Showing papers in "Journal of skin cancer in 2013"

AP1 transcription factors in epidermal differentiation and skin cancer.

Abstract: AP1 (jun/fos) transcription factors (c-jun, junB, junD, c-fos, FosB, Fra-1, and Fra-2) are key regulators of epidermal keratinocyte survival and differentiation and important drivers of cancer development. Understanding the role of these factors in epidermis is complicated by the fact that each protein is expressed, at different levels, in multiple cells layers in differentiating epidermis, and because AP1 transcription factors regulate competing processes (i.e., proliferation, apoptosis, and differentiation). Various in vivo genetic approaches have been used to study these proteins including targeted and conditional knockdown, overexpression, and expression of dominant-negative inactivating AP1 transcription factors in epidermis. Taken together, these studies suggest that individual AP1 transcription factors have different functions in the epidermis and in cancer development and that altering AP1 transcription factor function in the basal versus suprabasal layers differentially influences the epidermal differentiation response and disease and cancer development.

Merkel Cell Carcinoma: Chemotherapy and Emerging New Therapeutic Options

Abstract: Merkel cell carcinoma (MCC) is a rare neuroendocrine skin tumor that typically occurs in elderly, immunosuppressed patients Infection with Merkel cell virus (MCV) and immunosuppression play an important role in the development of MCC Different staging systems make it difficult to compare the existing clinical data Furthermore, there predominantly exist single case reports and case series, but no randomized controlled trials However, it is necessary to develop further therapy options because MCC tends to grow rapidly and metastasizes early In the metastatic disease, therapeutic attempts were made with various chemotherapeutic combination regimens Because of the high toxicity of these combinations, especially those established in SCLC, and regarding the unsatisfying results, the challenge is to balance the pros and cons of chemotherapy individually and carefully Up to now, emerging new therapy options as molecular-targeted agents, for example, pazopanib, imatinib, or somatostatin analogues as well as immunologicals, for example, imiquimod and interferons, also showed less success concerning the disease-free response rates According to the literature, neither chemotherapy nor molecular-targeted agents or immunotherapeutic strategies have shown promising effects in the therapy of the metastatic disease of MCC so far There is a great demand for randomized controlled studies and a need for an MCC registry and multicenter clinical trials due to the tumors curiosity

Potential Role of Meiosis Proteins in Melanoma Chromosomal Instability

Abstract: Melanomas demonstrate chromosomal instability (CIN). In fact, CIN can be used to differentiate melanoma from benign nevi. The exact molecular mechanisms that drive CIN in melanoma have yet to be fully elucidated. Cancer/testis antigens are a unique group of germ cell proteins that are found to be primarily expressed in melanoma as compared to benign nevi. The abnormal expression of these germ cell proteins, normally expected only in the testis and ovaries, in somatic cells may lead to interference with normal cellular pathways. Germ cell proteins that may be particularly critical in CIN are meiosis proteins. Here, we review pathways unique to meiosis with a focus on how the aberrant expression of meiosis proteins in normal mitotic cells “meiomitosis” could impact chromosomal instability in melanoma and other cancers.

Safety and efficacy of 188-rhenium-labeled antibody to melanin in patients with metastatic melanoma.

Abstract: There is a need for effective “broad spectrum” therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of 188Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM) patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10 mCi 188Re-6D2 were given while unlabeled antibody preload was escalated. In Phase Ib, the dose of 188Re-6D2 was escalated to 54 mCi. SPECT/CT revealed 188Re-6D2 uptake in melanoma metastases. The mean effective half-life of 188Re-6D2 was 12.4 h. Transient HAMA was observed in 9 patients. Six patients met the RECIST criteria for stable disease at 6 weeks. Two patients had durable disease stabilization for 14 weeks and one for 22 weeks. Median overall survival was 13 months with no dose-limiting toxicities. The data demonstrate that 188Re-6D2 was well tolerated, localized in melanoma metastases, and had antitumor activity, thus warranting its further investigation in patients with metastatic melanoma.

