GOPC-ROS1 mosaicism in agminated Spitz naevi: report of two cases.

Spitz tumors are genetically associated with activating HRAS point mutations or fusions of either ALK, ROS1, NTRK1, NTRK3, RET, MET, MERTK, LCK, BRAF, MAP3K8, or MAP3K3. All these driver gene alterations are mutually exclusive. We report two cases of agminated Spitz naevi with a GOPC-ROS1 fusion. Both cases occurred on the lower limb of young adults. Since adolescence, pigmented or pink-colored papules have been periodically arising in a limited area of skin. In one case, an ill-defined hyperpigmented macule known since childhood was present in the background. Morphologically, at least five lesions were analyzed from each patient. In one case, all were predominantly junctional pigmented Spitz naevi, and in the other case, all were compound unpigmented Spitz naevi. No atypical features were present. RNA-sequencing revealed a GOPC-ROS1 gene translocation in both cases. Split signals of ROS1 gene in fluorescence in situ hybridization were observed not only in the nests of spitzoid melanocytes but also in the bland basal melanocytes surrounding the proliferations. These findings suggest the presence of a GOPC-ROS1 mosaicism in melanocytes with further emergence of agminated Spitz naevi potentially triggered by other genetic alterations. This expands the spectrum of genetic anomalies described in agminated Spitz naevi and our understanding of the mechanisms involved in their emergence.

Diagnostic Performance of a Support Vector Machine for Dermatofluoroscopic Melanoma Recognition: The Results of the Retrospective Clinical Study on 214 Pigmented Skin Lesions.

The need for diagnosing malignant melanoma in its earliest stages results in an increasing number of unnecessary excisions. Objective criteria beyond the visual inspection are needed to distinguish between benign and malignant melanocytic tumors in vivo. Fluorescence spectra collected during the prospective, multicenter observational study ("FLIMMA") were retrospectively analyzed by the newly developed machine learning algorithm. The formalin-fixed paraffin-embedded (FFPE) tissue samples of 214 pigmented skin lesions (PSLs) from 144 patients were examined by two independent pathologists in addition to the first diagnosis from the FLIMMA study, resulting in three histopathological results per sample. The support vector machine classifier was trained on 17,918 fluorescence spectra from 49 lesions labeled as malignant (1) and benign (0) by three histopathologists. A scoring system that scales linearly with the number of the "malignant spectra" was designed to classify the lesion as malignant melanoma (score > 28) or non-melanoma (score ≤ 28). Finally, the scoring algorithm was validated on 165 lesions to ensure model prediction power and to estimate the diagnostic accuracy of dermatofluoroscopy in melanoma detection. The scoring algorithm revealed a sensitivity of 91.7% and a specificity of 83.0% in diagnosing malignant melanoma. Using additionally the image segmentation for normalization of lesions' region of interest, a further improvement of sensitivity of 95.8% was achieved, with a corresponding specificity of 80.9%.

Treatment of plaque-type psoriasis with the 308 nm excimer laser in combination with dithranol or calcipotriol.

PURPOSE: The combination of excimer laser and topical treatment has not been studied in clinical trials. This within-patient comparison study evaluates the response rates of plaque-type psoriasis after treatment with topical only (dithranol or calcipotriol), laser only, and combination therapy with topical medication and laser. MATERIALS AND METHODS: A total of 61 patients with psoriatic plaques located at symmetric body areas (PASI ≥ 6) were screened, 59 were enrolled, 54 completed treatment and 45 completed the 6 months follow-up. Treatments with the excimer laser were performed twice weekly until resolution or a maximum of 15 treatments. Each ointment was applied on one of the test lesions, which had to be at least 10 cm apart from each other. Efficacy was rated with a modified PASI score. RESULTS: At the end of the treatment phase only one patient in both topical therapy regimens met the criteria of partial clearance (modified PASI ≤ 2). The combined therapies resulted in 23 cases of partial clearance in both treatment arms. Four areas treated with calcipotriol, respectively six areas treated with dithranol resulted in total clearance at the end of the treatment phase. The average reduction of modified PASI scores was higher in combination than in topical treatment alone (49.8% calcipotriol + excimer versus 22.9% calcipotriol, 49.7% dithranol + excimer versus 26.8% dithranol). After six months there was a total clearance of 30.5% dithranol + excimer. CONCLUSIONS: Treatment of plaque-type psoriasis with laser in combination with topical treatment is a safe and effective therapy. The best long-term results can be obtained by the application of dithranol and excimer laser.

Eosinophilic cellulitis (Wells' syndrome) in association with angioimmunoblastic lymphadenopathy.

Eosinophilic cellulitis (Wells' syndrome) is an uncommon inflammatory disease with clinical polymorphism. It is often associated with infectious, allergic or myeloproliferative diseases; however, the exact aetiology is unknown. This report describes a rare case of eosinophilic cellulitis in association with angioimmunoblastic lymphadenopathy. The typical skin findings of Wells' syndrome disappeared completely following chemotherapy and autologous stem cell transplantation.

Ultraviolet-B irradiation enhances melanoma cell motility via induction of autocrine interleukin 8 secretion.

