New horizons in dermatological education: Skin cancer screening with virtual reality.

BACKGROUND: Technological advances in the field of virtual reality (VR) offer new opportunities in many areas of life, including medical education. The University of Münster has been using VR scenarios in the education of medical students for several years, especially for situations that are difficult to reproduce in reality (e.g., brain death). Due to the consistently positive feedback from students, a dermatological VR scenario for skin cancer screening was developed. OBJECTIVES: Presentation and first evaluation of the skin cancer screening VR scenario to determine to what extent the technical implementation of the scenario was evaluated overall by the students and how their subjective competence to perform a skin cancer screening changed over the course of the teaching unit (theory seminar, VR scenario, theoretical debriefing). METHODS: Students (n = 140) participating in the curricular pilot project during the 2023 summer term were surveyed throughout the teaching unit using several established questionnaires (System Usability Scale, Simulation Task-Load-Index, Realism and Presence Questionnaire) as well as additional questions on cybersickness and subjective learning. RESULTS: (i) The use of VR is technically feasible, (ii) students evaluate the VR scenario as a useful curricular supplement, and (iii) from the students' subjective perspective, a good learning outcome is achieved. Although preparation and follow-up appear to be important for overall learning, the greatest increase in subjective competence to perform a skin cancer screening is achieved by the VR scenario. CONCLUSIONS: Technically feasible and positively evaluated by students, VR can already be a useful addition to dermatology education, although costs are still high. As a visual discipline, dermatology offers special opportunities to create VR scenarios that are not always available or comfortable for patients in reality. Additionally, VR scenarios guarantee the same conditions for all students, which is essential for a high-quality education.

Histology-based classifier to distinguish early mycosis fungoides from atopic dermatitis.

BACKGROUND: Histopathological differentiation of early mycosis fungoides (MF) from benign chronic inflammatory dermatoses remains difficult and often impossible, despite the inclusion of all available diagnostic parameters. OBJECTIVE: To identify the most impactful histological criteria for a predictive diagnostic model to discriminate MF from atopic dermatitis (AD). METHODS: In this multicentre study, two cohorts of patients with either unequivocal AD or MF were evaluated by two independent dermatopathologists. Based on 32 histological attributes, a hypothesis-free prediction model was developed and validated on an independent patient's cohort. RESULTS: A reduced set of two histological features (presence of atypical lymphocytes in either epidermis or dermis) was trained. In an independent validation cohort, this model showed high predictive power (95% sensitivity and 100% specificity) to differentiate MF from AD and robustness against inter-individual investigator differences. LIMITATIONS: The study investigated a limited number of cases and the classifier is based on subjectively evaluated histological criteria. CONCLUSION: Aiming at distinguishing early MF from AD, the proposed binary classifier performed well in an independent cohort and across observers. Combining this histological classifier with immunohistochemical and/or molecular techniques (such as clonality analysis or molecular classifiers) could further promote differentiation of early MF and AD.

Comparison of Complication Rates Between Subpectoral vs Prepectoral Techniques in Prosthetic Breast Reconstruction.

BACKGROUND: The location of tissue expanders in implant-based breast reconstruction remains controversial due to variation in surgical techniques and devices. OBJECTIVES: The aim of this study was to provide a comprehensive assessment of early and late complication rates between prepectoral and subpectoral placement of tissue expanders. METHODS: A retrospective cohort study was conducted of all adult female patients who had undergone 2-stage implant-based breast reconstruction between 2013 and 2019 in our institution. Early complication was defined as complications that occurred within 30 days after surgery. Time-to-event analyses were performed and Cox proportional hazard models were used to adjust for confounders. RESULTS: In total, 854 patients were included; 76% of patients underwent a subpectoral tissue expander placement. After the first-stage procedure, the early complication rate was 34% and the late complication rate was 36.4%. After the second-stage procedure, the early complication rate was 16.3% and the late complication rate was 16.1%. Location of the tissue expander did not predict either overall early or late complication rates, regardless of the stages of reconstruction, after adjusting for confounders. Tissue expanders placed in prepectoral plane were associated with a higher hazard ratio (HR) for developing early and late infection after the first stage of reconstruction (HR, 2.1 and 2.4, respectively) as well as late infection after the second stage of reconstruction (HR, 5.3; all P < .05). CONCLUSIONS: Location of tissue expanders did not predict risk of complication. However, the prepectoral group was associated with an increased risk of developing infection.

Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts.

Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors.

