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.

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.

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.

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.

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.

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.

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.