The simultaneous siRNA-mediated downregulation of PD-1 and CTLA-4 to improve CAR-T cell immunotherapy of melanoma - Simon, B.; Harrer, D.; Schuler-Thurner, Beatrice; Dörrie, Jan; Schaft, Niels; Schuler, Gerold; Uslu, Ugur (2018)
EVALuna2:34395

The siRNA-mediated downregulation of PD-1 alone or simultaneously with CTLA-4 shows enhanced in vitro CAR-T-cell functionality for further clinical development towards the potential use in immunotherapy of melanoma - Simon, Bianca; Harrer, Dennis C.; Schuler-Thurner, Beatrice; Schaft, Niels; Schuler, Gerold; Dörrie, Jan; Uslu, Ugur (Experimental Dermatology, 2018)
Chimeric antigen receptor (CAR)-T cells have been used successfully for cancer immunotherapy. While substantial tumor regression was observed in leukaemia and lymphoma, CAR therapy of solid tumors needs further improvement. A major obstacle to the efficiency of engineered T cells is posed by triggering of inhibitory receptors, for example programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), leading to an impaired antitumor activity. To boost CAR-T-cell function, we co-electroporated T cells with both, mRNA encoding a CAR specific for chondroitin sulphate proteoglycan 4 (CSPG4) and small-interfering RNAs (siRNAs) to downregulate PD-1 (siPD-1) and CTLA-4 (siCTLA-4). Flow cytometry revealed that activation-induced upregulation of both PD-1 and CTLA-4 was suppressed when compared to CAR-T cells electroporated with negative control siRNA. The siRNA transfection showed no influence on CAR expression of engineered T cells. Functionality assays were performed using PD-L1- and CD80-transfected melanoma cells endogenously expressing CSPG4. CAR-T cells transfected with siPD-1 alone showed improvement in cytokine secretion. Additionally, CAR-T cells transfected with either siPD-1 alone or together with siCTLA-4 exhibited a significantly increased cytotoxicity. No or only little effects were observed when CAR-T cells were co-transfected with siCTLA-4 only. Taken together, it is feasible to optimize CAR-T cells by co-transfection of CAR-encoding mRNA and siRNAs to downregulate inhibitory receptors. Our in vitro data indicate an improvement of the functionality of these CAR-T cells, suggesting that this strategy could represent a novel method to enhance CAR-T-cell immunotherapy of cancer.
EVALuna2:34375

The soluble CD83 molecule accelerates wound closure and improves wound healing quality - Royzman, Dmytro; Peckert-Maier, Katrin; Stich, Lena; Wild, Andreas; Ostalecki, Christian; Seyferth, Stefan; Eming, Sabine A.; Fuchs, Maximilian; Kunz, Meik; Sturmer, Ewa K.; Peters, Eva M. J.; Berking, Carola; et al. (WOUND REPAIR AND REGENERATION, 2022)
CRIS-Team WoS Importer:2022-09-16

The soluble CD83 protein prevents bone destruction by inhibiting the formation of osteoclasts and inducing resolution of inflammation in arthritis - Royzman, Dmytro; Andreev, Darja; Stich, Lena; Peckert, Katrin; Wild, Andreas; Zinser, Elisabeth; Mühl-Zürbes, Petra; Jones, Evan; Adam, Susanne; Frey, Silke; Fuchs, Maximilian; Kunz, Meik; et al. (Frontiers in Immunology, 2022)
Here we show that soluble CD83 induces the resolution of inflammation in an antigen-induced arthritis (AIA) model. Joint swelling and the arthritis-related expression levels of IL-1 beta, IL-6, RANKL, MMP9, and OC-Stamp were strongly reduced, while Foxp3 was induced. In addition, we observed a significant inhibition of TRAP(+) osteoclast formation, correlating with the reduced arthritic disease score. In contrast, cell-specific deletion of CD83 in human and murine precursor cells resulted in an enhanced formation of mature osteoclasts. RNA sequencing analyses, comparing sCD83- with mock treated cells, revealed a strong downregulation of osteoclastogenic factors, such as Oc-Stamp, Mmp9 and Nfatc1, Ctsk, and Trap. Concomitantly, transcripts typical for pro-resolving macrophages, e.g., Mrc1/2, Marco, Klf4, and Mertk, were upregulated. Interestingly, members of the metallothionein (MT) family, which have been associated with a reduced arthritic disease severity, were also highly induced by sCD83 in samples derived from RA patients. Finally, we elucidated the sCD83-induced signaling cascade downstream to its binding to the Toll-like receptor 4/(TLR4/MD2) receptor complex using CRISPR/Cas9-induced knockdowns of TLR4/MyD88/TRIF and MTs, revealing that sCD83 acts via the TRIF-signaling cascade. In conclusion, sCD83 represents a promising therapeutic approach to induce the resolution of inflammation and to prevent bone erosion in autoimmune arthritis.
CRIS-Team WoS Importer:2022-09-09

The tanning habits and interest in sunscreen of Google users: what happened in 12 years? - Kirchberger, Michael C.; Heppt, Markus V.; Eigentler, Thomas K.; Kirchberger, Markus A.; Schuler, Gerold; Heinzerling, Lucie (Photodermatology Photoimmunology & Photomedicine, 2017)
BACKGROUND: The incidence of melanoma has been rising worldwide. One possible reason for this is natural and artificial UV exposure. Only little data on actual consumer statistics from tanning studios and the usage of sunscreen are available. Therefore, it is difficult to describe trends for both and identify the impact of preventive measures. METHODS: To gain knowledge about the popularity of 'tanning bed' and 'sunscreen', normalized search volumes for both search queries were obtained from Google Trends for 11 countries between January 2004 and June 2016. RESULTS: With few exceptions, worldwide interest in 'tanning bed' has been declining, whereas interest in 'sunscreen' has been increasing. The assessed countries from the Southern Hemisphere showed minor interest in tanning compared to the Northern Hemisphere. Both search queries were observed to fluctuate in a seasonal pattern. Skin cancer prevention measures influence the interest in tanning beds and sunscreen. CONCLUSION: Google Trends data can act as a first surrogate marker to evaluate the influence of skin cancer campaigns on the popularity of tanning beds and sunscreen. Fine-tuning of skin cancer campaigns according to seasonal and geographic trends and behaviors may help to maximize their success.
EVALuna2:34324

The Topical Effect of rhGDF-5 Embedded in a Collagen–Gelatin Scaffold for Accelerated Wound Healing - Eisler, Wiebke; Held, Manuel; Rahmanian-Schwarz, Afshin; Schiefer, Jennifer; Rahmanian, Shahab; Daigeler, Adrien; Baur, Jan-Ole (Applied Sciences, 2022)
The application of exogenous growth factors such as the recombinant human growth and differentiation factor 5 (rhGDF-5) represents a major research topic with great potential for the treatment of complex wounds. In a randomized, controlled minipig study, the topical effect of rhGDF-5 on full-thickness skin defects was evaluated. A total of 60 deep dermal wounds were either treated with rhGDF-5 embedded in an innovative collagen scaffold or another commonly used collagen matrix or left untreated. Wound healing was analyzed by planimetric analysis to determine wound closure over time. After 21 days, the areas of the initial wounds were excised, and the newly formed tissue was examined histologically. In comparison to untreated wounds, all examined matrices accelerated dermal wound healing. The largest acceleration of wound healing was seen with the high-dose rhGDF-5-treated wounds, which, compared to the untreated wounds, accelerated wound healing by 2.58 days, improved the neoepidermal thickness by 32.40 µm, and increased the epidermal cell density by 44.88 cells. The innovative collagen scaffold delivered rhGDF-5 adequately, served as a template to guide proliferating and restructuring cells, and accelerated wound healing. Thus, this composite product offers a novel tool for developing effective wound dressings in regenerative medicine.
CRIS-Team Scopus Importer:2022-01-28
Keywords: Collagen scaffold; Composite biomaterial; Growth factor; RhGDF-5; Wound healing

The transfection of natural killer T cells with a tumor-antigen specific chimeric antigen receptor (CAR) for melanoma immunotherapy - Simon, B.; Wiesinger, M.; Maerz, J.; Wistuba-Hamprecht, K.; Weide, B.; Schuler-Thurner, Beatrice; Schuler, Gerold; Dörrie, Jan; Uslu, Ugur (EXPERIMENTAL DERMATOLOGY, 2019)
CRIS-Team WoS Importer:2019-03-26

The value of convolutional neural networks in the diagnosis of melanoma simulators - Heppt, Markus; Berking, Carola (Journal of the European Academy of Dermatology and Venereology, 2020)
CRIS-Team Scopus Importer:2020-06-26

The value of total body photography for the early detection of melanoma: A systematic review - Hornung, Annkathrin; Steeb, Theresa; Wessely, Anja; Brinker, Titus J.; Breakell, Thomas; Erdmann, Michael; Berking, Carola; Heppt, Markus (International Journal of Environmental Research and Public Health, 2021)
Early detection of melanoma is critical to reduce the mortality and morbidity rates of this tumor. Total body photography (TBP) may aid in the early detection of melanoma. To summarize the current evidence on TBP for the early detection of melanoma, we performed a systematic literature search in Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) for eligible records up to 6th August 2020. Outcomes of interest included melanoma incidence, incisional and excisional biopsy rates, as well as the Breslow’s index of detected tumors. Results from individual studies were described qualitatively. The risks of bias and applicability of the included studies was assessed using the QUADAS-2 checklist. In total, 14 studies published between 1997 and 2020 with an overall sample size of n = 12082 (range 100–4692) were included in the qualitative analysis. Individuals undergoing TBP showed a trend towards a lower Breslow’s thickness and a higher proportion of in situ melanomas compared to those without TBP. The number needed to excise one melanoma varied from 3:1 to 14.3:1 and was better for lesions that arose de novo than for tracked ones. The included studies were judged to be of unclear methodological concern with specific deficiencies in the domains “flow and timing” and “reference standard”. The use of TBP can improve the early detection of melanoma in high-risk populations. Future studies are warranted to reduce the heterogeneity of phenotypic risk factor definition and the technical implementation of TBP. Artificial intelligence-assisted analysis of images derived from 3-D TBP systems and digital dermoscopy may further improve the early detection of melanoma.
CRIS-Team Scopus Importer:2021-03-05
Keywords: Artificial intelligence; Early detection; Melanoma; Photography; Prevention; Skin cancer; Total body photographic cutaneous surveillance

The α4β1 Homing Pathway Is Essential for Ileal Homing of Crohn's Disease Effector T Cells In Vivo - Zundler, Sebastian; Fischer, Anika; Schillinger, Daniela; Binder, Marie-Theres; Atreya, Raja; Rath, Timo; Lopez Posadas, Rocío; Voskens, Caroline J.; Watson, Alastair; Atreya, Imke; Neufert, Clemens; Neurath, Markus (Inflammatory Bowel Diseases, 2017)
BACKGROUND: The precise mechanisms controlling homing of T effector (Teff) cells to the inflamed gut in Crohn's disease (CD) are still unclear, and clinical outcome data from patients with inflammatory bowel disease treated with the anti-α4β7 integrin antibody vedolizumab suggest differences between ulcerative colitis and CD. METHODS: Expression of homing molecules was studied with flow cytometry and immunohistochemistry. Their functional role was investigated in in vitro adhesion assays and in a humanized mouse model of T cell homing to the inflamed gut in vivo. RESULTS: Despite in vitro blockade of CD Teff adhesion to mucosal vascular addressin cell adhesion molecule-1 (MadCAM-1) and in contrast to previous observations in ulcerative colitis, anti-α4β7 treatment did not result in reduced Teff cell homing to the colon in vivo. However, the integrin α4β1 was expressed in higher levels on Teffs from patients with CD compared with controls, while its expression in the peripheral blood declined, and its expression in the intestine increased during the course of clinical vedolizumab treatment. Consistently, adhesion of CD Teffs to vascular cell adhesion molecule-1 (VCAM-1) was blocked by inhibition of α4 and α4β1 in vitro. Moreover, in vivo homing of CD Teffs to the ileum was reduced by inhibition of α4 and α4β1 integrins, but not α4β7 integrins. CONCLUSIONS: Our findings suggest that Teff cell homing to the ileum through the axis α4β1-VCAM-1 is an essential and nonredundant pathway in CD in vivo, possibly affecting efficacy of clinical treatment with antiadhesion compounds.
EVALuna2:33825

Third-Kind Encounters in Biomedicine: Immunology Meets Mathematics and Informatics to Become Quantitative and Predictive - Eberhardt, Martin; Lai, Xin; Tomar, Namrata; Gupta, Shailendra; Schmeck, Bernd; Steinkasserer, Alexander; Schuler, Gerold; Vera, Julio (Methods in Molecular Biology, 2016)
The understanding of the immune response is right now at the center of biomedical research. There are growing expectations that immune-based interventions will in the midterm provide new, personalized, and targeted therapeutic options for many severe and highly prevalent diseases, from aggressive cancers to infectious and autoimmune diseases. To this end, immunology should surpass its current descriptive and phenomenological nature, and become quantitative, and thereby predictive.Immunology is an ideal field for deploying the tools, methodologies, and philosophy of systems biology, an approach that combines quantitative experimental data, computational biology, and mathematical modeling. This is because, from an organism-wide perspective, the immunity is a biological system of systems, a paradigmatic instance of a multi-scale system. At the molecular scale, the critical phenotypic responses of immune cells are governed by large biochemical networks, enriched in nested regulatory motifs such as feedback and feedforward loops. This network complexity confers them the ability of highly nonlinear behavior, including remarkable examples of homeostasis, ultra-sensitivity, hysteresis, and bistability. Moving from the cellular level, different immune cell populations communicate with each other by direct physical contact or receiving and secreting signaling molecules such as cytokines. Moreover, the interaction of the immune system with its potential targets (e.g., pathogens or tumor cells) is far from simple, as it involves a number of attack and counterattack mechanisms that ultimately constitute a tightly regulated multi-feedback loop system. From a more practical perspective, this leads to the consequence that today's immunologists are facing an ever-increasing challenge of integrating massive quantities from multi-platforms.In this chapter, we support the idea that the analysis of the immune system demands the use of systems-level approaches to ensure the success in the search for more effective and personalized immune-based therapies.
EVALuna2:19605

THP-1-derived macrophages render lung epithelial cells hypo-responsive to Legionella pneumophila - a systems biology study - Schulz, Christine; Lai, Xin; Bertrams, Wilhelm; Jung, Anna Lena; Sittka-Stark, Alexandra; Herkt, Christina Elena; Janga, Harshavadhan; Zscheppang, Katja; Stielow, Christina; Schulte, Leon; Hippenstiel, Stefan; Vera, Julio; et al. (Scientific Reports, 2017)
Immune response in the lung has to protect the huge alveolar surface against pathogens while securing the delicate lung structure. Macrophages and alveolar epithelial cells constitute the first line of defense and together orchestrate the initial steps of host defense. In this study, we analysed the influence of macrophages on type II alveolar epithelial cells during Legionella pneumophila-infection by a systems biology approach combining experimental work and mathematical modelling. We found that L. pneumophila-infected THP-1-derived macrophages provoke a pro-inflammatory activation of neighboring lung epithelial cells, but in addition render them hypo-responsive to direct infection with the same pathogen. We generated a kinetic mathematical model of macrophage activation and identified a paracrine mechanism of macrophage-secreted IL-1β inducing a prolonged IRAK-1 degradation in lung epithelial cells. This intercellular crosstalk may help to avoid an overwhelming inflammatory response by preventing excessive local secretion of pro-inflammatory cytokines and thereby negatively regulating the recruitment of immune cells to the site of infection. This suggests an important but ambivalent immunomodulatory role of macrophages in lung infection.
EVALuna2:35404

Three generations of suffering: cryopyrin-associated periodic syndrome with NLRP3 mutation in a family - Wagner, Nicola; Manger, Bernhard; Kittler, Julia; Rech, Jürgen; Sticherling, Michael; Berking, Carola; Kirchberger, Michael Constantin (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-12-24

Threshold Optimization for Tumor Markers S100b and MIA in Uveal Melanoma - A Single Center Analysis - Glaser, Naemi; Petzold, Anne; Wessely, Anja; Kaufmann, Matthias; Koch, Elias; Knorr, Harald; Voskens, Caroline; Heppt, Markus; Berking, Carola; Erdmann, Michael (Anticancer Research, 2023)
Background/Aim: Uveal melanoma (UM) is the most common malignant tumor of the eye in adults. Metastases develop in 50% of the patients, predominantly in the liver. In UM, the cut-off concentrations of the bloodbased tumor markers S100b and MIA are inconclusive. Patients and Methods: In this retrospective monocenter study, we statistically evaluated 1,878 S100b and 1,768 MIA measurements in 244 patients with UM from 2011-2020. Threshold optimization was performed using receiver operating characteristic (ROC) curves. Results: A total of 171 patients with non-metastatic UM (nmUM) and 73 patients with metastatic UM (mUM) showed no differences in sex, age at diagnosis or the affected eye. In mUM, 80% of the patients developed metastases to the liver at a median of 46 months after initial diagnosis. The sensitivity and specificity of S100b was 16.10% and 94.52%, and that of MIA was 31.86% and 81.42%, respectively. ROC curves revealed poor values for the area under the curve of 0.57 for S100b and 0.55 for MIA. The optimal cut-off concentration to detect metastases was 0.14 μg/l for S100b and 17.4 ng/ml for MIA. With at least one tumor marker elevated, optimized sensitivity was 20.40% and specificity 96.76%. Conclusion: Current thresholds for S100b and MIA in UM are not able to detect early metastatic disease and require additional diagnostics to clarify false positive results. Threshold optimization considering both S100b and MIA results in a better diagnostic validity with an acceptable specificity and a poor sensitivity. Highly sensitive blood-based and imaging methods to detect metastases early in UM are urgently needed.
CRIS-Team Scopus Importer:2023-11-03
Keywords: MIA; S100b; threshold optimization; tumor marker; Uveal melanoma

Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83 - Von Rohrscheidt, Julia; Petrozziello, Elisabetta; Nedjic, Jelena; Federle, Christine; Krzyzak, Lena; Ploegh, Hidde L.; Ishido, Satoshi; Steinkasserer, Alexander; Klein, Ludger (Journal of Experimental Medicine, 2016)
Deficiency of CD83 in thymic epithelial cells (TECs) dramatically impairs thymic CD4 T cell selection. CD83 can exert cell-intrinsic and -extrinsic functions through discrete protein domains, but it remains unclear how CD83's capacity to operate through these alternative functional modules relates to its crucial role in TECs. In this study, using viral reconstitution of gene function in TECs, we found that CD83's transmembrane domain is necessary and sufficient for thymic CD4 T cell selection. Moreover, a ubiquitination-resistant MHCII variant restored CD4 T cell selection in Cd83(-/-) mice. Although during dendritic cell maturation CD83 is known to stabilize MHCII through opposing the ubiquitin ligase March1, regulation of March1 did not account for CD83's TEC-intrinsic role. Instead, we provide evidence that MHCII in cortical TECs (cTECs) is targeted by March8, an E3 ligase of as yet unknown physiological substrate specificity. Ablating March8 in Cd83(-/-) mice restored CD4 T cell development. Our results identify CD83-mediated MHCII stabilization through antagonism of March8 as a novel functional adaptation of cTECs for T cell selection. Furthermore, these findings suggest an intriguing division of labor between March1 and March8 in controlling inducible versus constitutive MHCII expression in hematopoietic antigen-presenting cells versus TECs.
EVALuna2:26036

Thymic stromal lymphopoietin deficiency attenuates experimental autoimmune encephalomyelitis - Eckhardt, J.; Döbbeler, Marina; Koenig, C.; Kuczera, K.; Kuhnt, C.; Ostalecki, C.; Zinser, E.; Mak, T. W.; Steinkasserer, Alexander; Lechmann, Matthias (Clinical and Experimental Immunology, 2015)
In the present study we examined the role of thymic stromal lymphopoietin (TSLP) in experimental autoimmune encephalomyelitis (EAE). Here, we report that TSLP knock-out (KO) mice display a delayed onset of disease and an attenuated form of EAE. This delayed onset was accompanied by a reduced number of encephalitogenic T helper type 1 (Th1) cells in the central nervous system (CNS) of TSLP KO mice. In addition, CD4(+) and CD8(+) T cells from CNS of TSLP KO mice show a reduced activation status in comparison to wild-type mice. It is noteworthy that we could also show that lymph node cells from TSLP KO mice expanded less efficiently and that interleukin (IL)-6-, interferon (IFN)-? and tumour necrosis factor (TNF)-? levels were reduced. Furthermore, CD3(+) T cells isolated in the preclinical phase from myelin oligodendrocyte glycoprotein peptide 35-55 (MOG(35-55))-immunized TSLP KO mice showed a reduced response after secondary exposure to MOG(35-55), indicating that differentiation of naive T cells into MOG(35-55)-specific effector and memory T cells was impaired in KO mice. The addition of recombinant TSLP enhanced T cell proliferation during MOG(35-55) restimulation, showing that T cells also respond directly to TSLP. In summary, these data demonstrate that expression of, and immune activation by, TSLP contributes significantly to the immunopathology of EAE.
EVALuna2:19524

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes - Würfel, Franziska; Erber, Ramona; Hübner, Hanna; Hein, Alexander; Lux, Michael P.; Jud, Sebastian; Kremer, Anita; Kranich, Hannah; Mackensen, Andreas; Häberle, Lothar; Hack, Carolin; Rauh, Claudia; et al. (Breast Care, 2018)
Background: Despite advancements in the treatment of primary and metastatic breast cancer, many patients lack a durable response to these treatments. Patients with triplenegative breast cancer (TNBC) and human epidermal growth factor receptor 2(HER2)-positive breast cancer who do not have a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a very poor prognosis. Tumor-infiltrating lymphocytes (TILs) have been identified as a predictive marker for pCR after NACT in TNBC and HER2-positive breast cancer. These patient populations could also be suitable for novel treatment strategies including neoepitope-based therapies. This work analyses the effect of TILs on the pCR in neoadjuvantly treated patients in the TILGen study and presents the procedures aimed at establishing neoepitope-based therapies in this study. Methods: Neoadjuvantly treated HER2positive and TNBC patients were eligible for the presented analysis concerning the association between TILs and pCR. A total of 146 patients could be identified within the TILGen study. TILs were evaluated as percentage of stromal tumor tissue in core biopsies at primary diagnosis. The phenotype 'lymphocyte-predominant breast cancer' (LPBC) was associated with pCR by logistic regression adjusted for estrogen receptor status, progesterone receptor status, HER2 status, age at diagnosis, and grading. Results: LPBC was seen in 24 (16.4%) patients. In this patient group, 66.7% achieved a pCR, while the pCR rate was 32.8% in patients with a low TIL count. The adjusted odds ratio was 6.60 (95% confidence interval 2.02-21.56; p < 0.01). Conclusion: TILs are a strong predictor of pCR in TNBC and HER2-positive breast cancer patients. Implications for the use of this information including the effect on prognosis might help to identify patients most likely to benefit from a neoepitope-based therapy approach. (C) 2018 S. Karger GmbH, Freiburg
EVALuna2:34061
Keywords: Tumor-infiltrating lymphocytes; Response; Neoadjuvant chemotherapy; TILGen study

