Phototherapy: Theory and practice.

Despite the development of highly effective biologics for skin diseases such as psoriasis or atopic dermatitis, UVA and UVB therapy, alone or in combination, are still essential components of various guidelines. Phototherapy is not only a first-line treatment and highly effective for a number of skin diseases, but is also economical and has few side effects. The targeted use of UVA and UVB, if necessary, in combination with the photosensitizer psoralen in the context of PUVA therapy, enables the dermatologist to effectively treat a wide variety of skin diseases. Indications for phototherapy include epidermal diseases such as atopic dermatitis, psoriasis and vitiligo, as well as photodermatoses, mycosis fungoides, graft-versus-host disease and deep dermal diseases such as scleroderma. This article reviews the physical principles, molecular mechanisms, current treatment regimens, and individual indications for phototherapy and photochemotherapy.

[Multilocular pyoderma gangrenosum : Association with primary manifestation of primary biliary cholangitis]. / Multilokuläres Pyoderma gangraenosum : Assoziation mit der Erstmanifestation einer primär biliären Cholangitis.

A 16-year-old female patient with previously diagnosed acne vulgaris was transferred to our clinic in reduced general condition with rapidly progressive and extremely painful ulcerations. In the laboratory exam, inflammatory parameters were highly elevated, but she was normothermic. Based on the findings, we diagnosed multilocular pyoderma gangrenosum. Further investigations established the diagnosis of primary biliary cholangitis as the underlying condition. Treatment with systemic corticosteroids was initiated and we started therapy with ursodeoxycholic acid. This led to improvement within a few days. PAPA-syndrome (pyogenic arthritis, pyoderma gangrenosum and acne vulgaris) could be ruled out by genetic analysis.

Indurated erythema of abdominal skin: An unusual presentation of metastatic endometrial carcinoma-Case report with literature review.

Carcinoma erysipelatoides (CE) is a rare clinical manifestation of cutaneous metastasis, which mimics inflammatory conditions such as erysipelas. Depending on the site of the originating tumour, unusual manifestations involving different sites of the body may occur. We herein report a case of a 60-year-old female patient with metastatic endometrial carcinoma presenting as CE of the abdominal skin and the inguinal folds. Even though the diagnosis of advanced malignancy had been established before and she was currently receiving chemotherapy (carboplatin and paclitaxel), the clinical appearance closely resembled fungal (candidal intertrigo) and consecutively bacterial (erysipelas) infection, which resulted in treatment with antimycotics and antibiotics at first. Dermatohistopathological examination of skin biopsies revealed a diffuse and nodular infiltrate of pleomorphic atypical tumour cells with strong expression of cytokeratin 7 and PAX8, also detectable within lymphatic vessels. Therapy comprised antiseptic ointments to prevent superinfection, palliative electron beam radiation and supportive care. Since there were no targetable KRAS-, NRAS- and BRAF-gene mutations, systemic therapy was switched to checkpoint inhibition (pembrolizumab) in combination with lenvatinib. The overall prognosis of cutaneous metastasis of endometrial carcinoma is dismal with most patients succumbing to disease within few months. Similarly, our patient died after 3 months due to sepsis in the course of malignant pleural effusion. We aim to highlight the possibility of unusual sites of CE and the risk of respective clinical misdiagnoses.

Degree of Actinic Elastosis Is a Surrogate of Exposure to Chronic Ultraviolet Radiation and Correlates More Strongly with Cutaneous Squamous Cell Carcinoma than Basal Cell Carcinoma.

(1) Background: Keratinocyte cancer (KC) is associated with exposure to ultraviolet (UV) radiation. However, data are controversial as to whether chronic UV exposure or high intermittent UV exposure are key drivers of carcinogenesis in cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). Prolonged sun exposure of the skin causes photo-aging, which is associated with actinic elastosis, a condition characterized by the degeneration of elastin in the upper dermis, which is assessable via conventional histology. In this study, we aimed to compare the degree of actinic elastosis in different types of KC with regard to various patient characteristics. (2) Methods: We defined a semiquantitative score for the degree of actinic elastosis ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration). The extent was measured histometrically by two independent dermatohistopathologists in the immediate vicinity of 353 KC. The scores were merged and matched with tumor types (cSCC and BCC with subtypes), and clinical variables such as body site, sex and age. (3) Results: As expected, the degree of actinic elastosis correlated with age. However, it was significantly higher in cSCC compared to BCC irrespective of age, sex, body site and tumor subtypes. (4): Conclusions: Lifetime sun exposure may be estimated via routine histology using this scoring technique for actinic elastosis as a surrogate marker. cSCCs are more strongly associated with chronic UV exposure than BCCs, even in sun-exposed localizations such as the face.

