Sonnenschutz bei Beschäftigten im Freien. Entwicklung und Validierung von standardisierten Fragebögen für Verhalten und Wissen: Sun protection in outdoor workers ­ Development and validation of standardized questionnaires for behavior and knowledge.

BACKGROUND AND OBJECTIVES: Outdoor workers are at increased risk of developing non-melanoma skin cancer. We aimed to address the lack of validated German-language measurement instruments for outdoor workers' sun safety behavior and knowledge by compiling and validating two questionnaires. PARTICIPANTS AND METHODS: By expert consensus, items for the assessment of protective behavior (OccuSun) were compiled based on existing instruments. For knowledge, a translation of the Skin Cancer and Sun Knowledge (SCSK) scale was selected. After a pre-test, a validation study including 68 outdoor workers (62% female) was conducted in 2020. RESULTS: The retest reliability was r = 0.93 (95% confidence interval: 0.86-0.96) for the protection score and rs = 0.78 (0.67-0.86) for the knowledge score. Protective behaviors were correlated with respective diary data (0.38 ≤ rs ≤ 0.74, p < 0.001) and skin pigmentation changes (-0.23 ≥ rs ≥ -0.42, 0.007 ≤ p ≤ 0.165) but not with self-reported sunburn frequency (0.21 ≥ rs ≥ -0.04). CONCLUSIONS: Among German outdoor workers, two questionnaires for the assessment of sun protection behavior (OccuSun) and knowledge (SCSK) demonstrated good reliability. The OccuSun had generally good validity. Both instruments are fit for subsequent validation to determine their sensitivity to change.

Gene network-based and ensemble modeling-based selection of tumor-associated antigens with a predicted low risk of tissue damage for targeted immunotherapy.

BACKGROUND: Tumor-associated antigens and their derived peptides constitute an opportunity to design off-the-shelf mainline or adjuvant anti-cancer immunotherapies for a broad array of patients. A performant and rational antigen selection pipeline would lay the foundation for immunotherapy trials with the potential to enhance treatment, tremendously benefiting patients suffering from rare, understudied cancers. METHODS: We present an experimentally validated, data-driven computational pipeline that selects and ranks antigens in a multipronged approach. In addition to minimizing the risk of immune-related adverse events by selecting antigens based on their expression profile in tumor biopsies and healthy tissues, we incorporated a network analysis-derived antigen indispensability index based on computational modeling results, and candidate immunogenicity predictions from a machine learning ensemble model relying on peptide physicochemical characteristics. RESULTS: In a model study of uveal melanoma, Human Leukocyte Antigen (HLA) docking simulations and experimental quantification of the peptide-major histocompatibility complex binding affinities confirmed that our approach discriminates between high-binding and low-binding affinity peptides with a performance similar to that of established methodologies. Blinded validation experiments with autologous T-cells yielded peptide stimulation-induced interferon-γ secretion and cytotoxic activity despite high interdonor variability. Dissecting the score contribution of the tested antigens revealed that peptides with the potential to induce cytotoxicity but unsuitable due to potential tissue damage or instability of expression were properly discarded by the computational pipeline. CONCLUSIONS: In this study, we demonstrate the feasibility of the de novo computational selection of antigens with the capacity to induce an anti-tumor immune response and a predicted low risk of tissue damage. On translation to the clinic, our pipeline supports fast turn-around validation, for example, for adoptive T-cell transfer preparations, in both generalized and personalized antigen-directed immunotherapy settings.

Elevated aluminum excretion in patients by long-term subcutaneous immunotherapy - A cross-sectional case-control study.

BACKGROUND: Aluminum (Al) adjuvants have been used in vaccines and subcutaneous immunotherapy (SCIT) for decades. Despite indisputable neurotoxic properties of Al, there is no clear evidence of a causal relationship between their use and any neurotoxic side effects. However, recent rat studies have shown an accumulation of Al from adjuvants in tissues, especially in bones. OBJECTIVES: Since the human toxicokinetics of Al-adjuvants are poorly understood, this study aimed to evaluate whether up-dosed or long-term SCIT with Al-coupled extracts leads to increased Al load in humans. METHODS: This observational cross-sectional case-control study explored Al excretion in hymenoptera venom allergy patients recruited in 2020 before initiation (n = 10) and during ongoing (n = 12) SCIT with Al-based preparations. Urine samples were collected before and 24 h after the SCIT injections and analyzed for aluminum content by using atomic absorption spectrometry. The cumulative administered Al dose was extracted from patient records. Patients receiving long-term immunotherapy were treated between 2.8 and 13.6 years (mean 7.1). Other potential sources of Al exposure were surveyed. RESULTS: Patients who had received Al-coupled immunotherapy for several years showed significantly (p < 0.001) higher Al excretion than the controls at initiation of immunotherapy (mean 18.2 µg/gC vs. 7.9 µg/gC) and predominantly (73%) were above the 95th percentile of the general populations' exposure (>15 µg/gC), however, without reaching levels of toxicological concern (>50 µg/gC). Taking both groups together excreted Al levels correlated with the cumulative administered Al dose from SCIT (linear regression: Alurine = 8.258 + 0.133*Alcum; p = 0.001). DISCUSSION: These results suggest a relevant iatrogenic contribution of long-term SCIT to human internal Al burden and potential accumulation. Considering the medical benefits of Al-adjuvants and SCIT a differentiated risk-benefit analysis is needed. For certain scenarios of potential toxicological concern in clinical practice biomonitoring might be advisable.