Latest approved therapies for metastatic melanoma: what comes next?

Abstract: Nowadays, oncogene-directed therapy and immunotherapy represent the two most promising avenues for patients with metastatic melanoma The recent oncogene-directed therapeutic, vemurafenib, usually produces high level of tumor shrinkage and survival benefits in many patients with B-RAFV600E mutant melanomas, although the fast and high degrees of responses are likely short-lived Conversely, the newly-approved immunotherapeutic, ipilimumab, produces durable responses in patients presenting CTLA-4 T-cell surface protein Nevertheless, the possible synergy in combining these two therapeutic strategies primarily rely on the rational design of medical protocols (eg, sequence and timing of agent administration; drug selectivity; compatibility of combined therapies ie, adoptive T cell or agents, ie, MEK inhibitor trametinib, PD-1 and PDL-1 blockers) Improved therapeutic protocols shall overcome therapeutic limitations such as the (i) tolerability and safety (ie, minimal toxic side-effects); (ii) progression free survival (eg, reduced relapse disease frequency); (iii) duration response (ie, decreased drug resistance) Eventually, multidisciplinary approaches are still requested (eg, genomics for personalized medicine, nanomedicine to overcome low free-drug bioavailability and targeting, systematic search of “melanoma stem cells” to enhance the prognosis and develop more valuable theranostics) In this paper, I will mainly present and discuss the latest and promising treatments for advanced cutaneous melanomas

Simulators of Squamous Cell Carcinoma of the Skin: Diagnostic Challenges on Small Biopsies and Clinicopathological Correlation

Abstract: Squamous cell carcinoma (SCC) is a common and important primary cutaneous malignancy. On skin biopsies, SCC is characterized by significant squamous cell atypia, abnormal keratinization, and invasive features. Diagnostic challenges may occasionally arise, especially in the setting of small punch biopsies or superficial shave biopsies, where only part of the lesion may be assessable by the pathologist. Benign mimics of SCC include pseudoepitheliomatous hyperplasia, eccrine squamous syringometaplasia, inverted follicular keratosis, and keratoacanthoma, while malignant mimics of SCC include basal cell carcinoma, melanoma, and metastatic carcinoma. The careful application of time-honored diagnostic criteria, close clinicopathological correlation and a selective request for a further, deeper, or wider biopsy remain the most useful strategies to clinch the correct diagnosis. This review aims to present the key differential diagnoses of SCC, to discuss common diagnostic pitfalls, and to recommend ways to deal with diagnostically challenging cases.

Merkel Cell Carcinoma: The Past, the Present, and the Future

Abstract: Since the first description of the Merkel cell carcinoma by Cyril Toker in 1972, the number of studies has significantly increased over the last 4 decades. In this review, we will illustrate the historical background of the Merkel cell carcinoma beginning with the 19th century, the first description of the Merkel cell to the finding of the CK20 as a highly specific diagnostic marker and finally to the recently detected Merkel cell polyomavirus (MCPyV). Moreover, we will highlight the beginning of adjuvant therapeutic regimens with radiotherapy and chemotherapy and discuss the diagnostic work-up including imaging and histology of patients with Merkel cell carcinoma. Another very rapidly growing and interesting field of research is the development of patients' specific and tailored targeted therapy, in particular in patients with distant metastatic disease.

Imaging in patients with merkel cell carcinoma.

Abstract: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumor of the skin with a mortality rate of approximately 25% (Peloschek et al., 2010). Accurate assessment of nodal involvement in patients with MCC predicts significantly overall outcome (Smith et al., 2012 and Ortin-Perez et al., 2007). Due to the rarity of this highly aggressive disease, only a few imaging reports on MCC were published, and subsequently still to date no accepted imaging algorithm for MCC is available. For primary staging of MCC, general recommendations have included ultrasonography, chest X-ray CT, and MRI, but recent articles show that the use of sentinel node and FDG-PET/PET-CT is gaining more and more importance.

