BAP1-inactivated melanocytic tumour with borderline histopathological features (BAP1-inactivated melanocytoma): A case report and a reappraisal.

We describe a case of BRCA1-associated protein (BAP1)-inactivated melanocytic tumour (BIMT) in a 22-year-old woman, documenting for the first time with dermoscopy its sudden development with the onset of an atypical vascular pattern within a Miescher naevus. The tumour was histopathologically atypical because of the presence of confluent pleomorphism, solid sheets of cells and grouped mitotic figures: these features were consistent with a melanocytic neoplasm with intermediate morphology ('BAP1-inactivated melanocytoma'; BIM) between a BAP1-inactivated melanocytic naevus and a BAP1-inactivated melanoma. The atypical histopathological features of the present case were different from the criteria quoted for BIM in the World Health Organization 2018 classification of skin tumours.

The tripeptide KdPT ameliorates ongoing psoriasis-like skin inflammation in murine and human skin.

Psoriasis is a chronic inflammatory disease appearing as scaly erythematous cutaneous lesions, which are characterized by parakeratosis and acanthosis as well as the infiltration of immune cells, such as T helper-1 and T helper-17 cells. Here, we demonstrated that KdPT, a tripeptide structurally related to the C-terminal amino acids of alpha-melanocyte-stimulating hormone, which was previously shown to exhibit anti-inflammatory effects in intestinal inflammation, ameliorated ongoing disease in the mouse model of imiquimod-induced psoriasis-like skin inflammation and in the small xenotransplant mouse model of psoriasis. We could show that systemic KdPT treatment significantly reduced hyperkeratosis and acanthosis in murine as well as human skin. Moreover, KdPT upregulated Foxp3 in CD4+ T cells from mice and from peripheral blood of individuals with psoriasis and decreased the expression of type 1 inflammatory cytokines, indicating that the beneficial effect of KdPT was, at least in part, mediated by the induction of functional regulatory T cells that suppressed the activation of pathogenic CD4+ IFN-γ+ and CD4+ IL-17+ T cells. Thus, these data might suggest KdPT as a potential novel therapeutic alternative for the treatment of psoriasis.

Polypodium leucotomos supplementation in the treatment of scalp actinic keratosis: could it improve the efficacy of photodynamic therapy?

BACKGROUND: Actinic keratoses (AKs) are a common premalignant skin condition. Many treatments are available for AKs. Photodynamic therapy (PDT) is one of the most effective treatments. However, major concerns exist on the possibility of PDT-induced DNA-mutagenesis/immunosuppression, leading to AKs recurrence/treatment failure. An extract (PLE) from the fern polypodium leucotomos reduces UV-induced immunosuppression and mutagenesis. OBJECTIVE: To assess the ability of PLE to enhance the efficacy of PDT treatment, reducing AKs recurrence on the scalp. MATERIALS AND METHODS: Thirty-four bald patients presenting at least two AKs on the scalp were alternatively assigned to two groups. Both groups underwent two PDT-sessions one-week apart. The first group began oral PLE supplementation one week after the last PDT session. Evaluation of the effect of PLE supplementation was performed by direct inspection of the bald areas, lesions count, and photodynamic diagnosis assessment at 2 and 6 months. RESULTS: Both groups were homogeneous in terms of skin phototype and previous UV exposure. Mean age was 75.7 ± 7.8 years and 76.5 ± 5.5 years, respectively. Both treatment modalities were successful in reducing AKs number (p < .001). However, PLE supplementation increased clearance rate compared with PDT alone (p = .040). CONCLUSION: Polypodium leucotomos improves PDT clearance and decreases AK recurrence rate at 6 months, suggesting its use as a complementary agent in the treatment of field cancerization.

Galectin-2 suppresses contact allergy by inducing apoptosis in activated CD8+ T cells.

Galectins, a family of structurally related beta-galactoside-binding proteins, are expressed by various cells of the immune systems and seem to be important for the regulation of immune responses and immune cell homeostasis. Since it has been demonstrated that galectin-2 regulates cell-mediated inflammatory bowel disease and colitis in mice, we intended to investigate the role of galectin-2 in inflammatory cutaneous T cell-mediated immune responses. To address this issue, groups of naive mice were sensitized to the contact allergen 2,4-dinitro-1-fluorobenzene and systemically treated with galectin-2 to analyze the effects of galectin-2 on contact allergy. Here we show that galectin-2 is expressed in murine skin and is up-regulated upon cutaneous inflammation. Interestingly, treatment of mice with galectin-2 significantly reduced the contact allergy response. This effect was long-lasting since rechallenge of galectin-2-treated mice after a 14-day interval still resulted in a decreased ear swelling. We were able to demonstrate that galectin-2 induced a reduction of MHC class I-restricted immune responses in the treated animals, which was mediated by the induction of apoptosis specifically in activated CD8(+) T cells. Additionally, we report that the galectin-2-binding protein CD29 is up-regulated on the surface of activated CD8(+) T cells compared with naive CD8(+) T cells or CD4(+) T cells, suggesting that increased galectin-2/CD29 signaling might be responsible for the proapoptotic effects of galectin-2 on activated CD8(+) T cells. Taken together, these data indicate that galectin-2 may represent a novel therapeutic alternative for the treatment of CD8-mediated inflammatory disorders such as contact allergy.