Cold Atmospheric Plasma Triggers Apoptosis via the Unfolded Protein Response in Melanoma Cells.

Cold atmospheric plasma (CAP) describes a partially ionized gas carrying large amounts of reactive oxygen (ROS) and nitrogen species (RNS). Numerous studies reported strong antitumor activity of CAP, thus rendering it a promising approach for tumor therapy. Although several cellular mechanisms of its cytotoxicity were identified in recent years, the exact molecular effects and contributing signaling pathways are yet to be discovered. We discovered a strong activation of unfolded protein response (UPR) after CAP treatment with increased C/EBP homologous protein (CHOP) expression, which was mainly caused by protein misfolding and calcium loss in the endoplasmic reticulum. In addition, both ceramide level and ceramide metabolism were reduced after CAP treatment, which was then linked to the UPR activation. Pharmacological inhibition of ceramide metabolism resulted in sensitization of melanoma cells for CAP both in vitro and ex vivo. This study identified a novel mechanism of CAP-induced apoptosis in melanoma cells and thereby contributes to its potential application in tumor therapy.

Subtypes of Melanomas Associated with Different Degrees of Actinic Elastosis in Conventional Histology, Irrespective of Age and Body Site, Suggesting Chronic Ultraviolet Light Exposure as Driver for Lentigo Maligna Melanoma and Nodular Melanoma.

(1) Background: Ultraviolet (UV) radiation and sunburns are associated with an increased incidence of acquired nevi and melanomas. However, the data are controversial as to whether chronic UV exposure or high intermittent UV exposure is the major carcinogenic factor in melanocytic tumors. In this study, we compared the degree of actinic elastosis (AE) as a surrogate for lifetime UV exposure in nevi and different clinical melanoma subtypes (i.e., superficial spreading melanoma (SSM), nodular malignant melanoma (NMM), acral lentiginous melanoma (ALM), and lentigo maligna melanoma (LMM)) with respect to clinical variables (age, sex, and body site). (2) Methods: We defined a semi-quantitative score for the degree of AE ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration) and multiplied it by the perilesional vertical extent (depth), measured histometrically (tumor-associated elastosis grade (TEG)). We matched the TEG of n = 595 melanocytic lesions from 559 patients with their clinical variables. (3) Results: The TEG was correlated with age and UV-exposed body sites. Furthermore, the TEG was significantly higher in LMM than in all other types of melanomas and the TEG in NMM was higher than in SSM, irrespective of patient age and tumor site. (4) Conclusions: High cumulative UV exposure is more strongly associated with LMM and NMM than with other melanoma subtypes.

[Development of spindle cell squamous cell carcinoma within a longstanding pyoderma gangrenosum]. / Entwicklung eines spindelzelligen Plattenepithelkarzinoms auf dem Boden eines lang bestehenden Pyoderma gangraenosum.

Pyoderma gangrenosum (PG) is classified as a neutrophilic dermatosis and presents clinically as painful ulcerations with undermined livid erythema at the margin. Treatment with immunosuppressive drugs is often protracted. The development of malignant tumors in pyoderma gangrenosum has not been reported in the literature.

Systemic therapy of necrobiotic xanthogranuloma: a systematic review.

BACKGROUND: Even though a plethora of systemic therapies have been proposed for necrobiotic xanthogranuloma (NXG), there is no systematic review on this topic in literature. OBJECTIVE: To review all existing literature on the systemic therapy of NXG in order to identify the most effective therapies. METHODS: All reported papers in the literature were screened for systemic treatments of NXG. Papers without proper description of the therapies, papers describing topical therapy, and articles without assessment of effectiveness were excluded. Subsequently, we analyzed 79 papers and a total of 175 cases. RESULTS: The most effective treatments for NXG are intravenous immunoglobulins (IVIG), corticosteroids, and combination therapies including corticosteroids. CONCLUSIONS: Corticosteroids and IVIG should therefore be considered first-line treatments in patients with NXG.

An uncommon cause of tinea: Trichophyton violaceum in a German kindergarten - outbreak report and quantitative analysis of epidemiological data from Europe.

