Molecular effects of photon irradiation and subsequent aftercare treatment with dexpanthenol-containing ointment or liquid in 3D models of human skin and non-keratinized oral mucosa.

This study aimed to investigate the molecular effects of radiation and subsequent aftercare treatment with dexpanthenol-containing ointment and liquid on established full-thickness 3D skin models depicting acute radiodermatitis and mucositis. To mimic radiomucositis and radiodermatitis, non-keratinized mucous membrane and normal human skin models were irradiated with 5 Gray. Afterwards, models were treated topically every second day with dexpanthenol-containing ointment or liquid in comparison with placebo and untreated controls. On day 7 after irradiation, histological examination showed impairments in irradiated models. In contrast, models treated with dexpanthenol-containing ointment or liquid showed a completely restored epidermal part. While gene expression profiling revealed an induction of genes related to a pro-inflammatory milieu, oxidative stress and an impaired epidermal differentiation after irradiation of the models, aftercare treatment with dexpanthenol-containing ointment or liquid revealed anti-oxidative and anti-inflammatory effects and had a positive effect on epidermal differentiation and structures important for physical and antimicrobial barrier function. Our findings confirm the potential of our established models as in vitro tools for the replacement of pharmacological in vivo studies regarding radiation-induced skin injuries and give indications of the positive effects of dexpanthenol-containing externals after radiation treatments as part of supportive tumor treatment.

Stevens-Johnson syndrome and toxic epidermal necrolysis: a 10-year experience in a burns unit.

OBJECTIVE: Stevens-Johnson syndrome (SJS) and its more severe counterpart, toxic epidermal necrolysis (TEN), are skin hypersensitivity reactions defined by epidermal blistering and necrosis. The exact pathophysiology of SJS/TEN is yet to be deciphered, but a number of risk factors have been identified including adverse drug reactions. The diagnosis of SJS/TEN is made on a clinical basis, and treatment consists of supportive care and occasionally immunosuppressants, such as cyclosporin, high-dose intravenous immunoglobulins and/or corticosteroids. Mortality rates can reach 20-25% in adults but are reduced with early intervention. To identify optimal treatment regimens, to better understand the patient cohort affected, and to help identify key risk factors for mortality, we report our experience with the treatment and management of SJS/TEN patients. METHODS: A retrospective review of consecutive patients with SJS and/or TEN admitted to a single burns centre in Germany, between 2008 and 2018, was conducted. The primary outcomes of demographics, clinical course, treatment and patient-reported outcomes were recorded and compared with a control group of patients with burns without a diagnosis of SJS/TEN. RESULTS: A total of 23 patients with SJS/TEN met the inclusion criteria: 17 (74%) with TEN; four (17%) with SJS/TEN overlap; and two (9%) with SJS. Of the patients, 14 (61%) were female and nine (39%) were male. Patient age ranged from 32-78 years (mean: 52 years). A matched cohort of 23 patients with burns served as the control group. All patients received standard of care with a multidisciplinary team. Compared with the control group, SJS/TEN patients had higher mortality rates (n=6, 26% versus n=8, 35%, respectively). The average age of death was 69 years in SJS/TEN patients versus 63 years in control group patients. Age and SCORTEN scores were significant predictors of mortality. CONCLUSIONS: SJS and TEN are rare but extreme reactions of the skin and mucosa, associated with high disease mortality rates. This 10-year single-centre retrospective review contributes to the bank of information for reviews evaluating the management of SJS/TEN patients.

Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis.