[Skin manifestations of COVID-19 and after COVID-19 vaccination]. / Hautveränderungen bei COVID-19 und nach COVID-19-Impfung.

Coronavirus disease 2019 (COVID-19) is a systemic disease induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that frequently presents with skin manifestations. The five most common skin lesions are pseudo-chilblain and maculopapular, urticarial, vesicular, and livedo/necrotizing skin lesions. These skin lesions are of diagnostic and prognostic relevance. For example, in children, typical skin lesions may indicate a life-threatening inflammatory syndrome, which rarely occurs after corona infection. Skin lesions have also been described after COVID-19 vaccination. These usually show an uncomplicated, self-limiting course and therefore do not represent a contraindication for completing the vaccination status in the vast majority of cases.

Psoriasis on the Leg: Site-specific Histopathological and Immuno-histochemical Features and Diagnostic Difficulties.

The histopathology of psoriasis can lack classical features on certain anatomical sites. The aim of this study was to detail the histopathology and immunophenotype of psoriasis on the legs, in order to differentiate it from other inflammatory dermatoses, such as stasis dermatitis. The histopathology of psoriasis on the legs was retrospectively compared with psoriasis on the trunk and stasis dermatitis. Statistically, psoriasis on the legs was significantly less likely to show typical histological criteria of psoriasis, such as regular hyperplasia, suprapapillary thinning, and "kissing vessels". The most valuable criteria to distinguish psoriasis on the legs from stasis dermatitis were the presence of neutrophils in the cornified layer and staggered parakeratosis. In addition, an immunohistochemical panel (Ki-67, Bcl-2alpha, S100A7, CD3, MPO, CK10, CK16) revealed that staining with Ki-67 and MPO could be diagnostically useful. Since the cornified layer contains important histopathological clues to differentiate psoriasis on the legs from stasis dermatitis, clinicians should refrain from unnecessary rubbing during disinfection before taking a biopsy.

Histopathological Spectrum and Immunophenotypic Characterization of Symmetrical Drug-Related Intertriginous and Flexural Exanthema.

INTRODUCTION: Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a clinically very well-defined drug eruption, but the histopathological findings are still considered to be nonspecific. OBJECTIVES: To characterize the histopathological and immunophenotypical features of SDRIFE. MATERIAL AND METHODS: We performed a retrospective study that identified 11 biopsies from 9 patients with SDRIFE. The histopathological features were analyzed in conjunction with the immunohistochemical findings. RESULTS: The most common histopathological feature was basal cell vacuolization, which was often associated with necrotic keratinocytes and focal spongiosis. TIA1+ T cells and neutrophils were frequently detected in the epidermis and at the dermoepidermal junction. The dermal inflammatory infiltrate was mixed, consisting of CD3+ T cells, macrophages, granulocytes, low numbers of CD20+ B cells, and plasma cells. A combination of histopathological patterns was observed in 5 cases. The most frequent combined histopathological patterns were interface dermatitis, spongiotic dermatitis, and psoriasiform dermatitis. Other histopathological patterns found in different combinations were pustular dermatitis, perivascular and interstitial neutrophilic dermatitis, and interstitial granulomatous dermatitis. In the other 4 cases, a single histopathological pattern predominated, such as psoriasiform dermatitis, vacuolar interface dermatitis of erythema multiforme-like type, or superficial and deep perivascular and interstitial dermatitis with eosinophils and neutrophils. CONCLUSIONS: SDRIFE is characterized histologically by a vacuolar interface dermatitis induced by cytotoxic T lymphocytes and neutrophilic granulocytes. This pattern may be obscured by accompanying spongiotic, psoriasiform, or pustular features combined with a mixed superficial and sometimes deep dermal infiltrate.

EGFR/Ras-induced CCL20 production modulates the tumour microenvironment.

BACKGROUND: The activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment. METHODS: The effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo. RESULTS: Tumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system. CONCLUSION: We propose that the chemokine axis CCL20-CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy.

Vemurafenib acts as an aryl hydrocarbon receptor antagonist: Implications for inflammatory cutaneous adverse events.

