Network Biology Approaches in Ophthalmological Diseases: A Case Study of Glaucoma - Choudhari, Jyoti Kant; Chatterjee, Tanushree; Gupta, Shailendra; Garcia-Garcia, Jose G.; Vera González, Julio (Systems Medicine - Integrative, Qualitative and Computational Approaches, 2020)
Glaucoma is an eye disease characterized by progressive damage to the optic nerve, often associated to high intraocular pressure, which causes vision impairment and vision loss in long term at the terminal phase. Glaucoma is a multifactorial disease because polymorphisms and deregulation of multiple genes are involved in the onset and development of the disease. However, deregulated genes do not act in isolation but are integrated into large networks of molecular entities. Systems and network biology are emerging disciplines in biomedicine in which mathematical modeling and computational biology tools are employed to integrate and analyze high-throughput quantitative biological data. In this article we discuss how these two new methodologies can be used to reconstruct the networks of deregulated genes behind glaucoma, networks that can be used to obtain mechanistic insights about the pathogenesis of the disease, and eventually to design molecular evidence-based therapies.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Angle closure glaucoma (ACG); Bioinformatics; Intraocular pressure (IOP); Network biology; Personalized medicine; Primary congenital glaucoma (PCG); Primary normal-tension glaucoma (NTG); Primary open angle glaucoma (POAG); Systems biology; Systems medicine

Neues in der Diagnostik und Therapie der aktinischen Keratose - Heppt, Markus (Die Dermatologie, 2024)
Actinic keratosis (AK) is among the most common conditions in dermatology in an increasingly aging population. However, the presence of severe field cancerization with large treatment fields showing multiple lesions with distinct features often poses a therapeutic challenge. The most accurate possible characterization of the treatment field, risk assessment concerning the occurrence of cutaneous squamous cell carcinoma, and knowledge of the efficacy and local side effects of the available interventions are of paramount importance for effective management and preventive efforts. This article summarizes current developments in the diagnosis and treatment of AK and discusses their application in everyday clinical practice. In particular, the focus is on the increasing value of non-invasive diagnostic techniques like “line-field” confocal optical coherence tomography, and the recently approved topical agents tirbanibulin 1% ointment and 5‑fluorouracil 4% cream, as well as current developments of photodynamic therapy and prevention.
CRIS-Team Scopus Importer:2024-10-11
Keywords: 5‑Fluorouracil; Guideline; Line-field optical coherence tomography; Real-world evidence; Tirbanibulin

Neural Networks for Distinguishing Rheumatoid Arthritis from Psoriatic Arthritis by Using Magnetic Resonance Imaging - Folle, Lukas; Bayat, Sara; Kleyer, Arnd; Fagni, Filippo; Kapsner, Lorenz; Schlereth, Maja; Meinderink, Timo; Breininger, Katharina; Tascilar, Koray; Krönke, Gerhard; Uder, Michael; Sticherling, Michael; et al. (Arthritis Rheumatol., 2022)

Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy - Zimmer, Lisa; Goldinger, Simone M.; Hofmann, Lars; Loquai, Carmen; Ugurel, Selma; Thomas, Ioannis; Schmidgen, Maria I.; Gutzmer, Ralf; Utikal, Jochen S.; Goeppner, Daniela; Hassel, Jessica C.; Meier, Friedegund; et al. (European Journal of Cancer, 2016)
Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail.Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
EVALuna2:19571

Neurological side effects of checkpoint inhibitors - Knauss, S.; Roque, L. Ginesta; Huehnchen, P.; Heinzerling, Lucie; Boehmerle, W.; Endres, M. (Der Nervenarzt, 2019)
Background. In recent years the treatment of many tumor entities has been revolutionized by the use of modern immunotherapies with checkpoint inhibitors; however, good response rates are contrasted by many immune-mediated side effects. Neurological immune-mediated side effects are rare but often severe complications of checkpoint inhibitor treatment.
CRIS-Team WoS Importer:2019-02-27

Neuromuscular Side Effects of Immune Checkpoint Inhibitors - Moreira, Alvaro; Loquai, C.; Knauss, S.; Gutzmer, R.; Dimitriou, F.; Meier, F.; Heppt, M.; Mitzel-Rink, H.; Schuler, Gerold; Terheyden, P.; Thoms, K. M.; Zimmer, L.; et al. (2018)
EVALuna2:34768

Neutrophil extracellular traps and DNases orchestrate formation of peritoneal adhesions. - Elrod, Julia; Heuer, Annika; Knopf, Jasmin; Schoen, Janina; Schönfeld, Lavinia; Trochimiuk, Magdalena; Stiel, Carolin; Appl, Birgit; Raluy, Laia Pagerols; Saygi, Ceren; Zlatar, Leticija; Hosari, Sami; et al. (iScience, 2023)
Peritoneal adhesions are poorly understood but highly prevalent conditions that can cause intestinal obstruction and pelvic pain requiring surgery. While there is consensus that stress-induced inflammation triggers peritoneal adhesions, the molecular processes of their formation still remain elusive. We performed murine models and analyzed human samples to monitor the formation of adhesions and the treatment with DNases. Various molecular analyses were used to evaluate the adhesions. The experimental peritoneal adhesions of the murine models and biopsy material from humans are largely based on neutrophil extracellular traps (NETs). Treatment with DNASE1 (Dornase alfa) and the human DNASE1L3 analog (NTR-10), significantly reduced peritoneal adhesions in experimental models. We conclude that NETs serve as essential scaffold for the formation of adhesions; DNases interfere with this process. Herein, we show that therapeutic application of DNases can be employed to prevent the formation of murine peritoneal adhesions. If this can be translated into the human situation requires clinical studies.
EVALuna2:551953

