Prognostic factors in head and neck melanoma according to facial aesthetic units.

BACKGROUND: Head and neck melanoma is a clinical challenge. Indeed, cutaneous head and neck melanoma shows a worse prognosis in comparison to melanomas of other body sites. Although the emphasis on facial cosmetic preservation plays a pivotal role in comparison to other body areas, specific Facial Aesthetic Units (FAU) could also play a key role in the prognostic evaluation of the malignancy. METHODS: The aim of the current study was to evaluate the general outcome and clinicopathological features of head and neck melanoma and to detect prognostic differences according to each FAU. The Kaplan-Meier product was used to calculate survival curves, while Cox proportional-hazard regression was performed to evaluate the predictive value of each FAU. RESULTS: A total of 221 head and neck melanoma patients was included in our analysis. In the nasal FAU, we found a high rate of local recurrence, which affected significantly disease-free survival. The worse prognosis was observed in melanoma of the scalp, which showed a greater tendency to skip metastases in internal organs. Moreover, we found that scalp showed a low incidence of non-melanoma skin cancers, if compared to other FAU, highlighting that the scalp local milieu might play a more prominent role in melanoma biology than chronic UV exposition. CONCLUSIONS: Although FAUs have an aesthetic function, they could also play a role in the evaluation and follow-up of melanoma.

Vitamin D and melanoma: state of the art and possible therapeutic uses.

Despite the presence of several studies in literature, the real connection between vitamin D serological levels, vitamin D receptor and melanoma remains unclear, probably because of the complex correlation between vitamin D and melanoma. Indeed, UV radiations are not reported as the main risk factor for melanoma in non-sun-exposed, while systemic immunosuppression, anatomical and physiological features may contribute to malignancy. Therefore, the correlation between melanoma cells in sun-exposed areas and vitamin D, as well as vitamin D receptor could be different from the one in melanoma of sun-shielded sites. These differences may also explain the controversial results reported in the literature regarding the correlation between melanoma and vitamin D, as well as the different outcomes in melanoma patients treated with vitamin D as adjuvant therapy. The aim of this review is to highlight the most recent findings about vitamin D and melanoma, focusing on the anatomic site of the primary tumor as well as on the possible therapeutic uses of vitamin D in melanoma patients.

Serum tryptase levels in melanoma patients: case-control study and review of the literature.

BACKGROUND: Serum tryptase results from the constant release of the enzyme from mast cells and serum tryptase levels are commonly considered to be related to the total number of mast cells. They are increased in several malignancies, as pancreatic carcinoma, angiosarcoma, hepatic carcinoma and proliferative and/or non-proliferative hematological disorders. Contrariwise, it has been reported that the number of tryptase- and chymase-positive mast cells was lower in deeply invasive melanoma compared to in-situ melanoma and dysplastic nevi. Considering the underlying pathophysiological linkages between mast cells and melanocytes and that serum tryptase is related to angiogenesis, tissue-degrading proprieties and metastatization, we have decided to evaluate serum tryptase levels in melanoma patients and in a healthy control. METHODS: We performed a case-control study evaluating serum tryptase in melanoma and in healthy group. Starting from an initial general analysis, we have performed a sub-analysis for each sample. RESULTS: In general population serum tryptase was statistically higher in elderly patients. Generally, in melanoma patients, median serum tryptase was in lower normal range. We found a decreasing of serum tryptase levels from the healthy control to thin (≤1.00 mm Breslow thickness), reaching the lowest levels in thicker melanoma (≥1.01 mm Breslow thickness), in ulcerated and metastatic melanoma. CONCLUSIONS: Tryptase may have a protective role in melanoma or in the early stage of the tumorigenesis. Serum tryptase is an easy and useful biomarker to better investigate melanoma biology.

Cost-efficacy analysis of 3% diclofenac sodium, ingenol mebutate, and 3.75% imiquimod in the treatment of actinic keratosis.

Actinic keratosis (AK) is a clinical condition characterized by keratinocytic dysplastic lesions of the epidermis, affecting individuals chronically exposed to sunlight. Topical therapies allow the treatment of a whole area of affected skin and currently include diclofenac sodium gel, 5-fluorouracil cream, 5-fluorouracil and acetylsalicylic acid solution, imiquimod cream, and ingenol mebutate gel. Due to the comparable efficacy of 3% diclofenac, ingenol mebutate, and 3.75% imiquimod in treating AK multiple lesions, a pharmacoeconomic evaluation of cost-effectiveness of the three treatments was needed. A cost-efficacy analysis comparing 3% diclofenac sodium with ingenol mebutate and 3.75% imiquimod was performed. In this analysis, efficacy data were combined with quality-of-life measurement derived from previous studies as well as the costs associated with the management of these lesions in Italy. Patients' demographics and clinical characteristics were assumed to reflect those from the clinical studies considered.