BACKGROUND: In recent years, the BRAF inhibitor vemurafenib has been successfully established in the therapy of advanced melanoma. Despite its superior efficacy, the use of vemurafenib is limited by frequent inflammatory cutaneous adverse events that affect patients' quality of life and may lead to dose reduction or even cessation of anti-tumor therapy. To date, the molecular and cellular mechanisms of vemurafenib-induced rashes have remained largely elusive. METHODS: In this study, we deployed immunohistochemistry, RT-qPCR, flow cytometry, lymphocyte activation tests, and different cell-free protein-interaction assays. RESULTS: We here demonstrate that vemurafenib inhibits the downstream signaling of the canonical pathway of aryl hydrocarbon receptor (AhR) in vitro, thereby inducing the expression of proinflammatory cytokines (eg, TNF) and chemokines (eg, CCL5). In line with these results, we observed an impaired expression of AhR-regulated genes (eg, CYP1A1) and an upregulation of the corresponding proinflammatory genes in vivo. Moreover, results of lymphocyte activation tests showed the absence of drug-specific T cells in respective patients. CONCLUSION: Taken together, we obtained no hint of an underlying sensitization against vemurafenib but found evidence suggesting that vemurafenib enhances proinflammatory responses by inhibition of canonical AhR signaling. Our findings contribute to our understanding of the central role of the AhR in skin inflammation and may point toward a potential role for topical AhR agonists in supportive cancer care.

Interest in Skin Cancer in Urban Populations: A Retrospective Analysis of Google Search Terms in Nine Large German Cities.

Skin cancer is a major public health issue, which could be reduced through prevention programmes. How-ever, prevention utilization is not very prevalent. It is therefore important to understand individuals' interest in skin cancer. Google AdWords Keyword Planner was used to identify the search volume of terms relating to skin cancer in 9 German cities between July 2014 and June 2018. From a total of 1,203 identified keywords, 1,047 search terms were related to skin cancer, which had a search volume of 3,460,980 queries for the study period. Most terms referred to "identifying skin cancer". For melanoma, the number of Google searches per 100,000 inhabitants correlated with the cancer registry data for melanoma incidence rates (men: r = 0.810, women: r = 0.569). Assessment of this data for the different cities further enabled identification of regional variations, which could help to identify areas with a high need for targeted prevention campaigns.

Time-lapse imaging points towards a non-toxic, mainly immune-driven mode of action of ingenol mebutate in the treatment of anogenital warts.

Recently, it has been reported that ingenol mebutate (IM) is an effective treatment option for anogenital warts (AGW), inducing fast wart necrosis within 24 hours in vivo. With regard to its mode of action, IM is thought to act both as an inducer of direct cytotoxic effects and immunologic mechanisms. To distinguish whether the wart necrosis is mainly caused by cytotoxic effects, or whether immune mechanisms are leading, we used time-lapse imaging to analyse IM-treated warts ex vivo over 24 hours. Ex vivo IM-treated warts, which have been detached from the immune system, did not show destructive necrosis, pointing towards a primarily immune-driven mode of action of IM in the treatment of AGW.

Fast Ablation of Anogenital Warts of the Urinary Meatus by Low-dose Ingenol Mebutate Gel.

Therapeutic options of anogenital warts (AGW) at the urethral meatus are limited and often require effortful and time-consuming procedures under general anesthesia. Here, we present two cases of AGW at the urethral meatus, which we have successfully treated with low-dose topical ingenol mebutate gel.

Laser assisted Drug Delivery: Grundlagen und Praxis.

Die topische Applikation von Wirkstoffen ist eine zentrale Therapieoption der Dermatologie. Allerdings mindert die effektive Barrierefunktion der Haut die Bioverfügbarkeit der meisten Externa. Fraktionierte ablative Laser stellen ein innovatives Verfahren dar, um die epidermale Barriere standardisiert, kontaktfrei zu überwinden. Die Bioverfügbarkeit im Anschluss applizierter Externa wird im Sinne einer laser assisted drug delivery (LADD) signifikant gesteigert. Das Prinzip der LADD wird bereits in einigen Bereichen der Dermatologie erfolgreich eingesetzt. Die vorliegende Übersichtsarbeit soll einen Überblick über die aktuellen aber auch perspektivischen Einsatzmöglichkeiten der LADD bieten.

Laser-assisted drug delivery: mode of action and use in daily clinical practice.

Topical application of pharmaceutical agents is a basic principle of dermatological therapy. However, the effective barrier function of the skin significantly impairs the bioavailability of most topical drugs. Fractional ablative lasers represent an innovative strategy to overcome the epidermal barrier in a standardized, contact-free manner. The bioavailability of topical agents can be significantly enhanced using laser-assisted drug delivery (LADD). In recent years, the principle of LADD has become well established for various dermatological indications. Herein, we review the current literature on LADD and present potential future applications.