Polyglandular autoimmune diseases in a dermatological clinical setting: vitiligo-associated autoimmune diseases.

Vitiligo is an acquired hypomelanotic disorder characterized by depigmented macules resulting from the loss of functional melanocytes. Many different etiological hypotheses have been suggested for vitiligo, the most recent of which involves a combination of interacting environmental and genetic factors. Among the various pieces of evidence in support of an autoimmune origin of vitiligo, there is the epidemiological association with several autoimmune diseases. The most frequently reported association is with autoimmune thyroiditis; however, other diseases such as rheumatoid arthritis, diabetes mellitus, pernicious anemia and chronic urticaria have been described in variable percentages, depending upon the genetics of the population studied. Among the diseases described in association with vitiligo there are the so-called autoimmune polyglandular syndromes (APS). Here we report 31 cases of APS diagnosed in 113 vitiligo patients, according to the newest classification. Autoimmune association was more present in generalized non segmental vitiligo and was more frequent in females. The most frequent association was with thyroid autoimmune disease, followed by autoimmune gastritis and alopecia areata. ANA positivity was similar to that reported previously in the general population. We stress the importance of an assessment for autoimmune diseases in vitiligo patients.

Serological landscape of cytokines in cutaneous melanoma.

BACKGROUND: To date, serological markers to monitor melanoma progression and response to therapy are lacking. In this context cytokines appear to be promising biomarkers of the disease. OBJECTIVE: To compare cytokine and chemokine levels in melanoma patients and in healthy controls and to assess possible variations according to melanoma stage. METHODS: Serum chemokine and cytokine levels were determined by ELISA in 34 patients diagnosed histologically of malignant melanoma. Seven healthy volunteers were used as controls. RESULTS: We found a subset of cytokines (CCL3, CCL4, IFN-γ and IL-10) to be significantly higher in melanoma patients than in control group, thus confirming the importance of the inflammation in cancer. While CCL3 increased with tumor progression, IFN-γ and IL-10 showed higher levels in stage I patients. Moreover, we noticed a direct correlation between CCL3 level and the presence of ulceration in the primary tumor; on the contrary, CCL4, IL-10 and IFN-γ were lowered down in patients with ulcerated melanoma. CONCLUSIONS: These results expand and confirm observations made in other studies focusing on a more limited number of molecules. This extended panel of cytokines examines the potential roles of type2 cytokines (such as IL-4) and many chemokines (mainly CCL3) as biomarkers in melanoma progression.

Atopic dermatitis treatment: what's new on the horizon?

Atopic dermatitis (AD) is an inflammatory disorder of the skin characterized by an impaired immune response and skin barrier function. It is very frequent in adult population being present in up to 10% of population. Quality of life is often reduced in AD patients due to disease burden and symptoms like itch. AD is also frequently associated with psychological diseases such as anxiety or depression. Due to its chronic nature and severity of presentation AD often may not respond to topical treatment and requires systemic treatments which can be associated with significant side effects. A Medline search of the last five years with the keywords "Atopic dermatitis" and "treatment" was performed. Moreover a search throughout the clinicaltrial.gov webpage was performed with the keyword AD. Several topical and systemic treatments are being studied in randomized controlled trials or in case series or in pivotal studies. The progression of the insight on AD pathogenesis have made possible to target single molecules responsible for key aspect of the development of this disease. We discuss the various molecules (small anti-inflammatory molecules, monoclonal antibodies against cytokines) that will be hopefully soon available for the treatment of this disease which still carries an important burden of unmet needs for its treatment.

Skin toxicity evaluation in patients treated with cetuximab for metastatic colorectal cancer: a new tool for more accurate comprehension of quality of life impacts.