Role of Stat3 in Skin Carcinogenesis: Insights Gained from Relevant Mouse Models

Abstract: Signal transducer and activator of transcription 3 (Stat3) is a cytoplasmic protein that is activated in response to cytokines and growth factors and acts as a transcription factor. Stat3 plays critical roles in various biological activities including cell proliferation, migration, and survival. Studies using keratinocyte-specific Stat3-deficient mice have revealed that Stat3 plays an important role in skin homeostasis including keratinocyte migration, wound healing, and hair follicle growth. Use of both constitutive and inducible keratinocyte-specific Stat3-deficient mouse models has demonstrated that Stat3 is required for both the initiation and promotion stages of multistage skin carcinogenesis. Further studies using a transgenic mouse model with a gain of function mutant of Stat3 (Stat3C) expressed in the basal layer of the epidermis revealed a novel role for Stat3 in skin tumor progression. Studies using similar Stat3-deficient and gain-of-function mouse models have indicated its similar roles in ultraviolet B (UVB) radiation-mediated skin carcinogenesis. This paper summarizes the use of these various mouse models for studying the role and underlying mechanisms for the function of Stat3 in skin carcinogenesis. Given its significant role throughout the skin carcinogenesis process, Stat3 is an attractive target for skin cancer prevention and treatment.

Sociodemographic and Psychological Correlates of Sun Protection Behaviors among Outdoor Workers: A Review

Abstract: Outdoor workers are at a higher risk for developing skin cancer due to their increased sun exposure. The primary objective of this review was to synthesize the current research literature that addresses sociodemographic and psychological factors related to sun protection behaviors in outdoor workers. Two additional purposes were to provide an overview of sun exposure and describe sun protection behaviors of outdoor workers. To identify the studies for this review, a methodical search was performed in the PubMed, PsycInfo, MEDLINE, and ERIC databases. Fifteen studies met the review criteria. Despite regular and prolonged sun exposure, many outdoor workers fail to engage in sufficient sun protection behaviors. Correlates of outdoor workers' sun protection behaviors include being female, older age, being white, personal skin cancer history, time (hours/years) spent at work, sun safety training, perceived prioritization of sun protection, concern about sun exposure, workplace support, families' expectations, and familial information giving. However, limited attention is given to designing theoretically grounded studies to identify factors to inform future research. There is a need to conduct research based on solid theoretical foundations that explains the relationships among the factors in this domain.

Sentinel Lymph Node Biopsy in Nonmelanoma Skin Cancer Patients

Abstract: The management of lymph nodes in nonmelanoma skin cancer patients is currently still debated. Merkel cell carcinoma (MCC), squamous cell carcinoma (SCC), pigmented epithelioid melanocytoma (PEM), and other rare skin neoplasms have a well-known risk to spread to regional lymph nodes. The use of sentinel lymph node biopsy (SLNB) could be a promising procedure to assess this risk in clinically N0 patients. Metastatic SNs have been observed in 4.5–28% SCC (according to risk factors), in 9–42% MCC, and in 14–57% PEM. We observed overall 30.8% positive SNs in 13 consecutive patients operated for high-risk nonmelanoma skin cancer between 2002 and 2011 in our institution. These high rates support recommendation to implement SLNB for nonmelanoma skin cancer especially for SCC patients. Completion lymph node dissection following positive SNs is also a matter of discussion especially in PEM. It must be remembered that a definitive survival benefit of SLNB in melanoma patients has not been proven yet. However, because of its low morbidity when compared to empiric elective lymph node dissection or radiation therapy of lymphatic basins, SLNB has allowed sparing a lot of morbidity and could therefore be used in nonmelanoma skin cancer patients, even though a significant impact on survival has not been demonstrated.