OBJECTIVE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and severe skin and mucosal reactions that are associated with high mortality. Despite the severity, an evidence-based treatment protocol for SJS/TEN is still lacking. METHOD: In this systematic review and meta-analysis, the PubMed database was searched using the following terms: [Stevens-Johnson syndrome] OR [toxic epidermal necrolysis] AND [therapy] OR [treatment] over a 20-year period (1999-2019) in the German and English language. All clinical studies reporting on the treatment of SJS/TEN were included, and epidemiological and diagnostic aspects of treatment were analysed. A meta-analysis was conducted on all comparative clinical studies that met the inclusion criteria. RESULTS: A total of 88 studies met the inclusion criteria, reporting outcomes in 2647 patients. Treatment was either supportive or used systemic corticosteroid, intravenous immunoglobulin, plasmapheresis, cyclosporine, thalidomide or cyclophosphamide therapy. The meta-analysis included 16 (18%) studies, reporting outcomes in 976 (37%) patients. Systemic glucocorticoids showed a survival benefit for SJS/TEN patients in all analyses compared with other forms of treatment. Cyclosporine treatment also showed promising results, despite being used in a small cohort of patients. No beneficial effects on mortality could be demonstrated for intravenous immunoglobulins. CONCLUSION: Glucocorticoids and cyclosporine may be tentatively recommended as the most promising immunomodulatory therapies for SJS/TEN, but these results should be investigated in future prospective controlled trials.

[Hyperplasia-associated cutaneous paraneoplasia]. / Hyperplasie-assoziierte obligate Paraneoplasien der Haut.

BACKGROUND: Hyperplasia-associated cutaneous paraneoplasia is an important differential diagnosis in everyday clinical practice. An early diagnosis of the underlying tumor disease can significantly improve the patient's prognosis. PATHOGENESIS: Hyperplasia is probably mainly cytokine-mediated. The primary tumor and/or the metastases release growth factors and transcription factors which, via epidermal growth factors, lead to hyperproliferation of keratinocytes. ACANTHOSIS NIGRICANS MALIGNA: Symmetrical mainly intertriginous hyperpigmentation with partially verrucous hyperplasia and lichenification mostly in association with gastric adenocarcinoma. Special forms are florid cutaneous papillomatosis and tripe palms. Pseudoacanthosis nigricans is to be distinguished (metabolic and hormonal disorders). LESER-TRéLAT SYNDROME: Eruptive occurrence of seborrheic keratosis associated with visceral tumors. ACROKERATOSIS BAZEX: Erythema and scaling initially at the bridge of the nose, ear helix and acra with later spread, associated with tumors of the upper aerodigestive system. It should be clinically differentiated from psoriasis. THERAPY: The treatment of the primary tumor is decisive, which also leads to a decrease of cutaneous symptoms. Reappreance suggests tumor recurrence.

Artificial Intelligence and Its Effect on Dermatologists' Accuracy in Dermoscopic Melanoma Image Classification: Web-Based Survey Study.

BACKGROUND: Early detection of melanoma can be lifesaving but this remains a challenge. Recent diagnostic studies have revealed the superiority of artificial intelligence (AI) in classifying dermoscopic images of melanoma and nevi, concluding that these algorithms should assist a dermatologist's diagnoses. OBJECTIVE: The aim of this study was to investigate whether AI support improves the accuracy and overall diagnostic performance of dermatologists in the dichotomous image-based discrimination between melanoma and nevus. METHODS: Twelve board-certified dermatologists were presented disjoint sets of 100 unique dermoscopic images of melanomas and nevi (total of 1200 unique images), and they had to classify the images based on personal experience alone (part I) and with the support of a trained convolutional neural network (CNN, part II). Additionally, dermatologists were asked to rate their confidence in their final decision for each image. RESULTS: While the mean specificity of the dermatologists based on personal experience alone remained almost unchanged (70.6% vs 72.4%; P=.54) with AI support, the mean sensitivity and mean accuracy increased significantly (59.4% vs 74.6%; P=.003 and 65.0% vs 73.6%; P=.002, respectively) with AI support. Out of the 10% (10/94; 95% CI 8.4%-11.8%) of cases where dermatologists were correct and AI was incorrect, dermatologists on average changed to the incorrect answer for 39% (4/10; 95% CI 23.2%-55.6%) of cases. When dermatologists were incorrect and AI was correct (25/94, 27%; 95% CI 24.0%-30.1%), dermatologists changed their answers to the correct answer for 46% (11/25; 95% CI 33.1%-58.4%) of cases. Additionally, the dermatologists' average confidence in their decisions increased when the CNN confirmed their decision and decreased when the CNN disagreed, even when the dermatologists were correct. Reported values are based on the mean of all participants. Whenever absolute values are shown, the denominator and numerator are approximations as every dermatologist ended up rating a varying number of images due to a quality control step. CONCLUSIONS: The findings of our study show that AI support can improve the overall accuracy of the dermatologists in the dichotomous image-based discrimination between melanoma and nevus. This supports the argument for AI-based tools to aid clinicians in skin lesion classification and provides a rationale for studies of such classifiers in real-life settings, wherein clinicians can integrate additional information such as patient age and medical history into their decisions.

