Perioperative antibiotic prophylaxis in skin surgery - Position paper of the Antibiotic Stewardship working group of the German Society for Dermatologic Surgery (DGDC), Part 2: Special indications and situations.

In addition to prevention of surgical site infections after skin surgery, perioperative antibiotic prophylaxis (PAP) aims to prevent the occurrence of other postoperative infectious complications, especially bacterial endocarditis and hematogenous joint prosthesis infections. This article discusses specific indications for the use of PAP. For example, patients who have undergone any type of heart valve replacement, including transcatheter valve replacement or use of prosthetic material to correct the heart valve, or patients who have experienced bacterial endocarditis, require PAP during skin surgery on mucosal membranes or ulcerated tumors. The use of PAP in special situations such as secondary wound healing, septic dermatosurgery or ulcer surgery is also presented and discussed in detail in this paper based on the current scientific literature. This paper represents the second part of the position paper of the Antibiotic Stewardship Working Group of the German Society for Dermatologic Surgery (DGDC) and summarizes evidence-based recommendations for the administration of PAP during skin surgery for special indications and situations. This is particularly important because, as detailed in Part 1 of this position paper, PAP can and usually should be avoided in skin surgery.

Perioperative antibiotic prophylaxis in skin surgery - Position paper of the Antibiotic Stewardship working group of the German Society for Dermatologic Surgery (DGDC), Part 1: Procedure- and patient-related risk factors.

The aim of perioperative antibiotic prophylaxis (PAP) is to prevent the occurrence of surgical site infections (SSIs) or other infectious complications (especially bacterial endocarditis or septic arthritis). PAP is effective in surgeries where overall infection rates are high even without considering patient-related risk factors (such as orthopedic surgery or fracture repair). Surgery on airways, gastrointestinal, genital, or urinary tract is also considered to be associated with a risk of infection and may require PAP. Overall, SSIs in skin surgery are relatively rare and vary between 1% and 11% depending on the localization, complexity of the wound closure and patient cohort. Therefore, the general surgical recommendations regarding PAP only partially reflect the needs of dermatologic surgery. In contrast to the USA, where recommendations on the use of PAP in skin surgery already exist, there are currently no guidelines for the use of PAP specifically designed for dermatologic surgery in Germany. In the absence of an evidence-based recommendation, the use of PAP is guided by the experience of the surgeons and leads to a heterogeneous use of antimicrobial substances. In this work, we summarize the current scientific literature on the use of PAP and make a recommendation depending on procedure- and patient-related risk factors.

Imaging Mass Spectrometry for the Classification of Melanoma Based on BRAF/NRAS Mutational Status.

Mutations of the oncogenes v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS) are the most frequent genetic alterations in melanoma and are mutually exclusive. BRAF V600 mutations are predictive for response to the two BRAF inhibitors vemurafenib and dabrafenib and the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib. However, inter- and intra-tumoral heterogeneity and the development of acquired resistance to BRAF inhibitors have important clinical implications. Here, we investigated and compared the molecular profile of BRAF and NRAS mutated and wildtype melanoma patients' tissue samples using imaging mass spectrometry-based proteomic technology, to identify specific molecular signatures associated with the respective tumors. SCiLSLab and R-statistical software were used to classify peptide profiles using linear discriminant analysis and support vector machine models optimized with two internal cross-validation methods (leave-one-out, k-fold). Classification models showed molecular differences between BRAF and NRAS mutated melanoma, and identification of both was possible with an accuracy of 87-89% and 76-79%, depending on the respective classification method applied. In addition, differential expression of some predictive proteins, such as histones or glyceraldehyde-3-phosphate-dehydrogenase, correlated with BRAF or NRAS mutation status. Overall, these findings provide a new molecular method to classify melanoma patients carrying BRAF and NRAS mutations and help provide a broader view of the molecular characteristics of these patients that may help understand the signaling pathways and interactions involving the altered genes.

Role of the SEC62 gene in dermato-oncology - impact on tumor cell biology, prognostication, and personalized therapy management.