Melanoma-Targeted Chemothermotherapy and In Situ Peptide Immunotherapy through HSP Production by Using Melanogenesis Substrate, NPrCAP, and Magnetite Nanoparticles.

Abstract: Exploitation of biological properties unique to cancer cells may provide a novel approach to overcome difficult challenges to the treatment of advanced melanoma. In order to develop melanoma-targeted chemothermoimmunotherapy, a melanogenesis substrate, N-propionyl-4-S-cysteaminylphenol (NPrCAP), sulfur-amine analogue of tyrosine, was conjugated with magnetite nanoparticles. NPrCAP was exploited from melanogenesis substrates, which are expected to be selectively incorporated into melanoma cells and produce highly reactive free radicals through reacting with tyrosinase, resulting in chemotherapeutic and immunotherapeutic effects by oxidative stress and apoptotic cell death. Magnetite nanoparticles were conjugated with NPrCAP to introduce thermotherapeutic and immunotherapeutic effects through nonapoptotic cell death and generation of heat shock protein (HSP) upon exposure to alternating magnetic field (AMF). During these therapeutic processes, NPrCAP was also expected to provide melanoma-targeted drug delivery system.

Merkel Cell Carcinoma of the Head and Neck: A Single Institutional Experience

Abstract: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy occurring mostly in older immunocompromized Caucasian males. A growing incidence of MCC has been reported in epidemiological studies. Treatment of MCC usually consists of surgical excision, pathological lymph node evaluation, and adjuvant radiotherapy. This paper reports the experience of a single tertiary center institution with 17 head and neck Merkel cell carcinoma patients. Median followup for the cohort was 37.5 months. After five years, recurrence-free survival, disease specific survival, and overall survival were 85%, 90%, and 83%, respectively. Our limited data support the use of adjuvant radiotherapy. We also report two cases of MCC located at the vestibule of the nose and two cases of spontaneous regression after diagnostic biopsy. About 40% of our patients were referred to our center for surgical revision and pathological lymph node evaluation. Increased awareness of MCC and an interdisciplinary approach are essential in the management of MCC.

Merkel Cell Carcinoma: Interdisciplinary Management of a Rare Disease

Abstract: Background. The goal of this paper is to review contemporary multidisciplinary treatment with reference to Merkel cell carcinoma. Management of this rare but highly aggressive skin cancer is a complex undertaking that necessitates an understanding of its etiology, epidemiology, clinical presentation, and the coordinated work of several clinical specializations. Recent Findings. The contemporary literature employs a multidisciplinary approach to achieve the best patient's treatment. Conclusion. This paper presents an algorithm for contemporary management for the rare and aggressive Merkel cell carcinoma. Multidisciplinary approach in a tumor center provides high-quality care for patients with Merkel cell carcinoma.

Ipilimumab: A First-in-Class T-Cell Potentiator for Metastatic Melanoma.

Abstract: Ipilimumab, a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody that potentiates antitumor T-cell responses, has demonstrated improved survival in previously treated and treatment-naive patients with unresectable stage III/IV melanoma. Survival benefit has also been shown in diverse patient populations, including those with brain metastases. In 2011, ipilimumab (3 mg/kg every 3 weeks for 4 doses) was approved by the Food and Drug Administration for unresectable or metastatic melanoma. Ipilimumab can induce novel response patterns for which immune-related response criteria have been proposed. irAEs are common but are usually low grade; higher grades can be severe and life-threatening. irAEs are usually manageable using established guidelines emphasizing vigilance and prompt intervention. This agent provides an additional therapeutic option in metastatic melanoma, and guidelines for management of adverse events facilitate clinical implementation of this new agent.

Prediction of sentinel node status and clinical outcome in a melanoma centre.