Postoperative complications in dermatological patients undergoing microscopically controlled surgery in inpatient setting (next-day surgery): A single-center epidemiological study.

BACKGROUND: Surgical site infections (SSI), bleeding, and necrosis are possible complications of dermatological surgery, and their rates are well described for Mohs surgery (same-day surgery). However, there are only limited data on their occurrence in microscopically controlled surgery of the form in which it is practiced in German hospitals (next-day surgery). MATERIALS AND METHODS: We performed a retrospective analysis of patient records of patients hospitalized for microscopically controlled surgery during the year 2017 (12 months) in the Department of Dermatology and Allergology at the University Hospital of the RWTH Aachen (Aachen, Germany). The investigation addressed postoperative outcomes. RESULTS: 319 patients underwent 528 dermatosurgical procedures in the defined period. Bleeding and necrosis occurred in 3.8 % (20/528) and 1.7 % (9/528) of the procedures, respectively. SSI occurred in 5.1 % (27/528) of the cases. The occurrence of bleeding was a statistically significant risk factor for SSI (p  =  0.01). Furthermore, bleeding, SSI, and wound closure with a full-thickness graft were statistically significant risk factors for the development of necrosis (p < 0.05). Diabetes or immunosuppression were not found to be statistically significant risk factors for the development of SSI or necrosis after dermatologic surgery (p > 0.05). CONCLUSIONS: Complication rates in microscopically controlled surgery (next-day surgery) are generally low and similar to those reported for Mohs surgery (same-day surgery). Therefore, it appears that some evidence-based perioperative recommendations that have been developed for Mohs surgery could be applied to German inpatient dermatosurgery. However, prospective studies with larger patient numbers are required to offer concrete recommendations specifically for microscopically controlled surgery (next-day surgery).

Novel Human Full-Thickness Three-Dimensional Nonkeratinized Mucous Membrane Model for Pharmacological Studies in Wound Healing.

INTRODUCTION: Efforts are increasingly aiming to develop in vitro models that can provide effective alternatives to in vivo experiments. The main aim of this study was the establishment of an in vitro model of the nonkeratinized mucous membrane that can be used as a standardized tool to evaluate biological and therapeutic effects of pharmaceuticals for mucosal wound healing. METHODS: We established a full-thickness in vitro model of the nonkeratinized mucous membrane. While histological examination was performed to assess morphological characteristics, we utilized gene expression profiling using microarray and qRT-PCR analyses to identify molecular effects of treatment with a dexpanthenol-containing ointment after laser wounding. RESULTS: Performing histological and immunofluorescence analyses we proved that our model mimics the two distinctive layers of the mucous membrane - the stratified squamous epithelium and the lamina propria. We used this model to investigate molecular effects of a dexpanthenol-containing ointment that is commonly used for the wound treatment of mucous membranes. For that purpose, our model exhibits a unique feature in that dexpanthenol and proliferation-enhancing additives that may interfere with our studies are not required for the maintenance of the model culture. After setting standardized lesions with a nonsequential fractional ultrapulsed CO2 laser, topical treatment with the dexpanthenol-containing ointment enhanced wound closure in the model compared to placebo and untreated controls. Furthermore, microarray analysis revealed that the treatment of the laser-wounded model with the dexpanthenol-containing ointment evoked an upregulated expression of various genes related to accelerated wound healing. CONCLUSION: Overall, we verified that this novel mucous membrane model can be utilized in future to monitor ex vivo effects of various topical therapies on mucosa morphology, physiology, and gene expression. Our findings confirm the potential of the model as an in vitro tool for the replacement of pharmacological in vivo studies regarding mucosal wound healing.