Anti-PD-(L)1 plus BRAF/MEK inhibitors (triplet therapy) after failure of immune checkpoint inhibition and targeted therapy in patients with advanced melanoma.

BACKGROUND: Effective treatment options are limited for patients with advanced melanoma who have progressed on immune checkpoint inhibitors (ICI) and targeted therapies (TT). Preclinical models support the combination of ICI with TT; however, clinical trials evaluating the efficacy of triplet combinations in first-line setting showed limited advantage compared to TT only. METHODS: We conducted a retrospective, multicenter study, that included patients with advanced melanoma who were treated with BRAF/MEK inhibitors in combination with an anti-PD-(L)1 antibody (triplet therapy) after failure of at least one anti-PD-(L)1-based therapy and one TT in seven major melanoma centers between February 2016 and July 2022. RESULTS: A total of 48 patients were included, of which 32 patients, 66.7% had brain metastases, 37 patients (77.1%) had three or more metastatic organs and 21 patients (43.8%) had three or more treatment lines. The median follow-up time was 31.4 months (IQR, 22.27-40.45 months). The treatment with triplet therapy resulted in an ORR of 35.4% (n = 17) and a DCR of 47.9% (n = 23). The median DOR was 5.9 months (range, 3.39-14.27 months). Patients treated with BRAF/MEK inhibitors as the last treatment line showed a slightly lower ORR (29.6%) compared to patients who received ICI or chemotherapy last (ORR: 42.9%). Grade 3-4 treatment-related adverse events occurred in 25% of patients (n = 12), with seven patients (14.6%) requiring discontinuation of treatment with both or either drug. CONCLUSIONS: Triplet therapy has shown activity in heavily pretreated patients with advanced melanoma and may represent a potential treatment regimen after failure of ICI and TT.

Sun protection in outdoor workers - Development and validation of standardized questionnaires for behavior and knowledge.

BACKGROUND AND OBJECTIVES: Outdoor workers are at increased risk of developing non-melanoma skin cancer. We aimed to address the lack of validated German-language measurement instruments for outdoor workers' sun safety behavior and knowledge by compiling and validating two questionnaires. PARTICIPANTS AND METHODS: By expert consensus, items for the assessment of protective behavior (OccuSun) were compiled based on existing instruments. For knowledge, a translation of the Skin Cancer and Sun Knowledge (SCSK) scale was selected. After a pre-test, a validation study including 68 outdoor workers (62% female) was conducted in 2020. RESULTS: The retest reliability was r = 0.93 (95% confidence interval: 0.86-0.96) for the protection score and rs = 0.78 (0.67-0.86) for the knowledge score. Protective behaviors were correlated with respective diary data (0.38 ≤ rs ≤ 0.74, p < 0.001) and skin pigmentation changes (-0.23 ≥ rs ≥ -0.42, 0.007 ≤ p ≤ 0.165) but not with self-reported sunburn frequency (0.21 ≥ rs ≥ -0.04). CONCLUSIONS: Among German outdoor workers, two questionnaires for the assessment of sun protection behavior (OccuSun) and knowledge (SCSK) demonstrated good reliability. The OccuSun had generally good validity. Both instruments are fit for subsequent validation to determine their sensitivity to change.

European consensus-based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes).

A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology, the European Dermatology Forum, the European Academy of Dermatology and Venereology, and the European Union of Medical Specialists was formed to develop European recommendations on AK diagnosis and treatment, based on current literature and expert consensus. This guideline addresses the epidemiology, diagnostics, risk stratification and treatments in immunocompetent as well as immunosuppressed patients. Actinic keratoses (AK) are potential precursors of cutaneous squamous cell carcinoma (cSCC) and display typical histopathologic and immunohistochemical features of this malignancy in an early stage. They can develop into cSSC in situ and become invasive in a low percentage of cases. AK is the most frequent neoplasia in white populations, frequently occurring within a cancerous field induced by ultraviolet radiation. Since it cannot be predicted, which lesion will progress to cSCC and when treatment is usually recommended. The diagnosis of AK and field cancerization is made by clinical examination. Dermatoscopy, confocal microscopy, optical coherence tomography or line-field confocal-OCT can help in the differential diagnosis of AK and other skin neoplasms. A biopsy is indicated in clinically and/or dermatoscopically suspicious and/or treatment-refractory lesions. The choice of treatment depends on patients' and lesion characteristics. For single non-hyperkeratotic lesions, the treatment can be started upon patient's request with destructive treatments or topical treatments. For multiple lesions, field cancerization treatment is advised with topical treatments and photodynamic therapy. Preventive measures such as sun protection, self-examination and repeated field cancerization treatments of previously affected skin areas in high-risk patients are advised.