Abstract: Background. Sentinel lymph node biopsy (SLNB) is a standard procedure for patients with localized cutaneous melanoma. The National Comprehensive Cancer Network (NCCN) Melanoma Panel has reinforced the status of the sentinel lymph node (SLN) as an important prognostic factor for melanoma survival. We sought to identify predictive factors associated with a positive SLNB and overall survival in our population. Methods. We performed a retrospective chart review of 221 patients who have done a successful SLNB for melanoma between 2004 and 2010 at our department. Univariate and multivariate analyses were done. Results. The SLNB was positive in 48 patients (21.7%). Univariate analysis showed that male gender, increasing Breslow thickness, tumor type, and absence of tumor-infiltrating lymphocytes were significantly associated with a positive SLNB. Multivariate analysis confirmed that Breslow thickness and the absence of tumor-infiltrating lymphocytes are independently predictive of SLN metastasis. The 5-year survival rates were 53.1% for SLN positive patients and 88.2% for SLN negative patients. Breslow thickness and the SLN status independently predict overall survival. Conclusions. The risk factors for a positive SLNB are consistent with those found in the previous literature. In addition, the SLN status is a major determinant of survival, which highlights its importance in melanoma management.

Sunscreen Use on the Dorsal Hands at the Beach

Abstract: Background. Since skin of the dorsal hands is a known site for the development of cutaneous squamous cell carcinoma, an epidemiologic investigation was needed to determine if beachgoers apply sunscreen to the dorsal aspect of their hands as frequently as they apply it to other skin sites. Aim. The aim of the current study was to compare the use of sunscreen on the dorsal hands to other areas of the body during subtropical late spring and summer sunlight exposure at the beach. Materials and Methods. A cross-sectional survey from a convenience sample of beachgoers was designed to evaluate respondent understanding and protective measures concerning skin cancer on the dorsal hands in an environment with high natural UVR exposure. Results. A total of 214 surveys were completed and analyzed. Less than half of subjects (105, 49%) applied sunscreen to their dorsal hands. Women applied sunscreen to the dorsal hands more than men (55% women versus 40% men, P = 0.04). Higher Fitzpatrick Skin Type respondents were less likely to protect their dorsal hands from ultraviolet radiation (P = 0.001). Conclusions. More public education focused on dorsal hand protection from ultraviolet radiation damage is necessary to reduce the risk for squamous cell carcinomas of the hands.

Delineating Molecular Mechanisms of Squamous Tissue Homeostasis and Neoplasia: Focus on p63

Abstract: Mouse models have informed us that p63 is critical for normal epidermal development and homeostasis. The p53/p63/p73 family is expressed as multiple protein isoforms due to a combination of alternative promoter usage and C-terminal alternative splicing. These isoforms can mimic or interfere with one another, and their balance ultimately determines biological outcome in a context-dependent manner. While not frequently mutated, p63, and in particular the ΔNp63 subclass, is commonly overexpressed in human squamous cell cancers. In vitro keratinocytes and murine transgenic and transplantation models have been invaluable in elucidating the contribution of altered p63 levels to cancer development, and studies have identified the roles for ΔNp63 isoforms in keratinocyte survival and malignant progression, likely due in part to their transcriptional regulatory function. These findings can be extended to human cancers; for example, the novel recognition of NFκB/c-Rel as a downstream effector of p63 has identified a role for NFκB/c-Rel in human squamous cell cancers. These models will be critical in enhancing the understanding of the specific molecular mechanisms of cancer development and progression.

Protein Kinase Cε, Which Is Linked to Ultraviolet Radiation-Induced Development of Squamous Cell Carcinomas, Stimulates Rapid Turnover of Adult Hair Follicle Stem Cells

Abstract: To find clues about the mechanism by which kinase C epsilon (PKCe) may impart susceptibility to ultraviolet radiation (UVR)-induced development of cutaneous squamous cell carcinomas (SCC), we compared PKCe transgenic (TG) mice and their wild-type (WT) littermates for (1) the effects of UVR exposures on percent of putative hair follicle stem cells (HSCs) and (2) HSCs proliferation. The percent of double HSCs (CD34