Accelerated wound healing with a dexpanthenol-containing ointment after fractional ablative CO2 laser resurfacing of photo-damaged skin in a randomized prospective clinical trial.

Background: Laser therapy with an ablative CO2 laser is a prominent treatment option for photo-damaged skin. The healing process and therefore the success of a laser can be supported by an appropriate postoperative treatment of the laser-treated skin. Objective: The effect of a dexpanthenol-containing ointment with petroleum jelly on wound healing after fractional ablative CO2 laser therapy of photo-damaged skin. Methods: A total of 38 patients with photo-damaged skin received fractional ablative CO2 laser treatment. Occlusive wound care was conducted for a period of 7 days. The complete wound area was divided into two sections: one that was treated with a dexpanthenol-containing ointment and a section that was treated with petroleum jelly. This study had three primary outcome measures: (1) Overview images as well as dermatoscopic images of the laser treated skin were taken immediately after laser treatment and on days 1, 2, 5 and 14 (study visits). Dermatoscopic images were analysed to determine changes of the diameter of the individual lesions between the study visits. (2) Wound-healing rate was visually assessed, based on the measure of re-epithelialization. (3) Cosmetic results were evaluated during study visits by patients and physicians applying a visual analogue scale (VAS). Results: Measuring the diameter of laser-generated lesions revealed a significantly faster cure of the lesions in wound sections that were treated with the dexpanthenol-containing ointment on days 1 and 2, in comparison to the lesions that were treated with petroleum jelly. Concordantly, visual evaluation of the wounds revealed significantly better cosmetic results and re-epithelialization on days 1, 2 and 5 after laser treatment in wound sites that were treated with the dexpanthenol-containing ointment. All patients exhibited a completed wound healing on day 14 after laser treatment. Conclusion: In this comparative study, post-operative treatment of laser-treated skin with a dexpanthenol-containing ointment led to a significantly faster wound closure in comparison to petroleum jelly, especially during the early phase of wound healing. Moreover, assessment of the cosmetic result exhibited beneficial effects of the dexpanthenol-containing ointment in the post-operative wound care after laser treatment. These results emphasize that the use of a dexpanthenol-containing ointment in the post-operative phase following CO2 laser therapy could be a promising alternative to the routinely used treatment with petroleum jelly.

Analysis of the status quo of perioperative antibiotic prophylaxis in dermatosurgery in Germany: results of the DESSI-study.

BACKGROUND: Perioperative antibiotic prophylaxis (PAP) is recommended for the prevention of postoperative infections by the Commission for Hospital Hygiene and Infection Prevention (KRINKO) at the Robert Koch Institute. However, how PAP is currently used in the field of dermatosurgery in Germany is unclear. METHODS: All members of the German Society for Dermatosurgery (DGDC) were asked to participate in a web-based survey in order to investigate the use of PAP by German dermatological surgeons. RESULTS: 78 DGDC members completed the questionnaire. Of these, 89.7 % (70/78) were medical specialists with a median work experience of 15 years in the field of dermatosurgery, and 53.8 % (42/78) of the respondents regularly use PAP in dermatosurgery. Of these, 35.7 % (15/42) reported that they perform PAP for immunocompromised patients. Only a small proportion of skin surgeons stated that they administer PAP parenterally (5.9 %, 4/67). The most commonly used drug was cephalosporin cefuroxime. The duration of the PAP varied between single-dose and prolonged administration for more than five days. CONCLUSION: Currently, the use of PAP in dermatosurgical procedures in Germany is not standardized. Prospective randomized dermatosurgical studies are needed in order to investigate whether the PAP recommendations of KRINKO are applicable to the field of dermatological surgery.