Occlusive cutaneous vasculopathies as cause of chronic ulcers.

The term occluding vasculopathies covers a large number of different conditions. These often manifest as skin ulcers. Occluding vasculopathies should be considered in the differential diagnosis of leg ulcers. The term "occlusive vasculopathies" encompasses pathophysiologically related entities that share structural or thrombotic obliteration of small cutaneous vessels. In this article, we will focus on livedoid vasculopathy with and without antiphospholipid syndrome and calciphylaxis with differentiation from hypertonic leg ulcer as the most relevant differential diagnoses of leg ulcer. The term also includes vascular occlusion, for example due to oxalate or cholesterol embolism, and septic vasculopathy. This often leads to acral ulceration and is therefore not a differential diagnosis with classic leg ulcers. It will not be discussed in this article. Occlusive vasculopathy may be suspected in the presence of the typical livedo racemosa or (non-inflammatory) retiform purpura as a sign of reduced cutaneous perfusion in the wound area. Inflammatory dermatoses, especially vasculitides, must be differentiated. This is achieved by histopathological evaluation of a tissue sample of sufficient size and depth taken at the appropriate time. In addition, specific laboratory parameters, particularly coagulation parameters, can support the diagnosis.

Isolated melanoma cells in sentinel lymph node in stage IIIA melanoma correlate with a favorable prognosis similar to stage IB.

BACKGROUND: The American Joint Committee on Cancer 8th edition (AJCC v8) defines sentinel lymph nodes (SLN) containing any tumor cells as positive SLN. Consequently, even thin melanomas with isolated tumor cells (ic) in SLN are classified as stage IIIA, making them candidates for adjuvant therapy. OBJECTIVES AND ENDPOINTS: We aimed to evaluate survival outcomes of melanoma stage IIIA (ic) and compare them with stage IIIA with lymph node (LN) metastases > 0.1 mm. Primary endpoints were relapse-free survival (RFS) and distant metastases-free survival (DMFS). Secondary endpoint was melanoma specific survival (MSS). RESULTS: The discovery cohort from the Department of Dermatology, University Hospital Tuebingen, included 237 patients; confirmation cohort included 143 patients from the DeCOG trial. The Tuebingen cohort included 95 patients with stage IIIA (ic) and 142 patients with stage IIIA. The DeCOG trial included 39 patients with stage IIIA (ic) and 104 patients with stage IIIA. In the Tuebingen cohort, 10-year RFS rates for stage IIIA (ic) and IIIA were 84% (95% CI 75-94) and 49% (95% CI 39-59), respectively (p < 0.001). 10-year DMFS rates for stage IIIA (ic) and IIIA were 89% (95% CI 81-97) and 56% (95% CI 45-67), respectively; (p < 0.001). In the DeCOG cohort, 10-year RFS for stage IIIA (ic) and stage IIIA were 88% (95% CI 78-99) and 35% (95% CI 7-62), respectively; (p = 0.009). 10-year DMFS for stage IIIA (ic) and IIIA was 88% (95% CI 77-99) and 60% (95% CI 39-80), respectively (p = 0.061). CONCLUSION: Stage IIIA (ic) melanoma exhibits a prognosis similar to stage IB. Recommendation of adjuvant therapy in Stage IIIA (ic) warrants thorough discussion.

[Recognition and management of relevant comorbidities in chronic spontaneous urticaria]. / Erkennen und Management relevanter Komorbiditäten bei chronischer spontaner Urtikaria.

Various mechanisms contributing to the activity of chronic spontaneous urticaria (CU) have been postulated. Associated comorbidities are increasingly leading to the discovery of further signaling pathways which may support the activity of chronic urticaria or contribute to low-grade systemic inflammation. Moreover psychoimmunological factors may also be involved. The aim of this work is to improve the clinical care of patients with CU by increasing knowledge regarding optional influencing factors due to comorbidities and to possibly influence disease activity. Chronic urticaria due to autoimmune mechanisms may dispose to other autoimmune diseases, especially autoimmune thyroiditis, which can trigger chronic disease. Association of CU with metabolic syndrome has received little attention to date. Obesity may contribute to low-grade systemic inflammation by cytokine-secreting adipose tissue and hence to mediator-release of mast cells. Furthermore, neuroimmunological pathways, especially increased release of substance P, an activating ligand of Mas-related G protein-coupled receptor X2 (MRGPX2) on mast cells, should be addressed when optimizing therapy.