The SEC62 gene encodes for a transmembrane protein of the endoplasmic reticulum (ER). Sec62 protein is involved in the post-translational transport of secretory and membrane-bound proteins in eukaryotic cells, regulates intracellular calcium homeostasis through direct interaction with the Sec61 channel and makes a decisive contribution to the cellular compensation of ER stress in the context of recovER-phagy. A significantly increased expression of the SEC62 gene has already been demonstrated in various tumor entities. First approaches of a targeted therapy have been tested for various tumor entities in vitro and in vivo with promising results that motivate further preclinical and clinical studies. Nevertheless, many questions remain unanswered, in particular with regard to the molecular mechanisms underlying the observed clinical effects, and require further investigation in future studies. The protein also plays a relevant role in dermato-oncology. The overexpression of SEC62 in atypical fibroxanthomas and malignant melanomas has already been demonstrated and a correlation of SEC62 expression with various clinical and pathological features has been observed. Future studies, especially in vivo and clinical, will show whether Sec62 can be established as a prognostic marker in dermato-oncology and whether it can serve as a starting point for targeted therapy.

[Pitfalls in dermatohistology : Stumbling blocks and problems in routine dermatopathology]. / Fallstricke in der Dermatohistologie : Von Stolpersteinen und Problemen im dermatopathologischen Alltag.

Excisions and biopsies are firmly anchored in everyday dermatology. The biopsy, excision or diagnostic-therapeutic confirmation of the clinical diagnosis of neoplasms or inflammatory diseases is decisive for the dermatopathological diagnosis of tissue samples. Dermatopathology, however, is not a magic box into which a tissue sample can be placed without comment or information and receive-within 24 h at the latest-a complete, high-quality diagnosis. The present article describes problems, hurdles, and challenges in everyday dermatopathology that occur on the way to the microscope, even before the actual dermatopathological diagnosis takes place.

Inpatient care for skin diseases in Germany: multi-source analysis on the current and future health care needs.

BACKGROUND: In Germany, skin diseases are mainly treated in the 115 dermatological hospitals. METHODS: Health care and health economic analysis of dermatological inpatient care and prediction of future care needs based on primary and secondary data. RESULTS: Outpatient and inpatient care for dermatologic treatment indications is predominantly provided by dermatology specialists. Inpatient treatment was provided for 833,491 cases in 2018, corresponding to 4.21 % of all inpatient cases (19,808,687). Most common treatment cases were: epithelial skin cancer (total 87,386, of which dermatology clinics 52,608), followed by melanoma (23,917/17,774), psoriasis (19,291/13,352), erysipelas (73,337/11,260), other dermatitis (12,671/10,842), atopic dermatitis (AD) (11,421/9,734), and herpes zoster (26,249/9,652). With an average length of stay of 5.69 days, dermatology hospitals were in the bottom third. The proportion of inpatient indications cared for in dermatology hospitals was highest for prurigo (95.2 %), pemphigus (94.9 %), parapsoriasis (94.6 %), pemphigoid (90.3 %), eczema other than AD (85.6 %), and AD (85.2 %). While the total number of inpatient treatment cases in Germany has increased by an average of 17.5 % between 2000 and 2018, this is the case for 26.6 % of skin diseases and over 150 % for individual ones. The projection of current to future inpatient care suggests a continued high demand for inpatient care by dermatology hospitals. CONCLUSION: Inpatient dermatological care will continue to be an indispensable component of qualified, socially necessary care in Germany.

Skin cancer classification via convolutional neural networks: systematic review of studies involving human experts.