Effects of a ceramide-containing water-in-oil ointment on skin barrier function and allergen penetration in an IL-31 treated 3D model of the disrupted skin barrier.

Atopic dermatitis (AD) is a chronically relapsing, pruritic inflammation of the skin with dryness and disturbed skin barrier function. Recently, we established that IL-31 treatment of human 3D skin models resulted in a disrupted skin barrier phenotype resembling AD. In this model, we found that IL-31 interferes with the differentiation of keratinocytes and inhibits the expression of terminal differentiation markers. In the present study, we investigated the effects of a ceramide-containing water-in-oil skin care ointment on the physical skin barrier structure and function in disrupted skin barrier models, generated either by using primary normal human epidermal keratinocytes (NHEK) or HaCaT cells. We observed that the physical skin barrier of the models recovered after daily topical treatment with the ceramide-containing ointment. Topical application of the ointment prevented downregulation of filaggrin and disorganization of other differentiation markers, such as keratin 10 and ß4-integrin, as demonstrated by immunohistological analysis. The expression of Ki67 was also upregulated in response to the ointment. Furthermore, functional studies revealed that local application of the ointment diminished the increased uptake of fluorescently labelled recombinant allergens of timothy grass (phl p1) in our model. In conclusion, our data revealed that topical application of a ceramide-containing skin care ointment reduced IL-31 induced impairments of the physical skin barrier and skin barrier function in an in vitro model of the disrupted skin barrier. This standardized model can be utilized in the future to monitor ex vivo effects of various topical therapies on skin morphology, physiology, and gene expression.

Surgical Site Infections After Dermatologic Surgery in Immunocompromised Patients: A Single-Center Experience.

BACKGROUND: Immunosuppression is often considered as an indication for antibiotic prophylaxis to prevent surgical site infections (SSI) while performing skin surgery. However, the data on the risk of developing SSI after dermatologic surgery in immunosuppressed patients are limited. PATIENTS AND METHODS: All patients of the Department of Dermatology and Allergology at the University Hospital of RWTH Aachen in Aachen, Germany, who underwent hospitalization for a dermatologic surgery between June 2016 and January 2017 (6 months), were followed up after surgery until completion of the wound healing process. The follow-up addressed the occurrence of SSI and the need for systemic antibiotics after the operative procedure. Immunocompromised patients were compared with immunocompetent patients. The investigation was conducted as a retrospective analysis of patient records. RESULTS: The authors performed 284 dermatologic surgeries in 177 patients. Nineteen percent (54/284) of the skin surgery was performed on immunocompromised patients. The most common indications for surgical treatment were nonmelanoma skin cancer and malignant melanomas. Surgical site infections occurred in 6.7% (19/284) of the cases. In 95% (18/19), systemic antibiotic treatment was needed. Twenty-one percent of all SSI (4/19) were seen in immunosuppressed patients. CONCLUSION: According to the authors' data, immunosuppression does not represent a significant risk factor for SSI after dermatologic surgery. However, larger prospective studies are needed to make specific recommendations on the use of antibiotic prophylaxis while performing skin surgery in these patients.

Effectiveness and Safety of Surgical Excision in the Treatment of Digital Mucoid Cysts.

BACKGROUND: Digital mucoid cysts have a tendency for recurrence after operative intervention. Several procedures are in use. OBJECTIVE: Retrospective evaluation for effectiveness, safety and patient satisfaction by using a questionnaire after treatment for digital mucoid cysts with targeted surgical excision and closure by flap-design. MATERIALS AND METHODS: All patients treated with surgical excision for digital mucoid cysts at the Dermatology Department of the Ludwigshafen City Hospital between 2007 and 2011 were evaluated using a specially designed questionnaire. RESULTS: We evaluated 31 patients. The patient group consisted of 65% women, the median age was 61 years. Seventy-eight percent of patients with nail involvement had a marked improvement or complete resolution of this complaint after surgery. A few complications (e.g., redness, pain or hematoma) were observed after treatment, but no patients required oral antibiotics. Patient evaluation of cosmetic outcome revealed high satisfaction with the procedure, nevertheless recurrence of the digital mucoid cysts was observed in 22.5% of all cases. CONCLUSION: Surgical excision in treatment of digital mucoid cysts was shown to be effective and safe. However, possible advantages and disadvantages of this treatment option should be discussed with the patients before a decision on the kind of therapy is reached.