Tilting the Balance: Therapeutic Prospects of CD83 as a Checkpoint Molecule Controlling Resolution of Inflammation - Peckert-Maier, Katrin; Royzman, Dmytro; Langguth, Pia; Marosán, Anita; Strack, Astrid; Sadeghi Shermeh, Atefeh; Steinkasserer, Alexander; Zinser, Elisabeth; Wild, Andreas (International Journal of Molecular Sciences, 2022)
Chronic inflammatory diseases and transplant rejection represent major challenges for modern health care. Thus, identification of immune checkpoints that contribute to resolution of inflammation is key to developing novel therapeutic agents for those conditions. In recent years, the CD83 (cluster of differentiation 83) protein has emerged as an interesting potential candidate for such a “pro-resolution” therapy. This molecule occurs in a membrane-bound and a soluble isoform (mCD83 and sCD83, respectively), both of which are involved in resolution of inflammation. Originally described as a maturation marker on dendritic cells (DCs), mCD83 is also expressed by activated B and T cells as well as regulatory T cells (Tregs) and controls turnover of MHC II molecules in the thymus, and thereby positive selection of CD4+ T cells. Additionally, it serves to confine overshooting (auto-)immune responses. Consequently, animals with a conditional deletion of CD83 in DCs or regulatory T cells suffer from impaired resolution of inflammation. Pro-resolving effects of sCD83 became evident in pre-clinical autoimmune and transplantation models, where application of sCD83 reduced disease symptoms and enhanced allograft survival, respectively. Here, we summarize recent advances regarding CD83-mediated resolution of inflammatory responses, its binding partners as well as induced signaling pathways, and emphasize its therapeutic potential for future clinical trials.
CRIS-Team Scopus Importer:2022-01-14
Keywords: Adoptive transfer; CD83; IDO/TGF-β-axis; Pro-resolving macrophages; Resolution of inflammation; Transplantation

Tirbanibulin 1% Ointment Significantly Reduces the Actinic Keratosis Area and Severity Index in Patients with Actinic Keratosis: Results from a Real-World Study - Kirchberger, Michael; Gfesser, Michael; Erdmann, Michael; Schliep, Stefan; Berking, Carola; Heppt, Markus (Journal of Clinical Medicine, 2023)
Background: Actinic keratosis (AK) is a cutaneous lesion resulting from the proliferation of atypical epidermal keratinocytes caused by long-term exposure to ultraviolet radiation. AK may progress to cutaneous squamous cell carcinoma (cSCC) and therefore is often treated with topical agents such as 5-fluorouracil, diclofenac, imiquimod, and photodynamic therapy. Tirbanibulin has been approved based on two phase III trials in the USA. However, real-world evidence for tirbanibulin is absent. Methods: This was a single-centre study of adult patients with clinically typical, visible AK on the face or scalp treated with tirbanibulin 1% ointment. Treatment was administered as per label once daily for 5 consecutive days on the same lesions or field. Treatment outcomes were assessed 4 weeks after treatment, with additional optional assessments conducted at later time points. Efficacy was measured using the actinic keratosis area and severity index (AKASI) and digital dermoscopy. Results: A total of 33 patients were treated of whom 30 were analysed. The median AKASI score was 5.6 (1.4–11) pre-treatment and 1.2 (0–7.4) post-treatment (p < 0.0001). Complete clearance as defined by AKASI scores less than 1 was achieved in 47% (n = 14) and 57% (n = 13) at the first and second follow-up, respectively. All local reactions resolved spontaneously and without sequelae. The most common local reactions were erythema (80%, n = 26) and flaking or scaling (43%, n = 13). Conclusions: Tirbanibulin 1% ointment significantly and rapidly reduced the AKASI score in a real-world setting. The complete clearance rates were in line with those observed in the two pivotal trials.
CRIS-Team Scopus Importer:2023-08-11
Keywords: actinic keratosis; AKASI score; Klisyri

TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection - Schleicher, Ulrike; Paduch, Katrin; Debus, Andrea; Obermeyer, Stephanie; Koenig, Till; Kling, Jessica C.; Ribechini, Eliana; Dudziak, Diana; Mougiakakos, Dimitrios; Murray, Peter J.; Ostuni, Renato; Koerner, Heinrich; et al. (Cell Reports, 2016)
Neutralization or deletion of tumor necrosis factor (TNF) causes loss of control of intracellular pathogens in mice and humans, but the underlying mechanisms are incompletely understood. Here, we found that TNF antagonized alternative activation of macrophages and dendritic cells by IL-4. TNF inhibited IL-4-induced arginase 1 (Arg1) expression by decreasing histone acetylation, without affecting STAT6 phosphorylation and nuclear translocation. In Leishmania major-infected C57BL/6 wild-type mice, type 2 nitric oxide (NO) synthase (NOS2) was detected in inflammatory dendritic cells or macrophages, some of which co-expressed Arg1. In TNF-deficient mice, Arg1 was hyperexpressed, causing an impaired production of NO in situ. A similar phenotype was seen in L. major-infected BALB/c mice. Arg1 deletion in hematopoietic cells protected these mice from an otherwise lethal disease, although their disease-mediating T cell response (Th2, Treg) was maintained. Thus, deletion or TNF-mediated restriction of Arg1 unleashes the production of NO by NOS2, which is critical for pathogen control.
EVALuna2:7700

Tolerability and efficacy of BRAF and MEK inhibitors for metastasized melanoma after intra-class switch: a multicenter, retrospective study - Salzmann, M.; Wald, A.; Stege, H.; Loquai, C.; Zimmer, L.; Hayani, K.; Heinzerling, Lucie; Gutzmer, R.; Enk, A.; Hassel, J. C. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

Tolerability of BRAF/MEK inhibitor combinations: Adverse event evaluation and management - Heinzerling, Lucie; Eigentler, Thomas K.; Fluck, Michael; Hassel, Jessica C.; Heller-Schenck, Daniela; Leipe, Jan; Pauschinger, Mathias; Vogel, Arndt; Zimmer, Lisa; Gutzmer, Ralf (ESMO Open, 2019)
The inhibition of the mitogen-activated protein kinases signalling pathway through combined use of BRAF and MEK inhibitors (BRAFi+MEKi) represents an established therapeutic option in patients with BRAF-mutated, advanced melanoma. These efficient therapies are well tolerated with mostly moderate and reversible side effects and a discontinuation rate due to adverse events of 11.5%-15.7%. Median duration of therapy ranges between 8.8 and 11.7 months. Based on data from confirmatory trials, safety profiles of three BRAFi+MEKi combinations were reviewed, that is, dabrafenib plus trametinib, vemurafenib plus cobimetinib and encorafenib plus binimetinib. Many adverse events are class effects, such as cutaneous, gastrointestinal, ocular, cardiac and musculoskeletal events; some adverse events are substance associated. Fever (dabrafenib) and photosensitivity (vemurafenib) are the most common and clinically prominent examples. Other adverse events are less frequent and the association to one substance is less strong such as anaemia, facial paresis (encorafenib), neutropenia (dabrafenib), skin rash, QTc prolongation and increased liver function tests (vemurafenib). This narrative review provides recommendations for monitoring, adverse event evaluation and management focusing on the clinically relevant side effects of the three regimens.
CRIS-Team Scopus Importer:2019-06-04
Keywords: adverse events; BRAF; MEK; melanoma; safety

"Toolkit Dermatology for minor surgical Procedures" - Options of Use at various University Locations during the Corona Pandemic - Wittbecker, Linda; Pham, Christina; Bandholz, Thyra Caroline; Schuh, Sandra; Welzel, Julia; Busse, Laura; Hornung, Thorsten; Gihl, Julia; Erfurt-Berge, Cornelia; Glaeser, Regine (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-02-04

Topical application of soluble CD83 induces IDO-mediated immune modulation, increases Foxp3+ T cells, and prolongs allogeneic corneal graft survival - Bock, Felix; Roessner, Susanne; Onderka, Jasmine; Lechmann, Matthias; Pallotta, Maria Teresa; Fallarino, Francesca; Boon, Louis; Nicolette, Charles; Debenedette, Mark A.; Tcherepanova, Irina Y.; Grohmann, Ursula; Steinkasserer, Alexander; et al. (Journal of Immunology, 2013)
Modulation of immune responses is one of the main research aims in transplant immunology. In this study, we investigate the local immunomodulatory properties of soluble CD83 (sCD83) at the graft-host interface using the high-risk corneal transplantation model. In this model, which mimics the inflammatory status and the preexisting vascularization of high-risk patients undergoing corneal transplantation, allogeneic donor corneas are transplanted onto sCD83-treated recipient animals. This model allows the direct and precise application of the immune modulator at the transplantation side. Interestingly, sCD83 was able to prolong graft survival after systemic application as well as after topical application, which is therapeutically more relevant. The therapeutic effect was accompanied by an increase in the frequency of regulatory T cells and was mediated by the immune-regulatory enzyme IDO and TGF-?. In vitro, sCD83 induced long-term IDO expression in both conventional and plasmacytoid dendritic cells via autocrine or paracrine production of TGF-?, a cytokine previously shown to be an essential mediator of IDO-dependent, long-term tolerance. These findings open new treatment avenues for local immune modulation after organ and tissue transplantation.
EVALuna2:21223

Topical therapy of psoriasis vulgaris - a treatment pathway - Koerber, Andreas; Wilsmann-Theis, Dagmar; Augustin, Matthias; Von Kiedrowski, Ralph; Mrowietz, Ulrich; Rosenbach, Thomas; Meller, Stephan; Pinter, Andreas; Sticherling, Michael; Gerdes, Sascha (Journal der Deutschen Dermatologischen Gesellschaft, 2019)
In daily practice topical treatment of psoriasis and its subtypes is of high importance. It is standard for the treatment of mild psoriasis and is used to support treatment of moderate-to-severe psoriasis. When optimizing psoriasis treatment not only the choice of suitable compounds, but also the formulation aspect matters. Developments in the latter field were not considered in the 2017 published update of the current S3-guideline on psoriasis. The presented pathway was prepared during a PsoNet speaker conference and confirmed by the national psoriasis care conference. It aims to illustrate current treatment options.
CRIS-Team WoS Importer:2019-05-09

Towards a pro-resolving concept in systemic lupus erythematosus - Böltz, Sebastian; Hagen, Melanie; Knopf, Jasmin; Mahajan, Aparna; Schick, Maximilian; Zhao, Yi; Erfurt-Berge, Cornelia; Rech, Jürgen; Munoz Becerra, Luis; Herrmann, Martin (Seminars in Immunopathology, 2019)
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with prominent chronic inflammatory aspects. SLE most often affects women (9:1) in childbearing age. The multifactorial nature of the etiopathogenesis of SLE involves a deficient clearance of dead and dying cells. This is supported by the occurrence of autoantibodies directed against autoantigens modified in dying and dead cells (dsDNA, high mobility group box 1 protein, apoptosis-associated chromatin modifications, e.g., histones H3-K27-me3; H2A/H4 AcK8,12,16; and H2B-AcK12) that are deposited in various tissues, including skin, kidneys, joints, muscles, and brain. The subsequent hyperinflammatory response often leads to irreparable tissue damage and organ destruction. In healthy individuals, dead and dying cells are rapidly removed by macrophages in an anti-inflammatory manner, referred to as efferocytosis. In SLE, extensive and prolonged cell death (apoptosis, necrosis, neutrophil extracellular trap (NET) formation) leads to autoantigens leaking out of the not cleared cell debris. These neo-epitopes are subsequently presented to B cells by follicular dendritic cells in the germinal centers of secondary lymphoid tissues conditioning the break of self-tolerance. Activation of autoreactive B cells and subsequent production of autoantibodies facilitate the formation of immune complexes (ICs) fueling the inflammatory response and leading to further tissue damage. ICs may also be ingested by phagocytes, which then produce further pro-inflammatory cytokines. These processes establish a vicious circle that leads to sustained inflammation. This review highlights the cell death–related events in SLE, the protagonists involved in SLE pathogenesis, the resolution of inflammation in various tissues affected in SLE, and explores strategies for intervention to restore hemostasis in a hyperinflammatory state.
CRIS-Team Scopus Importer:2019-11-19
Keywords: Apoptosis; Clearance; Inflammation; Neutrophil extracellular traps (NETs); Resolution; Secondary necrosis; Systemic lupus erythematosus (SLE)

Transcriptional Analysis identifies long non-coding RNAs as potential biomarkers in pneumonia and COPD exacerbation - Bertrams, W.; Griss, K.; Han, M.; Seidel, K.; Klemmer, A.; Sittka-Stark, A.; Hippenstiel, S.; Suttorp, N.; Finkernagel, F.; Wilhelm, J.; Greulich, T.; Vogelmeier, C.; et al. (PNEUMOLOGIE, 2020)
CRIS-Team WoS Importer:2020-11-27

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation - Bertrams, W.; Griss, K.; Han, M.; Eberhardt, M.; Seidel, K.; Klemmer, A.; Sittka-Stark, A.; Hippenstiel, S.; Suttorp, N.; Finkernagel, F.; Wilhelm, J.; Greulich, T.; et al. (PNEUMOLOGIE, 2020)
CRIS-Team WoS Importer:2020-11-27

Transcriptional analysis identifies potential biomarkers and molecular regulators in pneumonia and COPD exacerbation - Bertrams, Wilhelm; Griss, Kathrin; Han, Maria; Seidel, Kerstin; Klemmer, Andreas; Sittka-Stark, Alexandra; Hippenstiel, Stefan; Suttorp, Norbert; Finkernagel, Florian; Wilhelm, Jochen; Greulich, Timm; Vogelmeier, Claus F.; et al. (Scientific Reports, 2020)
Lower respiratory infections, such as community-acquired pneumonia (CAP), and chronic obstructive pulmonary disease (COPD) rank among the most frequent causes of death worldwide. Improved diagnostics and profound pathophysiological insights are urgent clinical needs. In our cohort, we analysed transcriptional networks of peripheral blood mononuclear cells (PBMCs) to identify central regulators and potential biomarkers. We investigated the mRNA- and miRNA-transcriptome of PBMCs of healthy subjects and patients suffering from CAP or AECOPD by microarray and Taqman Low Density Array. Genes that correlated with PBMC composition were eliminated, and remaining differentially expressed genes were grouped into modules. One selected module (120 genes) was particularly suitable to discriminate AECOPD and CAP and most notably contained a subset of five biologically relevant mRNAs that differentiated between CAP and AECOPD with an AUC of 86.1%. Likewise, we identified several microRNAs, e.g. miR-545-3p and miR-519c-3p, which separated AECOPD and CAP. We furthermore retrieved an integrated network of differentially regulated mRNAs and microRNAs and identified HNF4A, MCC and MUC1 as central network regulators or most important discriminatory markers. In summary, transcriptional analysis retrieved potential biomarkers and central molecular features of CAP and AECOPD.
CRIS-Team Scopus Importer:2020-02-07

Transcriptional control of dendritic cell development and functions - Amon, Lukas; Lehmann, Christian; Baranska, Anna; Schoen, Janina; Heger, Lukas; Dudziak, Diana (Immunobiology of Dendritic Cells Part B, 2019)
Dendritic cells (DCs) are major regulators of adaptive immunity, as they are not only capable to induce efficient immune responses, but are also crucial to maintain peripheral tolerance and thereby inhibit autoimmune reactions. DCs bridge the innate and the adaptive immune system by presenting peptides of self and foreign antigens as peptide MHC complexes to T cells. These properties render DCs as interesting target cells for immunomodulatory therapies in cancer, but also autoimmune diseases. Several subsets of DCs with special properties and functions have been described. Recent achievements in understanding transcriptional programs on single cell level, together with the generation of new murine models targeting specific DC subsets, advanced our current understanding of DC development and function. Thus, DCs arise from precursor cells in the bone marrow with distinct progenitor cell populations splitting the monocyte populations and macrophage populations from the DC lineage, which upon lineage commitment can be separated into conventional cDC1, cDC2, and plasmacytoid DCs (pDCs). The DC populations harbor intrinsic programs enabling them to react for specific pathogens in dependency on the DC subset, and thereby orchestrate T cell immune responses. Similarities, but also varieties, between human and murine DC subpopulations are challenging, and will require further investigation of human specimens under consideration of the influence of the tissue micromilieu and DC subset localization in the future.
CRIS-Team Scopus Importer:2019-11-29
Keywords: Antigen presentation; BatF3; CDP; Cross-presentation; DC; Dendritic cell; IRF; Lineage commitment; Ontogeny; Progenitor; Transcription factor; Zbtb46

Transcriptional Profiling of Ligand Expression in Cell Specific Populations of the Adult Mouse Forebrain That Regulates Neurogenesis - Azim, Kasum; Akkermann, Rainer; Cantone, Martina; Vera, Julio; Jadasz, Janusz J.; Kuery, Patrick (Frontiers in Neuroscience, 2018)
In the adult central nervous system (CNS), the subventricular zone (SVZ) of the forebrain is the largest and most active source of neural stem cells (NSCs) that generates mainly neurons and few glial cells lifelong. A large body of evidence has shed light on the distinct families of signaling ligands (i.e., morphogens, growth factors, secreted molecules that alter signaling pathways) in regulating NSC biology. However, most of the research has focused on the mRNA expression of individual or few signaling ligands and their pathway components in specific cell types of the CNS in the context of neurogenesis. A single unifying study that underlines the expression of such molecules comprehensively in different cell types in spatial contexts has not yet been reported. By using whole genome transcriptome datasets of individual purified cell specific populations of the adult CNS, the SVZ niche, NSCs, glial cells, choroid plexus, and performing a bioinformatic meta-analysis of signaling ligands, their expression in the forebrain was uncovered. Therein, we report that a large plethora of ligands are abundantly expressed in the SVZ niche, largely from the vasculature than from other sources that may regulate neurogenesis. Intriguingly, this sort of analysis revealed a number of ligands with unknown functions in neurogenesis contexts that warrants further investigations. This study therefore serves as a framework for investigators in the field for understanding the expression patterns of signaling ligands and pathways regulating neurogenesis.
EVALuna2:34797

Transcriptional Targeting of Mature Dendritic Cells with Adenoviral Vectors via a Modular Promoter System for Antigen Expression and Functional Manipulation - Knippertz, Ilka; Deinzer, Anja; Dörrie, Jan; Schaft, Niels; Nettelbeck, Dirk M.; Steinkasserer, Alexander (International Journal of Microbiology and Immunology Research, 2016)
To specifically target dendritic cells (DCs) to simultaneously express different therapeutic transgenes for inducing immune responses against tumors, we used a combined promoter system of adenoviral vectors. We selected a 216 bp short Hsp70B'. core promoter induced by a mutated, constitutively active heat shock factor (mHSF) 1 to drive strong gene expression of therapeutic transgenes Melan A, BclxL, and IL-12p70 in HeLa cells, as well as in mature DCs ( mDCs). As this involves overexpressing mHSF1, we first evaluated the resulting effects on DCs regarding upregulation of heat shock proteins and maturation markers, toxicity, cytokine profile, and capacity to induce antigen-specific CD8+ T cells. Second, we generated the two-vector-based "modular promoter" system, where one vector contains the mHSF1 under the control of the human CD83 promoter, which is specifically active only in DCs and after maturation. mHSF1, in turn, activates the Hsp70B.. core promotor-driven expression of transgenes MelanA and IL-12p70 in the DC-like cell line XS52 and in human mature and hence immunogenic DCs, but not in tolerogenic immature DCs. These in vitro experiments provide the basis for an in vivo targeting of mature DCs for the expression of multiple transgenes. Therefore, this modular promoter system represents a promising tool for future DC-based immunotherapies in vivo.
EVALuna2:19603

Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis - Hannemann, Nicole; Cao, Shan; Eriksson, Daniel; Schnelzer, Anne; Jordan, Jutta; Eberhardt, Martin; Schleicher, Ulrike; Rech, Jürgen; Uebe, Steffen; Ekici, Arif Bülent; Canete, Juan D.; Chen, Xiaoxiang; et al. (Journal of Clinical Investigation, 2019)
The polarization of macrophages is regulated by transcription factors, such as NF-κB and activator protein 1 (AP-1). In this manuscript, we delineated the role of the transcription factor Fos-related antigen 1 (Fra-1) during macrophage activation and development of arthritis. Network level interaction analysis of microarray data derived from Fra-1- or Fra-2-deficient macrophages revealed a central role of Fra-1, but not of Fra-2, in orchestrating the expression of genes related to wound response, Toll-like receptor activation, and interleukin signaling. ChIP sequencing and standard ChIP analyses of macrophages identified arginase 1 (Arg1) as a target of Fra-1. Luciferase reporter assays revealed that Fra-1 downregulated Arg1 expression by direct binding to the promoter region. Using macrophage-specific Fra-1- or Fra-2-deficient mice, we observed enhanced expression and activity of Arg1 and a reduction of arthritis in the absence of Fra-1, but not of Fra-2. This phenotype was reversed by treatment with the arginase inhibitor Nω-hydroxy-nor-arginine, while -arginine supplementation increased arginase activity and alleviated arthritis, supporting the notion that reduced arthritis in macrophage-specific Fra-1-deficient mice resulted from enhanced Arg1 expression and activity. Moreover, patients with active rheumatoid arthritis (RA) showed increased Fra-1 expression in the peripheral blood and elevated Fra-1 protein in synovial macrophages compared with RA patients in remission. In addition, the Fra-1/ARG1 ratio in synovial macrophages was related to RA disease activity. In conclusion, these data suggest that Fra-1 orchestrates the inflammatory state of macrophages by inhibition of Arg1 expression and thereby impedes the resolution of inflammation.
CRIS-Team Scopus Importer:2019-07-16

Transcription factor Sox10 induces the microRNAs miR-335, miR-338 and miR-155 to ensure correct timing of oligodendrocyte development - Küspert, Melanie; Reiprich, Simone; Cantone, Martina; Weider, Matthias; Baroti, Tina; Wittstatt, Jan; Vera, Julio; Wegner, Michael (GLIA, 2019)
CRIS-Team WoS Importer:2020-01-10

