of in transit cutaneous metastases and Circulating Melanoma Cells recognizes an expression panel potentially related to disease progression.

Isolating circulating melanoma cells (CMCs) represents a powerful method to monitor minimal residual disease. We documented that MCAM/MUC18/CD146 expression is strongly associated with disease progression. ABCB5 is melanoma-stem antigen with self-renewal, proliferation, differentiation, tumorigenicity capabilities. These findings supported us to improve CMC detection, investigating MCAM/MUC18/CD146 and ABCB5 as enrichment targets in MM progression. Moreover, we decided to compare possible molecular diversity of these CMC fractions with metastatic tissue expression, collecting concomitantly cutaneous in transit metastases (CTM). We enriched CMCs from eight melanoma patients staged ≥pT1b AJCC, who developed CTMs at baseline or during follow up. We assessed a gene expression panel comprising ABCB5, the differentiation markers (Tyrosinase, MART1), angiogenic factors (VEGF, bFGF), the cell-cell adhesion molecules (MCAM/MUC18/CD146 5'-portion, Long, and Short isoforms, E-Cadherin, N-Cadherin, VE-Cadherin) and matrix-metallo-proteinases (MMP2 and MMP9) via high-sensitive RT-PCR. Preliminary findings defined three distinct sub-populations: "endothelial" CD45-CD146+CMCs, "stem" CD45-ABCB5+CMCs and a "hybrid- stem-endothelial"- CD45-MCAM+ABCB5+CMCs. The expression panel documented that - almost high expression found in CTMs - like in 73.5% of CMCs resulted positive for at least one transcript at baseline, showing gene-expression variability. Longitudinal monitoring documented shut-down of all gene-expressions in "endothelial"- and "hybrid stem-endothelial"-subsets, whilst persistency or acquisition of MCAM/MUC18/CD146, VE-CADH and MMPs was documented in disease-progression status.Conversely, a drastic expression shut-down was documented when patients achieved clinical remission. The "stem"- CMCs fraction" showed quite lower gene expression frequencies. MCAM/MUC18/CD146 and ABCB5 as melanoma-specific-targets are effective in the selection of highly primitive CMCs and highlights those putative genes associated with disease spreading progression.

Stem-Mesenchymal Signature Cell Genes Detected in Heterogeneous Circulating Melanoma Cells Correlate With Disease Stage in Melanoma Patients.

During the process of metastasis, cancer cells dissociate from primary tumors, migrate to distal sites, and finally colonize, eventually leading to the formation of metastatic tumors. These cancer cells, defined circulating tumor cells (CTCs) spreading through the blood stream, may develop metastatic lesions or remain dormant. Some emerging clinical evidence supports that some tumor cells may possess metastatic properties already in the earlier stages of tumorigenesis. Because the initiation and progression of vertical growth in human melanoma is fundamental to the notion of tumor virulence and progression, we decided to immune-magnetic collect and molecularly characterize circulating melanoma cells (CMCs) from melanoma patients AJCC staged = pT1b (i.e., transition from radial to vertical phase). CMCs are phenotypically and molecularly heterogeneous, thus we performed a "home-made Liquid-Biopsy," by targeting the melanoma-associated-antigen, MCAM/MUC18/CD146, and/or the melanoma-initiating marker, ABCB5. We assessed a biomarker qualitative expression panel, contemplating the angiogenic-potential, melanoma-initiating and melanoma-differentiation drivers, cell-cell adhesion molecules, matrix-metallo-proteinases, which was performed on three enriched subpopulations from a total of 61 blood-samples from 21 melanoma patients. At first, a significant differential expression of the specific transcripts was documented between and within the CMC fractions enriched with MCAM-, ABCB5-, and both MCAM/ABCB5-coated beads, when analyzing two distinct groups: early AJCC- (stage I-II) and advanced- staged patients (stage II-IV). Moreover, in the early-AJCC staged-group, we could distinguish "endothelial," CD45-MCAM+ enriched-, "stem" S-CMCs, CD45-ABCB5+ enriched- and a third hybrid bi-phenotypic CD45-MCAM+/ABCB5+ enriched-fractions, due to three distinct gene-expression profiles. In particular, the endothelial-CMCs were characterized by positive expression of genes involved in migration and invasion, whilst the stem CMC-fraction only expressed stem and differentiation markers. The third subpopulation isolated based on concurrent MCAM and ABCB5 protein expression showed an invasive phenotype. All three distinct CMCs sub-populations, exhibited a primitive, "stem-mesenchymal" profile suggesting a highly aggressive and metastasizing phenotype. This study confirms the phenotypic and molecular heterogeneity observed in melanoma and highlights those putative genes involved in early melanoma spreading and disease progression.