Melanoma in Buckinghamshire: Data from the Inception of the Skin Cancer Multidisciplinary Team

Abstract: Background. Melanoma incidence is increasing faster than any other cancer in the UK. The introduction of specialist skin cancer multidisciplinary teams intends to improve the provision of care to patients suffering from melanoma. This study aims to investigate the management and survival of patients diagnosed with melanoma around the time of inception of the regional skin cancer multidisciplinary team both to benchmark the service against published data and to enable future analysis of the impact of the specialisation of skin cancer care. Methods. All patients diagnosed with primary cutaneous melanoma between January 1, 2003 and December 3, 2005 were identified. Data on clinical and histopathological features, surgical procedures, complications, disease recurrence and 5-year survival were collected and analysed. Results. Two hundred and fourteen patients were included, 134 female and 80 males. Median Breslow thickness was 0.74 mm (0.7 mm female and 0.8 mm male). Overall 5-year survival was 88% (90% female and 85% male). Discussion. Melanoma incidence in Buckinghamshire is in keeping with published data. Basic demographics details concur with classic melanoma distribution and more recent trends, with increased percentage of superficial spreading and thin melanomas, leading to improved survival are reflected.

Ambulatory melanoma care patterns in the United States.

Abstract: Objective. To examine trends in melanoma visits in the ambulatory care setting. Methods. Data from the National Ambulatory Medical Care Survey (NAMCS) from 1979 to 2010 were used to analyze melanoma visit characteristics including number of visits, age and gender of patients, and physician specialty. These data were compared to US Census population estimates during the same time period. Results. The overall rate of melanoma visits increased () at an apparently higher rate than the increase in population over this time. The age of patients with melanoma visits increased at approximately double the rate (0.47 year per interval year, ) of the population increase in age (0.23 year per interval year). There was a nonsignificant decline in the proportion of female patients seen over the study interval. Lastly, ambulatory care has shifted towards dermatologists and other specialties managing melanoma patients and away from family/internal medicine physicians and general/plastic surgeons. Conclusions. The number and age of melanoma visits has increased over time with respect to the overall population, mirroring the increase in melanoma incidence over the past three decades. These trends highlight the need for further studies regarding melanoma management efficiency.

Extended UVB Exposures Alter Tumorigenesis and Treatment Efficacy in a Murine Model of Cutaneous Squamous Cell Carcinoma

Abstract: Epidemiological studies support a link between cumulative sun exposure and cutaneous squamous cell carcinoma (SCC) development. However, the presumed effects of extended ultraviolet light B (UVB) exposure on tumorigenesis in the sexes have not been formally investigated. We examined differences in ultimate tumorigenesis at 25 weeks in mice exposed to UVB for either 10 or 25 weeks. Additionally, we investigated the effect of continued UVB exposure on the efficacy of topical treatment with anti-inflammatory (diclofenac) or antioxidant (C E Ferulic or vitamin E) compounds on modulating tumorigenesis. Vehicle-treated mice in the 25-week UVB exposure model exhibited an increased tumor burden and a higher percentage of malignant tumors compared to mice in the 10-week exposure model, which correlated with increases in total and mutant p53-positive epidermal cells. Only topical diclofenac decreased tumor number and burden in both sexes regardless of UVB exposure length. These data support the commonly assumed but not previously demonstrated fact that increased cumulative UVB exposure increases the risk of UVB-induced SCC development and can also affect therapeutic efficacies. Our study suggests that cessation of UVB exposure by at-risk patients may decrease tumor development and that topical NSAIDs such as diclofenac may be chemopreventive.