Molecular effects of fractional ablative erbium:YAG laser treatment with multiple stacked pulses on standardized human three-dimensional organotypic skin models.

The molecular changes in gene expression following ablative laser treatment of skin lesions, such as atrophic scars and UV-damaged skin, are not completely understood. A standardized in vitro model of human skin, to study the effects of laser treatment on human skin, has been recently developed. Therefore, the aim of the investigation was to examine morphological and molecular changes caused by fractional ablative erbium:YAG laser treatment on an in vitro full-thickness 3D standardized organotypic model of human skin. A fractional ablative erbium:YAG laser was used to irradiate organotypic human 3D models. Laser treatments were performed at four different settings using a variety of stacked pulses with similar cumulative total energy fluence (60 J/cm2). Specimens were harvested at specified time points and real-time PCR (qRT-PCR) and microarray studies were performed. Frozen sections were examined histologically. Three days after erbium:YAG laser treatment, a significantly increased mRNA expression of matrix metalloproteinases and their inhibitors (MMP1, MMP2, MMP3, TIMP1, and TIMP2), chemokines (CXCL1, CXCL2, CXCL5, and CXCL6), and cytokines such as IL6, IL8, and IL24 could be detected. qRT-PCR studies confirmed the enhanced mRNA expression of IL6, IL8, IL24, CXCLs, and MMPs. In contrast, the mRNA expression of epidermal differentiation markers, such as keratin-associated protein 4, filaggrin, filaggrin 2, and loricrin, and antimicrobial peptides (S100A7A, S100A9, and S100A12) as well as CASP14, DSG2, IL18, and IL36ß was reduced. Four different settings with similar cumulative doses have been tested (N10%, C10%, E10%, and W25%). These laser treatments resulted in different morphological changes and effects on gene regulations. Longer pulse durations (1000 µs) especially had the strongest impact on gene expression and resulted in an upregulation of genes, such as collagen-1A2, collagen-5A2, and collagen-6A2, as well as FGF2. Histologically, all treatment settings resulted in a complete regeneration of the epidermis 3 days after irradiation. Fractional ablative erbium:YAG laser treatment with a pulse stacking technique resulted in histological alterations and shifts in the expression of various genes related to epidermal differentiation, inflammation, and dermal remodeling depending on the treatment setting applied. A standardized in vitro 3D model of human skin proved to be a useful tool for exploring the effects of various laser settings both on skin morphology and gene expression during wound healing. It provides novel data on the gene expression and microscopic architecture of the exposed skin. This may enhance our understanding of laser treatment at a molecular level.

Synthesis of a Sulfonimidamide-Based Analog of Tasisulam and Its Biological Evaluation in the Melanoma Cell Lines SKMel23 and A375.

Tasisulam is a promising antitumor agent with complex pharmacology, which is used as an antiproliferative agent in patients with metastatic melanoma and other solid tumors. Phase 2 melanoma studies showed promising results but had to be stopped because of insufficient tasisulam clearance leading to toxic side effects. To reduce the negative effects of tasisulam, we synthesized a novel sulfonimidamide-based analog to evaluate its antiproliferative effects in comparison to the original compound by performing a cell proliferation assay in melanoma cell lines SKMel23 and A375. The results revealed that the analog had inhibitory effects on the proliferation comparable to tasisulam in both investigated cell lines. These results could contribute to a reduced toxicity of tasisulam and lead to further clinical trials in metastatic melanoma.