Transcription factor Sox10 regulates oligodendroglial Sox9 levels via microRNAs. - Reiprich, Simone; Cantone, Martina; Weider, Matthias; Baroti, Tina; Wittstatt, Jan; Schmitt, Christian; Küspert, Melanie; Vera, Julio; Wegner, Michael (Glia, 2017)
During development of myelin-forming oligodendrocytes in the central nervous system the two closely related transcription factors Sox9 and Sox10 play essential roles that are partly shared and partly unique. Whereas Sox9 primarily functions during oligodendroglial specification, Sox10 is uniquely required to induce terminal differentiation and myelination. During this process, Sox10 protein levels rise substantially. As this coincides with a reciprocal decrease in Sox9, we postulated that Sox10 influences Sox9 amounts in differentiating oligodendrocytes. Here we show that Sox9 levels are indeed inversely coupled to Sox10 levels such that Sox10 deletion in oligodendroglial cells evokes a reciprocal increase in Sox9. We furthermore provide evidence that this coupling involves upregulation of microRNAs miR335 and miR338 as direct transcriptional targets of Sox10. The two microRNAs in turn recognize the 3′-UTR of Sox9 mRNA and may thereby reduce Sox9 protein levels posttranscriptionally in oligodendroglial cells. Such a mechanism may enable oligodendroglial cells to adapt the ratio of both related Sox proteins in a manner required for successful lineage progression and differentiation. Mathematical modeling furthermore shows that the identified regulatory circuit has the potential to convert a transient stimulus into an irreversible switch of cellular properties and may thus contribute to terminal differentiation of oligodendrocytes.
EVALuna2:33479
Keywords: glia; HMG; miR338; oligodendrocyte; Sox

Transcriptomes of MPO-deficient patients with generalized pustular psoriasis reveals expansion of CD4+cytotoxic T cells and an involvement of complement system and interferon pathways - Hüffmeier, Ulrike; Frey, Benjamin; Becker, Ina; Atreya, Imke; Berking, Carola; Moessner, R.; Wilsmann-Theis, D.; Uebe, Steffen; Kirchner, P.; Haskamp, Stefan (JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-11-05

Transcriptomes of MPO-Deficient Patients with Generalized Pustular Psoriasis Reveals Expansion of CD4+ Cytotoxic T Cells and an Involvement of the Complement System - Haskamp, Stefan; Frey, Benjamin; Becker, Ina; Schulz-Kuhnt, Anja; Atreya, Imke; Berking, Carola; Pauli, David; Ekici, Arif Bülent; Berges, Johannes; Mößner, Rotraut; Wilsmann-Theis, Dagmar; Sticherling, Michael; et al. (Journal of Investigative Dermatology, 2022)
Generalized pustular psoriasis is a severe psoriatic subtype characterized by epidermal neutrophil infiltration. Although variants in IL36RN and MPO have been shown to affect immune cells, a systematic analysis of neutrophils and PBMC subsets and their differential gene expression dependent on MPO genotypes was not performed yet. We assessed the transcriptomes of MPO-deficient patients using single-cell RNA sequencing of PBMCs and RNA sequencing of neutrophils in a stable disease state. Cell-type annotation by multimodal reference mapping of single-cell RNA-sequencing data was verified by flow cytometry of surface and intracellular markers; the proportions of CD4+ cytotoxic T lymphocytes and other CD4+ effector cells were increased in generalized pustular psoriasis, whereas the frequencies of naïve CD4+ T cells were significantly lower. The expression of FGFBP2 marking CD4+ cytotoxic T lymphocytes and CD8+ effector memory T cells was elevated in patients with generalized pustular psoriasis with disease-contributing variants compared with that in noncarriers (P = 0.0015). In neutrophils, differentially expressed genes were significantly enriched in genes of the classical complement activation pathway. Future studies assessing affected cell types and pathways will show their contribution to generalized pustular psoriasis's pathogenesis and indicate whether findings can be transferred to the acute epidermal situation and whether depletion or inactivation of CD4+ cytotoxic T lymphocytes may be a reasonable therapeutic approach.
CRIS-Team Scopus Importer:2022-07-08

Transfer of mRNA Encoding Invariant NKT Cell Receptors Imparts Glycolipid Specific Responses to T Cells and γδT Cells. - Shimizu, Kanako; Shinga, Jun; Yamasaki, Satoru; Kawamura, Masami; Dörrie, Jan; Schaft, Niels; Sato, Yusuke; Iyoda, Tomonori; Fujii, Shin-Ichiro (PLoS ONE, 2015)
Cell-based therapies using genetically engineered lymphocytes expressing antigen-specific T cell receptors (TCRs) hold promise for the treatment of several types of cancers. Almost all studies using this modality have focused on transfer of TCR from CD8 cytotoxic T lymphocytes (CTLs). The transfer of TCR from innate lymphocytes to other lymphocytes has not been studied. In the current study, innate and adaptive lymphocytes were transfected with the human NKT cell-derived TCRα and β chain mRNA (the Vα24 and Vβ11 TCR chains). When primary T cells transfected with NKT cell-derived TCR were subsequently stimulated with the NKT ligand, α-galactosylceramide (α-GalCer), they secreted IFN-γ in a ligand-specific manner. Furthermore when γδT cells were transfected with NKT cell-derived TCR mRNA, they demonstrated enhanced proliferation, IFN-γ production and antitumor effects after α-GalCer stimulation as compared to parental γδT cells. Importantly, NKT cell TCR-transfected γδT cells responded to both NKT cell and γδT cell ligands, rendering them bi-potential innate lymphocytes. Because NKT cell receptors are unique and universal invariant receptors in humans, the TCR chains do not yield mispaired receptors with endogenous TCR α and β chains after the transfection. The transfection of NKT cell TCR has the potential to be a new approach to tumor immunotherapy in patients with various types of cancer.
EVALuna2:19544

Transfer of mRNA encoding recombinant immunoreceptors reprograms CD4+ and CD8+ T cells for use in the adoptive immunotherapy of cancer - Birkholz, K.; Hombach, A.; Krug, C.; Reuter, S.; Kershaw, Michael; Kämpgen, Eckhart; Schuler, Gerold; Abken, H.; Schaft, Niels; Dörrie, Jan (Gene Therapy, 2009)
Human T lymphocytes can be redirected with a new defined specificity by expression of a chimeric T-cell receptor (immunoreceptor) for the use in adoptive immunotherapy of cancer. Whereas standard procedures use retroviral gene transduction to constitutively express immunoreceptors in T cells, we here explored for the first time mRNA electroporation to achieve transient immunoreceptor expression, and thereby minimizing the risk of persistence of potential autoaggression. CD4+ and CD8+ T cells were efficiently transfected with immunoreceptors specific for ErbB2 and CEA. The immunoreceptor expression was transient with half-maximal expression at day 2 and no detectable immunoreceptor expression at day 9 after electroporation. Immunoreceptor-transfected T cells were specifically activated upon coincubation with ErbB2+ and CEA+ tumor cells, respectively, resulting in secretion of interferon-γ (IFNγ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNFα). Furthermore, immunoreceptor-transfected CD8+ T cells specifically lysed ErbB2+ and CEA+ tumor cells, respectively. The RNA-transfected T cells retained their cytotoxic function after 2 days of activation and exhibited cytolytic activities like retrovirally transduced T cells. RNA electroporation of T cells thereby provides a versatile tool for transient immunoreceptor expression, which may be of advantage in avoiding the persistence of unintended autoaggression.
CRIS-Team Scopus Importer:2021-10-01

Transient response to nivolumab and relapse after infliximab in a patient with primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma - Toussaint, Frédéric; Erdmann, M.; Grosch, Ella; Schliep, S.; Schuler, Gerold; Dummer, R.; Heinzerling, Lucie (British Journal of Dermatology, 2020)
CRIS-Team WoS Importer:2020-10-02

Trauma as a Trigger Factor for the First clinical Manifestation of cutaneous Leishmaniasis - Hiernickel, J.; Bogdan, Christian; Erfurt-Berge, Cornelia (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Travel-associated infectious skin diseases - Rongisch, Robert; Schmidt, Enno; Deresz, Nicolai; Deresz, Katharina; Schoefer, Helmut; Schaekel, Knut; Jakob, Thilo; Maurer, Marcus; Sticherling, Michael; Sunderkoetter, Cord; Babilas, Philipp; Spornraft-Ragaller, Petra; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-05-12

Treatment at the end of life in patients with advanced melanoma. A multicenter DeCOG study of 1067 patients from the prospective skin cancer registry ADOReg. - Forschner, Andrea; Kähler, Katharina C.; Gschnell, Martin; Langan, Ewan A.; Weishaupt, Carsten; Meiss, Frank; Thoms, Kai Martin; Wahl, Renate U.; Göppner, Daniela; Garzarolli, Marlene; Sachse, Michael; Schlaak, Max; et al. (Frontiers in Immunology, 2025)
BACKGROUND: Although systemic therapies have improved considerably over the last decade, up to 50% of patients with metastatic melanoma still die due to disease progression. Oncological treatment at the end-of-life phase is challenging. The aim of this study was to investigate the frequency and type of systemic therapy received by melanoma patients in their end-of-life phase. METHODS: Patients with metastatic melanoma who had died between January 1, 2018 and October 31, 2022 were identified from the prospective multicenter skin cancer registry ADOReg. Study endpoints were percentage of patients who had been treated with systemic therapy within the last three months of life, timepoint of initiation of the last-line therapy, overall survival, treatment benefit and the incidence of treatment-related adverse events. RESULTS: In total, 1067 patients from 46 skin cancer centers were included. Most of the patients (63%) had received immune checkpoint inhibitors (ICI) as last-line therapy, 22% targeted therapies (TT) and 12% chemotherapy (CTX). Comparing last-line ICI and TT, patients with TT were significantly more likely to benefit from treatment and had significantly fewer and milder treatment-related AE than patients with ICI. Even though two thirds of patients had received ICI as a last-line therapy, the majority of these patients (61%) had stopped therapy within the last 30 days of life, whereas the majority of patients with TT (66%) still continued their treatment to the end of life. We found markedly fewer patients with initiation of ICI within 30 days before their death (19%) compared to a historic cohort including patients who died in 2016 or 2017 (39%). CONCLUSION: Treatment approaches near the end of life have markedly changed in skin cancer centers in Germany over recent years, with ICI prescribed less frequently in the end-of-life phase. In contrast, TT are frequently administered, even within the last 30 days of life. It should also be considered that discontinuation of TT can result in rapid tumor progression. Due to the oral administration and a low rate of severe toxicity, TT appear to be a suitable treatment option, even in the end-of-life situation of melanoma patients.
EVALuna2:597729

Treatment Decision when there is an Indication for adjuvant Therapy for Melanoma - multicenter Real World Data - Lodde, G.; Forschner, A.; Wulfken, L. M.; Meier, F.; Mohr, P.; Kaehler, K. C.; Schilling, B.; Loquai, C.; Berking, Carola; Gebhardt, C.; Huening, S.; Schatton, K.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-09-11

Treatment management for BRAF-mutant melanoma patients with tumor recurrence on adjuvant therapy: a multicenter study from the prospective skin cancer registry ADOREG - Haist, Maximilian; Stege, Henner; Rogall, Friederike; Tan, Yuqi; von Wasielewski, Imke; Klespe, Kai Christian; Meier, Friedegund; Mohr, Peter; Kähler, Katharina C.; Weichenthal, Michael; Hauschild, Axel; Schadendorf, Dirk; et al. (Journal for ImmunoTherapy of Cancer, 2023)
BACKGROUND: Adjuvant therapy with immune-checkpoint inhibitors (CPI) or BRAF/MEK-directed targeted therapy (TT) improves recurrence-free survival (RFS) for patients with advanced, BRAFV600-mutant (BRAFmut) resected melanoma. However, 40% of these patients will develop distant metastases (DM) within 5 years, which require systemic therapy. Little data exist to guide the choice of upfront adjuvant therapy or treatment management upon DM. This study evaluated the efficacy of subsequent treatments following tumor recurrence upon upfront adjuvant therapy. METHODS: For this multicenter cohort study, we identified 515 BRAFmut patients with resected stage III melanoma who were treated with PD-1 inhibitors (anti-PD1) or TT in the adjuvant setting. Disease characteristics, treatment regimens, details on tumor recurrence, subsequent treatment management, and survival outcomes were collected within the prospective, real-world skin cancer registry ADOReg. Primary endpoints included progression-free survival (PFS) following DM and best tumor response to first-line (1L) treatments. RESULTS: Among 515 eligible patients, 273 patients received adjuvant anti-PD1 and 242 adjuvant TT. At a median follow-up of 21 months, 54.6% of anti-PD1 patients and 36.4% of TT patients recurred, while 39.6% (anti-PD1) and 29.3% (TT) developed DM. Risk of recurrence was significantly reduced in patients treated with TT compared with anti-PD1 (adjusted HR 0.52; 95% CI 0.40 to 0.68, p<0.001). Likewise, median RFS was significantly longer in TT-treated patients (31 vs 17 months, p<0.001). Patients who received TT as second adjuvant treatment upon locoregional recurrence had a longer RFS2 as compared with adjuvant CPI (41 vs 6 months, p=0.009). Patients who recurred at distant sites following adjuvant TT showed favorable response rates (42.9%) after switching to 1L ipilimumab+nivolumab (ipi+nivo). Patients with DM during adjuvant anti-PD1 achieved response rates of 58.7% after switching to 1L TT and 35.3% for 1L ipi+nivo. Overall, median PFS was significantly longer in patients who switched treatments for stage IV disease (median PFS 9 vs 5 months, p=0.004). CONCLUSIONS: BRAFmut melanoma patients who developed DM upon upfront adjuvant therapy achieve favorable tumor control and prolonged PFS after switching treatment modalities in the first-line setting of stage IV disease. Patients with locoregional recurrence benefit from complete resection of recurrence followed by a second adjuvant treatment with TT.
CRIS-Team Scopus Importer:2023-09-29
Keywords: Adjuvant Drug Therapy; Immune Checkpoint Inhibitors; Melanoma; Molecular Targeted Therapy; Recurrence

Treatment Motivations and Expectations in Patients with Actinic Keratosis: A German-Wide Multicenter, Cross-Sectional Trial - Steeb, Theresa; Wessely, Anja; Von Bubnoff, Dagmar; Dirschka, Thomas; Drexler, Konstantin; Falkenberg, Conrad; Hassel, Jessica C.; Hayani, Kinan; Huening, Svea; Kaehler, Katharina C.; Karrer, Sigrid; Krammer, Christian; et al. (Journal of Clinical Medicine, 2020)
Patient-centered motives and expectations of the treatment of actinic keratoses (AK) have received little attention until now. Hence, we aimed to profile and cluster treatment motivations and expectations among patients with AK in a nationwide multicenter, cross-sectional study including patients from 14 German skin cancer centers. Patients were asked to complete a self-administered questionnaire. Treatment motives and expectations towards AK management were measured on a visual analogue scale from 1-10. Specific patient profiles were investigated with subgroup and correlation analysis. Overall, 403 patients were included. The highest motivation values were obtained for the items "avoid transition to invasive squamous cell carcinoma" (mean +/- standard deviation; 8.98 +/- 1.46), "AK are considered precancerous lesions" (8.72 +/- 1.34) and "treating physician recommends treatment" (8.10 +/- 2.37; p < 0.0001). The highest expectation values were observed for the items "effective lesion clearance" (8.36 +/- 1.99), "safety" (8.20 +/- 2.03) and "treatment-related costs are covered by health insurance" (8.00 +/- 2.41; p < 0.0001). Patients aged >= 77 years and those with >= 7 lesions were identified at high risk of not undergoing any treatment due to intrinsic and extrinsic motivation deficits. Heat mapping of correlation analysis revealed four clusters with distinct motivation and expectation profiles. This study provides a patient-based heuristic tool for a personalized treatment decision in patients with AK.
CRIS-Team WoS Importer:2020-06-26

Treatment of generalised vitiligo with tacrolimus 0.1% ointment vs. UVB intense pulsed light phototherapy: a pilot study - Hartmann, Arndt; Löhberg, Lisa; Keikavoussi, Petra; Eichner, Saskia; Schuler, Gerold (Acta Dermato-Venereologica, 2014)
EVALuna2:19436

Treatment of moderate-to-severe atopic dermatitis with baricitinib: Results from an interim analysis of the TREATgermany registry - Traidl, Stephan; Heinrich, Luise; Siegels, Doreen; Heratizadeh, Annice; Kind, Barbara; Haufe, Eva; Abraham, Susanne; Schäfer, Thomas; Augustin, Matthias; Harder, Inken; Pinter, Andreas; Schäkel, Knut; et al. (Journal of the European Academy of Dermatology and Venereology, 2024)
CRIS-Team Scopus Importer:2024-04-12

Treatment of vitiligo using targeted UVB-Intense Pulsed Light (IPL)- phototherapy: evaluation of variables affecting therapeutic success - Hartmann, Arndt; Schmidt-Habel, Anne; Löhberg, Lisa; Zajitschek, Jörg; Englbrecht, Matthias; Eichner, Saskia; Schuler, Gerold (European Journal of Dermatology, 2014)
Targeted UVB intense pulsed light (IPL)-phototherapy has gained interest for repigmentation of vitiligo as it allows selective treatment, sparing the surrounding skin. However, optimal treatment frequency and duration are not known.We compared the efficacy and safety of two treatment protocols, weekly and every two weeks, for a maximum of 12 months. Variables affecting treatment response were evaluated.22 patients (16 female, 6 male; aged 15 - 67 years) with generalised vitiligo were evaluated retrospectively. UVB-IPL had been administered weekly (13 patients, group A), or every second week (9 patients, group B). In cases of no response, treatment stopped after 6 months. Regimentation was evaluated qualitatively and quantitatively.After 6 months, 12/13 patients (A), 3/9 patients (B) showed repigmentation. Due to lack of success, treatment was stopped after 6 months in 1 group A patient and 6/9 group B patients. After 12 months, lesions on the face and trunk in group A showed a mean of 70 ± 27% and 60 ± 29% repigmentation, respectively. Moderate to good repigmentation was seen in 78% of group A patients on the ulnar region on the forearms and the shins. Side effects were minimal. Treatment success depended on treatment frequency, number of treatments and the anatomical site of lesions.UVB-IPL phototherapy seems to be effective and well-tolerated in non-segmental vitiligo. A treatment frequency of weekly intervals rather than every two weeks appears preferable. Our observations will help in designing a sufficiently powered prospective clinical trial to test this hypothesis.
EVALuna2:13137

Treatment-resistant actinic keratoses are characterized by distinct clinical and histological features - Schmitz, Lutz; Brehmer, Amrei; Falkenberg, Conrad; Gambichler, Thilo; Heppt, Markus; Steeb, Theresa; Gupta, Girish; Malvehy, Josep; Dirschka, Thomas (Giornale Italiano di Dermatologia e Venereologia, 2021)
BACKGROUND: Actinic keratoses (AK) are generally treated to reduce the risk of progression into invasive cutaneous squamous cell carcinoma (cSCC). However, this risk of transformation is low, and rather than focusing on these lesions, current treatment studies report on complete clearance of AKs in an entire field. This study aimed to investigate treatment-resistant AKs (trAK) after field therapy compared to randomly chosen AKs prior to treatment. METHODS: AKs were clinically assessed according to the grade of hyperkeratosis and pain on palpation, prior to treatment. TrAKs were biop-sied and compared to AKs which were biopsied prior to any treatment. AKs were evaluated regarding histological severity (AKI-III), their basal growth grading (PROI-III), acantholysis, elastosis, follicular extension of atypical keratinocytes and accompanying infiltrate. RESULTS: Two hundred eleven AKs in 171 patients were identified. TrAKs (N.=79) were significantly more painful (64.6% vs. 22.0%; P<0.0001), showing acantholysis (57.0% vs. 33.3%; P=0.0007); and with distinct basal proliferation (PROIII) (64.4% vs. 46.2%; P=0.0099) compared to the control group (N.=132). In a multivariate analysis using logistic regression, pain and PRO III graded lesions were significant independent (P<0.0001 and P=0.0179) predictors for trAKs. Focusing on individual histological features in the trAK group, AKs with grade AKIII, PROIII or follicular extension reaching the sebaceous gland were the most common findings with 51.9%, 64.6%, and 59.5% AKs demonstrating this, respectively. CONCLUSIONS: TrAKs are often painful, showing a distinct basal proliferation (PROIII) and acantholysis. As these features are also seen in invasive cSCCs, trAKs may represent a subgroup of AKs and, for this reason, it requires further evaluations.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Acantholysis; Actinic; Disease progression; Keratosis; Pain

Trial watch : the gut microbiota as a tool to boost the clinical efficacy of anticancer immunotherapy - Daillere, Romain; Derosa, Lisa; Bonvalet, Melodie; Segata, Nicola; Routy, Bertrand; Gariboldi, Manuela; Budinska, Eva; De Vries, I. Jolanda M.; Naccarati, Alessio Gordon; Zitvogel, Valerie; Caldas, Carlos; Engstrand, Lars; et al. (OncoImmunology, 2020)
Accumulating evidence demonstrates the decisive role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade in preclinical tumor models, as well as in cancer patients. In synthesis, it appears that a normal intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. These findings have led to the design of clinical trials that evaluate the capacity of modulation of the gut microbiota to synergize with treatment and hence limit tumor progression. Along the lines of this Trial Watch, we discuss the rationale for harnessing the gut microbiome in support of cancer therapy and the progress of recent clinical trials testing this new therapeutic paradigm in cancer patients.
CRIS-Team WoS Importer:2020-06-26

Triggering of NF-κB in cytokine-matured human DCs generates superior DCs for T-cell priming in cancer immunotherapy. - Pfeiffer, Isabell; Hoyer, Stefanie; Gerer, Kerstin; Voll, Reinhard E.; Knippertz, Ilka; Gueckel, Eva; Schuler, Gerold; Schaft, Niels; Dörrie, Jan (European Journal of Immunology, 2014)
Understanding the signaling that governs the immunogenicity of human dendritic cells (DCs) is a prerequisite for improving DC-based therapeutic vaccination strategies, in which the ability of DCs to induce robust and lasting Ag-specific CTL responses is of critical importance. Cytokine-matured DCs are regularly used, but to induce memory-type CTLs, they require additional activation stimuli, such as CD4+ T-cell help or TLR activation. One common denominator of these stimuli is the activation of NF-?B. Here, we show that human monocyte-derived, cytokine cocktail-matured DCs transfected with constitutively active mutants of I?B kinases (caIKKs) by mRNA electroporation, further upregulated maturation markers, and secreted enhanced amounts of cytokines, including IL-12p70, which was produced for more than 48 h after transfection. Most importantly, cytotoxic T cells induced by caIKK-transfected DCs combined high CD27 expression, indicating a more memory-like phenotype, and a markedly enhanced secondary expandability with a high lytic capacity. In contrast, CTLs primed and expanded with unmodified cytokine cocktail-matured DCs did not maintain their proliferative capacity upon repetitive stimulations. We hypothesize that "designer" DCs expressing constitutively active I?B kinases will prove highly immunogenic also in vivo and possibly emerge as a new strategy to improve the clinical efficacy of therapeutic vaccinations against cancer and other chronic diseases.
EVALuna2:19501