Background: Global mobility is increasingly associated with the emergence of "unusual" infectious agents. At the beginning of 2019, a putative outbreak of Impetigo contagiosa occurred in a kindergarten in Regensburg, Germany, that was mainly attended by children with a migrant background. After thorough examination, the outbreak was classified as infection with Trichophyton (T.) violaceum. Methods: Based on case investigations, infection control measures, disinfection, and cleaning were implemented. Microscopy of native specimens, fungal cultures, and polymerase chain reaction were used for diagnosis. Additionally, a systematic literature search in Medline, followed by a quantitative analysis of epidemiological data from Europe, were performed. Results: Between January and November 2019, 12 cases of tinea were diagnosed in 7 educators and 2 household members. Children were initially not affected. T. violaceum was only detected in 2 patients. No extensive screening measures were carried out after risk-benefit assessment. Studies on T. violaceum in Europe are heterogeneous, and the number of cases and the prevalence vary considerably. The pathogen is mainly found in children of African descent who clinically present with tinea capitis. Discussion: In the present case, the source of infection and the chain of transmission remained unclear. The pathogen could only be diagnosed in 2 cases. In Europe, the (re)emergence of pathogens such as T. violaceum is likely to be caused by increasing migration and travel. Pathogens should be identified for epidemiological reasons in all cases. In outbreaks, measures must be adapted to the dynamics of the individual outbreak after assessment of the risks, benefits, and proportionality.

The Anti-Fibrotic Effect of Cold Atmospheric Plasma on Localized Scleroderma In Vitro and In Vivo.

Cold Atmospheric Plasma (CAP) has shown promising results in the treatment of various skin diseases. The therapeutic effect of CAP on localized scleroderma (LS), however, has not yet been evaluated. We investigated the effects of CAP on LS by comparing human normal fibroblasts (hNF), human TGF-ß-activated fibroblasts (hAF), and human localized scleroderma-derived fibroblasts (hLSF) after direct CAP treatment, co-cultured with plasma-treated human epidermal keratinocytes (hEK) and with an experimental murine model of scleroderma. In hAF and hLSF, 2 min CAP treatment with the MicroPlaSterß® plasma torch did not affect pro-fibrotic gene expression of alpha smooth muscle actin, fibroblast activating protein, and collagen type I, however, it promoted re-expression of matrix metalloproteinase 1. Functionally, CAP treatment reduced cell migration and stress fiber formation in hAF and hLSF. The relevance of CAP treatment was confirmed in an in vivo model of bleomycin-induced dermal fibrosis. In this model, CAP-treated mice showed significantly reduced dermal thickness and collagen deposition as well as a decrease in both alpha smooth muscle actin-positive myofibroblasts and CD68-positive macrophages in the affected skin in comparison to untreated fibrotic tissue. In conclusion, this study provides the first evidence for the successful use of CAP for treating LS and may be the basis for clinical trials including patients with LS.

Cold Atmospheric Plasma Changes the Amino Acid Composition of Solutions and Influences the Anti-Tumor Effect on Melanoma Cells.

Cold Atmospheric Plasma (CAP) is an ionized gas near room temperature. Its anti-tumor effect can be transmitted either by direct treatment or mediated by a plasma-treated solution (PTS), such as treated standard cell culture medium, which contains different amino acids, inorganic salts, vitamins and other substances. Despite extensive research, the active components in PTS and its molecular or cellular mechanisms are not yet fully understood. The purpose of this study was the measurement of the reactive species in PTS and their effect on tumor cells using different plasma modes and treatment durations. The PTS analysis yielded mode- and dose-dependent differences in the production of reactive oxygen and nitrogen species (RONS), and in the decomposition and modification of the amino acids Tyrosine (Tyr) and Tryptophan (Trp). The Trp metabolites Formylkynurenine (FKyn) and Kynurenine (Kyn) were produced in PTS with the 4 kHz (oxygen) mode, inducing apoptosis in Mel Im melanoma cells. Nitrated derivatives of Trp and Tyr were formed in the 8 kHz (nitrogen) mode, elevating the p16 mRNA expression and senescence-associated ß-Galactosidase staining. In conclusion, the plasma mode has a strong impact on the composition of the active components in PTS and affects its anti-tumor mechanism. These findings are of decisive importance for the development of plasma devices and the effectiveness of tumor treatment.

Cold Atmospheric Plasma Promotes the Immunoreactivity of Granulocytes In Vitro.

Cold atmospheric plasma (CAP) reduces bacteria and interacts with tissues and cells, thus improving wound healing. The CAP-related induction of neutrophils was recently described in stained sections of wound tissue in mice. Consequently, this study aimed to examine the functionality of human polymorphonuclear cells (PMN)/granulocytes through either a plasma-treated solution (PTS) or the direct CAP treatment with different plasma modes and treatment durations. PTS analysis yielded mode-dependent differences in the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) after CAP treatment. Live-cell imaging did not show any chemo-attractive or NETosis-inducing effect on PMNs treated with PTS. The time to maximum ROS production (TmaxROS) in PMNs was reduced by PTS and direct CAP treatment. PMNs directly treated with CAP showed an altered cell migration dependent on the treatment duration as well as decreased TmaxROS without inducing apoptosis. Additionally, flow cytometry showed enhanced integrin and selectin expression, as a marker of activation, on PMN surfaces. In conclusion, the modification of PMN immunoreactivity may be a main supporting mechanism for CAP-induced improvement in wound healing.