OBJECTIVES: The effectiveness of evaluation of the severity of epidermal growth-factor receptor inhibitor (EGFRI)-associated dermatological toxicities remains a topic of debate. This study was designed to assess the correlation between quality of life (QoL) and severity of dermatological toxicity, evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) and our novel scale, the Eruption Scoring System (ESS), in metastatic colorectal cancer (CRC) patients treated with first-line chemotherapy combined with cetuximab. METHODS: Cutaneous toxicity was evaluated, by oncologists and dermatologists, in patients (n=30) with histologically confirmed metastatic CRC who were scheduled to begin first-line chemotherapy combined with the EGFRI, cetuximab, using the NCI-CTCAE and ESS tools. Health-related QoL (HRQoL) was evaluated using the Skindex-29 and Skindex-17 dermatology-specific instruments. Correlations between QoL and skin toxicity severity were assessed using Spearman's rank tests. Interclass correlation coefficients were used to assess interoperator agreement for ESS and NCI-CTCAE v4.0 scoring. RESULTS: A positive correlation was identified between dermatology HRQoL and the severity of dermatological toxicities assessed using the NCI-CTCAE v4.0 scale for cutaneous papulopustular acneiform rash; however, a stronger correlation was observed between HRQoL and toxicities evaluated using the ESS tool. Both NCI-CTCAE v4.0 and ESS tools demonstrated good interobserver agreement for grading of skin toxicity. CONCLUSION: There is a strong correlation between the scores generated by the ESS and NCI-CTCAE tools to grade cutaneous toxicity related to treatment with the anti-EGFR monoclonal antibody, cetuximab. ESS can be considered a valid instrument for identification and grading of the severity of skin toxicity induced by cetuximab, with some advantages over the standard NCI-CTCAE scoring system.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL): a possible pathogenic role in chronic plaque psoriasis.

BACKGROUND: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine member of the tumour necrosis factor (TNF) family. Its role has been investigated in skin cancers and some inflammatory and/or immune-mediated skin diseases. An involvement of TRAIL in psoriasis pathogenesis has recently been hypothesized. We investigated the expression and localization of TRAIL and its receptors in psoriatic skin and measured serum TRAIL. The intracellular pathways activated by TRAIL were assessed to investigate its potential role in the pathogenesis of psoriasis. METHODS: Twenty-four consecutive patients with plaque psoriasis and age- and sex-matched healthy subjects were recruited. Serum TRAIL was measured by means of an enzyme-linked immunosorbent assay (ELISA). TRAIL and TRAIL receptors were evaluated by reverse transcription - polymerase chain reaction (RT-PCR) (RNA of lesional and non-lesional psoriatic skin) and by immunohistochemistry (lesional skin). Caspase 8 and NF-kB immunoexpression were also evaluated by immunohistochemistry. RESULTS: RT-PCR demonstrated increased synthesis of TRAIL and its receptors in lesional vs. non-lesional skin. Immunohistochemistry showed a strong staining of TRAIL and TRAIL receptors both in the epidermis and in the dermal infiltrate. Finally, a correlation emerged between caspase 8 and TRAIL immunoexpression in the dermis. CONCLUSIONS: Our findings suggest an involvement of TRAIL in psoriasis pathogenesis, probably through an action at the site of the inflammatory infiltrate, likely via caspase 8.

Cytokines and T cells in atopic dermatitis.

Atopic dermatitis (AD) is an inflammatory disorder of the skin characterized by an impaired immune response. Several effector T cell subsets, such as pro-inflammatory cells like Th9, Th17 and Th22 cells, expressing high levels of IL-9, IL-17 and IL-22, together with the anti-inflammatory, immuno-modulating Treg cells constitutively producing IL-10, seem to play a role in this condition. IL-9 and IL-9 receptors are significantly increased in lesional AD skin compared to normal control skin. In addition, some polymorphisms in IL-9 and IL-9r genes have been associated with AD. The role of IL-17 and IL-17-producing T cells remains under debate and conflicting data are available. IL-22-producing T-cells seem to correlate with the severity of the AD. The number and function of Treg cells, producing IL-10, have been widely investigated in AD with conflicting results. Other studies suggest that high levels of IL-31 or low levels of IL-21 might be involved in the pathogenesis of AD. This review was undertaken in order to provide a better understanding of the relevance of certain cytokines in AD. We have analysed the new insight into the pathogenesis of AD, with special attention to those cytokines produced by the different T cell subpopulations.

α-MSH-stimulated tolerogenic dendritic cells induce functional regulatory T cells and ameliorate ongoing skin inflammation.

The neuropeptide α-melanocyte-stimulating hormone (α-MSH) is a well-known mediator of skin pigmentation. More recently, it has been shown that α-MSH also exerts a strong anti-inflammatory and immunosuppressive activity. To elucidate the mechanisms underlying α-MSH-induced immunosuppression, we investigated whether α-MSH affects dendritic cell/T cell communication, as especially this interaction has an important role in the regulation of immune responses. Here, we show that α-MSH, by binding to MC-1R, induced tolerogenic dendritic cells, which were capable of expanding CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in vitro, as well as in vivo. Notably, those α-MSH-induced Tregs were functional as they efficiently inhibited cutaneous contact allergy and ongoing psoriasis-like skin inflammation in mice. Furthermore, α-MSH induced tolerogenic dendritic cells capable of generating functional Tregs in human blood. Interestingly, human Tregs expanded via α-MSH-stimulated dendritic cells suppressed the proliferation and cytokine secretion of pathogenic T-helper-17 (Th17) cells from individuals with psoriasis. Taken together, these data indicate that α-MSH induced immunosuppressive Tregs in vitro and in vivo, which inhibited disease progression in a mouse model of psoriasis-like skin inflammation and suppressed the activation and proliferation of effector T cells from subjects with psoriasis.