BACKGROUND: Multiple studies have compared the performance of artificial intelligence (AI)-based models for automated skin cancer classification to human experts, thus setting the cornerstone for a successful translation of AI-based tools into clinicopathological practice. OBJECTIVE: The objective of the study was to systematically analyse the current state of research on reader studies involving melanoma and to assess their potential clinical relevance by evaluating three main aspects: test set characteristics (holdout/out-of-distribution data set, composition), test setting (experimental/clinical, inclusion of metadata) and representativeness of participating clinicians. METHODS: PubMed, Medline and ScienceDirect were screened for peer-reviewed studies published between 2017 and 2021 and dealing with AI-based skin cancer classification involving melanoma. The search terms skin cancer classification, deep learning, convolutional neural network (CNN), melanoma (detection), digital biomarkers, histopathology and whole slide imaging were combined. Based on the search results, only studies that considered direct comparison of AI results with clinicians and had a diagnostic classification as their main objective were included. RESULTS: A total of 19 reader studies fulfilled the inclusion criteria. Of these, 11 CNN-based approaches addressed the classification of dermoscopic images; 6 concentrated on the classification of clinical images, whereas 2 dermatopathological studies utilised digitised histopathological whole slide images. CONCLUSIONS: All 19 included studies demonstrated superior or at least equivalent performance of CNN-based classifiers compared with clinicians. However, almost all studies were conducted in highly artificial settings based exclusively on single images of the suspicious lesions. Moreover, test sets mainly consisted of holdout images and did not represent the full range of patient populations and melanoma subtypes encountered in clinical practice.

Imaging Mass Spectrometry-Based Proteomic Analysis to Differentiate Melanocytic Nevi and Malignant Melanoma.

The discrimination of malignant melanoma from benign nevi may be difficult in some cases. For this reason, immunohistological and molecular techniques are included in the differential diagnostic toolbox for these lesions. These methods are time consuming when applied subsequently and, in some cases, no definitive diagnosis can be made. We studied both lesions by imaging mass spectrometry (IMS) in a large cohort (n = 203) to determine a different proteomic profile between cutaneous melanomas and melanocytic nevi. Sample preparation and instrument setting were tested to obtain optimal results in term of data quality and reproducibility. A proteomic signature was found by linear discriminant analysis to discern malignant melanoma from benign nevus (n = 113) with an overall accuracy of >98%. The prediction model was tested in an independent set (n = 90) reaching an overall accuracy of 93% in classifying melanoma from nevi. Statistical analysis of the IMS data revealed mass-to-charge ratio (m/z) peaks which varied significantly (Area under the receiver operating characteristic curve > 0.7) between the two tissue types. To our knowledge, this is the largest IMS study of cutaneous melanoma and nevi performed up to now. Our findings clearly show that discrimination of melanocytic nevi from melanoma is possible by IMS.

Expression of SEC62 Oncogene in Benign, Malignant and Borderline Melanocytic Tumors-Unmasking the Wolf in Sheep's Clothing?

SEC62 oncogene located at chromosomal region 3q26 encodes for a transmembrane protein of the endoplasmic reticulum (ER) and is expressed at high levels in numerous human malignancies. SEC62 overexpression has been associated with worse prognosis and high risk for lymphatic and distant metastases in head and neck cancer, cervical cancer, hepatocellular cancer, and lung cancer. However, its role in the development and tumor biology of melanocytic lesions has not been investigated so far. An immunohistochemical study including 209 patients with melanocytic lesions (malignant melanoma (MM), n = 93; melanoma metastases (MET), n = 28; Spitz nevi (SN), n = 29; blue nevi (BN), n = 21; congenital nevi (CN), n = 38) was conducted and SEC62 expression was correlated with clinical data including patient survival and histopathological characteristics. SN showed the highest SEC62 expression levels followed by MET, MM, CN, and BN. High SEC62 expression correlated with a shorter overall and progression-free survival in MM patients. Additionally, high Sec62 levels correlated significantly with higher tumor size (T stage), the presence of tumor ulceration, and the presence of lymph node as well as distant metastases. Strikingly, SEC62 expression showed a strong correlation with Clark level. Taken together, these data demonstrate that SEC62 is a promising prognostic marker in MM and has the potential to predict biological behavior and clinical aggressiveness of melanocytic lesions.