NFATc1 deficiency in T cells protects mice from experimental autoimmune encephalomyelitis - Reppert, Sarah; Zinser, Elisabeth; Holzinger, Corinna; Sandrock, Lena; Koch, Sonja; Finotto, Susetta (European Journal of Immunology, 2015)
NFATc1 is a member of the nuclear factor of activated T cells (NFAT) family of transcription factors. NFAT is activated upon T-cell receptor activation followed by intracytoplasmatic calcium influx where calmodulin, a calcium sensor protein, activates the phosphatase calcineurin that dephosphorylates NFAT proteins and results in NFAT nuclear import. Here, we show the analysis of conditional NFATc1-deficient mice bearing a deletion of NFATc1 in CD4(+) and CD8(+) T cells. NFATc1-deficient CD4(+) T cells polarized under Th17 conditions express reduced levels of the Th17-associated transcription factor ROR?T (where ROR is RAR-related orphan receptor) as well as the Th17-associated cytokines IL-17A, IL-17F, IL-21, and IL-10. In the murine model of experimental EAE, we found a strong reduction of the disease outcome in conditional NFATc1-deficient mice, as compared with control littermates. This was accompanied by a diminished inflammation in the brain and spinal cord and reduced IL-17A and IFN-? expression by antigen-specific spleen, spinal cord, and brain cells. Altogether, these results reveal an important role of NFATc1 in inducing Th17-cell responses and IFN-?, both being relevant for the EAE development.
EVALuna2:25967

NFATc1 in CD4+ T cells and CD11c+ dendritic cells drives TH2-mediated eosinophilic inflammation in allergic asthma - Yang, Zuqin; Krammer, Susanne; Mitländer, Hannah; Grund, Janina; Zirlik, Sabine; Wirtz, Stefan; Rauh, Manfred; Sadeghi Shermeh, Atefeh; Finotto, Susetta (Journal of Allergy and Clinical Immunology: Global, 2025)
Background: Asthma, a chronic lung disease, is a significant public health problem worldwide. It is marked by increased TH2 response resulting in eosinophil accumulation. The pathophysiology of asthma involves various cell types, including epithelial cells, dendritic cells (DCs), innate lymphoid cells, B cells, and effector cells. Nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a critical transcription factor for immune regulation, is known for its role in T cells and, more recently, in myeloid cells. However, the specific contributions of NFATc1 in T cells and DCs in the context of asthma are not well understood. Objective: We explored NFATc1’s role in T cells and DCs in modulating TH2 immune responses within the pathophysiology of allergic asthma. Methods: We induced asthma in mice lacking Nfatc1 in CD4+ T cells or CD11c+ DCs using house dust mite, thereby enabling investigation into NFATc1’s role in both cell types in experimental allergic asthma. Additionally, we examined NFATc1 expression in these cell types and its correlation with blood eosinophil levels in an adult asthma cohort. Results: In a house dust mite–induced asthma model, we found that Nfatc1 deficiency either in CD4+ T cells or CD11c+ DCs resulted in reduced TH2-driven eosinophilic inflammation, IgE levels, and mast cell presence in the lung of asthmatic mice. Nfatc1’s absence in CD4+ T cells directly hampered TH2 cell polarization and functionality, whereas in CD11c+ DCs, it affected DC differentiation and maturation, thereby weakening T-cell priming, proliferation, and subsequent TH2 differentiation. Correspondingly, translational research indicated significant correlations between CD4+NFATc1+ and CD11c+NFATc1+ cell populations and eosinophil levels in asthmatic patients, but not in healthy controls. Conclusion: NFATc1 in T cells and DCs modulates TH2-mediated eosinophilic inflammation in allergic asthma, thus offering insight into asthma pathogenesis and identifying NFATc1 as a potential target for therapeutic intervention.
CRIS-Team Scopus Importer:2024-11-15
Keywords: allergic asthma; dendritic cells; eosinophils; NFATc1; T cells; T

NF-κB activation triggers NK-cell stimulation by monocyte-derived dendritic cells. - Bosch, Naomi C.; Voll, Reinhard E.; Voskens, Caroline J.; Gross, Stefanie; Seliger, Barbara; Schuler, Gerold; Schaft, Niels; Dörrie, Jan (Therapeutic Advances in Medical Oncology, 2019)
Background: In therapeutic cancer vaccination, monocyte-derived dendritic cells (moDCs) efficiently activate specific T-cell responses; however, optimizing the activation of innate immune cells could support and improve the antitumor effects. A major disadvantage of moDCs matured with the standard cytokine cocktail (consisting of IL-1 beta, IL-6, TNF alpha, and PGE(2)) is their inability to secrete IL-12p70. IL-12 prominently activates natural killer (NK) cells, which are crucial in innate antitumor immunity, as they act as helper cells for the induction of a cytotoxic T lymphocyte (CTL) response and are also able to directly kill the tumor. Methods: Previously we have shown that triggering the NF-kappa B pathway in moDCs by transfection of mRNA encoding constitutively active IKK beta (caIKK beta) led to IL-12p70 secretion and improved the dendritic cells' capability to activate and expand CTLs with a memory-like phenotype. In this study, we examined whether such dendritic cells could activate autologous NK cells. Results: moDCs matured with the standard cytokine cocktail followed by transfection with the caIKK beta-RNA were able to activate autologous NK cells, detected by the upregulation of CD54, CD69, and CD25 on the NK cells, their ability to secrete IFN gamma, and their high lytic activity. Moreover, the ability of NK-cell activation was not diminished by simultaneous T-cell activation. Conclusion: The capacity of caIKK beta-DCs to activate both the adaptive and innate immune response indicates an enhanced potential for clinical efficacy.
CRIS-Team WoS Importer:2019-12-27

NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism - Allouche, Jennifer; Rachmin, Inbal; Adhikari, Kaustubh; Pardo, Luba M.; Lee, Ju Hee; McConnell, Alicia M.; Kato, Shinichiro; Fan, Shaohua; Kawakami, Akinori; Suita, Yusuke; Wakamatsu, Kazumasa; Igras, Vivien; et al. (Cell, 2021)
Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.
CRIS-Team Scopus Importer:2021-08-13
Keywords: melanosome; MITF; nicotinamide nucleotide transhydrogenase; pigmentation; redox regulation; UVB

Non-Coding RNA in Tumor Cells and Tumor-Associated Myeloid Cells—Function and Therapeutic Potential - Binder, Amanda; Bremm, Franziska; Dörrie, Jan; Schaft, Niels (International Journal of Molecular Sciences, 2024)
The RNA world is wide, and besides mRNA, there is a variety of other RNA types, such as non-coding (nc)RNAs, which harbor various intracellular regulatory functions. This review focuses on small interfering (si)RNA and micro (mi)RNA, which form a complex network regulating mRNA translation and, consequently, gene expression. In fact, these RNAs are critically involved in the function and phenotype of all cells in the human body, including malignant cells. In cancer, the two main targets for therapy are dysregulated cancer cells and dysfunctional immune cells. To exploit the potential of mi- or siRNA therapeutics in cancer therapy, a profound understanding of the regulatory mechanisms of RNAs and following targeted intervention is needed to re-program cancer cells and immune cell functions in vivo. The first part focuses on the function of less well-known RNAs, including siRNA and miRNA, and presents RNA-based technologies. In the second part, the therapeutic potential of these technologies in treating cancer is discussed, with particular attention on manipulating tumor-associated immune cells, especially tumor-associated myeloid cells.
CRIS-Team Scopus Importer:2024-07-19
Keywords: cancer therapy; myeloid-derived suppressor cells; non-coding RNA; tumor-associated dendritic cells; tumor-associated macrophages; tumor-micro-environment

Non-magnetic chromatographic separation of colloidally metastable superparamagnetic iron oxide nanoparticles and suspension cells - Mühlberger, Marina; Janko, Christina; Unterweger, Harald; Band, Julia; Schreiber, Eveline; Lehmann, Christian; Dudziak, Diana; Lee, Geoffrey; Alexiou, Christoph; Tietze, Rainer (Journal of Chromatography B-Analytical Technologies in the Biomedical and Life Sciences, 2019)
For magnetic control of cells for biomedical applications such as targeting of immune cells to tumors, cells must be magnetizable. For that, cells are incubated with superparamagnetic iron oxide nanoparticles (SPIONs)to take them up and thus become magnetizable. When using adherent cells, non-ingested SPIONs can be easily removed by rinsing of the particles regardless of their colloidal stability in cell culture medium. However, if suspension cells such as T cells are to be loaded with SPIONs, established methods to separate excess nanoparticles from cells are based on physicochemical parameters such as density, size or magnetizability. Thus, colloidal stability of the particles is of great importance, since only colloidally stable SPIONs can be completely separated from the cells due to their physicochemical differences. Aggregates of colloidally meta- or unstable particles cannot, however, be separated from cells due to their overlapping sizes and densities. Thus, development of an alternative method for the separation of nanoparticle aggregates from suspension cells is urgently needed. Here, we present an affinity chromatographic separation method based on immunohistochemical properties of the respective cells. A desthiobiotinylated antibody against a cellular surface antigen (here CD90.2 receptor on EL4 T cells)is immobilized on a streptavidin agarose column optimized for cell purification. Subsequently the column is loaded with the particle/cell suspension so that the cells bind to the column. After removing the particles by washing, the cells can be gently eluted with biotin solution under physiological conditions. This allows >95% of the excess iron concentration to be removed while maintaining cell viability.
CRIS-Team Scopus Importer:2019-07-09
Keywords: Affinity chromatography; Antibody; Biotin; Cell viability; Desthiobiotin; Streptavidin

Non-professional phagocytosis: a general feature of normal tissue cells - Seeberg, Jacob; Loibl, Monika; Moser, Fabian; Schwegler, Manuela; Büttner-Herold, Maike; Daniel, Christoph; Engel, Felix; Hartmann, Arndt; Schlötzer-Schrehardt, Ursula; Goppelt-Strübe, Margarete; Schellerer, Vera; Naschberger, Elisabeth; et al. (Scientific Reports, 2019)
Non-professional phagocytosis by cancer cells has been described for decades. Recently, non-professional phagocytosis by normal tissue cells has been reported, which prompted us to take a closer look at this phenomenon. Non-professional phagocytosis was studied by staining cultured cells with live-cell staining dyes or by staining paraffin-embedded tissues by immunohistochemistry. Here, we report that each of 21 normal tissue cell lines from seven different organs was capable of phagocytosis, including ex vivo cell cultures examined before the 3rd passage as well as the primary and virus-transformed cell lines. We extended our analysis to an in vivo setting, and we found the occurrence of non-professional phagocytosis in healthy skin biopsies immediately after resection. Using dystrophin immunohistochemistry for membrane staining, human post-infarction myocardial tissue was assessed. We found prominent signs of non-professional phagocytosis at the transition zone of healthy and infarcted myocardia. Taken together, our findings suggest that non-professional phagocytosis is a general feature of normal tissue cells.
CRIS-Team Scopus Importer:2019-08-27