Treatment of cutaneous calciphylaxis with sodium thiosulfate: two case reports and a review of the literature.

Cutaneous calciphylaxis is a potentially fatal condition characterized by calcium deposition in dermal arterioles and the subsequent development of livedo reticularis, plaques, and extremely painful ulcers. This condition may be present in up to 4% of end-stage renal disease patients. Several treatments, which mainly attempt to control calcium phosphate metabolism, are available for this condition. We describe two patients treated with sodium thiosulfate with good results. Moreover, we also performed a PubMed literature search of sodium thiosulfate treatment for calciphylaxis. We found 41 cases of which most (> 90%) presented a rapid and sustained resolution, indicating this drug is a very good candidate for the treatment of this condition.

The neuropeptide alpha-melanocyte-stimulating hormone is critically involved in the development of cytotoxic CD8+ T cells in mice and humans.

BACKGROUND: The neuropeptide alpha-melanocyte-stimulating hormone is well known as a mediator of skin pigmentation. More recently, it has been shown that alpha-melanocyte-stimulating hormone also plays pivotal roles in energy homeostasis, sexual function, and inflammation or immunomodulation. Alpha-melanocyte-stimulating hormone exerts its antiinflammatory and immunomodulatory effects by binding to the melanocortin-1 receptor, and since T cells are important effectors during immune responses, we investigated the effects of alpha-melanocyte-stimulating hormone on T cell function. METHODOLOGY/PRINCIPAL FINDINGS: T cells were treated with alpha-melanocyte-stimulating hormone, and subsequently, their phenotype and function was analyzed in a contact allergy as well as a melanoma model. Furthermore, the relevance of alpha-melanocyte-stimulating hormone-mediated signaling for the induction of cytotoxicity was assessed in CD8(+) T cells from melanoma patients with functional and nonfunctional melanocortin-1 receptors. Here we demonstrate that the melanocortin-1 receptor is expressed by murine as well as human CD8(+) T cells, and we furthermore show that alpha-melanocyte-stimulating hormone/melanocortin-1 receptor-mediated signaling is critical for the induction of cytotoxicity in human and murine CD8(+) T cells. Upon adoptive transfer, alpha-melanocyte-stimulating hormone-treated murine CD8(+) T cells significantly reduced contact allergy responses in recipient mice. Additionally, the presented data indicate that alpha-melanocyte-stimulating hormone via signaling through a functional melanocortin-1 receptor augmented antitumoral immunity by up-regulating the expression of cytotoxic genes and enhancing the cytolytic activity in tumor-specific CD8(+) T cells. CONCLUSIONS/SIGNIFICANCE: Together, these results point to an important role of alpha-melanocyte-stimulating hormone in MHC class I-restricted cytotoxicity. Therefore, treatment of contact allergies or skin cancer with alpha-melanocyte-stimulating hormone or other more stable agonists of melanocortin-1 receptor might ameliorate disease or improve antitumoral immune responses.

Epidemiology and clinical and pathologic characteristics of cutaneous malignant melanoma in Abruzzo (Italy).

BACKGROUND: Malignant melanoma incidence has increased worldwide in recent decades. Cancer registry-derived epidemiologic data on malignant melanoma in Italy are available only in some northern regions of the country. AIM: To report the number and characteristics of incident cases of cutaneous malignant melanoma in Abruzzo, a central-southern Italian region. METHODS: Screening of the archives of the pathology departments of regional hospitals from 2002 to 2005 was performed. For each patient, clinical and pathologic data were collected. Cases of metastatic, multiple, or relapsing melanoma were excluded. RESULTS: Six hundred and seventy-two cases of primary melanoma were recorded, with an incidence rate of 14.1 per 100,000 inhabitants per year. Differences related to gender (41.1% males and 58.9% females) and age (35% in the 50-70-year age group) were found. The trunk (30.7%) and lower limbs (25.94%) were the most frequent sites observed. The superficial spreading histiotype and thin melanoma (< or = 1.00 mm) were more often recorded (44.8% and 62%, respectively). CONCLUSIONS: Despite the bias present in this study, linked to the nature and source of the data, we believe that the figures found in this report are comparable with those obtained in the international literature from other Mediterranean countries.