Anticarcinogenic activities of sulforaphane are influenced by Nerve Growth Factor in human melanoma A375 cells.

Melanoma is a severe form of cancer, resistant to conventional therapies. According to in vitro studies, sulforaphane, a dietary component, has been considered a promising antineoplastic candidate. The present study analyzes the in vitro biological effects of sulforaphane in A375 melanoma cell line with or without the addition of Nerve Growth Factor. For the first time, our results show that a supplementation of Nerve Growth Factor partially reverses the sulforaphane-induced: i) inhibition of cell migration, ii) pro apoptotic changes in cell cycle and iii) modulation of active caspase-3. Furthermore, we report the sulforaphane-induced modulation in the expression of Nerve Growth Factor receptors TrKA and p75NTR, shifting their ratio from pro survival to pro apoptotic. In conclusion, the present study evidences that in vivo the antineoplastic effects of sulforaphane may be reduced by the contemporaneous presence of other biological elements such as Nerve Growth Factor and it contributes to a better definition of the real in vivo potentiality of sulforaphane as antineoplastic candidate.

Non Melanoma Skin Cancer Pathogenesis Overview.

(1) Background: Non-melanoma skin cancer is the most frequently diagnosed cancer in humans. The process of skin carcinogenesis is still not fully understood. However, several studies have been conducted to better explain the mechanisms that lead to malignancy; (2) Methods: We reviewed the more recent literature about the pathogenesis of non-melanoma skin cancer focusing on basal cell carcinomas, squamous cell carcinoma and actinic keratosis; (3) Results: Several papers reported genetic and molecular alterations leading to non-melanoma skin cancer. Plenty of risk factors are involved in non-melanoma skin cancer pathogenesis, including genetic and molecular alterations, immunosuppression, and ultraviolet radiation; (4) Conclusion: Although skin carcinogenesis is still not fully understood, several papers demonstrated that genetic and molecular alterations are involved in this process. In addition, plenty of non-melanoma skin cancer risk factors are now known, allowing for an effective prevention of non-melanoma skin cancer development. Compared to other papers on the same topic, our review focused on molecular and genetic factors and analyzed in detail several factors involved in non-melanoma skin cancer.

Scleroderma with an update about clinico-pathological correlation.

Scleroderma is divided into a systemic form called systemic sclerosis and a localized form also called morphea. According to 2013 ACR/EULAR Classification Criteria for Systemic Sclerosis, developed by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for a patient to be classified as having scleroderma. Histological examination is not included in the diagnostic criteria and is not routinely performed. Skin biopsy is recommended only in the case of diagnostic doubt with other scleroderma like disorders (scleromyxedema, scleredema, nephrogenic systemic fibrosis). Alternatively, skin biopsy is also often performed for research purposes. Indeed, the first step analysis of new cytokines or pathways that may contribute to the pathogenesis of the disease requires the evaluation of their expression or activation in the skin of scleroderma patients compared to healthy controls. The histological picture of the skin in bot localized and systemic scleroder shows initially microvascular alterations and chronic inflammation while in the more advanced stages skin fibrosis prevails. Localized scleroderma (LS) or morphea includes a number of subtypes which are classified more according to their clinical presentation rather than histopathological pictures. However, some histopathologic changes may be useful in differentiating each entity from the others and from other sclerodermoid disorders.

Dermatofibrosarcoma protuberans: when the age makes the difference.

BACKGROUND: Dermatofibrosarcoma protuberans is a malignant tumor that affects exclusively the skin. It is a low-grade malignant tumor of subcutaneous tissues, characterized by a local recurrence but it seldom metastasizes. This study aimed to evaluate the impact of different clinical parameters on disease free survival and overall survival of dermatofibrosarcoma protuberans patients. METHODS: A retrospective study of data including seventeen cases of dermatofibrosarcoma protuberans (eleven male, six female) retrieved from the files of the Dermatology Clinics of La Sapienza University, Rome. We evaluated three clinical parameters (age, sex and anatomic site of the primary tumor) using the Kaplan-Meier product and the Log-Rank Test. RESULTS: The results highlighted that patients with an age ≤49 years showed a median disease free survival of 36 months, while patients with an age ≥50 years of 4 months (P<0.0003). In addition, performing Rank-correlation, only the variable age (P<0.0001) reached the statistical significance. Regarding overall survival, performing Rank-correlation only the variable age reached the statistical significance (P=0.02). CONCLUSIONS: Our data suggests that age has a statistically significant role on disease free survival and overall survival of dermatofibrosarcoma protuberans patients.