Mouse Models of the Skin: Models to Define Mechanisms of Skin Carcinogenesis

Abstract: The multistep model of mouse skin carcinogenesis has facilitated identification of irreversible genetic events of initiation and progression, and epigenetic events of tumor promotion. Mouse skin tumor initiation can be accomplished by a single exposure to a sufficiently small dose of a carcinogen, and this step is rapid and irreversible. However, promotion of skin tumor formation requires a repeated and prolonged exposure to a promoter, and that tumor promotion is reversible. Investigations focused on the mechanisms of mouse carcinogenesis have resulted in the identifications of potential molecular targets of cancer induction and progression useful in planning strategies for human cancer prevention trials. This special issue contains eight papers that focus on mouse models used to study individual proteins expressed in the mouse skin and the role they play in differentiation, tissue homeostasis, skin carcinogenesis, and chemoprevention of skin cancer. In the paper entitled “Ap1 transcription factors in epidermal differentiation and skin cancer,” R. Eckert et al. highlight the role of AP1, a transcription factor composed of c-jun and c-fos, that serves as a central node in epidermal keratinocyte survival and differentiation. The authors discuss how AP1 deregulation leads to key steps in driving the development of cancer and how these functions in cancer may be different in epidermal development. Finally, they summarize the various mouse models that have helped elucidate the role of this very interesting molecule. In the paper entitled “The role of TGFβ signaling in squamous cell cancer: lessons from mouse models,” A. Glick summarizes the current literature on the role of TGFβ1 in normal tissues and in carcinogenesis. TGFβ1 is a member of a large growth factor family including activins/inhibins and bone morphogenic proteins (BMPs) that have potent growth regulatory and immunomodulatory functions in normal skin homeostasis, regulation of epidermal stem cells, extracellular matrix production, angiogenesis, and inflammation. The author presents a thorough comparison between the role of TGFβ1 in signaling in human HNSCC and cutaneous SCC and the various mouse models that have been developed to elucidate the role this molecule plays in oncogenesis. In the paper entitled “Multiple roles for VEGF in non-melanoma skin cancer: angiogenesis and beyond,” K. Johnson and T. Wilgus overview how vascular endothelial growth factor (VEGF), a potent proangiogenic factor in mouse and human skin tumors, plays a role in the development of non-melanoma skin cancers. The authors have detailed the use of both transgenic and knockout mice that have provided key clues, primarily alteration of proliferation, survival, and stemness, that have helped elucidate the function of VEGF in carcinogenesis. In the paper entitled “Protein kinase Ce, which is linked to ultraviolet radiation-induced development of squamous cell carcinomas, stimulates rapid turnover of adult hair follicle stem cells,” A. Singh et al. report that protein kinase C epsilon (PKCe), a member of the protein kinase C superfamily, plays a critical step in the development of cutaneous SCC induced by repeated exposures to ultraviolet radiation (UV). The authors focus their investigation on how PKCe, using transgenic mice, may modulate the hair follicle stem cell (HSC). The authors report that overexpression of PKCe in the skin, driven by the K14 promoter, leads to a 7-fold increase in the proliferation of the HSC, indicating a rapid turnover of these cells. In the paper entitled “Patched knockout mouse models of basal cell carcinoma,” the authors discuss the link Patched (PTCH), the receptor for the hedgehog ligand, in the development of Basal cell carcinoma (BCC), the most common form of human skin cancer. In this comprehensive review, the authors compare conventional and conditional PTCH knockout mouse models to investigate BCC as well as for potential use in preclinical research. In the paper entitled “Delineating molecular mechanisms of squamous tissue homeostasis and neoplasia: focus on p63,” K. King et al. focus on summarizing mouse models that have highlighted the importance of p63, a transcription factor that plays an essential role in the development and maintenance of normal stratified squamous epithelium. The authors present that p63 has multiple splice variants and p63 plays a critical role in normal skin biology and neoplastic development. In the paper entitled “Role of Stat3 in skin carcinogenesis: insights gained from relevant mouse models,” E. Macias et al. review the role of signal transducer and activator of transcription 3 (Stat3) in skin biology. The authors detail the various transgenic, knockout, and conditional knockout mice that have led to the understanding of STAT3 in normal skin homeostasis, migration, wound healing, and hair follicle growth and maintenance as well as skin carcinogenesis. In the paper entitled “Topical curcumin-based cream is equivalent to dietary curcumin in a skin cancer model,” the authors present the first study that compares the use of topical curcumin versus the use of oral curcumin as a chemopreventive strategy for the development of SCC of the skin. This collection of papers provides an overview of mouse models investigating several intensely studied molecules involved in skin carcinogenesis. We hope the molecular mechanisms revealed in this special issue will enlighten readers and provide them with motivation to continue their research endeavors. Deric L. Wheeler Ajit K. Verma Mitchell F. Denning