Trotz einer großen Auswahl wirksame Medikamente: Psoriatiker scheinen immer noch untertherapiert zu sein - Pilz, Anna Caroline; Zink, Alexander; Schielein, Maximilian C.; Hell, Katharina; Romer, Katrin; Hillmann, Elena; Bäumer, Daniel; Reinhardt, Maximilian; Wagner, Nicola (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
Hintergrund und Ziele: Durch die Entwicklung neuer anti-psoriatischer Medikamente und verbesserte Strukturen zu deren flächendeckender Einführung hat sich die medizinische Versorgung von Psoriasis-Patienten deutlich verbessert. In dieser Studie haben wir die tatsächliche Inanspruchnahme des Gesundheitswesens untersucht und Gründe für die Unzufriedenheit der Betroffenen ermittelt. Patienten und Methodik: Diese nicht-interventionelle Querschnittsstudie wurde als anonyme Online-Befragung von 12/2018 bis 01/2019 in Deutschland durchgeführt. Teilnehmer mit einer selbstberichteten, von einem Arzt gestellten Psoriasis-Diagnose und Symptomen beantworteten Fragen zu ihrer Erkrankung, deren Einfluss auf das tägliche Leben und ihrer medizinischen Versorgung. Ergebnisse: 649 Teilnehmer mit einem mittleren Alter von 42,5 ± 13,7 Jahren und ausgewogener Geschlechterverteilung (männlich: 50,2 %) wurden ausgewertet. 54,1 % waren zum Zeitpunkt der Studie in ärztlicher Behandlung, 45,9 % nicht. Von den Teilnehmern mit medizinischer Versorgung waren 59,3 % nur mäßig oder weniger zufrieden mit ihrer Behandlung. Gründe für die Unzufriedenheit mit der Medikation waren unter anderem mangelnde Wirksamkeit und Nebenwirkungen. Von den nicht in ärztlicher Behandlung befindlichen Teilnehmern wurde “Zeitmangel des Arztes” als Hauptgrund für die Nichtinanspruchnahme ärztlicher Hilfe angegeben. Schlussfolgerungen: Trotz der Verfügbarkeit effizienter Therapieoptionen in Deutschland sind viele Betroffene mit Psoriasis unzufrieden. Diese unterbehandelte Gruppe wurde als neue Zielgruppe identifiziert.
CRIS-Team Scopus Importer:2021-08-06

Tumor Antigens beyond the Human Exome - Emilius, Lisabeth; Bremm, Franziska; Binder, Amanda; Schaft, Niels; Dörrie, Jan (International Journal of Molecular Sciences, 2024)
With the advent of immunotherapeutics, a new era in the combat against cancer has begun. Particularly promising are neo-epitope-targeted therapies as the expression of neo-antigens is tumor-specific. In turn, this allows the selective targeting and killing of cancer cells whilst healthy cells remain largely unaffected. So far, many advances have been made in the development of treatment options which are tailored to the individual neo-epitope repertoire. The next big step is the achievement of efficacious “off-the-shelf” immunotherapies. For this, shared neo-epitopes propose an optimal target. Given the tremendous potential, a thorough understanding of the underlying mechanisms which lead to the formation of neo-antigens is of fundamental importance. Here, we review the various processes which result in the formation of neo-epitopes. Broadly, the origin of neo-epitopes can be categorized into three groups: canonical, noncanonical, and viral neo-epitopes. For the canonical neo-antigens that arise in direct consequence of somatic mutations, we summarize past and recent findings. Beyond that, our main focus is put on the discussion of noncanonical and viral neo-epitopes as we believe that targeting those provides an encouraging perspective to shape the future of cancer immunotherapeutics.
CRIS-Team Scopus Importer:2024-05-24
Keywords: alternative splicing; cancer immunotherapy; cryptic epitopes; neo-antigens; neo-epitopes; somatic mutation

Tumor location determines tissue-specific recruitment of tumor-associated macrophages and antibody-dependent immunotherapy response - Lehmann, Birgit; Biburger, Markus; Brückner, Christin; Ipsen Escobedo, Andrea; Gordan, Sina; Lehmann, Christian; Vöhringer, David; Winkler, Thomas; Schaft, Niels; Dudziak, Diana; Sirbu, Horia; Nimmerjahn, Falk; et al. (Science immunology, 2017)
Despite recent advances in activating immune cells to target tumors, the presence of some immune cells, such as tumor-associated macrophages (TAMs) or tumor-associated neutrophils (TANs), may promote rather than inhibit tumor growth. However, it remains unclear how antibody-dependent tumor immunotherapies, such as cytotoxic or checkpoint control antibodies, affect different TAM or TAN populations, which abundantly express activating Fcγ receptors. In this study, we show that the tissue environment determines which cellular effector pathways are responsible for antibody-dependent tumor immunotherapy. Although TAMs derived from Ly6Chigh monocytes recruited by the CCL2-CCR2 axis were critical for tumor immunotherapy of skin tumors, the destruction of lung tumors was CCL2-independent and required the presence of colony-stimulating factor 2–dependent tissue-resident macrophages. Our findings suggest that TAMs may have a dual role not only in promoting tumor growth in certain tissue environments on the one hand but also in contributing to tumor cell destruction during antibody-mediated immunotherapy on the other hand.
EVALuna2:15237
Keywords: Cancer; Macrophages; Tumor associated macrophages; Antibodies; Tumor therapy; Immunotherapy

Tumors as chaotic attractors - Nikolov, Svetoslav; Wolkenhauer, Olaf; Vera González, Julio (Molecular Biosystems, 2014)
Malignant tumor growth, progression and evolution share several of the features associated with strange attractors, a special type of dynamical behavior of non-linear systems. In this framework, the genetic instability of tumor cells represents a local-scale driving force for instability that lets the tumor evolve with time, while selective pressures discarding inefficient cell clones play the role of a dissipative process, providing the tumor with global stability and robustness with respect to perturbations. This setup induces global stability combined with local instability, and is in our opinion the real source of tumor robustness and plasticity, and ultimately the origin of the remarkable resistance of many tumors to anti-cancer therapies. A scientific program taking into consideration the vision of tumors as strange attractors requires the development of experimental and computational tools to link the micro- and mesoscopic perspectives of tumor biology. We here develop the idea of a tumor as a dynamical system, sharing characteristics with strange attractors and investigate several features of such systems, including: (a) local instability combined with global stability, a property inherent to the tremendous non-linearity of the biochemical regulatory circuits governing the individual fate and the interactions between tumor cells; (b) self-similarity at different levels; (c) and strong sensitivity to initial conditions in the composition and features of the tumor and its microenvironment.
EVALuna2:19516

Tumor-suppressing Plasma extracellular Vesicles (pEV) from Melanoma Patients are secreted by Liver Cells and PBMC - Baur, A.; Lee, J. H.; Eberhardt, Martin; Blume, K.; Schuler, Gerold; Vera González, Julio (2018)
EVALuna2:34773

Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011 - Schoffer, Olaf; Schuelein, Stefanie; Arand, Gerlinde; Arnholdt, Hans; Baaske, Dieter; Bargou, Ralf C.; Becker, Nikolaus; Beckmann, Matthias; Bodack, Yves; Boehme, Beatrix; Bozkurt, Tayfun; Breitsprecher, Regine; et al. (BMC Cancer, 2016)
Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients.Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival.The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97-0.97), sex (OR 1.18, 95% CI 1.11-1.25), date of diagnosis (OR 1.05, 95% CI 1.04-1.06), 'diagnosis during screening' (OR 3.24, 95% CI 2.50-4.19) and place of residence (OR 1.23, 95% CI 1.16-1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8-83.9%).No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008.
EVALuna2:19618

Twelve-year survival and immune correlates in dendritic cell-vaccinated melanoma patients - Gross, Stefanie; Erdmann, Michael; Haendle, Ina; Voland, Steve; Berger, Thomas; Schultz, Erwin; Strasser, Erwin; Dankerl, Peter; Janka, Rolf Matthias; Schliep, Stefan; Heinzerling, Lucie; Sotlar, Karl; et al. (JCI Insight, 2017)
BACKGROUND: Reports on long-term (≥10 years) effects of cancer vaccines are missing. Therefore, in 2002, we initiated a phase I/II trial in cutaneous melanoma patients to further explore the immunogenicity of our DC vaccine and to establish its long-term toxicity and clinical benefit after a planned 10-year followup. METHODS: Monocyte-derived DCs matured by TNFα, IL-1β, IL-6, and PGE2 and then loaded with 4 HLA class I and 6 class II-restricted tumor peptides were injected intradermally in high doses over 2 years. We performed serial immunomonitoring in all 53 evaluable patients. RESULTS: Vaccine-specific immune responses including high-affinity, IFNγ-producing CD4+ and lytic polyfunctional CD8+ T cells were de novo induced or boosted in most patients. Exposure of mature DCs to trimeric soluble CD40 ligand, unexpectedly, did not further enhance such immune responses, while keyhole limpet hemocyanin (KLH) pulsing to provide unspecific CD4+ help promoted CD8+ T cell responses - notably, their longevity. An unexpected 19% of nonresectable metastatic melanoma patients are still alive after 11 years, a survival rate similar to that observed in ipilimumab-treated patients and achieved without any major (>grade 2) toxicity. Survival correlated significantly with the development of intense vaccine injection site reactions, and with blood eosinophilia after the first series of vaccinations, suggesting that prolonged survival was a consequence of DC vaccination. CONCLUSIONS: Long-term survival in advanced melanoma patients undergoing DC vaccination is similar to ipilimumab-treated patients and occurs upon induction of tumor-specific T cells, blood eosinophilia, and strong vaccine injection site reactions occurring after the initial vaccinations. TRIAL REGISTRATION: ClinicalTrials.gov NCT00053391. FUNDING: European Community, Sixth Framework Programme (Cancerimmunotherapy LSHC-CT-2006-518234; DC-THERA LSHB-CT-2004-512074), and German Research Foundation (CRC 643, C1, Z2).
EVALuna2:14632

TYPE 3 INNATE LYMPHOID CELLS ARE KEY DRIVERS OF PSORIATIC ARTHRITIS - Raimondo, M. G.; Rauber, S.; Luber, M.; Rigau, A. Rius; Weber, Stefanie; Anchang, Charles Gwellem; Agarwal, Rahul; Soare, A.; Sticherling, Michael; Rech, Jürgen; Kleyer, Arnd; Distler, Jörg; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Überdiagnose von Melanomen – Ursachen, Konsequenzen und Lösungsansätze - Kutzner, Heinz; Jutzi, Tanja B.; Krahl, Dieter; Krieghoff-Henning, Eva I.; Heppt, Markus; Hekler, Achim; Schmitt, Max; Maron, Roman C.R.; Fröhling, Stefan; von Kalle, Christof; Brinker, Titus J. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-12-11

Ulcerative colitis: yet another paradoxical effect of tumour necrosis factor blockers? - Sticherling, Michael (British Journal of Dermatology, 2018)
EVALuna2:34402

Ultraviolet Filters: Dissecting Current Facts and Myths - Breakell, Thomas; Kowalski, Isabel; Foerster, Yannick; Kramer, Rafaela; Erdmann, Michael; Berking, Carola; Heppt, Markus (Journal of Clinical Medicine, 2024)
Skin cancer is a global and increasingly prevalent issue, causing significant individual and economic damage. UV filters in sunscreens play a major role in mitigating the risks that solar ultraviolet ra-diation poses to the human organism. While empirically effective, multiple adverse effects of these compounds are discussed in the media and in scientific research. UV filters are blamed for the dis-ruption of endocrine processes and vitamin D synthesis, damaging effects on the environment, induction of acne and neurotoxic and carcinogenic effects. Some of these allegations are based on scientific facts while others are simply arbitrary. This is especially dangerous considering the risks of exposing unprotected skin to the sun. In summary, UV filters approved by the respective governing bodies are safe for human use and their proven skin cancer-preventing properties make them in-dispensable for sensible sun protection habits. Nonetheless, compounds like octocrylene and ben-zophenone-3 that are linked to the harming of marine ecosystems could be omitted from skin care regimens in favor of the myriad of non-toxic UV filters.
CRIS-Team Scopus Importer:2024-06-14
Keywords: benzophenones; carcinogen; endocrine disruption; marine environment; octocrylene; prevention; skin cancer; sunscreen; UV filters; vitamin D

Unbiased high-dimensional flow cytometry identified NK and DC immune cell signature in Luminal A-type and triple negative breast cancer - Heger, Lukas; Heidkamp, Gordon Frederik; Amon, Lukas; Nimmerjahn, Falk; Bäuerle, Tobias; Maier, Andreas; Erber, Ramona; Hartmann, Arndt; Hack, Carolin; Rübner, Matthias; Hübner, Hanna; Fasching, Peter; et al. (OncoImmunology, 2024)
Breast cancer is the most common malignancy in women worldwide and a highly heterogeneous disease. Four different subtypes are described that differ in the expression of hormone receptors as well as the growth factor receptor HER2. Treatment modalities and survival rate depend on the subtype of breast cancer. However, it is still not clear which patients benefit from immunotherapeutic approaches such as checkpoint blockade. Thus, we aimed to decipher the immune cell signature of the different breast cancer subtypes based on high-dimensional flow cytometry followed by unbiased approaches. Here, we show that the frequency of NK cells is reduced in Luminal A and B as well as triple negative breast cancer and that the phenotype of residual NK cells is changed toward regulatory CD11b−CD16− NK cells. Further, we found higher frequencies of PD-1+ CD4+ and CD8+ T cells in triple negative breast cancer. Moreover, while Luminal A-type breast cancer was enriched for CD14+ cDC2 (named type 3 DC (DC3)), CD14− cDC2 (named DC2) were more frequent in triple negative breast cancer. In contrast, HER2-enriched breast cancer did not show major alterations in the composition of the immune cell compartment in the tumor microenvironment. These findings suggest that patients with Luminal A- and B-type as well as triple negative breast cancer might benefit from immunotherapeutic approaches targeting NK cells.
CRIS-Team Scopus Importer:2024-01-12
Keywords: Breast cancer; immune cell signature; NK cells; PD-1; tumor microenvironment

Uncommon Presentation of Scleromyxoedema with a Distribution Pattern Mimicking a Photodermatosis - Kirchberger, Michael Constantin; Sticherling, Michael; Erdmann, Michael (Acta Dermato-Venereologica, 2017)
EVALuna2:34345

Understanding microRNA-mediated gene regulatory networks through mathematical modelling - Lai, Xin; Wolkenhauer, Olaf; Vera González, Julio (Nucleic Acids Research, 2016)
The discovery of microRNAs (miRNAs) has added a new player to the regulation of gene expression. With the increasing number of molecular species involved in gene regulatory networks, it is hard to obtain an intuitive understanding of network dynamics. Mathematical modelling can help dissecting the role of miRNAs in gene regulatory networks, and we shall here review the most recent developments that utilise different mathematical modelling approaches to provide quantitative insights into the function of miRNAs in the regulation of gene expression. Key miRNA regulation features that have been elucidated via modelling include: (i) the role of miRNA-mediated feedback and feedforward loops in fine-tuning of gene expression; (ii) the miRNA-target interaction properties determining the effectiveness of miRNA-mediated gene repression; and (iii) the competition for shared miRNAs leading to the cross-regulation of genes. However, there is still lack of mechanistic understanding of many other properties of miRNA regulation like unconventional miRNA-target interactions, miRNA regulation at different sub-cellular locations and functional miRNA variant, which will need future modelling efforts to deal with. This review provides an overview of recent developments and challenges in this field.
Keywords: miRNAs; network biology; systems biology; computational modelling

Understanding microRNA-mediated immunogenicity of dendritic cells using an integrative approach - Lai, Xin; Dreyer, Florian; Jaitly, T.; Cantone, Martina; Gerer, K. F.; Schuler, Gerold; Dörrie, Jan; Schaft, Niels; Vera, Julio (2018)
EVALuna2:34381

Unilateral, intermittent, pulsating Swelling of the Forehead - Heppt, Franz; Meder, Christine; Wagner, N. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Unraveling a tumor type-specific regulatory core underlying E2F1-mediated epithelial-mesenchymal transition to predict receptor protein signatures - Khan, Faiz M.; Marquardt, Stephan; Gupta, Shailendra K.; Knoll, Susanne; Schmitz, Ulf; Spitschak, Alf; Engelmann, David; Vera, Julio; Wolkenhauer, Olaf; Puetzer, Brigitte M. (Nature Communications, 2017)
Cancer is a disease of subverted regulatory pathways. In this paper, we reconstruct the regulatory network around E2F, a family of transcription factors whose deregulation has been associated to cancer progression, chemoresistance, invasiveness, and metastasis. We integrate gene expression profiles of cancer cell lines from two E2F1-driven highly aggressive bladder and breast tumors, and use network analysis methods to identify the tumor type-specific core of the network. By combining logic-based network modeling, in vitro experimentation, and gene expression profiles from patient cohorts displaying tumor aggressiveness, we identify and experimentally validate distinctive, tumor type-specific signatures of receptor proteins associated to epithelial-mesenchymal transition in bladder and breast cancer. Our integrative network-based methodology, exemplified in the case of E2F1-induced aggressive tumors, has the potential to support the design of cohort- as well as tumor type-specific treatments and ultimately, to fight metastasis and therapy resistance.Deregulation of E2F family transcription factors is associated with cancer progression and metastasis. Here, the authors construct a map of the regulatory network around the E2F family, and using gene expression profiles, identify tumour type-specific regulatory cores and receptor expression signatures associated with epithelial-mesenchymal transition in bladder and breast cancer.
EVALuna2:35407

Unusual presentation of a cutaneous metastasis in the face arising from gastric cancer: a case report - Kirchberger, Michael (SAGE Open Medical Case Reports, 2018)
A well-known example of gastrointestinal cancers metastasizing to the skin is Sister Mary Joseph's nodule, which usually presents as a cutaneous nodule on the umbilicus. In this case, a 91-year-old man was referred to our dermatology clinic for a rapidly growing 3 cm × 2 cm ulcerative nodule at his chin. Biopsy showed skin metastasis originating from a gastric adenocarcinoma. The subcutaneous and cutaneous manifestation of gastric cancer is very rare and associated with a poor prognosis and widespread metastatic disease as presented in this case. However, skin metastasis may be the first clinically apparent sign of underlying systemic malignancy and therefore immediate clarification in case of uncertainty is recommended.
EVALuna2:212813

Unveiling Metabolic Similarities of Entheses in Patients with Psoriasis and Psoriatic Arthritis Using Noninvasive In Vivo Molecular Imaging: Results From a Cross-sectional Exploratory Study - Fagni, Filippo; Tascilar, Koray; Noversa de Sousa, Rita; Bayat, Sara; Sollfrank, Lukas; Kleyer, Arnd; Sticherling, Michael; Regensburger, Adrian; Knieling, Ferdinand; Neurath, Markus; Schett, Georg; Waldner, Maximilian; et al. (Arthritis and Rheumatology, 2024)
Objective: We assessed and compared molecular tissue changes at the entheses in patients with psoriasis (PsO) and psoriatic arthritis (PsA) and in healthy controls (HCs) in vivo using multispectral optoacoustic tomography (MSOT) and described their relationship with clinical and ultrasound findings of enthesitis. Methods: A cross-sectional study (MSOT and Arthrosonography in PsA) in biologic disease-modifying antirheumatic drug–naïve patients with PsA and PsO and HCs was performed. Participants underwent clinical, ultrasonographic, and MSOT examination of six entheses (lateral humeral epicondyle, distal patellar tendon attachment, and Achilles tendon attachment). MSOT-measured hemoglobin (Hb), oxygen saturation (SO2), collagen, and lipid levels were quantified, and mean differences between groups were calculated using linear mixed effects models. MSOT-measured analytes were compared between entheses with and without clinical and ultrasound anomalies. Results: Ninety participants were included (30 PsO, 30 PsA, and 30 HCs), 540 entheses were clinically assessed, and 540 ultrasound and 830 MSOT scans were obtained. Patients with PsA and PsO showed increased oxygenated Hb (PsA: P = 0.003; PsO: P = 0.054) and SO2 (PsA: P < 0.001; PsO: P = 0.001) levels and decreased collagen signals (PsA: P < 0.001; PsO: P < 0.001) compared with HCs, with more pronounced changes in PsA. Significantly lower collagen levels (P = 0.01) and increased lipids (P = 0.03) were recorded in tender entheses compared with nontender ones. Erosions and enthesophytes on ultrasound were associated with significant differences in SO2 (P = 0.014) and lipid signals (P = 0.020), respectively. Conclusion: Patients with PsA and PsO exhibit an analogous metabolic pattern at the entheses that is exacerbated in the presence of inflammation. These findings support the notion of a psoriatic disease spectrum characterized by common immunometabolic tissue changes.
CRIS-Team Scopus Importer:2024-07-19

Updated results of 100 patients on clinical features and therapeutic options in necrobiosis lipoidica in a retrospective multicentre study - Dissemond, Joachim; Schwede, Katharina; Seitz, Anna-Theresa; Al Ghazal, Philipp; Wollina, Uwe; Renner, Regina; Erfurt-Berge, Cornelia (European Journal of Dermatology, 2015)
Necrobiosis lipoidica (NL) is a rare granulomatous disorder of unknown aetiology which can manifest in ulcerative skin lesions and is widely recognised in association with diabetes. We evaluated in total 100 patients to improve knowledge about the epidemiology and clinical course of NL. Additionally we focused on treatment options according to evidence level and expert opinion.To examine the clinical features of patients with necrobiosis lipoidica and to give recommendations for topical and systemic treatment.This multicentre retrospective study covers data from 100 patients with the diagnosis of NL of the lower leg, treated during the period between 01/2006 and 06/2014. Data from 5 German dermatological centres with 23 men and 77 women with a median age of 52 years were evaluated. We also asked 15 dermatological experts for their opinions about ulceration, associated diseases and their preferences for treatment modalities of NL.Patients' ages ranged from 15 to 95 years (median age 52 years, mean age 49.8 years). NL was significantly more common in women (77%). Ulceration of the NL was observed in 33% of cases, in particular in male patients and in patients with concomitant diabetes mellitus. Thyroidal disorders were found in 15% of all cases.Our data confirm that female sex, middle age and endocrine disorders like diabetes mellitus or thyroid dysfunction are characteristics of patients suffering from NL. Existing therapeutic options were very variable and - according to the opinion of our experts - only a few highly effective.
EVALuna2:19576