Antitumor activity and expression profiles of genes induced by sulforaphane in human melanoma cells.

PURPOSE: Human melanoma is a highly aggressive incurable cancer due to intrinsic cellular resistance to apoptosis, reprogramming, proliferation and survival during tumour progression. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, plays a role in carcinogenesis in many cancer types. However, the cytotoxic molecular mechanisms and gene expression profiles promoted by SFN in human melanoma remain unknown. METHODS: Three different cell lines were used: two human melanoma A375 and 501MEL and human epidermal melanocytes (HEMa). Cell viability and proliferation, cell cycle analysis, cell migration and invasion and protein expression and phosphorylation status of Akt and p53 upon SFN treatment were determined. RNA-seq of A375 was performed at different time points after SFN treatment. RESULTS: We demonstrated that SFN strongly decreased cell viability and proliferation, induced G2/M cell cycle arrest, promoted apoptosis through the activation of caspases 3, 8, 9 and hampered migration and invasion abilities in the melanoma cell lines. Remarkably, HEMa cells were not affected by SFN treatment. Transcriptomic analysis revealed regulation of genes involved in response to stress, apoptosis/cell death and metabolic processes. SFN upregulated the expression of pro-apoptotic genes, such as p53, BAX, PUMA, FAS and MDM2; promoted cell cycle inhibition and growth arrest by upregulating EGR1, GADD45B, ATF3 and CDKN1A; and simultaneously acted as a potent inhibitor of genotoxicity by launching the stress-inducible protein network (HMOX1, HSPA1A, HSPA6, SOD1). CONCLUSION: Overall, the data show that SFN cytotoxicity in melanoma derives from complex and concurrent mechanisms during carcinogenesis, which makes it a promising cancer prevention agent.

Superiority of a vitamin B12-containing emollient compared to a standard emollient in the maintenance treatment of mild-to-moderate plaque psoriasis.

Psoriasis is a chronic inflammatory skin disease affecting 2%-3% of the population. The wide range of drugs currently available for its treatment could be associated, in the long term, with organ toxicity and adverse events, thus, clinical monitoring throughout treatment is required. This investigator-initiated trial (IIT) evaluated the efficacy and the safety of a vitamin B12-containing ointment in comparison with glycerol-petrolatum-based emollient cream used twice a day to treat mild-to-moderate plaque psoriasis for a period over 12 weeks followed by a wash-out observation period of 4 weeks. This study was conducted as a randomized, controlled, single-blind, intra-patient left- to right-side trial comparing the efficacy and safety of vitamin B12-containing ointment (M-treatment) with a glycerol-petrolatum-based emollient cream (C-treatment). The Psoriasis Area Severity Index (PASI) was determined at baseline (T0), at time points T2 (14 days), T4 (4 weeks), T8 (8 weeks), T12 (12 weeks) and 4 weeks after the end of the wash-out period (F1). In total, 24 patients with plaque psoriasis were randomized to receive left- or right-side treatment with B12 ointment. From time point T2 to time point F1, there was a statistically significant difference in PASI reduction between M-treatment side and C-treatment side. At time point T 12, the difference between the mean reductions from baseline PASI scores by 5.92 ± 2.49 (87, 6%) in the M-treatment side versus 1.08 ± 1.02 (23, 1%) C-treatment side was statistically highly significant ( PWex < 0.001). On the contemporary panorama in the treatment of psoriasis, we conclude that vitamin B12 ointment will represent a new concrete therapy option and should be considered in the update of therapeutic algorithm for the treatment of psoriasis.

Neurodystrophic Hand Dermatitis: Sannino Barduagni Syndrome.