Efficacy of short-term cyclosporine treatment to control psoriasis-related events during efalizumab therapy.

Efalizumab is a recombinant humanized anti-CD11a monoclonal antibody that blocks the activation, adhesion and trafficking of T cells and has been approved for the treatment of moderate-to-severe plaque psoriasis. To document management of the fluctuations in symptom control that patients with psoriasis sometimes experience during treatment, we performed a retrospective analysis of our experience using cyclosporine as an intercurrent treatment to control psoriasis-related adverse events (AEs) in 10 patients who had received continuous efalizumab therapy for 20-200 weeks prior to recurrence of symptoms. Combination therapy with cyclosporine and efalizumab was generally well tolerated and controlled the relapse effectively. There were no reports of severe AEs during combination treatment, and no clinically significant changes were noted in clinical and laboratory values. Although mild, localized psoriasis recurred in most of these patients after cyclosporine termination, no patient experienced rebound or psoriasis flare and all continued with long-term efalizumab treatment.

Minimal residual disease in melanoma: circulating melanoma cells and predictive role of MCAM/MUC18/MelCAM/CD146.

Circulating tumour cells (CTCs), identified in numerous cancers including melanoma, are unquestionably considered valuable and useful as diagnostic and prognostic markers. They can be detected at all melanoma stages and may persist long after treatment. A crucial step in metastatic processes is the intravascular invasion of neoplastic cells as circulating melanoma cells (CMCs). Only a small percentage of these released cells are efficient and capable of colonizing with a strong metastatic potential. CMCs' ability to survive in circulation express a variety of genes with continuous changes of signal pathways and proteins to escape immune surveillance. This makes it difficult to detect them; therefore, specific isolation, enrichment and characterization of CMC population could be useful to monitor disease status and patient clinical outcome. Overall and disease-free survival have been correlated with the presence of CMCs. Specific melanoma antigens, in particular MCAM (MUC18/MelCAM/CD146), could be a potentially useful tool to isolate CMCs as well as be a prognostic, predictive biomarker. These are the areas reviewed in the article.

Programmed cell death in the skin.

Differently from the other cells of the body, epidermal cells of the skin undergo a specific programmed cell death form named cornification. Many events take part to control this process, which has been described as a terminal differentiation program. Going from the innermost layer to the outermost, epidermal cells stop dividing, change their shape, acquire new cellular structures and strengthen their cytoskeleton. This is corroborated by the fact that during this physical transition they change their gene expression, reprogramming in some way their biochemical activity. The activation of critical enzymes, including proteases and transglutaminases is a fundamental cellular event. These enzymes are involved in building the supramolecular and cornified structures which confer resistance to the epidermis which carries out a vital function as a skin barrier, preserving the organism from various insults. Here we review current concepts about cornification and the mechanisms by which this process is preserved in species.

Psoriasis, from pathogenesis to therapeutic strategies: IL-21 as a novel potential therapeutic target.

Psoriasis is a common (1-3% of the population worldwide), multifactorial, immune-mediated chronic skin disease. In psoriasis pathogenesis an over-reaction of local innate immune response initiates inflammation with subsequent involvement of adaptive immune response leading to the production of a panel of cytokines, chemokines and growth factors leading to epidermal hyperplasia. Recently, IL-21 has been involved in this process as this cytokine is overexpressed in psoriatic skin and can cause epidermal hyperplasia and inflammation when injected intradermally into mice. Moreover blockade of IL-21 with a human antibody against IL-21 reduces the epidermal thickness and the expression of Th1 and Th17 genes in the well-characterized model of human psoriasis-xenograft mouse. Therefore, the inhibition of this cytokine may be therapeutically effective in the treatment of psoriasis. Here we will review recent data on psoriasis pathogenesis focusing on the role of IL-21 as novel therapeutic target.