Update on the management of Bowen disease with a focus on patients' needs. - Berking, Carola (British Journal of Dermatology, 2023)
EVALuna2:517117

Upregulation of CCR4 in activated CD8(+) T cells indicates enhanced lung homing in patients with severe acute SARS-CoV-2 infection - Spoerl, Silvia; Kremer, Anita; Aigner, Michael; Eisenhauer, Nina; Koch, Pauline; Meretuk, Lina; Loeffler, Patrick; Tenbusch, Matthias; Maier, Clara; Überla, Klaus; Heinzerling, Lucie; Frey, Benjamin; et al. (European Journal of Immunology, 2021)
COVID-19 is a life-threatening disease leading to bilateral pneumonia and respiratory failure. The underlying reasons why a smaller percentage of patients present with severe pulmonary symptoms whereas the majority is only mildly affected are to date not well understood.
CRIS-Team WoS Importer:2021-05-07

Usage and effectiveness of systemic treatments in adults with severe atopic eczema: First results of the German Atopic Eczema Registry TREATgermany - Schmitt, Jochen; Abraham, Susanne; Trautmann, Freya; Stephan, Victoria; Foelster-Holst, Regina; Homey, Bernhard; Bieber, Thomas; Novak, Natalija; Sticherling, Michael; Augustin, Matthias; Kleinheinz, Andreas; Elsner, Peter; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2017)
BACKGROUND: The goal of clinical registries is to document the use and effectiveness of therapeutic interventions under real-life conditions. They are an indispensable prerequisite of evidence-based health care. METHODS: Initiated in 2011, the German Atopic Dermatitis Registry TREATgermany is the first registry of patients with severe atopic dermatitis worldwide. Adults with severe atopic dermatitis (current/prior systemic antiinflammatory treatment and/or objective SCORAD ≥ 40) are prospectively followed over the course of 24 months. Employed treatment modalities are documented, and validated measuring tools are used to assess clinical disease severity (EASI, objective SCORAD), quality of life (DLQI), symptoms (POEM), global disease severity, as well as patient satisfaction. Herein, we describe the characteristics, therapeutic selection, and effectiveness of systemic antiinflammatory treatments of patients enrolled in the registry until October 2014. RESULTS: Overall, 78 individuals (mean age 39 years, 61 % men) were enrolled at five recruitment centers. Patients frequently made use of inpatient and outpatient services. Not only was cyclosporine the most frequently administered systemic treatment, but also the most effective (EASI 50 response rate 51 %; EASI 75 response rate 34 % at 12 weeks). Azathioprine, methotrexate, oral prednisolone, mycophenolate, alitretinoin, and leflunomide were also used in some patients. CONCLUSIONS: The present analysis of the German Atopic Dermatitis Registry provides important data with respect to current medical care of adults with severe atopic dermatitis in Germany. It shows the high disease burden, the benefits of current treatment options, and the need for additional effective and safe long-term treatment options.
EVALuna2:34363

Using multiple real-world dermoscopic photographs of one lesion improves melanoma classification via deep learning - Hekler, Achim; Maron, Roman C.; Haggenmüller, Sarah; Schmitt, Max; Wies, Christoph; Utikal, Jochen S.; Meier, Friedegund; Hobelsberger, Sarah; Gellrich, Frank F.; Sergon, Mildred; Hauschild, Axel; French, Lars E.; et al. (Journal of the American Academy of Dermatology, 2024)
CRIS-Team Scopus Importer:2024-02-16
Keywords: artificial intelligence; deep learning; dermatology; dermoscopy; diagnosis; diagnostic accuracy; melanoma; robustness; uncertainty estimation

Using the Prediction Model Risk of Bias Assessment Tool (PROBAST) to Evaluate Melanoma Prediction Studies - Kaiser, Isabelle; Mathes, Sonja; Pfahlberg, Annette Bettina; Uter, Wolfgang; Berking, Carola; Heppt, Markus; Steeb, Theresa; Diehl, Katharina; Gefeller, Olaf (Cancers, 2022)
Rising incidences of cutaneous melanoma have fueled the development of statistical models that predict individual melanoma risk. Our aim was to assess the validity of published prediction models for incident cutaneous melanoma using a standardized procedure based on PROBAST (Prediction model Risk Of Bias ASsessment Tool). We included studies that were identified by a recent systematic review and updated the literature search to ensure that our PROBAST rating included all relevant studies. Six reviewers assessed the risk of bias (ROB) for each study using the published “PROBAST Assessment Form” that consists of four domains and an overall ROB rating. We further examined a temporal effect regarding changes in overall and domain-specific ROB rating distributions. Altogether, 42 studies were assessed, of which the vast majority (n = 34; 81%) was rated as having high ROB. Only one study was judged as having low ROB. The main reasons for high ROB ratings were the use of hospital controls in case-control studies and the omission of any validation of prediction models. However, our temporal analysis results showed a significant reduction in the number of studies with high ROB for the domain “analysis”. Nevertheless, the evidence base of high-quality studies that can be used to draw conclusions on the prediction of incident cutaneous melanoma is currently much weaker than the high number of studies on this topic would suggest.
CRIS-Team Scopus Importer:2022-07-22
Keywords: melanoma; prediction models; PROBAST; risk of bias; risk prediction

Uveal melanoma Uveamelanome - Hassel, Jessica C.; Heppt, Markus (Die Onkologie, 2023)
Uveal melanoma is rare and constitutes 5% of all melanomas. They develop mainly from pigment cells of the choroidea, less commonly from the ciliary body or the iris of the eye. The treatment of primary uveal melanoma includes surgery and radiation therapy. Especially large tumors and those with extraocular extension are enucleated. Smaller tumors can be irradiated with plaque brachytherapy or protons. Follow-up, which consists of ophthalmologic examinations, liver ultrasound, and may include assessment of the transaminases in the peripheral blood, is ideally based on the risk profile of the primary tumor and performed every 3–6 months. According to the genetic risk profile, 50% of patients develop distant metastasis, mainly in the liver. Therefore, in addition to systemic therapy, local liver-directed therapies such as chemoperfusion/chemosaturation, transarterial chemoembolization (TACE), and selective internal radiotherapy (SIRT) can be administered. To date, however, there is no definitive evidence that these treatments not only inhibit progression in the liver but improve overall survival. Treatment of choice in patients with metastases is the newly approved immunotherapy with tebentafusp, a bispecific protein consisting of a gp100-TCR (T cell receptor) fused to a CD3 antibody leading to activation of T cells in the microenvironment of the uveal melanoma. It is the first drug proven to lead to a significant survival benefit for patients with metastasized uveal melanoma compared with other systemic therapies such as immune checkpoint inhibitors and chemotherapy. Interestingly, patients with progressing metastases also have a survival benefit. However, treatment can only be given to patients with the human leukocyte antigen (HLA)-A0201 phenotype to which the TCR was designed and which is present in approximately 50% of patients. Further promising new drugs are under development.
CRIS-Team Scopus Importer:2023-08-11
Keywords: Immunotherapy; Local liver-directed therapies; Melanoma of the eye; Tebentafusp

Vaccination with dendritic Cells for metastasized Uveal Melanoma: immunological and clinical Responses - Moreira, Alvaro; Gross, S.; Uslu, Ugur; Dörrie, Jan; Kummer, Mirko; Schliep, S.; Sponagl, F.; Lischer, Christopher; Erdmann, M.; Heinzerling, Lucie; Schuler, Gerold; Schuler-Thurner, Beatrice (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Vasoactive Therapy in Systemic Sclerosis: Real-life Therapeutic Practice in More Than 3000 Patients - Moinzadeh, Pia; Riemekasten, Gabriela; Siegert, Elise; Fierlbeck, Gerhard; Henes, Joerg; Blank, Norbert; Melchers, Inga; Mueller-Ladner, Ulf; Frerix, Marc; Kreuter, Alexander; Tigges, Christian; Lahner, Nina; et al. (Journal of Rheumatology, 2016)
Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry.The data of 3248 patients with SSc were analyzed.Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005.These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.
EVALuna2:13183

Versorgungszustand von Patienten vor Zuweisung an ein universitäres Wundzentrum - Erfurt-Berge, Cornelia; Michler, Melanie; Renner, Regina (Hautarzt, 2021)
Background and objectives: Health care for patients with chronic wounds is often protracted. This can result in decreased quality of care or delayed diagnosis of the actual cause of disease. Concurrently, there are already certified facilities for these patients. The present work investigates possible reasons for delayed referral and whether a specific selection of patients is sent to these university-based centres. Patients and methods: A retrospective patient data chart review at the point of first admission to the certified wound centre was performed to identify concerning variables about the standard of care before university presentation. Results: Records of 177 patients were analysed (53% women, 47% men; patient age range 27–95 years). The mean duration of the wound was 22 months. Vascular diagnostics had already been performed in 32% (arterial diagnostics) and 36% (phlebological diagnostics), respectively. A tissue sample had been analysed in 9% of cases, especially when wound duration exceeded > 24 months. In only 45% of cases was the external diagnosis in accord with the final diagnosis in the wound centre. Discussion: The health care situation for patients with chronic wounds outside of specialised care structures is insufficient. Early and standardized diagnostics and therapy and a reasonable admission to specialised centres is desired.
CRIS-Team Scopus Importer:2021-02-05
Keywords: Basic diagnostics; Care structure; Leg ulcer; Primary care; Quality of care

Very late reactions in the patch test with fragrance mix I and oak moss absolute: Data of the Information Network of Departments of Dermatology (IVDK) - Schubert, Steffen; Schnuch, Axel; Bauer, Andrea; Wagner, Nicola; Schroeder-Kraft, Claudia; Dickel, Heinrich; Weisshaar, Elke; Effendy, Isaak; Becker, Detlef; Buhl, Timo; Simon, Dagmar; Koch, Andre; et al. (Contact Dermatitis, 2021)
CRIS-Team WoS Importer:2021-10-01

VEXAS syndrome mimicking lupus-like disease - Valor-Mendez, Larissa; Sticherling, Michael; Zeschick, Martin; Atreya, Raja; Schmidt, Daniela; Waldfahrer, Frank; Saake, Marc; Hüffmeier, Ulrike; Schett, Georg; Rech, Jürgen (Rheumatology, 2023)
CRIS-Team WoS Importer:2023-03-17

Vier Fälle einer Erysipel-ähnlichen Entzündung bei Patienten mit metastasiertem Melanom unter Therapie mit Checkpoint-Inhibitoren. - Pföhler, Claudia; Hassel, Jessica C.; Heinzerling, Lucie; Müller, Cornelia S.L. (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
EVALuna2:470343

Wahrnehmung der Corona-Pandemie durch Neurodermitispatienten – Ergebnisse aus dem Neurodermitisregister TREATgermany - Helmert, Claudia; Siegels, Doreen; Haufe, Eva; Abraham, Susanne; Heratizadeh, Annice; Kleinheinz, Andreas; Harder, Inken; Schäkel, Knut; Effendy, Isaak; Wollenberg, Andreas; Sticherling, Michael; Stahl, Maren; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
CRIS-Team Scopus Importer:2022-02-04

Was hat die Ernährung mit der Wundheilung zu tun? - Renner, R.; Erfurt-Berge, Cornelia (Aktuelle Dermatologie, 2020)
Interference during the complex wound healing process might lead to a delayed or absence of wound closure. One possible disruptive factor can be wrong nutrition. It is necessary to differentiate between quantitative and qualitative malnutrition. Preferential obese patients suffer from a qualitative malnutrition and sarkopenia. Specific diseases require a specific nutritional recommendation. For example, patients with dialysis, decubitus, or leg ulcers often have a lack of proteins. In addition, other nutrient deficiencies with Vitamin C, zinc, folate, Vitamin D or trace elements might have a negative impact on wound healing. Prospective studies should clarify if substitution of those nutrient deficiencies might improve wound healing. It seems to be reasonable to strive for an improvement in the consumption of vitamins, trace elements and proteins adopted to a balanced alimentation and adjusted to individual dietary habits.
CRIS-Team Scopus Importer:2020-07-10

What does the general population know about nonmelanoma skin cancer? Representative cross-sectional data from Germany - Brokmeier, Luisa; Görig, Tatiana; Spähn, Bianca A.; Breitbart, Eckhard W.; Heppt, Markus; Diehl, Katharina (Journal of Public Health, 2024)
Aim: Nonmelanoma skin cancer (NMSC) is the most common form of cancer in white-skinned populations. However, there is a lack of comprehensive research on the general population’s knowledge about NMSC. Subjects and methods: As part of wave 8 of the German National Cancer Aid Monitoring (NCAM), 4000 participants aged 16–65 years (49.3% female) were interviewed by telephone about NMSC. Questions included awareness of (colloquial) terms for NMSC, its signs, consequences, risk factors, prevalence, and severity. Results: Colloquial terms for skin cancer were heard of more often than medical terms (60.9–82.1% vs. 22.6–51.5%). In our sample, there was little familiarity with signs (15.8–36.4%), possible consequences (14.7–56.3%), prevalence (27.4%), and severity (29.0%) of NMSC. Most participants knew about UV-related risk factors for NMSC (73.0–78.7%). Women, those with higher education levels, full-time employment, lighter skin type, presence of more than 40 nevi, frequent childhood sunburns, or frequent intentional tanners achieved a higher knowledge score. Concern about NMSC was associated with more NMSC knowledge. Conclusion: We found knowledge gaps regarding signs, consequences, and prevalence of NMSC. To ensure early recognition and treatment, the general population should be further educated, specifically targeting male, less educated, and unemployed individuals.
CRIS-Team Scopus Importer:2024-05-24
Keywords: Health literacy; Knowledge; Nonmelanoma skin cancer; Prevention

What Goes Around, Comes Around - HSV-1 Replication in Monocyte-Derived Dendritic Cells - Grosche, Linda; Kummer, Mirko; Steinkasserer, Alexander (Frontiers in Microbiology, 2017)
HSV-1 is a very successful human pathogen, known for its high sero-prevalence and the ability to infect a wide range of different cell types, including dendritic cells (DCs). As very potent antigen-presenting cells DCs play an important role in the induction of antiviral immune responses and therefore represent a strategic target for viral-mediated immune escape mechanisms. It is known that HSV-1 completes its gene expression profile in immature as well as in mature DCs, while lytic infection is only found in immature DCs (iDCs). Notably, HSV-1 infected mature DCs (mDCs) fail to release infectious progeny virions into the supernatant. Apart from HSV-1 dissemination via extracellular routes cell-to-cell spread counteracts a yet unknown mechanism by which the virus is trapped in mDCs and not released into the supernatant. The dissemination in a cell-cell contact-dependent manner enables HSV-1 to infect bystander cells without the exposure toward the extracellular environment. This supports the virus to successfully infect the host and establish latency. In this review the mechanism of HSV-1 replication in iDCs and mDCs and its immunological as well as virological implications, will be discussed.
EVALuna2:36216

What is the current State of Knowledge of Skin Cancer Patients about fertility-preserving Measures? an exploratory Cross Sectional Survey - Hornung-Eichler, Annkathrin; Steeb, Theresa; Erdmann, M.; Berking, Carola; Heppt, Markus (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Wheat Anaphylaxis in Adults Differs from Reactions to Other Types of Food - Kraft, Magdalena; Dölle-Bierke, Sabine; Renaudin, Jean Marie; Ruëff, Franziska; Scherer Hofmeier, Kathrin; Treudler, Regina; Pföhler, Claudia; Hawranek, Thomas; Poziomkowska-Gęsicka, Iwona; Jappe, Uta; Christoff, George; Müller, Sabine; et al. (The Journal of Allergy and Clinical Immunology: In Practice, 2021)
Background: Wheat is one of the most commonly consumed foods and a known elicitor of anaphylaxis in children and adults. Reactions in adults are often cofactor dependent and characterized by a prolonged time between food intake and the onset of symptoms making the diagnosis of wheat anaphylaxis challenging. Objective: To characterize a cohort of patients with the history of wheat anaphylaxis to better understand this atypical phenotype of anaphylaxis. Methods: Data from the European Anaphylaxis Registry from 2007 to 2019 (n = 10,636) including 250 patients (213 adults and 37 children) with a history of anaphylaxis caused by wheat were analyzed. Results: Wheat was the most common food elicitor of anaphylaxis in adults in the registry in Central Europe. Reactions to wheat in adults were frequently associated with exercise as a cofactor (82.8%) and partially delayed (57.5%). Only 36.9% of patients had atopic comorbidities, which was uncommonly low for adult patients allergic to other kinds of foods (63.2%). Anaphylaxis to wheat presented frequently with cardiovascular symptoms (86.7%) including severe symptoms such as loss of consciousness (41%) and less often with respiratory symptoms (53.6%). The reactions to wheat were more severe than reactions to other foods (odds ratio [OR] = 4.33), venom (OR = 1.58), or drugs (OR = 2.11). Conclusions: Wheat is a relevant elicitor of anaphylaxis in adults in Central Europe. Wheat anaphylaxis is highly dependent on the presence of cofactors and less frequently associated with atopic diseases compared with other food allergies. More data on mechanisms of wheat-induced anaphylaxis are required to develop preventive measures for this potentially life-threatening disease.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Anaphylactic reaction; Anaphylaxis; FDEIA; Food allergy; Omega-5-gliadin; Tri a 19; WDEIA; Wheat allergy; Wheat-dependent exercise-induced anaphylaxis

Where do we stand with immune checkpoint blockade for advanced cutaneous squamous cell carcinoma? A systematic review and critical appraisal of existing evidence - Steeb, Theresa; Wessely, A.; Heppt, Franz; Harlaß, M.; Berking, Carola; Heppt, Markus (British Journal of Dermatology, 2020)
Immune checkpoint blockade (ICB) has tremendously changed the field of oncological therapy. Recently, the PD-1-blocking antibody cemiplimab was approved by the FDA and the EMA for the treatment of advanced cutaneous squamous cell carcinoma (cSCC).1 However, clinical practice guidelines currently do not cover specific recommendations regarding the management of advanced cSCC with ICB. Hence, we have performed a systematic review on the current use of ICB for advanced cSCC.
EVALuna2:212852

Which patients should receive adjuvant treatment - an analysis of stage IIA-IIIA patients of the CMMR - Leiter-Stoppke, U.; Keim, U.; Amaral, T.; Forschner, A.; Berking, Carola; Gesierich, A.; Gutzmer, R.; Sunderkotter, C.; Utikal, J. S.; Zimmer, L.; Flatz, L.; Garbe, C. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

Whither systems medicine? - Apweiler, Rolf; Beissbarth, Tim; Berthold, Michael R.; Bluethgen, Nils; Burmeister, Yvonne; Dammann, Olaf; Deutsch, Andreas; Feuerhake, Friedrich; Franke, Andre; Hasenauer, Jan; Hoffmann, Steve; Hoefer, Thomas; et al. (Experimental and Molecular Medicine, 2018)
New technologies to generate, store and retrieve medical and research data are inducing a rapid change in clinical and translational research and health care. Systems medicine is the interdisciplinary approach wherein physicians and clinical investigators team up with experts from biology, biostatistics, informatics, mathematics and computational modeling to develop methods to use new and stored data to the benefit of the patient. We here provide a critical assessment of the opportunities and challenges arising out of systems approaches in medicine and from this provide a definition of what systems medicine entails. Based on our analysis of current developments in medicine and healthcare and associated research needs, we emphasize the role of systems medicine as a multilevel and multidisciplinary methodological framework for informed data acquisition and interdisciplinary data analysis to extract previously inaccessible knowledge for the benefit of patients.
EVALuna2:34798

Willingness to pay for a cure of low-risk melanoma patients in Germany - Augustin, Matthias; Blome, Christine; Forschner, Andrea; Gutzmer, Ralf; Hauschild, Axel; Heinzerling, Lucie; Livingstone, Elisabeth; Loquai, Carmen; Schadendorf, Dirk; Utikal, Jochen; Wagner, Tobias; Wilden, Sophia; et al. (PLoS ONE, 2018)
Malignant melanoma is potentially life-threatening but in most cases curable if detected early. Willingness to pay (WTP) is a preference-based construct that reflects burden of disease by assessment of the monetary value for a hypothetical cure from disease. Since WTP (directly as total amount of money) has not been assessed so far in patients with low risk melanoma, it was interesting to gain insights in this patient population and then, in a second step, compare it directly with the WTP of their treating dermato-oncologists. WTP was assessed in 125 patients with low-risk melanoma and additionally in 105 treating physicians, asking for the one-time and continuous payments they would be willing to make for a sustainable cure, both as absolute sums and as percentages of monthly income. The median WTP based on one-time payment was €10,000 for patients and €100,000 for physicians; relative numbers were 100% versus 300% of monthly income. For continuous monthly payments, WTP was €500 for patients and €1000 for physicians, relative numbers 25% and 50% of income, respectively. Even after controlling for income differences, there was a significantly higher WTP in physicians for all four questions. Compared to patients with chronic skin diseases such as vitiligo, rosacea, atopic eczema and psoriasis, patients with low-risk melanoma showed a significantly higher WTP. Our data suggest that there is a relevant burden of disease even in patients with low-risk tumors. Higher WTP of physicians underlines the prevalence of differences in disease perception.
EVALuna2:34380

Wissen über nicht-melanozytären Hautkrebs in der Allgemeinbevölkerung: eine multi-methodische Studie - Brokmeier, Luisa; Görig, Tatiana; Spaehn, Bianca Annika; Heppt, Markus; Breitbart, Eckhard W.; Diehl, Katharina (33. Deutscher Hautkrebskongress, 2023)

Wound care - A teaching topic with potential Wundversorgung - ein Lehrthema mit Potenzial - Erfurt-Berge, Cornelia (Aktuelle Dermatologie, 2024)
The treatment of patients with chronic wounds is part of basic dermatological care. The prevalence of chronic wounds increases with age and a rise in the number of patients can be expected in the future. At the same time, the topic of wound management is a prime example of interdisciplinary and interprofessional patient care and can therefore be followed up as a teaching topic in many medical disciplines. The student working as a general physician in the future will later take on the role of a pilot and must be able to refer the patient to the necessary specialties for diagnosis and treatment within a reasonable period of time. Having to deal with chronic wounds as a comorbidity can occur in any specialist discipline. In the field of wound management, dermatology not only covers the phlebological diagnostic, but also plays a key role in the diagnosis of rare causes of chronic wounds. The indication and performance of further diagnostics, such as a histological examination of a deep tissue sample, can be part of a learning unit for many dermatological diseases that present with ulceration as a symptom. There are therefore many didactic possibilities for integrating this topic into a teaching unit. In addition to cognitive learning objectives on the pathophysiology and differential diagnosis of chronic wounds, practical skills such as the application of dressings, sonography or debridement procedures can be taught. Affective learning objectives can also be integrated into curricula concerning the care for people with chronic illnesses or implementation of preventative measures.
CRIS-Team Scopus Importer:2025-04-01
Keywords: chronic wound; leg ulcer; venous insufficiency; wound managemenet