Hand eczema is a chronic disease (1), commonly considered the expression of a contact allergic or irritative dermatitis. However, when the prick/patch tests and laboratory investigations are negative, important diagnostic challenges may arise. Peripheral nerve fibers are in fact capable of releasing neuromediators. Thus, an alteration of the central and/or peripheral nervous system can cause the exacerbation as well as the onset of a cutaneous disease (2). From September 1, 2013 to August 31, 2015, we observed 5 female patients between 20 and 40 years old, with particular hand dermatitis lesions on the volar area, unilateral on the right hand in 3 patients and bilateral in 2 patients. In one case, the dermopathy extended to all the fingers, up to the area of the metacarpophalangeal joints, thenar, and hypothenar eminences. The skin appeared dry (Figure 1), anhidrotic, inelastic, thinned, scaly, and slightly erythematous (Figure 2). In some cases, the fingertips appeared sclerotic, while in other cases the transversal fissures on the flexural joints caused painful and incomplete finger flexion. The dorsal surface was unaffected and the nails healthy. Symptoms were paresthesia and burning sensation. All of the patients were in good general health, with negative routine laboratory investigations, IgE serum levels and prick/patch tests. One patient had just given childbirth three months before the onset of the disease. The patients had been suffering of their hand dermatitis for a duration ranging from 2 months and 2 years and had been treated unsuccessfully with topical and systemic drugs, mainly corticosteroids. We performed a cervical spine X-ray in different projections. In all patients, we observed a degenerative disease of the cervical spine with a reduction of intersomatic discs, primarily C5-C6 (Figure 3). This led us to establish a diagnosis of neurodystrophic hand dermatitis (NHD). Patients started specific treatment programs for the spinal disorder, intake of a vitamin B complex and repairing/soothing skin creams, with a partial improvement. NHD is rarely described in the literature; in 1964 Sannino et al. reported 89 female patients with skin alterations similar to the ones observed in our case series as well as negative patch/prick tests and laboratory investigations, and the main finding was the presence of a cervical spine disease between C5-C7 (3). Recently, Azimi et al. performed a review of skin diseases at sites affected by neurological deficits. They started to collect data from 1966, but did not mention cases attributable to NHD, which is an underestimated and misdiagnosed disorder (2). Cervical spine disease is a predisposing factor for the development of NHD. Additionally, thermoreceptors may be mainly involved, as also reported in brachio-radial pruritus (4-5), explaining the presence of burning sensation. However, in our opinion, NHD should not be classified as a "neurogenic inflammation". This term describes the vasodilation and protein extravasation caused by inflammatory neuropeptides and adrenergic transmitters that influence the antigen presentation, mast-cell degranulation, and cytokine release (2). In fact, corticosteroids and other immunosuppressors are ineffective. Specific treatments for cervical spine disease remain the treatment of choice, as does constant use of repairing/soothing skin creams. Antidepressants, physiotherapy, postural exercises, neuromodulators, and vitamin B complex may be also helpful.

Vitamin D receptor immunohistochemistry variability in sun-exposed and non-sun-exposed melanomas.

Ultraviolet rays are one of the leading factors in the development of melanoma (MM); however, ultraviolet rays seem not to play a role in non-sun-exposed MM, where systemic immunosuppression, anatomical, and physiological features may contribute toward the development of the malignancy. Our aim was to evaluate vitamin D receptor (VDR) expression in shield-site melanoma (ST-MM) and non-shield-site melanoma (NST-MM) to find features that could explain the different biological behavior of MM according to the area of onset. We reviewed 118 specimens of MM. VDR expression was assayed using immunohistochemistry by dividing the specimens according to the anatomical area. We included MM of the soles, feet, hands, gluteus, scrotum, skin of the penile shaft, and large vaginal labia in the ST-MM group. The NST-MM group was divided into two main categories: NST-MM of chronic sun-exposed areas, including MM of the face, scalp, neck, back of the hands, and NST-MM of intermittent sun-exposed areas, including MM of the trunk, lower, and upper limbs. In shield sites, 66.67% of MMs showed VDR expression; in intermittent sun-exposed areas, 33.3% showed VDR expression; and in chronic sun-exposed areas, only 4.66% showed VDR expression. A similar behavior was observed for Breslow's thickness, where VDR staining intensity was higher in thicker lesions, ranging between 60 and 100%. We found that VDR expression decreased from ST-MM to NST-MM. These findings confirm the hypothesis that different pathways are involved in ST-MM and NST-MM.

Skin lesions in patients treated with imatinib mesylate: a 5-year prospective study.

Imatinib mesylate (IM) represents the first-line treatment of patients with chronic myeloid leukemia (CLM) or gastrointestinal stromal tumor (GIST). It presents several side effects. However, less than 10% are nonhematologic including nausea, vomiting, diarrhea, muscle cramps, and cutaneous reactions. The aim of our study was to identify data regarding IM cutaneous adverse effects (AEs) to improve the clinical diagnosis and management of the more frequent side effects. Skin examination should be done before and during IM treatment so that AEs can be diagnosed and treated early with less impact on chemotherapy treatments and on the quality of life of the patient.