[Personal preference, experience, intuition and school of surgery dominate the use of wound drainage in dermatosurgery]. / Persönliche Präferenz, Erfahrung, Intuition und operative Schule dominieren die Verwendung postoperativer Wunddrainagen in der Dermatochirurgie.

BACKGROUND: The use of drainage systems in dermatosurgery has so far been carried out without evidence-based data. The indications, complications and contraindications are traditionally passed on from surgeon to surgeon but have so far not been defined. METHOD: An Internet-based survey was created and sent out to members of the German Society for Dermatosurgery (DGDC). The questions were on the general treatment approach in German language countries with reference to the use of wound drainage following dermatological operations as well as the utilization habits and experiences with drainage-associated complications. RESULTS: Of the DGDC members contacted 12.73% completed the questionnaire. Drainages were predominantly used in the clinical environment and all drainage systems in question were used. The extent and complexity of the intervention were essential criteria when evaluating the indications. The use of drainages was dependent on the age of the participant and mostly carried out in patients where complications in the postoperative course were to be expected (e.g. obesity, nicotine use, diabetes). CONCLUSION: In summary, the majority of the participants used wound drainages and mostly intuitively. Uniform and fixed evidence-based parameters for the use of wound drainages are lacking. In the assessment of the necessity for a wound drainage, an individually expressed need of safety seems to play a large role for some dermatosurgeons and an eminence-based action for others.

Adjuvant Therapy of High-Risk (Stages IIC-IV) Malignant Melanoma in the Post Interferon-Alpha Era: A Systematic Review and Meta-Analysis.

INTRODUCTION: Multiple agents are approved in the adjuvant setting of completely resected high-risk (stages IIC-IV) malignant melanoma. Subgroups may benefit differently depending on the agent used. We performed a systematic review and meta-analysis to evaluate the efficiency and tolerability of available options in the post interferon era across following subgroups: patient age, stage, ulceration status, lymph node involvement, BRAF status. METHODS: The PubMed and Cochrane Library databases were searched without restriction in year of publication in June and September 2020. Data were extracted according to the PRISMA Guidelines from two authors independently and were pooled according to the random-effects model. The predefined primary outcome was recurrence-free survival (RFS). Post-data extraction it was noted that one trial (BRIM8) reported disease-free survival which was defined in the exact same way as RFS. RESULTS: Five prospective randomized placebo-controlled trials were included in the meta-analysis. The drug regimens included ipilimumab, pembrolizumab, nivolumab, nivolumab/ipilimumab, vemurafenib, and dabrafenib/trametinib. Adjuvant treatment was associated with a higher RFS than placebo (HR 0.57; 95% CI= 0.45-0.71). Nivolumab/ipilimumab in stage IV malignant melanoma was associated with the highest RFS benefit (HR 0.23; 97.5% CI= 0.12-0.45), followed by dabrafenib/trametinib in stage III BRAF-mutant melanoma (HR 0.49; 95% CI= 0.40-0.59). The presence of a BRAF mutation was associated with higher RFS rates (HR 0.30; 95% CI= 0.11-0.78) compared to the wildtype group (HR 0.60; 95% CI= 0.44-0.81). Patient age did not influence outcomes (≥65: HR 0.50; 95% CI= 0.36-0.70, <65: HR 0.58; 95% CI= 0.46-0.75). Immune checkpoint inhibitor monotherapy was associated with lower RFS in non-ulcerated melanoma. Patients with stage IIIA benefited equally from adjuvant treatment as those with stage IIIB/C. Nivolumab/ipilimumab and ipilimumab monotherapy were associated with higher toxicity. CONCLUSION: Adjuvant therapy should not be withheld on account of advanced age or stage IIIA alone. The presence of a BRAF mutation is prognostically favorable in terms of RFS. BRAF/MEK inhibitors should be preferred in the adjuvant treatment of BRAF-mutant non-ulcerated melanoma.

Expression of 3q oncogene SEC62 in atypical fibroxanthoma-immunohistochemical analysis of 41 cases and correlation with clinical, viral and histopathologic features.