Wound treatment without curative intention: position paper of the Initiative Chronische Wunden (ICW) e. V. Wundbehandlung ohne kurative Zielsetzung: Ein Positionspapier der Initiative Chronische Wunden (ICW) e. V. - Dissemond, Joachim; Protz, Kerstin; Erfurt-Berge, Cornelia; Kröger, Knut; Kottner, Jan (Hautarzt, 2022)
Today, patients with chronic wounds are treated in many different fields of medicine. Despite this great interdisciplinary and interprofessional importance, there is still a lack of uniformly accepted definitions and classifications. Therefore, a group of experts from the professional society Initiative Chronische Wunden (ICW) e. V. translated and adapted the classification of chronic wounds into healable, maintenance and nonhealable wounds on the basis of the internationally published literature into German. This classification results in the aim of curative, limited respectively non-curative or palliative wound care, which are very important for everyday clinical practice. It thus becomes clear that complete wound closure is not always the central intention of wound treatment. For many patients with chronic wounds, other aspects such as the best possible quality of life and the promotion of health-related self-management as well as the avoidance of complications are important for treatment concepts. These therapy intentions should be differentiated and individually discussed with patients in order to facilitate shared decision making.
CRIS-Team Scopus Importer:2022-03-25
Keywords: Chronic wounds; Curative wound care; Maintenance wounds; Nonhealable wounds; Palliative wound care

XCR1 expression distinguishes human conventional dendritic cell type 1 with full effector functions from their immediate precursors - Heger, Lukas; Hatscher, Lukas; Liang, Chunguang; Lehmann, Christian; Amon, Lukas; Lühr, Jennifer J.; Kaszubowski, Tomasz; Nzirorera, Rayk; Schaft, Niels; Dörrie, Jan; Irrgang, Pascal; Tenbusch, Matthias; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2023)
Dendritic cells (DCs) are major regulators of innate and adaptive immune responses. DCs can be classified into plasmacytoid DCs and conventional DCs (cDCs) type 1 and 2. Murine and human cDC1 share the mRNA expression of XCR1. Murine studies indicated a specific role of the XCR1-XCL1 axis in the induction of immune responses. Here, we describe that human cDC1 can be distinguished into XCR1- and XCR1+ cDC1 in lymphoid as well as nonlymphoid tissues. Steady-state XCR1+ cDC1 display a preactivated phenotype compared to XCR1- cDC1. Upon stimulation, XCR1+ cDC1, but not XCR1- cDC1, secreted high levels of inflammatory cytokines as well as chemokines. This was associated with enhanced activation of NK cells mediated by XCR1+ cDC1. Moreover, XCR1+ cDC1 excelled in inhibiting replication of Influenza A virus. Further, under DC differentiation conditions, XCR1- cDC1 developed into XCR1+ cDC1. After acquisition of XCR1 expression, XCR1- cDC1 secreted comparable level of inflammatory cytokines. Thus, XCR1 is a marker of terminally differentiated cDC1 that licenses the antiviral effector functions of human cDC1, while XCR1- cDC1 seem to represent a late immediate precursor of cDC1.
CRIS-Team Scopus Importer:2023-08-25
Keywords: antiviral immunity; cDC1; DC differentiation; IL-12; XCR1

YouTube (R)-Videos about Skin Cancer as an Information Source for Patients: Assessment of quality, Comprehensibility and Reliability - Reinhardt, L.; Steeb, Theresa; Harlass, M.; Brutting, J.; Berking, Carola; Meier, F. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Zielgerichtete Therapie bei BRAF-mutiertem metastasierten papillären Schilddrüsenkarzinom und malignen Melanom - Bender-Säbelkampf, Sophia; Tüting, Thomas; Alter, Mareike; Horbrügger, M. (Abstractband anlässlich des 29. Deutschen Hautkrebskongresses (ADO–Jahrestagung), 2019)
We like to present a case study of an 80-year old male with a metastatic papillary thyroid cancer and malignant melanoma. A left hemithyroidectomy was performed in 2017. Due to a former existing single-sided recurrent laryngeal nerve palsy a R0-resection could not been carried through. The subsequent therapy consisted of thyroid hormone substitution and radio iodine therapy. Up until now the thyroid cancer cells don’t show an uptake anymore, further radio iodine therapy is therefor contraindicated. Further PET-CTs and ultrasounds showed an increase in size with a subtotal stenosis of the oesophagus and severe dysphagia. In January 2019 we excised a nodular melanoma occipital right. The subsequent staging showed progressive cervical lymph node metastasis and pulmonary lesions. We assign the infiltration of oesophagus and neck as metastasis of the thyroid cancer whereas the pulmonal lesions we see as metastatic stage IV melanoma. Via genomic sequencing there was a BRAF-V600-E mutation found in both melanoma and the papillary thyroid cancer. A prevalence of BRAF-mutations in thyroid cancer are found in 20–50 % and for malignant melanoma in 40–60 % (1). As there is currently no officially approved targeted therapy for BRAF mutant thyroid cancer in Europe, a few clinical studies (2) using targeted therapy however showed a therapy response rate of 70 %. As this therapy is also already indicated for mutation positive metastatic malignant melanoma and non-small cell lung cancer, the FDA recently approved Dabrafenib and Trametinib as targeted therapy in BRAF-positive anaplastic thyroid cancer. Due to the BRAF-positive malignant melanoma in our case, we could initiate a targeted therapy immediately. Recent studies showed a higher standardised uptake value and FDG PET acitivity in BRAF-positive thyroid cancer cells which leads to the hope that through a targeted therapy the once iodine-resistant thyroid cells of our patient could possibly regulate their uptake level for radio iodine therapy to be successful once again.<br

Zinc deficiency-associated dermatitis in a prematurely born infant - Grötsch, Jennifer; Sticherling, Michael (Journal der Deutschen Dermatologischen Gesellschaft, 2025)
CRIS-Team Scopus Importer:2025-02-14

β2-microglobulin triggers NLRP3 inflammasome activation in tumor-associated macrophages to promote multiple myeloma progression - Hofbauer, Daniel; Mougiakakos, Dimitrios; Broggini, Luca; Zaiss, Mario; Büttner-Herold, Maike; Bach, Christian; Spriewald, Bernd; Neumann, Frank; Bisht, Savita; Nolting, Jens; Zeiser, Robert; Hamarsheh, Shaima'a; et al. (Immunity, 2021)
As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone destruction, and immune impairment. We identify beta-2-microglobulin (β2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed β2m promotes β2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1β (IL-1β) and IL-18. This process depends on activation of the NLRP3 inflammasome after β2m accumulation, as macrophages from NLRP3-deficient mice lack efficient β2m-induced IL-1β production. Moreover, depletion or silencing of β2m in MM cells abrogates inflammasome activation in a murine MM model. Finally, we demonstrate that disruption of NLRP3 or IL-18 diminishes tumor growth and osteolytic bone destruction normally promoted by β2m-induced inflammasome signaling. Our results provide mechanistic evidence for β2m's role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeutic approach in MM.
CRIS-Team Scopus Importer:2021-08-13
Keywords: inflammation; macrophages; multiple myeloma; NLRP3; phagocytosis; tumor-associated macrophages

3-D-Ganzkörperhautscanner – eine neue Ära in Klinik und Forschung? - Sitaru, Sebastian; Kaczmarczyk, Robert; Erdmann, Michael; Biedermann, Tilo; Zink, Alexander (Hautarzt, 2022)
CRIS-Team Scopus Importer:2022-03-25

A European randomised controlled trial for venous leg ulcers: A mathematical model analysis - Renner, Regina (Journal of Wound Care, 2020)
CRIS-Team Scopus Importer:2020-11-27

A qualitative study on maternal attachment behaviour as a risk factor for the onset of atopic dermatitis in the infant - Schmidt, L. E. M.; Merdha, L.; Lang, V.; Preis, S.; Bleuel, R.; Schuch, A.; Da Silva, R.; Blasini, A.; Kuschel, B.; Hauenstein, E.; Sander, M.; Niedermeier, S.; et al. (BRITISH JOURNAL OF DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-09-10

ARIA-Leitlinie 2019: Behandlung der allergischen Rhinitis im deutschen Gesundheitssystem - Klimek, L.; Bachert, C.; Pfaar, O.; Becker, S.; Bieber, T.; Brehler, R.; Buhl, R.; Casper,; Chaker, A.; Czech, W.; Fischer, J.; Fuchs, T.; et al. (Allergologie, 2020)
CRIS-Team Scopus Importer:2020-02-28
Keywords: Allergen-specific immunotherapy; Allergic asthma; Allergic diseases; Health care system; Integrated care pathway

Atopic skin diathesis rather than atopic dermatitis is associated with specific contact allergies - Forkel, Susann; Cevik, Naciye; Schill, Tillmann; Worm, Margitta; Mahler, Vera; Weisshaar, Elke; Vieluf, Dieter; Pfützner, Wolfgang; Löffler, Harald; Schön, Michael P.; Geier, Johannes; Buhl, Timo (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
Background: The association of atopic dermatitis (AD) and allergic contact dermatitis has been a matter of considerable uncertainty. Study results range from lack of any association to increased sensitization for multiple allergens, but fail to identify consistent allergen associations. Objective: We studied a large patch test cohort of patients stratified by their atopic skin diathesis using the Erlangen Atopy Score (EAS), independent of active skin disease. Methods: Retrospective multi-center data analysis from five departments of dermatology in Germany with 4,509 patients. Patients were grouped as “no atopic skin diathesis” (n = 2,165) and “atopic skin diathesis” (n = 1,743), according to EAS. Results: Significantly more individuals with atopic skin diathesis showed at least one positive patch test reaction to the baseline series compared to individuals without atopic skin diathesis (49.1 % vs. 38.3 %). In logistic regression analyses, atopic skin diathesis was associated with a significantly higher risk of sensitization to methylchloroisothiazolinone/methylisothiazolinone (OR 2.383) and methylisothiazolinone (OR 1.891), thiuram mix (OR 1.614), as well as nickel (OR 1.530), cobalt (OR 1.683), and chromium (OR 2.089). Conclusions: Atopic skin diathesis proved to be the most important intrinsic risk factor for contact sensitization to few, specific allergens. Past or present AD was a less relevant variable.
CRIS-Team Scopus Importer:2021-02-26
Keywords: atopic dermatitis; atopy score; contact allergy; eczema; metal allergy

Atopische Hautdiathese ist stärker mit spezifischen Kontaktallergien assoziiert als atopische Dermatitis - Forkel, Susann; Cevik, Naciye; Schill, Tillmann; Worm, Margitta; Mahler, Vera; Weisshaar, Elke; Vieluf, Dieter; Pfützner, Wolfgang; Löffler, Harald; Schön, Michael P.; Geier, Johannes; Buhl, Timo (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-02-26

Atopy patch testing with aeroallergens in a large clinical population of dermatitis patients in Germany and Switzerland, 2000-2015: a retrospective multicentre study - Dickel, H.; Kuhlmann, L.; Bauer, A.; Bircher, A. J.; Breuer, K.; Fuchs, T.; Grabbe, J.; Mahler, Vera; Pföhler, C.; Przybilla, B.; Rieker-Schwienbacher, J.; Schröder-Kraft, C.; et al. (Journal of the European Academy of Dermatology and Venereology, 2020)
Background: The diagnostic significance of the atopy patch test for the management of dermatitis possibly triggered by aeroallergens is still controversial. However, sufficiently large studies with routinely tested standardized aeroallergen patch test preparations in dermatitis patients are lacking. Objective: To evaluate the reaction frequency and the reaction profiles of 10 until mid-2015 commercially available, standardized aeroallergen patch test preparations of the ‘Stallerpatch’ test series (Stallergenes, Antony Cedex, France) in a large multicentre patient cohort. Methods: A retrospective data analysis of patients with suspected aeroallergen-dependent eczematous skin lesions was performed, who were patch tested in 15 Information Network of Departments of Dermatology-associated clinics between 2000 and 2015. Patients were stratified according to their atopic dermatitis (AD) status. Results: The study group included 3676 patients (median age 41 years, 34.8% males, 54.5% AD). The most common aeroallergens causing positive patch test reactions were Dermatophagoides pteronyssinus (19.6%), Dermatophagoides farinae (16.9%), birch (6.2%), timothy grass (6.0%), cat dander (5.4%), mugwort (4.9%) and dog dander (4.6%). Reactions to other pollen allergen preparations, that is 5 grasses (3.2%), cocksfoot (2.1%) and plantain (1.6%), were less common. Positive patch test reactions to aeroallergens were consistently more frequent in patients with AD. These patients showed proportionally less dubious, follicular, irritant and weak positive reactions. Independent of AD status, a patient history of past or present allergic rhinitis was associated with an increased chance of a positive aeroallergen patch test reaction to pollen allergens. Conclusion: The aeroallergen patch test is a useful add-on tool in clinical routine, especially in patients with AD and/or respiratory allergy. A patch test series comprising Dermatophagoides pteronyssinus, Dermatophagoides farinae, birch, timothy grass, cat dander and mugwort seems to be suitable. Controlled studies with specific provocation and elimination procedures are required to further evaluate the diagnostic significance of the proposed screening series.
CRIS-Team Scopus Importer:2020-03-20

Challenging a paradigm: skin sensitivity to sodium lauryl sulfate is independent of atopic diathesis - Heetfeld, A. B.; Schill, T.; Schroeder, S. S.; Forkel, S.; Mahler, Vera; Pfuetzner, W.; Schoen, M. P.; Geier, J.; Buhl, T. (British Journal of Dermatology, 2019)
Background Sodium lauryl sulfate (SLS) is the best-studied detergent in irritant contact dermatitis. In atopic dermatitis, the two major pathophysiological abnormalities concern skin barrier function and regulation of cutaneous immune responses. The probability of atopic skin diathesis can be assessed by comprehensive analysis of patient history, as well as clinical and laboratory findings, resulting in the Erlangen Atopy Score (EAS). Objectives To investigate the impacts of (i) atopic skin diathesis according to the EAS and (ii) the physician-assessed diagnoses 'atopic dermatitis', 'allergic rhinitis' and 'allergic asthma' on SLS skin reactions. Methods This is a retrospective analysis of data from 2030 consecutive patients patch tested with SLS (0 center dot 25% aqueous) from two tertiary referral centres in Germany, from 2008 to 2014. Results Patients with a high probability of atopic skin diathesis showed no significant increase in positive SLS reactions compared with patients without atopic skin diathesis (14 center dot 2% vs. 16 center dot 8%). The grading of positive SLS skin reactions (1-4) revealed no differences in patients with or without atopic skin diathesis. Furthermore, diagnoses of atopic dermatitis, allergic rhinitis or allergic asthma had no impact on positive SLS skin reactions in multivariate logistic regression analysis. Conclusions We found no association of increased skin irritability to SLS with atopic skin diathesis, atopic dermatitis, allergic rhinitis or allergic asthma in a large patient cohort. It therefore seems that the test of skin irritability with SLS, which is currently common practice in many centres, does not allow prediction of susceptibility to irritant eczematous inflammation in atopic vs. nonatopic individuals. What's already known about this topic?
CRIS-Team WoS Importer:2019-12-06

Chronic hand eczema in Germany: 5-year follow-up data from the CARPE registry - Apfelbacher, Christian J.; Ofenloch, Robert F.; Weisshaar, Elke; Molin, Sonja; Bauer, Andrea; Mahler, Vera; Heinrich, Andreas; Von Kiedrowski, Ralph; Schmitt, Jochen; Elsner, Peter; Diepgen, Thomas L. (Contact Dermatitis, 2019)
Background: The CARPE registry was set up in 2009 to prospectively investigate the management of patients with chronic hand eczema (CHE). Objectives: To report comprehensive follow-up data from the CARPE registry. Patients and methods: We investigated sociodemographic and clinical characteristics, provision of medical care, physician-assessed outcomes, and patient-reported outcomes (PROs). Data were collected between 2009 and 2016, with up to 5 years of follow-up, and are reported descriptively. Results: Overall, 1281 patients were included in the registry (53.7% female). Mean age was 47.0 years. Of the patients, 793 and 231 completed the 2-year follow-up and 5-year follow-up, respectively. At baseline, 5.4% had changed or given up their job because of CHE, the average duration of CHE was 6.1 years, and, in 22.4%, the CHE was severe according to physician global assessment. Systemic treatment (alitretinoin, acitretin, and methotrexate) was prescribed at least once to 39.0% of the patients during the course of the follow-up. Disease severity, quality of life and treatment satisfaction improved over time, and the proportion of patients receiving systemic treatments decreased. Conclusions: Under continued dermatological care, substantial improvements in disease severity and PROs over time was achieved during the course of the CARPE registry, even in patients with long-standing and severe hand eczema.
CRIS-Team Scopus Importer:2019-05-24
Keywords: hand eczema; quality of life; registry; treatment

Contact allergy induced by bisphenol A diglycidyl ether leachables from aluminium tubes for pharmaceutical use - Breuer, K.; Lipperheide, C.; Lipke, U.; Zapf, T.; Dickel, H.; Treudler, R.; Molin, S.; Mahler, Vera; Pfoehler, C.; Loeffler, H.; Schwantes, H.; Schnuch, A. (Allergy, 2015)
Aluminium tubes for pharmaceutical use are internally lacquered with epoxy resins (ER) based on bisphenol A diglycidyl ether (BADGE). Recently, it was shown that remnants of ER polymerization like BADGE are extractable from epoxy-based coatings of commercially available tubes and may leach into semi-solid drug preparations. We aimed to evaluate the safety of BADGE-contaminated macrogol ointments in individuals sensitized to ER based on BADGE by use tests.Repeated open application testing (ROAT) in 11 patients sensitized to ER based on BADGE with BADGE in macrogol ointments (3 mg/kg; 30 mg/kg, equivalent to BADGE concentration determined in macrogol ointment after storage in a commercially available tube; 300 mg/kg).The 30 mg/kg BADGE ointment elicited reactions in three patients, and another three patients reacted to 300 mg/kg BADGE ointment. No reactions to the vehicle control and 3 mg/kg BADGE were observed.Elevated BADGE concentrations in ER-coated aluminium tubes pose a risk of developing contact dermatitis to patients sensitized to ER based on BADGE. Quality standards are deemed necessary for the production of ER-coated aluminium tubes intended for pharmaceutical use and should consider the results of the present ROAT study.
EVALuna2:19547

Contact allergy to preservatives: ESSCA* results with the baseline series, 2009-2012 - Gimenez-Arnau, A. M.; Deza, G.; Bauer, A.; Johnston, G. A.; Mahler, Vera; Schuttelaar, M. -L.; Sanchez-Perez, J.; Silvestre, J. F.; Wilkinson, M.; Uter, Wolfgang (Journal of the European Academy of Dermatology and Venereology, 2017)
BACKGROUND: Allergic contact dermatitis caused by biocides is common and causes significant patient morbidity. OBJECTIVE: To describe the current frequency and pattern of patch test reactivity to biocide allergens included in the baseline series of most European countries. METHODS: Data collected by the European Surveillance System on Contact Allergies (ESSCA) network between 2009 and 2012 from 12 European countries were analysed. RESULTS: Methylisothiazolinone 0.2% aq. produced the highest prevalence of sensitization during the study period, with an overall prevalence of 4.5%. The mixture methylchloroisothiazolinone /methylisothiazolinone tested at 0.02% aq. followed closely, with 4.1% of positive reactions. Other preservatives with lower rates of sensitization, but still over 1%, include methyldibromo glutaronitrile (MDBGN) 0.5% pet. and iodopropynyl butylcarbamate (IPBC) 0.2% pet. Formaldehyde releasers and parabens yielded less than 1% positive reactions during the study period. Some regional differences in the prevalence of contact allergy to biocides among European countries were observed. CONCLUSIONS: Contact allergy to biocides is common throughout Europe, and regional differences could be explained by differences in exposure or characteristics of the population tested. Timely regulatory action for isothiazolinones is required. Although MDBGN is banned from cosmetics products since 2005, sensitization prevalence has not appeared to plateau. IPBC is an emerging allergen with an increasing prevalence over the last few years, and its inclusion in the European baseline series may be appropriate.
EVALuna2:34200

Contact sensitization in metalworkers: Data from the information network of departments of dermatology (IVDK), 2010–2018 - Schubert, Steffen; Brans, Richard; Reich, Anna; Buhl, Timo; Skudlik, Christoph; Schröder-Kraft, Claudia; Gina, Michal; Weisshaar, Elke; Mahler, Vera; Dickel, Heinrich; Schön, Michael P.; John, Swen M.; et al. (Contact Dermatitis, 2020)
Background: Metalworkers are exposed to a variety of contact allergens by handling tools, metals, metalworking fluids (MWFs), oils and greases, rubber materials, and so on. Most large-scale reports on contact allergy due to MWFs are more than 10-years-old, and there are only few studies on contact allergy in mechanics and other metal workers not exposed to MWFs. Objectives: To describe a current spectrum of contact sensitization in metalworkers with occupational dermatitis (OD). Patients and Methods: Retrospective analysis of patch test data collected by the Information Network of Departments of Dermatology (IVDK; 2010–2018), stratifying for 804 cutting metalworkers, 2197 mechanics, and 355 other metalworkers. Results: Cutting metalworkers were most frequently sensitized to monoethanolamine (12.6%), colophonium/abietic acid (11.4%) and formaldehyde releasers (up to 8.5%) from the MWF series, and formaldehyde (4.6%) and iodopropynyl butylcarbamate (4.6%) from the baseline series. Sensitization among mechanics and other metalworkers indicates possible occupational exposure to MWFs, glues, and resins, although this may not be expected from their job titles. Conclusions: The spectrum of MWF contact allergens remained largely unchanged during the last years. Taking a comprehensive occupational history is indispensable in order to not miss relevant allergen exposures.
CRIS-Team Scopus Importer:2020-10-16
Keywords: colophonium; formaldehyde releaser; iodopropynyl butylcarbamate; mechanics; metalworkers; metalworking fluid; monoethanolamine; occupational dermatitis