Nonviral RNA transfection to transiently modify T cells with chimeric antigen receptors for adoptive therapy - Riet, Tobias; Holzinger, Astrid; Dörrie, Jan; Schaft, Niels; Schuler, Gerold; Abken, Hinrich (Synthetic Messenger RNA and Cell Metabolism Modulation, 2013)
Redirecting T cells with a chimeric antigen receptor (CAR) of prede fined specificity showed remarkable ef ficacy in the adoptive therapy trials of malignant diseases. The CAR consists of a single chain fragment of variable region (scFv) antibody targeting domain covalently linked to the CD3 z signalling domain of the T cell receptor complex to mediate T cell activation upon antigen engagement. By using an antibodyderived targeting domain a CAR can potentially redirect T cells towards any target expressed on the cell surface as long as a binding domain is available. Antibody-mediated targeting moreover circumvents MHC restriction of the targeted antigen, thereby broadening the potential of applicability of adoptive T cell therapy. While T cells were so far genetically modi fied by viral transduction, transient modification with a CAR by RNA transfection gained increasing interest during the last years. This chapter focuses on methods to modify human T cells from peripheral blood with a CAR by electroporation of in vitro transcribed RNA and to test modi fied T cells for function for use in adoptive immunotherapy. © Springer Science+Business Media New York 2013.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Adoptive cell therapy; Chimeric antigen receptor; Electroporation; In vitro transcription; RNA; T cell

Noonan Syndrome with multiple Lentigines (Leopard Syndrome) - Case Description of a 45-year-old Patient - Sponagl, F.; Sticherling, Michael; Seybold, H.; Erdmann, M.; Wagner, N. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Norm- and hypo-fractionated radiotherapy is capable of activating human dendritic cells - Kulzer, Lorenz; Rubner, Yvonne; Deloch, Lisa; Allgäuer, Andrea; Frey, Benjamin; Fietkau, Rainer; Dörrie, Jan; Schaft, Niels; Gaipl, Udo (Journal of Immunotoxicology, 2014)
Abstract Despite the transient immunosuppressive properties of local radiotherapy (RT), this classical treatment modality of solid tumors is capable of inducing immunostimulatory forms of tumor-cell death. The resulting 'immunotoxicity' in the tumor, but not in healthy tissues, may finally lead to immune-mediated destruction of the tumor. However, little is known about the best irradiation scheme in this setting. This study examines the immunological effects of differently irradiated human colorectal tumor cells on human monocyte-derived dendritic cells (DC). Human SW480 tumor cells were irradiated with a norm-fractionation scheme (5 × 2 Gy), a hypo-fractionated protocol (3 × 5 Gy), and with a high single irradiation dose (radiosurgery; 1 × 15 Gy). Subsequently, human immature DC (iDC) were co-incubated with supernatants (SN) of these differently treated tumor cells. Afterwards, DC were analyzed regarding the expression of maturation markers, the release of cytokines, and the potential to stimulate CD4(+) T-cells. The co-incubation of iDC with SN of tumor cells exposed to norm- or hypo-fractionated RT resulted in a significantly increased secretion of the immune activating cytokines IL-12p70, IL-8, IL-6, and TNF?, compared to iDC co-incubated with SN of tumor cells that received a high single irradiation dose or were not irradiated. In addition, DC-maturation markers CD80, CD83, and CD25 were also exclusively elevated after co-incubation with the SN of fractionated irradiated tumor cells. Furthermore, the SN of tumor cells that were irradiated with norm- or hypo-fractionated RT triggered iDC to stimulate CD4(+) T-cells not only in an allogenic, but also in an antigen-specific manner like mature DC. Collectively, these results demonstrate that norm- and hypo-fractionated RT induces a fast human colorectal tumor-cell death with immunogenic potential that can trigger DC maturation and activation in vitro. Such findings may contribute to the improvement of irradiation protocols for the most beneficial induction of anti-tumor immunity.
EVALuna2:18178

„Novel food“ – Was muss man beachten? - Toussaint, Frédéric; Wagner, Nicola (Die Dermatologie, 2025)
Novel foods are food products that were not in circulation for consumption to any significant extent in the European Union before 1997. The introduction of novel foods harbors the risk of allergic reactions to new allergens or new cross-reactions that need to be taken into account. The aim of the study is to highlight the allergenic potential of selected novel foods. Allergens in edible insects in particular harbor the risk of anaphylactic reactions. In western industrial nations cross-sensitivity to crustaceans and shellfish are likely to play an important role in the future. Chia seeds, which are rich in fiber and omega-3-fatty acids, are also embraced in the term novel foods. Cross-reactions to sesame seeds or to other labiates (mustard, thyme, rosemary, sage) are possible. Consumption of natto, a Japanese dish containing fermented soy beans, can lead to delayed anaphylaxis. Nattokinase as well as polyglutamic acid (PGA) are well-known triggering allergens. It is postulated that sensitization to PGA may be acquired from skin contact to jellyfish and potentially by cosmetics containing PGA.
CRIS-Team Scopus Importer:2025-05-16
Keywords: Allergy; Chia seeds; Cross-reactions; Edible insects; Natto