Atypical fibroxanthoma (AFX) is a rare mesenchymal tumor with predominance in older male patients located mainly in chronically UV-exposed skin. Differentiation from clinically more aggressive pleomorphic dermal sarcoma (PDS) is still under debate and immunohistochemical markers are not available yet. An immunohistochemical study, including 41 cases of AFX was conducted to investigate the expression of 3q encoded oncogene SEC62 in AFX and determine the associations with histomorphologic, clinical and viral parameters. Our cohort displayed a mean of 79.9 years at the onset of the disease. In total, 90.2% (37/41) AFXs were located in the head and neck area, whereas, four were located at the extremities (9.7%). Tumor diameter ranged between 0.06 and 40 cm2 with a mean of 5.7 cm2. SEC62 expression was markedly increased in lesional tissue compared with the adjacent healthy squamous epithelium. We found significantly higher expression of SEC62 in cases of AFX with tumor necrosis. Tendency of higher Sec62-IRS-scores were found for tumors with higher Clark levels and a tumor size >5 cm2. Sec62 is involved in endoplasmic reticulum stress tolerance and cell migration, and has been identified as a novel prognostic marker for non-small cell lung cancer as well as head and neck squamous cell carcinoma. For the first time, to the best of our knowledge, we suggest a role of 3q oncogene SEC62 in AFX and discuss a potential prognostic relevance in cases of disputable AFX with unfavorable histomorphologic features and may initiate a discussion on Sec62 serving as discriminating marker between AFX and PDS.

Chronic Inflammatory Microenvironment in Epidermodysplasia Verruciformis Skin Lesions: Role of the Synergism Between HPV8 E2 and C/EBPß to Induce Pro-Inflammatory S100A8/A9 Proteins.

Persistent genus ß-HPV (human papillomavirus) infection is a major co-factor for non-melanoma skin cancer in patients suffering from the inherited skin disease epidermodysplasia verruciformis (EV). Malignant EV lesions are particularly associated with HPV type 5 or 8. There is clinical and molecular evidence that HPV8 actively suppresses epithelial immunosurveillance by interfering with the recruitment of Langerhans cells, which may favor viral persistence. Mechanisms how persistent HPV8 infection promotes the carcinogenic process are, however, less well understood. In various tumor types chronic inflammation has a central role in tumor progression. The calprotectin complex consisting of S100A8 and S100A9 proteins has recently been identified as key driver of chronic and tumor promoting inflammation in skin carcinogenesis. It induces chemotaxis of neutrophil granulocytes and modulates inflammatory as well as immune responses. In this study, we demonstrate that skin lesions of EV-patients are massively infiltrated by inflammatory cells, including CD15+ granulocytes. At the same time we observed a very strong expression of S100A8 and S100A9 proteins in lesional keratinocytes, which was mostly confined to the suprabasal layers of the epidermis. Both proteins were hardly detected in non-lesional skin. Further experiments revealed that the HPV8 oncoproteins E6 and E7 were not involved in S100A8/A9 up-regulation. They rather suppressed differentiation-induced S100A8/A9 expression. In contrast, the viral transcription factor E2 strongly enhanced PMA-mediated S100A8/A9 up-regulation in primary human keratinocytes. Similarly, a tremendous up-regulation of both S100 proteins was observed, when minute amounts of the PMA-inducible CCAAT/enhancer binding protein ß (C/EBPß), which is expressed at low levels in the suprabasal layers of the epidermis, were co-expressed together with HPV8 E2. This confirmed our previous observation that C/EBPß interacts and functionally synergizes with the HPV8 E2 protein in differentiation-dependent gene expression. Potent synergistic up-regulation of S100A8/A9 was seen at transcriptional and protein levels. S100A8/A9 containing supernatants from keratinocytes co-expressing HPV8 E2 and C/EBPß significantly induced chemotaxis of granulocytes in migration assays supporting the relevance of our finding. In conclusion, our data suggest that the HPV8 E2 protein actively contributes to the recruitment of myeloid cells into EV skin lesions, which may support chronic inflammation and progression to skin cancer.