Developing a cosmetic series: Results from theESSCAnetwork, 2009-2018 - Horton, Emma; Uter, Wolfgang; Geier, Johannes; Ballmer-Weber, Barbara; Bauer, Andrea; Bircher, Andreas; Dickel, Heinrich; Gimenez-Arnau, Ana; Goncalo, Margarida; John, Swen Malte; Mahler, Vera; Schuttelaar, Marie L. A.; et al. (Contact Dermatitis, 2020)
Background There is considerable variability across European patch test centres as to which allergens are included in local and national cosmetics series. Objectives To propose a standardized, evidence-based cosmetic series for Europe based on up-to-date analysis of relevant contact allergens. Methods We collated data from the European Surveillance System on Contact Allergies (ESSCA) from 2009 to 2018 to determine which cosmetic allergens produce a high yield of contact allergy. Contact allergens with a prevalence of >0.3% that were considered relevant were included. Rare contact allergens were excluded if deemed no longer relevant or added to a supplemental cosmetic series for further analysis. Results Sensitization prevalences of 39 cosmetic contact allergens were tabulated. Thirty of these allergens yielded >0.3% positive reactions and are therefore included in our proposed European cosmetic series. Six were considered no longer relevant and therefore excluded. Three were included in a supplementary European cosmetic series. An additional nine allergens were included in either the core or supplemental European cosmetic series following literature review. Conclusion We have derived a potential European cosmetic series based upon the above methods. This will require ongoing investigation based upon the changing exposure profiles of cosmetic allergens as well as new and evolving substances.
CRIS-Team WoS Importer:2020-10-16

DKG statement on the use of metal alloy discs for patch testing in suspected intolerance to metal implants - Thomas, Peter; Geier, Johannes; Dickel, Heinrich; Diepgen, Thomas; Hillen, Uwe; Kreft, Burkhard; Schnuch, Axel; Szliska, Christiane; Mahler, Vera (Journal der Deutschen Dermatologischen Gesellschaft, 2015)
Intolerance reactions to metal implants may be caused by metal allergy. However, prior to implantation, 'prophetic'/prophylactic patch testing should not be performed. Pre-implant patch testing should only be done to verify or exclude metal allergy in patients with a corresponding history. In case of implant-related complications - in particular following replacement arthroplasty - such as pain, effusion, skin lesions, reduced range of motion or implant loosening, orthopedic causes should be ruled out first. Workup of suspected metal implant allergy should then be done using the DKG standard series, which includes nickel, cobalt, and chromium preparations. Various studies assessing the usefulness of metal alloy discs for patch testing have shown this particular approach to be ineffective with respect to providing reliable information on metal allergy. Any positive reaction in such tests cannot be assigned to a specific metal contained within the alloy. Furthermore, there is a risk of broad and indiscriminate use of these readily available discs. Accordingly, given the lack of additional benefit compared to patch testing with standardized metal salt preparations, we do not recommend patch testing with metal alloy discs.
EVALuna2:19562

Efficacy and safety of topical delgocitinib in patients with chronic hand eczema: data from a randomized, double-blind, vehicle-controlled phase IIa study - Worm, M.; Bauer, A.; Elsner, P.; Mahler, Vera; Molin, S.; Nielsen, T. S. S. (British Journal of Dermatology, 2019)
Background Management of chronic hand eczema (CHE) remains a challenge; effective topical treatment is limited to corticosteroids. Objectives To assess the efficacy and safety of a novel, pan-Janus kinase inhibitor (delgocitinib) in patients with CHE. Methods In this randomized, double-blind, phase IIa study, patients with CHE received delgocitinib ointment 30 mg g(-1) or vehicle ointment for 8 weeks. The primary end point was the proportion of patients achieving treatment success ['clear'/'almost clear' skin with >= 2-point improvement in the Physician's Global Assessment of disease severity (PGA)] at week 8. Secondary end points included Hand Eczema Severity Index (HECSI) score changes and the proportion of patients achieving treatment success on the Patient's Global Assessment of disease severity (PaGA). Results Ninety-one patients were randomized. More patients receiving delgocitinib (46%) than vehicle (15%) [odds ratio 4 center dot 89, 95% confidence interval (CI) 1 center dot 49-16 center dot 09; P = 0 center dot 009] achieved treatment success (PGA). Adjusted mean HECSI score at week 8 was lower with delgocitinib (13 center dot 0) than with vehicle (25 center dot 8) (adjusted mean difference -12 center dot 88, 95% CI -21 center dot 47 to -4 center dot 30; P = 0 center dot 003). More patients receiving delgocitinib than vehicle achieved treatment success by PaGA, but this did not reach statistical significance. The incidence of adverse events was similar with delgocitinib and vehicle; none led to discontinuation of delgocitinib. Conclusions Delgocitinib ointment was efficacious and well tolerated. As a plateau of efficacy was not observed, a longer treatment period may lead to increased efficacy. Further clinical studies are warranted to confirm these findings in patients with CHE.
CRIS-Team WoS Importer:2019-11-19

Factors increasing the risk for a severe reaction in anaphylaxis: An analysis of data from The European Anaphylaxis Registry - Worm, M.; Francuzik, Wojciech; Renaudin, J. -M.; Bilo, M. B.; Cardona, V.; Hofmeier, K. Scherer; Kohli, A.; Bauer, A.; Christoff, G.; Cichocka-Jarosz, E.; Hawranek, T.; Hourihane, J. O. 'B.; et al. (Allergy, 2018)
BACKGROUND: Preventive measures to decrease the frequency and intensity of anaphylactic events are essential to provide optimal care for allergic patients. Aggravating factors may trigger or increase the severity of anaphylaxis and therefore need to be recognized and avoided. OBJECTIVE: To identify and prioritize factors associated with an increased risk of developing severe anaphylaxis. METHODS: Data from the Anaphylaxis Registry (122 centers in 11 European countries) were used in logistic regression models considering existing severity grading systems, elicitors, and symptoms to identify the relative risk of factors on the severity of anaphylaxis. RESULTS: We identified higher age and concomitant mastocytosis (OR: 3.1, CI: 2.6-3.7) as the most important predictors for an increased risk of severe anaphylaxis. Vigorous physical exercise (OR: 1.5, CI: 1.3-1.7), male sex (OR: 1.2, CI: 1.1-1.3), and psychological burden (OR: 1.4, CI: 1.2-1.6) were more often associated with severe reactions. Additionally, intake of beta-blockers (OR: 1.9, CI: 1.5-2.2) and ACE-I (OR: 1.28, CI: 1.05, 1.51) in temporal proximity to allergen exposition was identified as an important factor in logistic regression analysis. CONCLUSION: Our data suggest it may be possible to identify patients who require intensified preventive measures due to their relatively higher risk for severe anaphylaxis by considering endogenous and exogenous factors.
EVALuna2:34790

Formaldehyde 2% is not a useful means of detecting allergy to formaldehyde releasers— results of the ESSCA network, 2015-2018 - Whitehouse, Heather; Uter, Wolfgang; Geier, Johannes; Ballmer-Weber, Barbara; Bauer, Andrea; Cooper, Susan; Czarnecka-Operacz, Magdalena; Dagmar, Simon; Dickel, Heinrich; Fortina, Anna Belloni; Gallo, Rosella; Gimenez-Arnau, Ana Maria; et al. (Contact Dermatitis, 2020)
Background: Studies suggest that patch testing with formaldehyde releasers (FRs) gives significant additional information to formaldehyde 1% aq. and should be considered for addition to the European baseline series (EBS). It is not known if this is also true for formaldehyde 2% aq. Objectives: To determine the frequency of sensitization to formaldehyde 2% aq. and co-reactivity with FRs. To establish whether there is justification for including FRs in the EBS. Materials and Methods: A 4-year, multi-center retrospective analysis of patients with positive patch test reactions to formaldehyde 2% aq. and five FRs. Results: A maximum of 15 067 patients were tested to formaldehyde 2% aq. and at least one FR. The percentage of isolated reactions to FR, without co-reactivity to, formaldehyde 2% aq. for each FR were: 46.8% for quarternium-15 1% pet.; 67.4% imidazolidinyl urea 2% pet.; 64% diazolidinyl urea 2% pet.; 83.3% 1,3-dimethylol-5, 5-dimethyl hydantoin (DMDM) hydantoin 2% pet. and 96.3% 2-bromo-2-nitropropane-1,3-diol 0.5% pet. This demonstrates that co-reactivity varies between FRs and formaldehyde, from being virtually non-existent in 2-bromo-2-nitropropane-1,3-diol 0.5% pet. (Cohen's kappa: 0, 95% confidence interval [CI] −0.02 to 0.02)], to only weak concordance for quaternium-15 [Cohen's kappa: 0.22, 95%CI 0.16 to 0.28)], where Cohen's kappa value of 1 would indicate full concordance. Conclusions: Formaldehyde 2% aq. is an inadequate screen for contact allergy to the formaldehyde releasers, which should be considered for inclusion in any series dependant on the frequency of reactions to and relevance of each individual allergen.
CRIS-Team Scopus Importer:2020-10-23
Keywords: 2-bromo-2-nitropropane-1; 3-diol; contact allergy; cosmetics; diazolidinyl urea; DMDM hydantoin; formaldehyde formaldehyde releasers; imidazolidinyl urea; quaternium-15

Guideline on diagnostic procedures for suspected hypersensitivity to beta-lactam antibiotics: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in collaboration with the German Society of Allergology (AeDA), German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Contact Dermatitis Research Group (DKG), the Austrian Society for Allergology and Immunology (ÖGAI), and the Paul-Ehrlich Society for Chemotherapy (PEG) - Wurpts, Gerda; Aberer, Werner; Dickel, Heinrich; Brehler, Randolf; Jakob, Thilo; Kreft, Burkhard; Mahler, Vera; Merk, Hans F.; Mülleneisen, Norbert; Ott, Hagen; Pfützner, Wolfgang; Röseler, Stefani; et al. (Allergo Journal, 2019)
This guideline on diagnostic procedures for suspected beta-lactam antibiotic (BLA) hypersensitivity was written by the German and Austrian professional associations for allergology, and the Paul-Ehrlich Society for Chemotherapy in a consensus procedure according to the criteria of the German Association of Scientific Medical Societies. BLA such as penicillins and cephalosporins represent the drug group that most frequently triggers drug allergies. However, the frequency of reports of suspected allergy in patient histories clearly exceeds the number of confirmed cases. The large number of suspected BLA allergies has a significant impact on, e.g., the quality of treatment received by the individual patient and the costs to society as a whole. Allergies to BLA are based on different immunological mechanisms and often manifest as maculopapular exanthema, as well as anaphylaxis; and there are also a number of less frequent special clinical manifestations of drug allergic reactions. All BLA have a beta-lactam ring. BLA are categorized into different classes: penicillins, cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors with different chemical structures. Knowledge of possible cross-reactivity is of considerable clinical significance. Whereas allergy to the common beta-lactam ring occurs in only a small percentage of all BLA allergic patients, cross-reactivity due to side chain similarities, such as aminopenicillins and aminocephalosporins, and even methoxyimino cephalosporins, are more common. However, the overall picture is complex and its elucidation may require further research. Diagnostic procedures used in BLA allergy are usually made up of four components: patient history, laboratory diagnostics, skin testing (which is particularly important), and drug provocation testing. The diagnostic approach—even in cases where the need to administer a BLA is acute—is guided by patient history and risk–benefit ratio in the individual case. Here again, further studies are required to extend the present state of knowledge. Performing allergy testing for suspected BLA hypersensitivity is urgently recommended not only in the interests of providing the patient with good medical care, but also due to the immense impact of putative BLA allergies on society as a whole.
CRIS-Team Scopus Importer:2019-08-02
Keywords: Allergy; Beta-lactam antibiotics; Cephalosporin; Drug hypersensitivity; Penicillin

H1-antihistamine-refractory chronic spontaneous urticaria: it's worse than we thought - first results of the multicenter real-life AWARE study - Maurer, M.; Staubach, P.; Raap, U.; Richter-Huhn, G.; Bauer, A.; Rueff, F.; Jakob, T.; Yazdi, A. S.; Mahler, Vera; Wagner, N.; Lippert, U.; Hillen, U.; et al. (Clinical and Experimental Allergy, 2017)
BACKGROUND: Most data on chronic spontaneous urticaria (CSU) originate from highly selected patient populations treated at specialized centres. Little is known about CSU patient characteristics and the burden of CSU in routine clinical practice. AWARE (A World-wide Antihistamine-Refractory chronic urticaria patient Evaluation) is an ongoing global study designed to assess chronic urticaria in the real-life setting. OBJECTIVE: To describe the baseline characteristics of the first 1539 German AWARE patients with H1-antihistamine-refractory CSU. METHODS: This prospective non-interventional study included patients (18-75 years) with a diagnosis of H1-antihistamine-refractory CSU for > 2 months. Baseline demographic and disease characteristics, comorbidities, and pharmacological treatments were recorded. Quality of life (QoL) was assessed using the dermatology life quality index (DLQI), chronic urticaria QoL questionnaire (CU-Q2 oL), and angioedema QoL questionnaire (AE-QoL, in cases of angioedema). Previous healthcare resource utilization and sick leave data were collected retrospectively. RESULTS: Between March and December 2014, 1539 patients were assessed in 256 sites across Germany. The percentage of females, mean age, and mean body mass index were 70%, 46.3 years, and 27 kg/m2 , respectively. The mean urticaria control test score was 7.9, one in two patients had angioedema, and the most frequent comorbidities were chronic inducible urticaria (CIndU; 24%), allergic rhinitis (18.2%), hypertension (18.1%), asthma (12%), and depression (9.5%). Overall, 57.6% of patients were receiving at least one pharmacological treatment including second-generation H1-antihistamines (46.3%), first-generation H1-antihistamines (9.1%), and corticosteroids (15.8%). The mean DLQI, total CU-Q2 oL, and total AE-QoL scores were 8.3, 36.2, and 46.8, respectively. CSU patients reported frequent use of healthcare resources, including emergency services (29.7%), general practitioners (71.9%), and additional allergists or dermatologists (50.7%). CONCLUSIONS AND CLINICAL RELEVANCE: This study reveals that German H1-antihistamine-refractory CSU patients have high rates of uncontrolled disease, angioedema, and comorbid CIndU, are undertreated, have impaired QoL, and rely heavily on healthcare resources.
EVALuna2:35410

Hand dermatitis - differential diagnoses, diagnostics, and treatment options - Mahler, Vera (Journal der Deutschen Dermatologischen Gesellschaft, 2016)
The pathogenesis of hand dermatitis is multifactorial, and includes factors such as genetic predisposition and exposure. A high incidence rate is associated with female gender, contact allergy, atopic dermatitis, and wet work. The most important risk factors for the persistence of hand dermatitis include its extent, contact allergic or atopic etiology, childhood dermatitis, and early onset (before the age of 20). The cost of illness of hand dermatitis corresponds to this seen in moderate to severe psoriasis. The diagnostic workup of hand dermatitis and its differential diagnoses requires a detailed assessment of occupational and recreational exposure. In case of possible work-related triggers, early notification of the accident insurer should be sought (via the dermatologist's report). Exposure to a contact allergen is a contributing factor in one-half of all cases of hand dermatitis. It is therefore imperative that all patients with hand dermatitis persisting for more than three months undergo patch testing. Successful and sustainable treatment of hand dermatitis starts with the proper identification and elimination of individual triggers, including the substitution of identified contact allergens and irritants, as well as optimizing preventive measures. Graded therapy taking the clinical severity into account is essential. Validated instruments may be used to monitor therapeutic efficacy.
EVALuna2:19543

High frequency of contact allergy to implant and bone cement components, in particular gentamicin, in cemented arthroplasty with complications: usefulness of late patch test reading - Thomas, Benjamin; Kulichova, Daniela; Wolf, Ronald; Summer, Burkhard; Mahler, Vera; Thomas, Peter (Contact Dermatitis, 2015)
Arthroplasty patients with complications may be sensitized to implant components.To quantify patch test reactions to implant materials in aseptic cemented arthroplasty patients with complications, and to evaluate the benefit of late patch test reading at D6.Analyses of patch test reactions to baseline series and bone cement components and of the questionnaire-aided histories of 250 consecutive patients with suspected implant allergy were performed. Patch tests were read at D2, D3, and D6.There were 187 positive reactions to the 29 allergens of the baseline series, and 52 to the seven allergens of the bone cement series. Forty-nine of 250 patients reacted to the bone cement series. In contrast to 'early allergens' such as fragrance mix, late reading at D6 increased the number of positive reactions by 11/32 for nickel, 1/5 for cobalt, and 2/4 for chromium. With bone cement components, most reactions were to gentamicin (25 of 250 patients), and 17 of 25 appeared only at D6.Late reading is useful for patch tests with metals and bone cement components. With only D2/D3 readings, 32 reactions to nickel, cobalt, chromium and bone cement components would have been missed. This underlines the utility of late reading in general and in complicated cemented arthroplasty patients, given the unexpectedly high number of gentamicin reactions.
EVALuna2:19557

HLA class II peptide tetramers vs allergen-induced proliferation for identification of allergen-specific CD4 T cells - Van Hemelen, D.; Mahler, Vera; Fischer, G.; Fae, I.; Reichl-Leb, V.; Pickl, W.; Jutel, M.; Smolinska, S.; Ebner, C.; Bohle, B.; Jahn-Schmid, B. (Allergy, 2015)
Fluorescence-labeled MHC class II/peptide tetramer complexes are considered as optimal tools to characterize allergen-specific CD4(+) T cells, but this technique is restricted to frequently expressed HLA class II molecules and knowledge of immunodominant epitopes. In contrast, allergen-stimulated proliferation assessed by CFSE dilution is less sophisticated and widely applicable. The major mugwort allergen, Art v 1, contains only one single, immunodominant, HLA-DR1-restricted epitope (Art v 125-36 ). Thus, essentially all Art v 1-reactive cells should be identified by a HLA-DRB1*01:01/Art v 119-36 tetramer.We compared specificity and sensitivity of tetramer(+) and allergen-induced proliferating (CFSE(lo) ) CD4(+) T cells by flow cytometry.The frequency of tetramer(+) CD4(+) T cells determined ex vivo in PBMC of mugwort-allergic individuals ranged from 0 to 0.029%. After 2-3 weeks of in vitro expansion, sufficient tetramer(+) T cells for phenotyping were detected in 83% of Art v 125-36 -reactive T-cell lines (TCL) from mugwort-allergic individuals, but not in TCL from healthy individuals. The tetramers defined bona fide Th2 cells. Notably, Art v 125-36 -reactive TCL depleted of tetramer(+) T cells still reacted to the peptide, and only 44% of Art v 125-36 -specific T-cell clones were detected by the tetramer. CFSE(lo) CD4(+) T cells contained only 0.3-10.7% of tetramer(+) T cells and very low proportions of Th2 cells.Allergen-specific T cells can be identified by HLA class II tetramers with high specificity, but unexpected low sensitivity. In contrast, allergen-stimulated CFSE(lo) CD4(+) T cells contain extremely high fractions of bystander cells. Therefore, for T-cell monitoring, either method should be interpreted with caution.
EVALuna2:19542

House dust mite-specific immunotherapy with two licensed vaccines: Outcome under clinical routine conditions - Mahler, Vera; Klein, Christian; Sager, Angelika; Zimmermann, Juergen (Immunity, Inflammation and Disease, 2017)
INTRODUCTION: House dust mite (HDM) allergens are major causes for the development of allergic diseases. A disease modifying effect and clinical benefit of allergen immunotherapy (AIT) has been demonstrated in a number of clinical trials. Clinical trials, however, are carried out in selected populations under specific conditions based on inclusion and exclusion criteria and may not represent the entire patient population from medical practice. Objective of this study conducted in patients with HDM allergy was to systematically collect information about the benefit of AIT under clinical routine conditions. METHODS: In this prospective, multi-center non-interventional study, 220 patients (117 adults, 103 children) with HDM allergy receiving subcutaneous AIT with Depigoid® were monitored for 2 years. Organ-specific key symptoms, health-related quality of life (QoL), and the use of concomitant anti-allergic medication were assessed at baseline and after 12 and 24 months. Effectiveness and tolerability of the AIT was assessed by physicians and patients. Occurrence of adverse events (AEs) was continuously monitored. RESULTS: Two hundred and nineteen patients (116 adults, 103 children) were evaluated. A major improvement of the total symptom-score was observed after 24 (12) months in 76% (72%) and 80% (79%) of adults and children, respectively, accompanied by a reduction in concomitant anti-allergic medication and a pronounced improvement in QoL. The effectiveness and tolerability of the AIT was estimated as very good/good by 80-90% of physicians and patients. AEs were observed in 4/117 adults (3.4%) and in 7/103 children (6.8%). Serious AEs were reported in three adults and one child: A grade-II anaphylactic reaction (one adult) controlled by oral antihistamines (no hospitalization) classified as "definitely," three others as not (2) or possibly (1) drug-related. CONCLUSIONS: The data collected from 220 patients confirm the efficacy, tolerability/safety, and acceptance of AIT with Depigoid® in adults and children with HDM allergy under routine clinical conditions.
EVALuna2:35421

Human AZFb deletions cause distinct testicular pathologies depending on their extensions in Yq11 and the Y haplogroup: new cases and review of literature - Vogt, P. H.; Bender, U.; Deibel, B.; Kiesewetter, Franklin; Zimmer, J.; Strowitzki, T. (Cell & Bioscience, 2021)
Genomic AZFb deletions in Yq11 coined “classical” (i.e. length of Y DNA deletion: 6.23 Mb) are associated with meiotic arrest (MA) of patient spermatogenesis, i.e., absence of any postmeiotic germ cells. These AZFb deletions are caused by non-allelic homologous recombination (NAHR) events between identical sequence blocks located in the proximal arm of the P5 palindrome and within P1.2, a 92 kb long sequence block located in the P1 palindrome structure of AZFc in Yq11. This large genomic Y region includes deletion of 6 protein encoding Y genes, EIFA1Y, HSFY, PRY, RBMY1, RPS4Y, SMCY. Additionally, one copy of CDY2 and XKRY located in the proximal P5 palindrome and one copy of BPY1, two copies of DAZ located in the P2 palindrome, and one copy of CDY1 located proximal to P1.2 are included within this AZFb microdeletion. It overlaps thus distally along 2.3 Mb with the proximal part of the genomic AZFc deletion. However, AZFb deletions have been also reported with distinct break sites in the proximal and/or distal AZFb breakpoint intervals on the Y chromosome of infertile men. These so called “non-classical” AZFb deletions are associated with variable testicular pathologies, including meiotic arrest, cryptozoospermia, severe oligozoospermia, or oligoasthenoteratozoospermia (OAT syndrome), respectively. This raised the question whether there are any specific length(s) of the AZFb deletion interval along Yq11 required to cause meiotic arrest of the patient’s spermatogenesis, respectively, whether there is any single AZFb Y gene deletion also able to cause this “classical” AZFb testicular pathology? Review of the literature and more cases with “classical” and “non-classical” AZFb deletions analysed in our lab since the last 20 years suggests that the composition of the genomic Y sequence in AZFb is variable in men with distinct Y haplogroups especially in the distal AZFb region overlapping with the proximal AZFc deletion interval and that its extension can be “polymorphic” in the P3 palindrome. That means this AZFb subinterval can be rearranged or deleted also on the Y chromosome of fertile men. Any AZFb deletion observed in infertile men with azoospermia should therefore be confirmed as “de novo” mutation event, i.e., not present on the Y chromosome of the patient’s father or fertile brother before it is considered as causative agent for man’s infertility. Moreover, its molecular length in Yq11 should be comparable to that of the “classical” AZFb deletion, before meiotic arrest is prognosed as the patient’s testicular pathology.
CRIS-Team Scopus Importer:2021-05-14
Keywords: AZFb Y genes; AZFb “de novo” and “polymorphic” deletions; AZFb-c amplicons; Meiotic arrest; OAT syndrome; Y-haplogroups; “Classical” and “non-classical” AZFb deletions