Ultraviolet radiation (UVR) is known to be involved in the initiation and progression of malignant melanoma. Many studies have focused on the initiation of melanoma, but less is known about the effect of UVR on established tumor cells. Here, we show that after ultraviolet-B (UVB) irradiation, melanoma cells (MM) are able to secrete autocrine factors that enhance their motility. Time-lapse videomicroscopy of UVB irradiated (15 or 30 mJ/cm(2)) MM showed an initial decrease in MM cell motility one hour after irradiation, with subsequent increase 24 h after UV-B treatment. Conditioned media harvested from MM 24 h following UV-B irradiation specifically enhanced the motility of un-irradiated MM, suggesting that a newly synthesized soluble factor released by UVB MM is involved. As interleukin 8 (IL-8) is known to be up-regulated by different cell types after UV-B irradiation, we investigated IL-8 expression after UVB exposure. Quantitative RT-PCR and ELISA demonstrated an induction of IL-8 in MM by UVB (15 or 30 mJ/cm(2)), and addition of recombinant IL-8 to cell cultures enhanced cell motility to a similar degree than UVB. Importantly, blocking IL-8 activity by a neutralizing anti IL-8 antibody inhibited the up-regulation of MM motility after UVB treatment. We conclude that UVB enhances MM motility and that this effect is mediated at least in part by IL-8 released by MM in an autocrine fashion. Our findings are consistent with the hypothesis that UVB is not only involved in the initiation of melanoma, but may also be important for some aspects of tumor progression.

Dermal fibroblasts induce maturation of dendritic cells.

To trigger an effective T cell-mediated immune response in the skin, cutaneous dendritic cells (DC) migrate into locally draining lymph nodes, where they present Ag to naive T cells. Little is known about the interaction of DC with the various cellular microenvironments they encounter during their migration from the skin to lymphoid tissues. In this study, we show that human DC generated from peripheral blood monocytes specifically interact with human dermal fibroblasts via the interaction of beta(2) integrins on DC with Thy-1 (CD90) and ICAM-1 on fibroblasts. This induced the phenotypic maturation of DC reflected by expression of CD83, CD86, CD80, and HLA-DR in a TNF-alpha- and ICAM-1-dependent manner. Moreover, fibroblast-matured DC potently induced T cell activation reflected by CD25 expression and enhanced T cell proliferation. Together these data demonstrate that dermal fibroblasts that DC can encounter during their trafficking from skin to lymph node can act as potent regulators of DC differentiation and function, and thus may actively participate in the regulation and outcome of DC-driven cutaneous immune responses.

Meta-analysis of published data on incompletely excised basal cell carcinomas of the ear and nose with introduction of an innovative treatment strategy.

BACKGROUND: Auricular/nasal basal cell carcinomas (BCC) often require more surgical procedures than BCCs at other sites. METHODS: A meta-analysis of incompletely excised BCCs compares those on the ear and nose to other sites. The combination of photodynamic diagnostics (PDD) and fresh-frozen sections is compared to multi-stage excisions; in each case, the tissue margins were histographically controlled. RESULTS: The relative risk of an incomplete excision of a BCC on the ear/nose is 2.5 fold higher than on the rest of the body. The combination of PDD and micrographic surgery with fresh-frozen sections reduces the length of stay by 42.86 % from median 14 d to 8 d as well as increasing the revenue per patient per day by 41.9 % from 320.61 euro to 454.95 euro with nearly a comparable rate of recurrences after one year. CONCLUSIONS: PDD in combination with single-stage surgery is an equivalent therapy with few side effects and conforming to guidelines. It takes into account both quality assurance and patient preferences. Multicenter, randomized trials seem desirable.

Photodynamic treatment of cutaneous leishmaniasis.

Leishmaniasis is a widespread arthropod-borne protozoan zoonosis caused by more than 21 Leishmania species. Vectors are sandflies of different genera. The disease is classified into "Old World" versus "New World" leishmaniasis and further subclassified in cutaneous, mucocutaneous and visceral forms. Most therapeutic approaches are not evidence-based. We report a patient with facial cutaneous Leishmania tropica infection which proved to be resistant to various therapeutic regimes. Excellent results were achieved with photodynamic therapy.

In situ profiling and quantification of cytokines released during ultraviolet B-induced inflammation by combining dermal microdialysis and protein microarrays.

In skin, an evolving inflammatory or immune response is triggered by early release of a cytokine cascade into the extracellular space. Investigation of extracellular cytokine secretion in situ has been limited by low cut-off filtering membranes and sample volume size and the inability to monitor changes in cytokine protein levels in real-time in situ. Here, we combine for the first time the methods of intradermal microdialysis and antibody protein arraying to profile the early cascade of multiple cytokines in a complex inflammatory response exemplified by ultraviolet B (UVB)-induced inflammation. We observed significant differences of the cytokine and growth factor responses after tissue injury by catheter placement and UVB-induced inflammation. UVB irradiation initiates a rapid proinflammatory response followed by a mixed TH1/TH2 response in which ultimately TH2 cytokines IL-4 and IL10 predominated after 24 h. This most likely indicates the termination and self limitation of the inflammatory response. We conclude that the combination of dermal microdialysis and protein microarray offers a powerful tool to analyze in real-time the complex and rapidly changing interstitial protein milieu during cutaneous inflammatory responses.