Identification of DLEC1 D215N Somatic Mutation in Formalin Fixed Paraffin Embedded Melanoma and Melanocytic Nevi Specimens

Abstract: DLEC1 has been suggested as a tumor suppressor gene in several cancers. DLEC1 D215N somatic mutation (COSM36702) was identified in a melanoma cell line through whole genome sequencing. However, little is known about the implication and prevalence of this mutation in primary melanomas or in melanocytic nevi. The aim of this study was to genotype DLEC1 D215N mutation in melanoma tissue and melanocytic nevi samples to confirm its occurrence and to estimate its prevalence. Primary melanomas ( ) paired with synchronous or asynchronous metastases ( ) from 81 melanoma patients and melanocytic nevi ( ) were screened for DLEC1 D215N mutation. We found the mutation in 3 primary melanomas and in 2 melanocytic nevi, corresponding to a relatively low prevalence (3.7% and 7.1%, resp.). The pathogenic role of DLEC1 215N mutation is unclear. However, since the mutation has not been previously described in general population, its involvement in nevogenesis and melanoma progression remains a possibility to be clarified in future studies.

Merkel Cell Carcinoma of the Head and Neck: Challenges in Diagnosis and Therapy

Abstract: Since the original description of the trabecular carcinoma of the skin, now known as Merkel cell carcinoma (MCC), by Toker in 1972, this malignancy has provided significant challenge to clinicians. With an increasing incidence and a known poor prognosis for advanced lesions, the disease continues to challenge physicians in the present time. New evidence indicates that not only the incidence is increasing in the overall population but also certain groups of patients such as those taking medications or immunosuppressed are at increased risk. Additionally, patients affected by MCC may be at risk for other malignant diseases. Therefore, it is likely that MCC will continue to challenge clinicians in the future. Current clinical questions regarding the optimal management of MCC include surgical challenges such as histologic diagnosis, sentinel lymph node biopsy, and margin control, as well as issues related to reconstruction. Radiation oncologists continue to evaluate the appropriate strategy for this rare disease in terms of locoregional control and appropriate dosing strategies. Medical oncologists continue their quest for effective treatments for this rare disease, which does not lend itself to randomized controlled trials due to the small number of eligible subjects. Recent new data regarding the analysis of MCC has resulted in a dramatic increase in our knowledge regarding this disease. The discovery of the Merkel cell polyomavirus by Feng, et al. and the subsequent work of Touze et al. which showed high antibody titers against the virus (anti-MCPyV) correlating to improved survival have provided us with new data with which to target this disease. Work in viral detection and protein expression continues to further elucidate the role of the virus in the genesis of MCC. The development of viral vaccines and targeted agents for the treatment of MCC is ongoing. The purpose of this special issue is to update the clinician on the current literature regarding Merkel cell carcinoma and provide a consolidated review of this disease for the clinician. A historical perspective as well as the current management strategies will be reviewed. Recent data will be presented regarding current diagnostic methods, and pathological evaluation as well as an evaluation of surgical, radiotherapeutic, and chemotherapeutic strategies employed in the treatment of MCC will be examined in the articles within the issue. In addition, future areas of research will be identified to allow the reader to plot the trajectory of our current understanding of this disease and where scientific and clinical research efforts are likely to yield advances in the future. Brett A. Miles