Nutritional and functional status in geriatric day hospital patients-MNA short form versus full MNA - Schrader, Eva; Grosch, Ella; Bertsch, T.; Sieber, Cornel; Volkert, Dorothee (Journal of Nutrition, Health & Aging, 2016)
The aims of this study were to determine the prevalence of malnutrition in patients of a geriatric day hospital using the Mini Nutritional Assessment short form (MNA-SF) and the full MNA, to compare both tools, and to examine the relationship between nutritional and functional status.Cross-sectional study.Geriatric day hospital.190 patients (72.1% female, median 80 years) aged 65 years or older.In consecutively admitted geriatric day hospital patients nutritional status was assessed by MNA-SF and full MNA, and agreement between both tools calculated by Cohen's kappa. Basic activities of daily living (ADL), instrumental activities of daily living (IADL) and short physical performance battery (SPPB) were determined and related to MNA categories (Chi(2)-test, Mann-Whitney-U-test).36.3 % and 44.7% of the patients were at risk of malnutrition, 8.9 % and 5.8 % were malnourished according to MNA-SF and full MNA, respectively. Agreement between both MNA forms was moderate (?=0.531). No significant associations between MNA-SF and ADL, IADL and SPPB, and between full MNA and SPPB were observed. According to full MNA, the proportion of patients with limitations in ADL and IADL significantly increased with declining nutritional status (ADL: 2.1 vs. 8.2 vs. 18.2 %, p=0.044; IADL: 25.5 vs. 47.1 vs. 54.5 %, p=0.005) with a simultaneous decrease of the proportion of patients without limitations. Well-nourished patients reached significantly higher ADL scores than patients at risk of malnutrition (95 (-100) vs. 95 (85- 100), p=0.005) and significantly higher IADL scores than patients at risk or malnourished (8 (6-8) vs. 7 (5-8) vs. 6 (4-8), p=0.004).The high prevalence of risk of malnutrition and the observed association between functional status and nutritional status according to full MNA call for routine nutritional screening using this tool in geriatric day hospital patients.
Keywords: Nutritional status; mini nutritional assessment; functional status; geriatric day hospital patients

Nutrition status in patients with wounds: a cross-sectional analysis of 50 patients with chronic leg ulcers or acute wounds - Renner, Regina; Garibaldi, Melina Da Silva; Benson, Sven; Ronicke, Moritz; Erfurt-Berge, Cornelia (European Journal of Dermatology, 2019)
Background: The possible impact of nutritional status on healing and course of disease in patients with chronic wounds is widely suggested, however, most data are based on small groups of patients with no control group and minor afflictions. Clear diagnostic strategies are missing. Objectives: To analyse in detail the nutritional status of chronic wound patients relative to healthy controls based on a large patient population. Material and Methods: We screened a group of 50 patients for their nutritional status based on body mass index (BMI), the Mini-Nutritional Assessment (MNA), and Nutritional Risk Screening (NRS), as well as additional laboratory investigations. Twenty-five patients suffered from chronic venous leg ulcers and were compared with a matching control group of 25 patients with acute surgical wounds. Results: Patients with chronic venous leg ulcers showed significantly higher BMI, hyperhomo-cysteinaemia, and higher levels of serum copper but significantly lower levels of vitamin B6, B9 and C, as well as a significantly lower level of zinc. Vitamin D deficiency was present in both groups, however, severe vitamin D deficiency was present only in the leg ulcer group. Mobility was significantly reduced in patients with leg ulcers. Conclusion: Ulcer patients are often obese but suffer from qualitative malnutrition, including a lack of vitamin D, which might be explained by reduced mobility and being housebound. Hypoalbuminaemia, as a sign of protein deficiency, was observed significantly more often in patients with chronic leg ulcers, irrespective of wound area or wound duration.
CRIS-Team WoS Importer:2020-02-14

Obesity is linked to disease severity in moderate to severe atopic dermatitis—Data from the prospective observational TREATgermany registry - Traidl, Stephan; Hollstein, Moritz M.; Kroeger, Nadine; Fischer, Sascha; Heratizadeh, Annice; Heinrich, Luise; Kind, Barbara; Siegels, Doreen; Abraham, Susanne; Schäfer, Thomas; Augustin, Matthias; Harder, Inken; et al. (Journal of the European Academy of Dermatology and Venereology, 2024)
Background: There are conflicting data on a potential association between obesity and atopic dermatitis (AD). The purpose of this study was to investigate the relationship between obesity and AD disease severity. Methods: Patients from the TREATgermany registry cohort were divided into three groups according to their body mass index (BMI). Due to low numbers, underweight patients (BMI <18.5 kg/m2) were excluded from the analysis. Physician- and patient-reported disease severity scores as well as additional phenotypic characteristics were evaluated for association with BMI. Generalized linear mixed models and multinomial logit models, respectively, were applied to investigate the association of BMI, age, sex and current systemic AD treatment with disease severity. Results: This study encompassed 1416 patients, of which 234 (16.5%) were obese (BMI ≥30 kg/m2). Obesity was associated with lower educational background and smoking. Otherwise, obese and non-obese AD patients had similar baseline characteristics. Increased BMI was associated with higher oSCORAD (adjusted β: 1.24, 95% CI: 1.05–1.46, p = 0.013) and Patient-oriented eczema measure (POEM) (adjusted β: 1.09, 95% CI: 1.01–1.17, p = 0.038). However, the absolute difference in the overall oSCORAD was small between obese and non-obese AD patients (Δ oSCORAD = 2.5). Allergic comorbidity was comparable between all three groups, with the exception of asthma which was more pronounced in obese patients (p < 0.001). Discussion: In this large and well-characterized AD patient cohort, obesity is significantly associated with physician- and patient-assessed measures of AD disease severity. However, the corresponding effect sizes were low and of questionable clinical relevance. The overall prevalence of obesity among the German AD patients was lower than in studies on other AD cohorts from different countries, which confirms previous research on the German population and suggests regional differences in the interdependence of AD and obesity prevalence.
CRIS-Team Scopus Importer:2024-05-03