Constitutional intraepidermal ascent of melanocytes: a potential pitfall in the diagnosis of melanocytic lesions.

BACKGROUND: Transepidermal melanocytic migration (TEM) is an important diagnostic criterion for malignancy, especially in association with cytologic atypia. However, TEM may also be observed in benign melanocytic tumors, such as Spitz nevus, acral nevi, or nevi in infancy. We discuss the value of TEM for the diagnosis of melanocytic tumors in a young patient previously diagnosed as having 11 cutaneous melanomas. OBSERVATION: A 17-year-old patient with a history of 11 cutaneous melanomas diagnosed in the past 3 years by different expert dermatopathologists presented in our department. The previous histological diagnoses of melanoma were mainly based on the presence of important TEM. A reevaluation of all histological specimens in light of the clinical context and the lack of genomic aberrations as detected by array-comparative genomic hybridization led to a revision of the previous diagnoses. The striking TEM observed represents, in our opinion, a constitutional element of the melanocytic nevi in this patient and not a marker of malignancy. CONCLUSION: Awareness of this finding is important to avoid overdiagnosis of melanoma in cases of melanocytic nevi.

Targeted therapy in nonmelanoma skin cancers.

Nonmelanoma skin cancer (NMSC) is the most prevalent cancer in light-skinned populations, and includes mainly Basal Cell Carcinomas (BCC), representing around 75% of NMSC and Squamous Cell Carcinomas (SCC). The incidence of these tumors is continuously growing. It was found that the overall number of procedures for NMSC in US rose by 76%, from 1,158,298 in 1992 to 2,048,517 in 2006. Although mortality from NMSC tends to be very low, clearly the morbidity related to these skin cancers is very high. Treatment options for NMSC include both surgical and nonsurgical interventions. Surgery was considered the gold standard therapy, however, advancements in the knowledge of pathogenic mechanisms of NMSCs led to the identification of key targets for drug intervention and to the consequent development of several targeted therapies. These represent the future in treatment of these common forms of cancer ensuring a high cure rate, preservation of the maximal amount of normal surrounding tissue and optimal cosmetic outcome. Here, we will review recent advancements in NMSC targeted therapies focusing on BCC and SCC.

Efalizumab.

INTRODUCTION: Conventional systemic therapies for psoriasis are associated with serious toxicities that can limit long-term use. In recent years, biological therapies have offered the possibility of long-term therapy with improved safety and efficacy for the treatment of psoriasis. Biological therapies can be classified into three categories: the T-cell modulating agents (alefacept and efalizumab), the inhibitors of TNF-α (adalimumab, etanercept, infliximab) and the inhibitors of IL-12 and -23 (ustekinumab). Efalizumab is a humanized recombinant monoclonal IgG1 antibody. It targets multiple stages in the immunopathogenesis of psoriasis: initial T-cell activation, migration of T-cells into dermal and epidermal tissues, and T-cell reactivation. On 19 February 2009, the Committee for Medicinal Products for Human Use (CHMP) recommended the suspension of the marketing authorisation for efalizumab. AREAS COVERED: Numerous clinical trials have demonstrated the efficacy, safety and health-related quality of life benefits of efalizumab in patients with moderate-to-severe chronic plaque psoriasis. Efalizumab was approved by the FDA in November 2003 and by the European Medicines Evaluation Agency in September 2004 for the treatment of adult patients with moderate-to-severe chronic plaque psoriasis. Recently, three cases of progressive multifocal leukoencephalopathy were described in patients on long-term (> 3 years) efalizumab therapy, leading to its withdrawal from the market. EXPERT OPINION: Although initially favorable, the safety profile of efalizumab revealed the appearance of severe adverse events in long-term treated patients. Therefore, post-marketing surveillance is essential for correct evaluation of drug potential.