Identification of Sola l 4 as Bet v 1 homologous pathogenesis related-10 allergen in tomato fruits - Wangorsch, Andrea; Jamin, Annette; Foetisch, Kay; Malczyk, Anna; Reuter, Andreas; Vierecke, Sabine; Schuelke, Stefan; Bartel, Detlef; Mahler, Vera; Lidholm, Jonas; Vieths, Stefan; Scheurer, Stephan (Molecular Nutrition & Food Research, 2015)
The aim was to investigate the potential contribution of a major birch pollen Bet v 1-homologous allergen to birch pollen-associated tomato fruit allergy.Two isoforms of a Bet v 1-homologous protein (designated Sola l 4) from tomato fruit were identified by cDNA-cloning and produced as recombinant proteins. Allergen-specific IgE levels to tomato, birch pollen, Bet v 1, and Sola l 4 were determined in birch pollen allergic patients with allergy or tolerance to tomato. Sola l 4 was recognized in 76% of birch/tomato allergic patients, while tomato- and Bet v 1-specific IgE was detectable in 64% and 81% of sera. Almost all patients sensitized to Bet v 1 reacted with Sola l 4. Both Sola l 4 isoforms displayed allergenic potency and IgE-cross-reactivity with Bet v 1 as investigated by competitive ELISA and in vitro mediator release assay. Nevertheless, the reactivity pattern of patients' sera was diverse.Sola l 4, a novel pathogenesis related-10 protein, qualifies as major allergen in tomato fruits. Data suggest Sola l 4 as class II allergen. IgE-testing using Sola l 4 showed low clinical specificity, but high sensitivity in tomato allergic patients and will further improve component-resolved allergy diagnosis.
EVALuna2:19548

Nickel and cobalt release from metal alloys of tools - a current analysis in Germany - Kickinger-Lörsch, Anja; Bruckner, Thomas; Mahler, Vera (Contact Dermatitis, 2015)
The former 'EU Nickel Directive' and, since 2009, the REACH Regulation (item 27 of Annex XVII) do not include all metallic objects. The nickel content of tools is not regulated by the REACH Regulation, even if they may come into in prolonged contact with the skin. Tools might be possible sources of nickel and cobalt sensitization, and may contribute to elicitation and maintenance of hand eczema.To perform a current analysis of the frequency of nickel or cobalt release from new handheld tools purchased in Germany.Six hundred unused handheld tools from the German market were investigated with the dimethylglyoxime test for nickel release and with disodium-1-nitroso-2-naphthol-3,6-disulfonate solution for cobalt release.Nickel release was detected in 195 of 600 (32.5%) items, and cobalt in only six (1%) of them. Positive nickel results were nearly twice as frequent in tools 'made in Germany' than in tools without a mark of origin. Tools made in other European countries did not release nickel. Cobalt release was only found in pliers and a saw. A correlation was found between price level and nickel release. Among toolkits, 34.2% were inhomogeneous concerning nickel release.The German market currently provides a large number of handheld tools that release nickel, especially tools 'made in Germany'. For consumer protection, it seems appropriate to include handheld tools in the REACH Regulation on nickel.
EVALuna2:19554

Non-celiac gluten/wheat sensitivity (NCGS)—a currently undefined disorder without validated diagnostic criteria and of unknown prevalence - Reese, Imke; Schaefer, Christiane; Kleine-Tebbe, Joerg; Ahrens, Birgit; Bachmann, Oliver; Ballmer-Weber, Barbara; Beyer, Kirsten; Bischoff, Stephan C.; Bluemchen, Katharina; Doelle, Sabine; Enck, Paul; Enninger, Axel; et al. (Allergo Journal, 2018)
Within the last decade, non-celiac gluten/wheat sensitivity (NCGS) has been increasingly discussed not only in the media but also among medical specialties. The existence and the possible triggers of NCGS are controversial. Three international expert meetings which proposed recommendations for NCGS were not independently organized and only partially transparent regarding potential conflicts of interest of the participants. The present position statement reflects the following aspects about NCGS from an allergist's and nutritionist's point of view: (A) Validated diagnostic criteria and/or reliable biomarkers are still required. Currently, this condition is frequently self-diagnosed, of unknown prevalence and non-validated etiology. (B) Gluten has not been reliably identified as an elicitor of NCGS because of high nocebo and placebo effects. Double-blind, placebo-controlled provocation tests are of limited value for the diagnosis of NCGS and should be performed in a modified manner (changed relation of placebo and active substance). (C) Several confounders hamper the assessment of subjective symptoms during gluten-reduced or gluten-free diets. Depending on the selection of food items, e.g., an increased vegetable intake with soluble fibers, diets may induce physiological digestive effects and can modify gastrointestinal transit times independent from the avoidance of gluten. (D) A gluten-free diet is mandatory in celiac disease based on scientific evidence. However, a medically unjustified avoidance of gluten may bear potential disadvantages and risks. (E) Due to a lack of diagnostic criteria, a thorough differential diagnostic work-up is recommended when NCGS is suspected. This includes a careful patient history together with a food-intake and symptom diary, if necessary an allergy diagnostic workup and a reliable exclusion of celiac disease. We recommend such a structured procedure since a medically proven diagnosis is required before considering the avoidance of gluten.
EVALuna2:50606

Non-Celiac Gluten-/Wheat Sensitivity (NCGS) - A previously undefined Symptoms with lack of Diagnostic Criteria and unknown Frequency Position Paper of the Working Group Food Allergy of the German Society of Allergology and clinical Immunology (DGAKI) - Reese, Imke; Schaefer, Christiane; Kleine-Tebbe, Joerg; Ahrens, Birgit; Bachmann, Oliver; Ballmer-Weber, Barbara; Beyer, Kirsten; Bischoff, Stephan C.; Bluemchen, Katharina; Doelle, Sabine; Enck, Paul; Enninger, Axel; et al. (Ernährungsumschau, 2018)
EVALuna2:51598

Omalizumab treatment in patients with chronic inducible urticaria: A systematic review of published evidence - Maurer, Marcus; Metz, Martin; Brehler, Randolf; Hillen, Uwe; Jakob, Thilo; Mahler, Vera; Pfohler, Claudia; Staubach, Petra; Treudler, Regina; Wedi, Bettina; Magerl, Markus (Journal of Allergy and Clinical Immunology, 2018)
BACKGROUND: Omalizumab, a recombinant anti-IgE antibody, effectively treats chronic spontaneous urticaria. Evidence is lacking in patients with chronic inducible urticarias (CIndUs), which are frequently H1-antihistamine resistant. OBJECTIVE: From the current published literature, we aimed to determine the strength of evidence for omalizumab efficacy and safety in the treatment of CIndUs. METHODS: We performed a PubMed search to identify evidence on omalizumab use in the following 9 CIndU subtypes: symptomatic dermographism, cold urticaria, delayed-pressure urticaria, solar urticaria, heat urticaria, vibratory angioedema, cholinergic urticaria, contact urticaria, and aquagenic urticaria. RESULTS: Forty-three trials, case studies, case reports, and analyses were identified. Our review indicates that omalizumab has substantial benefits in patients with various CIndUs. The evidence is strongest for symptomatic dermographism, cold urticaria, and solar urticaria. Little/no evidence was available on vibratory angioedema and aquagenic and contact urticaria. Our review supports rapid onset of action demonstrated through early symptom control in most cases, sometimes within 24 hours. Many patients gained complete/partial symptom relief and substantially improved quality of life. Adverse events were generally low, with omalizumab being well tolerated by most patients, including children. CONCLUSIONS: A strong body of evidence supports the use of omalizumab in the treatment of patients with therapy-refractory CIndU. More data from randomized controlled studies are warranted.
EVALuna2:34800

Patch test results with the European baseline series and additions thereof in the ESSCA network, 2015-2018 - Uter, Wolfgang; Bauer, Andrea; Belloni Fortina, Anna; Bircher, Andreas J.; Brans, Richard; Buhl, Timo; Cooper, Susan M.; Czarnecka-Operacz, Magdalena; Dickel, Heinrich; Dugonik, Aleksandra; Geier, Johannes; Gimenez-Arnau, Ana M.; et al. (Contact Dermatitis, 2020)
Background Clinical surveillance of the prevalence of contact allergy in consecutively patch tested patients is a proven instrument to continually assess the importance of contact allergens (haptens) assembled in a baseline series. Objectives To present current results from the European Surveillance System on Contact Allergies, including 13 countries represented by 1 to 11 departments. Methods Anonymized or pseudonymized patch test and clinical data from various data capture systems used locally or nationally as transferred to the Erlangen data centre were pooled and descriptively analysed after quality control. Results In the 4 years (2015-2018), data from 51 914 patients patch tested with the European baseline series (EBS) of contact allergens were analysed. Contact allergy to nickel was most frequent (17.6% positive), followed by contact allergy to fragrance mix I (6.9%), methylisothiazolinone (MI; 6.2%), andMyroxylon pereiraeresin (balsam of Peru; 5.8%). Conclusions While the prevalence of MI contact allergy decreased substantially following regulatory intervention, the persistently high levels of allergy to metals, fragrances, other preservatives, and rubber chemicals point to problems needing further research and, potentially, preventive efforts. Results with national additions to the baseline series provide important information on substances possibly to be considered for inclusion in the EBS.
CRIS-Team WoS Importer:2020-10-23

Patterns of chronic hand eczema: a semantic map analysis of the CARPE registry data - Cazzaniga, Simone; Apfelbacher, C.; Diepgen, T.; Ofenloch, R. F.; Weisshaar, E.; Molin, S.; Bauer, A.; Mahler, Vera; Elsner, P.; Schmitt, J.; Ballmer-Weber, B. K.; Spring, P.; et al. (British Journal of Dermatology, 2018)
BACKGROUND: Hand eczema has a high incidence and prevalence and has a negative impact on both physical and psychological well-being, with the risk of persistence as a chronic condition. Epidemiological studies on hand eczema provided mainly descriptive and risk analyses, but pattern analyses of variables associated with hand eczema, in particular chronic hand eczema, have not been explored to date. OBJECTIVES: To investigate and display the semantics of associations between variables of hand eczema obtained from the Swiss and German registries of chronic hand eczema (CARPE) to dissect patterns and novel links. METHODS: This was a cross-sectional study on selected variables from the CARPE registries. Associations between variables were analysed by means of an autoassociative system. A semantic connectivity map was generated by using a maximum spanning tree algorithm. RESULTS: Baseline datasets of 1466 patients with chronic hand eczema (Switzerland: 199; Germany: 1267) were analysed. Occupational exposure had the highest impact in the total and country cohorts. We identified two areas of exposure linked to corresponding occupations that clearly demarcated the sexes. CONCLUSIONS: This study, using semantic connectivity as a novel method of data analysis, reveals the complexity of features characterizing chronic hand eczema as well as novel association patterns that deserve further investigation.
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Quality of life and disease severity in dermatitis patients with fragrance allergy—A cross-sectional European questionnaire study - Bennike, Niels H.; Heisterberg, Maria S.; White, Ian R.; Mahler, Vera; Silvestre-Salvador, Juan F.; Giménez-Arnau, Ana; Johansen, Jeanne D. (Contact Dermatitis, 2019)
Background: Fragrance contact allergy is common, but few studies on quality of life (QoL) in affected patients exist. Recently, the disease-specific Fragrance Quality of Life Index (FQLI) was developed. Objectives: To characterize QoL in European dermatitis patients with fragrance contact allergy at the time of diagnosis. Methods: This was a cross-sectional study, in which 2011 Danish, British, Spanish and German adult consecutive dermatitis patients were invited to complete a questionnaire on self-reported disease severity, the Dermatology Life Quality Index (DLQI), and the FQLI immediately prior to being patch tested. Results: One thousand seven hundred and fifty-eight patients responded, and 259 (14.7%; country range 11.7%-18.5%) were fragrance-positive. Among these, the total (SD) DLQI score was 6.2 (5.6) and the total (SD) FQLI score was 60 (25), with both estimates being comparable to those in fragrance-negative patients. Adjusting the total FQLI score for age, sex and self-rated disease severity showed a higher (ie, worse) score in fragrance-positive patients (3.6-point increase; 95% confidence interval: 0.30-6.8 points; P = 0.03). Specifically, contact allergy to oxidized linalool was associated with greater impairment in QoL. Conclusions: QoL in patients with fragrance contact allergy is impaired at a level comparable to that in other patch tested dermatitis patients, at the time of diagnosis, across several European countries.
CRIS-Team Scopus Importer:2019-06-07
Keywords: allergic contact dermatitis; contact allergy; cross-sectional questionnaire; European; fragrance allergy; patch testing; patient-reported outcomes; quality of life

S2k-Leitlinie zum Gebrauch von Präparationen zur lokalen Anwendung auf der Haut (Topika) - Wohlrab, Johannes; Staubach, Petra; Augustin, Matthias; Eisert, Lisa; Huenerbein, Andreas; Nast, Alexander; Reimann, Holger; Stroemer, Klaus; Mahler, Vera (Journal der Deutschen Dermatologischen Gesellschaft, 2018)
Diese Leitlinie richtet sich an Assistenz- und Fachärzte der Dermatologie sowie an Kostenträger und politische Entscheidungsgremien. Die Leitlinie wurde im formellen Konsensusverfahren (S2k) von Dermatologen unter Einbindung von Apothekern erstellt. Die Leitlinie stellt allgemeine Aspekte der Pharmakokinetik sowie der regulatorischen Begrifflichkeiten dar. Es werden Empfehlungen zur Indikation von Magistralrezepturen sowie deren Qualitätssicherung gegeben. Die Bedeutung der galenischen Grundlagen und die Problematik bei einer Substitution gegeneinander verschiedener Grundlagen werden dargestellt. Die Leitlinie umfasst Kriterien zur Auswahl einer adäquaten Grundlage sowie spezifische Aspekte zur Therapieplanung. Die Leitlinie gibt Empfehlungen zum Management bei Unverträglichkeiten gegenüber Bestandteilen der Grundlagen oder Hilfsstoffe.
EVALuna2:34799

Severity and functional disability of patients with occupational contact dermatitis: validation of the German version of the Occupational Contact Dermatitis Disease Severity Index - Ofenloch, Robert F.; Diepgen, Thomas L.; Popielnicki, Ana; Weisshaar, Elke; Molin, Sonja; Bauer, Andrea; Mahler, Vera; Elsner, Peter; Schmitt, Jochen; Apfelbacher, Christian (Contact Dermatitis, 2015)
The Occupational Contact Dermatitis Disease Severity Index (ODDI) was designed in Australia to measure severity and functional disability in patients with occupational contact dermatitis (OCD) of the hands. The ODDI was translated into the German language with a linguistic validation process. The psychometric properties of the German version of the ODDI are still unclear.To report the linguistic validation procedure and to perform a psychometric validation by investigating the validity and reliability of the German ODDI version in a sample of patients with OCD.Data were drawn from the baseline assessment (T0) and first follow-up (T1) of the German chronic hand eczema (CHE) registry (CARPE). Spearman correlations of the ODDI with reference measures were computed to assess validity. Cronbach's alpha was calculated as a measure of internal consistency, and the intraclass correlation coefficient (ICC) was calculated to assess retest reliability. The smallest real difference (SRD) and minimal clinically important difference (MCID) were calculated to assess sensitivity to change. Physician Global Assessment (PGA) was used as an anchor for the MCID.Four hundred and twenty-two patients (54.5% female, mean age 45.1 years) were included for analysis. Cronbach's alpha was found to be 0.73. The ICC was 0.79. Correlations between the ODDI total and the Dermatology Life Quality Index (rho = 0.36), and between PGA (rho = 0.48) and patient-assessed disease severity (rho = 0.40), were of moderate strength. The MCID (1.29) was found to be smaller than the SRD (1.87).The German ODDI version is reliable and valid for the measurement of functional impairment and disease severity in patients suffering from OCD.
EVALuna2:19560

Statement of the German Contact Dermatitis Research Group (DKG) and the German Dermatological Society (DDG) on liability issues associated with patch testing using a patient's own materials - Mahler, Vera; Dickel, Heinrich; Diepgen, Thomas Ludwig; Hillen, Uwe; Geier, Johannes; Kaufmann, Roland; Kreft, Burkhard; Schnuch, Axel; Szliska, Christiane; Bender, Albrecht (Journal der Deutschen Dermatologischen Gesellschaft, 2017)
EVALuna2:35415

Topical delgocitinib is an efficacious and well tolerated treatment for patients with chronic hand eczema - Worm, Margitta; Bauer, Andrea; Elsner, Peter; Mahler, Vera; Molin, Sonja; Nielsen, Thor Schutt Svane (JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 2019)
CRIS-Team WoS Importer:2019-09-17

Type IV contact allergies in the food processing industry: an update - Bauer, A.; Schubert, S.; Geier, J.; Mahler, Vera (Hautarzt, 2018)
BACKGROUND: The food sector is one of the high-risk areas for occupational irritative and allergic contact eczema. OBJECTIVES: The present work provides an overview of the main allergens as well as sensitization frequencies and risk in various food industry occupations. METHODS: The literature on type IV sensitization in the food sector is summarized. RESULTS: The relative risk of developing a work-related eczema in food processing is increased by more than 3 times. The comparison group was calculated on the basis of the proportion of documented cases in the IVDK (Informationsverbund Dermatologischer Kliniken) network per 100,000 working persons in relation to the average of the years 2005 and 2010. For this purpose, the average risk of all patients was set as reference to 1. Bakers, pastry chefs, cooks and meat and fish processors are mainly affected. In addition to irritant contact eczema, allergic contact eczema and protein contact dermatitis often occur. Leading haptens (main allergens) are rubber ingredients, but also disinfectants and compositae. CONCLUSION: Only a few contact allergens are responsible for the majority of job-relevant sensitizations in the food industry.
EVALuna2:34791

Which factors are associated with the use of systemic antihistamines in patients with chronic hand eczema? Results from the CARPE registry - Apfelbacher, Christian; Weiss, M.; Molin, S.; Bauer, A.; Mahler, Vera; Schmitt, J.; Elsner, P.; Diepgen, T. L.; Weisshaar, E. (Journal of the European Academy of Dermatology and Venereology, 2016)
Antihistamines (AH) are often used to treat chronic skin diseases related to allergy and/or pruritus. Data on the use of AH in patients with chronic hand eczema (CHE) is scarce.The objective of this study was to investigate prevalence and determinants of AH use in patients with CHE.Data were drawn from the German CARPE registry. The relationship of clinical, demographic and treatment-related variables with AH use in the past 12 months was analysed by means of logistic regression. Odds ratios (OR) with corresponding 95% confidence intervals (CIs) were computed.A total of 1255 patients with CHE were eligible for analysis (54.1% female; mean age: 47.1 years, standard deviation (SD) 13.6 years). Mean subjective disease severity was 5.0 (SD 2.5). 25% of the sample reported to have used AH in the past 12 months. Significant positive associations with AH use were identified for moderate (OR = 3.05, 95% CI 1.81-5.15) or severe (OR = 4.27, 95% CI 2.40-7.59) pruritus, a history of systemic treatment (e.g. alitretinoin) (OR = 2.85, 95% CI: 2.06-3.96), UV phototherapy (OR = 1.78, 95% CI 1.28-2.46), flexural eczema (OR = 1.89, 95% CI 1.32-2.71), allergic rhinitis/conjunctivitis (OR = 2.41, 95% CI 1.71-3.39) and female gender (OR = 1.58, 95% CI 1.16-2.14) in multivariate analyses (N = 1184). Significant inverse associations were found for an eczema localization besides the hands (OR = 0.66, 95% CI 0.46-0.94) and for patients being recruited in hospital (vs. dermatological practice; OR = 0.47, 95% CI 0.33-0.67).This study suggests that AH use is frequent in patients with CHE and mainly related to female gender, disease severity, pruritus, comorbid atopic disease and treatment centre.
EVALuna2:19546

Year-round treatment initiation for a 6-grasses pollen allergoid in specific immunotherapy of allergic rhinoconjunctivitis and asthma - Mahler, Vera; Zielen, Stefan; Rosewich, Martin (Immunotherapy, 2019)
Aim: Allergen immunotherapy (AIT) is an effective treatment for allergic diseases. We investigate whether treatment-initiation during the pollen season is safe. Methods: RCT-IIIb-trial of 6-grass-pollen-allergoid (Allergovit (R)) in grass pollen-allergic patients (18-65 years) with moderate-severe rhinitis/rhinoconjunctivitis (+/- controlled asthma), randomized 2:1 to treatment-initiation during (Group-A) versus outside the pollen season (Group-B). Results: Of 240 patients (32.8 +/- 9.9 years, 19.5% asthma) treated, 84.9% (Group-A) and 86.6% (Group-B) reached maintenance dose without delay. Treatment-emergent adverse events occurred in 108 (68.4%/Group-A) and 41 patients (56.2%/Group-B) leading to premature trial-termination in 11 patients (7%/A) versus 3 (4.1%/B). Across groups, physicians (for 190 patients; 85.2%) and patients (192; 86.1%) rated the tolerability as 'very good'-'good'. Phleum pratense-specific IgG4 increased in both groups (p < 0.0001). Conclusion: Year-round allergen immunotherapy-initiation with this preparation is safe.
CRIS-Team WoS Importer:2020-02-04