Objective and subjective hand function reflect grade of tenosynovitis in patients with psoriasis and psoriatic arthritis - Coppers, Birte; Bayat, Sara; Elie-Tino, Godonou; Valor-Mendez, Larissa; Simon, David; Corte, Giulia; Tascilar, Koray; Hueber, Axel; Bohr, Daniela; Schönau, Verena; Sticherling, Michael; Schett, Georg; et al. (poster, Deutsche Gesellschaft für Rheumatologie Kongress, 2023)

Occlusive cutaneous vasculopathies as cause of chronic ulcers - Ronicke, Moritz; Berking, Carola; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2024)
The term occluding vasculopathies covers a large number of different conditions. These often manifest as skin ulcers. Occluding vasculopathies should be considered in the differential diagnosis of leg ulcers. The term “occlusive vasculopathies” encompasses pathophysiologically related entities that share structural or thrombotic obliteration of small cutaneous vessels. In this article, we will focus on livedoid vasculopathy with and without antiphospholipid syndrome and calciphylaxis with differentiation from hypertonic leg ulcer as the most relevant differential diagnoses of leg ulcer. The term also includes vascular occlusion, for example due to oxalate or cholesterol embolism, and septic vasculopathy. This often leads to acral ulceration and is therefore not a differential diagnosis with classic leg ulcers. It will not be discussed in this article. Occlusive vasculopathy may be suspected in the presence of the typical livedo racemosa or (non-inflammatory) retiform purpura as a sign of reduced cutaneous perfusion in the wound area. Inflammatory dermatoses, especially vasculitides, must be differentiated. This is achieved by histopathological evaluation of a tissue sample of sufficient size and depth taken at the appropriate time. In addition, specific laboratory parameters, particularly coagulation parameters, can support the diagnosis.
CRIS-Team Scopus Importer:2024-03-15
Keywords: calciphylaxis; chronic wounds; livedoid vasculopathy; Martorell's ulcer; vasculopathy

Occupational palmoplantar psoriasis: a clinical case series with consideration of the S1 guidelines on expert medical assessments of occupational psoriasis - Angelovska, Irena; Mahler, Vera (Journal der Deutschen Dermatologischen Gesellschaft, 2014)
Constitutional diseases represent a challenge in the expert assessment of occupational diseases. It is necessary to distinguish professional causes from the spontaneous course of the disease. Recently, a guideline for the assessment of work-related psoriasis has been consented in Germany. We present a case series in which it was applied.129 expert assessments from the Department of dermatology University hospital Erlangen and court cases in established juridical databases were researched for cases with psoriasis and the applicability of the guideline.The guideline was applicable in the n = 6 (3.6 %) identified medical expert opinions. They were fully recognized by the workers compensation boards. The search for law sentences on work-related psoriasis in German court cases yielded a total of four sentences, in one of which the psoriasis was recognized as an occupational disease (BK 5101).In comparison with hand eczema psoriasis of the hands is rare. As has been demonstrated in our case series psoriasis as a constitutional disease may be recognized as an occupational disease (BK 5101) according to the legal system in Germany, if the influence of occupational exposure can be made sufficiently probable and other legal conditions of an occupational disease are met.
EVALuna2:19456

Occupational skin diseases: actual state analysis of patient management pathways in 28 European countries - Mahler, Vera; Aalto-Korte, K.; Alfonso, J. H.; Bakker, J. G.; Bauer, A.; Bensefa-Colas, L.; Boman, A.; Bourke, J.; Bubas, M.; Bulat, Petar; Chaloupka, Jiri; Constandt, L.; et al. (Journal of the European Academy of Dermatology and Venereology, 2017)
BACKGROUND: Work-related skin diseases (WSD) are caused or worsened by a professional activity. Occupational skin diseases (OSD) need to fulfil additional legal criteria which differ from country to country. OSD range amongst the five most frequently notified occupational diseases (musculoskeletal diseases, neurologic diseases, lung diseases, diseases of the sensory organs, skin diseases) in Europe. OBJECTIVE: To retrieve information and compare the current state of national frameworks and pathways to manage patients with occupational skin disease with regard to prevention, diagnosis, treatment and rehabilitation in different European countries. METHODS: A questionnaire-based survey of the current situation regarding OSD patient management pathways was carried out with experts on occupational dermatology and/or occupational medicine from 28 European countries contributing to the European Cooperation in Science and Technology (COST) Action TD 1206 (StanDerm) (www.standerm.eu). RESULTS: Besides a national health service or a statutory health insurance, most European member states implemented a second insurance scheme specifically geared at occupational diseases [insurance against occupational risks (synonyms: insurance against work accidents and occupational injuries; statutory social accident insurance)]. Legal standards for the assessment of occupationally triggered diseases with a genetic background differ between different countries, however, in most European member states recognition as OSD is possible. In one-third of the countries UV light-induced tumours can be recognized as OSD under specific conditions. CONCLUSION: OSD definitions vary between European countries and are not directly comparable, which hampers comparisons between statistics collected in different countries. Awareness of this fact and further efforts for standardization are necessary.
EVALuna2:34186