Federated Learning for Decentralized Artificial Intelligence in Melanoma Diagnostics.

Importance: The development of artificial intelligence (AI)-based melanoma classifiers typically calls for large, centralized datasets, requiring hospitals to give away their patient data, which raises serious privacy concerns. To address this concern, decentralized federated learning has been proposed, where classifier development is distributed across hospitals. Objective: To investigate whether a more privacy-preserving federated learning approach can achieve comparable diagnostic performance to a classical centralized (ie, single-model) and ensemble learning approach for AI-based melanoma diagnostics. Design, Setting, and Participants: This multicentric, single-arm diagnostic study developed a federated model for melanoma-nevus classification using histopathological whole-slide images prospectively acquired at 6 German university hospitals between April 2021 and February 2023 and benchmarked it using both a holdout and an external test dataset. Data analysis was performed from February to April 2023. Exposures: All whole-slide images were retrospectively analyzed by an AI-based classifier without influencing routine clinical care. Main Outcomes and Measures: The area under the receiver operating characteristic curve (AUROC) served as the primary end point for evaluating the diagnostic performance. Secondary end points included balanced accuracy, sensitivity, and specificity. Results: The study included 1025 whole-slide images of clinically melanoma-suspicious skin lesions from 923 patients, consisting of 388 histopathologically confirmed invasive melanomas and 637 nevi. The median (range) age at diagnosis was 58 (18-95) years for the training set, 57 (18-93) years for the holdout test dataset, and 61 (18-95) years for the external test dataset; the median (range) Breslow thickness was 0.70 (0.10-34.00) mm, 0.70 (0.20-14.40) mm, and 0.80 (0.30-20.00) mm, respectively. The federated approach (0.8579; 95% CI, 0.7693-0.9299) performed significantly worse than the classical centralized approach (0.9024; 95% CI, 0.8379-0.9565) in terms of AUROC on a holdout test dataset (pairwise Wilcoxon signed-rank, P < .001) but performed significantly better (0.9126; 95% CI, 0.8810-0.9412) than the classical centralized approach (0.9045; 95% CI, 0.8701-0.9331) on an external test dataset (pairwise Wilcoxon signed-rank, P < .001). Notably, the federated approach performed significantly worse than the ensemble approach on both the holdout (0.8867; 95% CI, 0.8103-0.9481) and external test dataset (0.9227; 95% CI, 0.8941-0.9479). Conclusions and Relevance: The findings of this diagnostic study suggest that federated learning is a viable approach for the binary classification of invasive melanomas and nevi on a clinically representative distributed dataset. Federated learning can improve privacy protection in AI-based melanoma diagnostics while simultaneously promoting collaboration across institutions and countries. Moreover, it may have the potential to be extended to other image classification tasks in digital cancer histopathology and beyond.

Identifying biomarkers and novel therapeutic targets in uveal melanoma.

Uveal melanoma (UM) is an orphan cancer despite being the most common eye tumor in adults. Patients often present to skin cancer centers for treatment of metastatic disease although there are significant genetic, biological, and clinical differences from cutaneous melanoma. The treatments most commonly used for metastatic UM are tebentafusp and combined immune checkpoint blockade, both of which yield low response rates and may be accompanied by high treatment costs and significant immune-related toxicities. Thus, it is of paramount importance to identify biomarkers and clinical profiles predictive of treatment response and to find novel therapeutic targets. The use of immune checkpoint blockade showed more favorable outcomes in patients with extrahepatic disease and normal levels of serum lactate dehydrogenase in a panel of retrospective studies, making its use more reasonable in this subgroup. To identify novel drug targets, we will analyze the expression and relevance of neural crest transcription factors in patient bio-specimens using next-generation nanopore sequencing. Computer algorithms and network-based analysis will facilitate the identification of druggable targets which will subsequently be validated in patient-derived short-term cell cultures. This approach will help to find novel and personalized treatments for UM.

S3 guideline "actinic keratosis and cutaneous squamous cell carcinoma" - update 2023, part 2: epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.

Actinic keratosis (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline "actinic keratosis and cutaneous squamous cell carcinoma" was updated and expanded by the topics cutaneous squamous cell carcinoma in situ (Bowen's disease) and actinic cheilitis. The guideline is aimed at dermatologists, general practitioners, ear nose and throat specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings, as well as other medical specialties, policy makers and insurance funds involved in the diagnosis and treatment of patients with AK and cSCC. A separate guideline exists for patients and their relatives. In this part, we will address aspects relating to epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.