Acidified Nitrite Contributes to the Antitumor Effect of Cold Atmospheric Plasma on Melanoma Cells.

Cold atmospheric plasma (CAP) is partially ionized gas near room temperature with previously reported antitumor effects. Despite extensive research and growing interest in this technology, active components and molecular mechanisms of CAP are not fully understood to date. We used Raman spectroscopy and colorimetric assays to determine elevated nitrite and nitrate levels after treatment with a MiniFlatPlaster CAP device. Previously, we demonstrated CAP-induced acidification. Cellular effects of nitrite and strong extracellular acidification were assessed using live-cell imaging of intracellular Ca2+ levels, cell viability analysis as well as quantification of p21 and DNA damage. We further characterized these observations by analyzing established molecular effects of CAP treatment. A synergistic effect of nitrite and acidification was found, leading to strong cytotoxicity in melanoma cells. Interestingly, protein nitration and membrane damage were absent after treatment with acidified nitrite, thereby challenging their contribution to CAP-induced cytotoxicity. Further, phosphorylation of ERK1/2 was increased after treatment with both acidified nitrite and indirect CAP. This study characterizes the impact of acidified nitrite on melanoma cells and supports the importance of RNS during CAP treatment. Further, it defines and evaluates important molecular mechanisms that are involved in the cancer cell response to CAP.

Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGVHD remain poorly understood, and targeted therapies for clinical use are not well established. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGVHD (sclGVHD). WNT signaling was activated in human sclGVHD with increased nuclear accumulation of the transcription factor ß-catenin and a WNT-biased gene expression signature in lesional skin. Treatment with the highly selective tankryase inhibitor G007-LK, the CK1α agonist pyrvinium, or the LRP6 inhibitor salinomycin abrogated the activation of WNT signaling and protected against experimental cGVHD, without a significant impact on graft-versus-leukemia effect (GVL). Treatment with G007-LK, pyrvinium, or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d) → BALB/c (H-2d) and LP/J (H-2b) → C57BL/6 (H-2b) models of sclGVHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect inflammation-dependent effects in sclGVHD. Our findings may have direct translational potential, because pyrvinium is in clinical use, and tankyrase inhibitors are in clinical trials for other indications.

Repetitive Daylight Photodynamic Therapy versus Cryosurgery for Prevention of Actinic Keratoses in Photodamaged Facial Skin: A Prospective, Randomized Controlled Multicentre Two-armed Study.

Actinic keratoses are a chronic condition in ultraviolet-damaged skin, with a risk of progressing to invasive skin cancer. The aim of this study was to investigate the preventive potential of field-directed repetitive daylight photodynamic therapy for actinic keratoses. A randomized trial was performed, including 58 patients with ≥5 actinic keratoses on photodamaged facial skin, who received either 5 full-face sessions of daylight photodynamic therapy within a period of 2 years or lesion-directed cryosurgery. Primary outcome was the mean cumulative number of new actinic keratoses developed between visits 2 and 6 (visit 6 being a follow-up). This outcome was lower after daylight photo-dynamic therapy (7.7) compared with cryosurgery (10.2), but the difference did not reach significance (-2.5, 95% confidence interval -6.2 to 1.2; p=0.18). Several signs of photoageing (fine lines, pigmentation, roughness, erythema, sebaceous gland hyperplasia) were significantly reduced after daylight photodynamic therapy, but not after cryosurgery. Significantly less pain and fewer side-effects were reported during daylight photodynamic therapy than during cryosurgery. This study found that repetitive daylight photodynamic therapy had photo-rejuvenating effects. However, the prevention of actinic keratoses by this therapy could not be proven in a statistically reliable manner.

[Cutaneous mucinosis of infancy]. / Kutane Muzinose der Kindheit.

Cutaneous mucinosis of infancy is a rare skin disease with just a few reported cases in the literature. We report the case of an 11-year-old boy with asymptomatic, skin-coloured papules and plaques on his right arm that had appeared 9 months prior to presentation. Histology showed a dermal and deep dermal interstitial mucin deposition and fibroblast proliferation. However, because cutaneous mucinosis of infancy is a benign disease with a good prognosis, therapy is not mandatory.