Ocular diseases in metastatic cutaneous melanoma: review of 108 consecutive patients in two German tertiary centers - Grajewski, Rafael S.; Schuler-Thurner, Beatrice; Mauch, Cornelia; Kreuzberg, Nicole; Koch, Konrad R.; Bergua, Antonio; Cursiefen, Claus; Heindl, Ludwig M. (Graefes Archive For Clinical and Experimental Ophthalmology, 2014)
To analyze the incidence and spectrum of ocular disease in patients with metastatic cutaneous melanoma.One hundred and eight consecutive patients with metastatic cutaneous melanoma were screened for ocular diseases using standardized eye examination, including measurement of visual acuity and intraocular pressure, slit-lamp examination, funduscopy in mydriasis, and spectral-domain optical coherence tomography (SDOCT) of the retina. Selected cases with atypical findings underwent electrophysiological studies. One patient was examined for hypercortisolism by a dexamethasone suppression test.Ocular diseases were found in 65 out of 108 patients (60 %) with metastatic cutaneous melanoma, significantly more often in older patients (p = 0.004). Cataract was present in 27 patients (25 %), pseudophakia in 22 patients (20 %), macular disease in 29 patients (28 %), diabetic retinopathy in ten patients (9 %), hypertensive retinal disease in 14 patients (13 %), retinal venous and arterial occlusive disease in three patients (3 %), optic neuropathy in four patients (4 %), and uveitis in one patient (1 %). Eight patients (8 %) had choroidal or iridal nevi, one patient (1 %) choroidal hemangioma, and one patient (1 %) choroidal metastasis. No patient had periocular neoplastic lesions. Paraneoplastic retinopathy manifesting as acute exudative polymorphous vitelliform maculopathy (AEPVM)-like disease was diagnosed in two patients (2 %) with multifocal central serous chorioretinopathy and development of vitelliform or fibrin-like subretinal deposits in one patient.Patients with metastatic cutaneous melanoma reveal ocular diseases with a spectrum similar to the normal population of this age range. Very rarely, uveal metastasis as well as paraneoplastic retinopathy can occur.
EVALuna2:19483

Okkludierende kutane Vaskulopathien als Ursachen chronischer Unterschenkelulzerationen - Ronicke, Moritz; Berking, Carola; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2024)
CRIS-Team Scopus Importer:2024-04-12
Keywords: Calciphylaxie; chronische Wunden; Livedovaskulopathie; Ulcus cruris hypertonicum Martorell; Vaskulopathie

Old Age, nodular Melanoma, Tumor Thickness and Ulceration are Risk Factors for regional and systemic Metastases in Melanoma Patients after negative Sentinel Node Biopsy - Erdmann, M.; Dominik, S.; Göhl, Jonas; Grützmann, Robert; Schuler, Gerold; Schellerer, Vera (2017)
EVALuna2:15294

Oligoclonal CD4+CXCR5+ T cells with a cytotoxic phenotype appear in tonsils and blood - Liang, Chunguang; Spörl, Silvia; Xiao, Yin; Habenicht, Katharina M.; Haeusl, Sigrun S.; Sandner, Isabel; Winkler, Julia; Strieder, Nicholas; Eder, Rüdiger; Stanewsky, Hanna; Alexiou, Christoph; Dudziak, Diana; et al. (Communications Biology, 2024)
Most subsets of CD4+ T-follicular helper cells occur in blood and tonsils, but location enforces specific gene expression. One subtype reveals a cytotoxic phenotype, is circulating or extrafollicular, oligoclonal and shares TCRs with other clusters.
CRIS-Team Scopus Importer:2024-07-26

O-linked N-acetylglucosaminylation of Sp1 inhibits the human immunodeficiency virus type 1 promoter - Jochmann, Ramona; Thurau, Mathias; Jung, Susan; Hofmann, Christian; Naschberger, Elisabeth; Kremmer, Elisabeth; Harrer, Thomas; Miller, Matthew; Schaft, Niels; Stürzl, Michael (Journal of Virology, 2009)
Human immunodeficiency virus type 1 (HIV-1) gene expression and replication are regulated by the promoter/enhancer located in the U3 region of the proviral 5′ long terminal repeat (LTR). The binding of cellular transcription factors to specific regulatory sites in the 5′ LTR is a key event in the replication cycle of HIV-1. Since transcriptional activity is regulated by the posttranslational modification of transcription factors with the monosaccharide O-linked N-acetyl-D-glucosamine (O-GlcNAc), we evaluated whether increased O-GlcNAcylation affects HIV-1 transcription. In the present study we demonstrate that treatment of HIV-1-infected lymphocytes with the O-GlcNAcylation-enhancing agent glucosamine (GlcN) repressed viral transcription in a dose-dependent manner. Overexpression of O-GlcNAc transferase (OGT), the sole known enzyme catalyzing the addition of O-GlcNAc to proteins, specifically inhibited the activity of the HIV-1 LTR promoter in different T-cell lines and in primary CD4+ T lymphocytes. Inhibition of HIV-1 LTR activity in infected T cells was most efficient (>95%) when OGT was recombinantly overexpressed prior to infection. O-GlcNAcylation of the transcription factor Sp1 and the presence of Sp1-binding sites in the LTR were found to be crucial for this inhibitory effect. From this study, we conclude that O-GlcNAcylation of Sp1 inhibits the activity of the HIV-1 LTR promoter. Modulation of Sp1 O-GlcNAcylation may play a role in the regulation of HIV-1 latency and activation and links viral replication to the glucose metabolism of the host cell. Hence, the establishment of a metabolic treatment might supplement the repertoire of antiretroviral therapies against AIDS. Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Created from Fastlane, Scopus look-up

Oncological System Therapy to the bitter End? - Berking, Carola (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team WoS Importer:2021-10-08

One allergen is not enough - RNAi-based down regulation of multiple allergens in tomato plants - Paulus, Kathrin; Mahler,; Sonnewald, Uwe (Allergy, 2015)

One set to collect them all? The development of a core domain set for medium-to-giant congenital melanocytic naevi - Heppt, Markus; Steeb, Theresa; Berking, Carola (British Journal of Dermatology, 2021)
CRIS-Team Scopus Importer:2021-04-02

One Website to Gather them All: Usability Testing of the New German SKin Cancer INFOrmation (SKINFO) Website-A Mixed-methods Approach - Steeb, Theresa; Bruetting, Julia; Reinhardt, Lydia; Hoffmann, Julia; Weiler, Nina; Heppt, Markus; Erdmann, Michael; Doppler, Astrid; Weber, Christiane; Schadendorf, Dirk; Meier, Friedegund; Berking, Carola (Journal of Cancer Education, 2022)
Skin cancer patients increasingly search the internet to acquire disease-related information. However, information on the internet may be misleading. Recently, SKINFO has been launched, a website exclusively created for German-speaking skin cancer patients providing information as well as additional resources of verified quality. Here, we describe the results of the first usability test of SKINFO using a mixed-methods approach. Ten adult patients with skin cancer were recruited for usability testing in the skin cancer units of the University Hospitals of Erlangen and Dresden, Germany. Testing consisted of three different scenarios where patients were asked to find specific information on the SKINFO website guided by the think-aloud method. Descriptive analysis and content analyses were performed. All patients would recommend SKINFO and appreciated its content, design, and structure. Think-aloud analysis identified the topics layout, navigation, and content and structure which would benefit from refinement. Major criticism included the navigation through the website, and the desire for more specific information addressing patients' relatives and the latest, up-to-date information. Overall, usability testing showed that the unique web-based information platform has the potential to support patients coping with skin cancer and thus strengthen informed decision-making.
CRIS-Team WoS Importer:2023-01-27

Onkologische Systemtherapie bis zum bitteren Ende? - Berking, Carola (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
CRIS-Team Scopus Importer:2023-03-23

Online consensus conferences for the development and update of clinical practice guidelines: A survey among participants of the German S3 guideline on actinic keratosis and cutaneous squamous cell carcinoma - Steeb, Theresa; Follmann, Markus; Langer, Thomas; Nothacker, Monika; Wessely, Anja; Garbe, Claus; Leiter, Ulrike; Berking, Carola; Heppt, Markus (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-03-05

Online-Konsensuskonferenzen für die Entwicklung und Aktualisierung von Leitlinien für die klinische Praxis: Eine Umfrage unter den Teilnehmenden der deutschen S3-Leitlinie zur aktinischen Keratose und kutanem Plattenepithelkarzinom - Steeb, Theresa; Follmann, Markus; Langer, Thomas; Nothacker, Monika; Wessely, Anja; Garbe, Claus; Leiter, Ulrike; Berking, Carola; Heppt, Markus (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-04-30

Opportunities to inform German residents about the possibility of skin cancer screening and to inform stakeholders to take appropriate actions: A qualitative approach - Steeb, Theresa; Wessely, Anja; Heppt, Markus; Erdmann, Michael; Klug, Stefanie J.; Berking, Carola (Cancer Medicine, 2023)
Background: The national skin cancer screening (SCS) was introduced in Germany in 2008. However, public awareness and participation rates remain low. There are no campaigns or target group–specific invitation strategies for SCS yet. Thus, our aim was to derive potential suggestions on how to best inform German residents about the possibility of SCS. Methods: Semi–structured, individual interviews with male and female German residents aged =35 years were conducted in Erlangen (Germany) to explore opportunities on raising awareness of SCS. Interviews were audiotaped, transcribed verbatim, and analyzed using qualitative content analysis. Results: Overall, 39 persons were interviewed. About 79.5% (31/39) had already undergone at least one SCS. Numerous opportunities to raise awareness of the possibility of SCS were suggested which were categorized into three main topics: the role of public promotion, health–related caregivers, and health insurance. Similar themes were identified for inviting entitled persons to undergo SCS after 2 years. Furthermore, age–dependent communication approaches were proposed, that is, younger persons should be approached electronically, while the older generation should be targeted with traditional media like mail. Conclusions: The results of this project will inform stakeholders to take appropriate actions. The findings may contribute to increase participation rates in SCS and thus lead to earlier detection of skin cancer.
CRIS-Team WoS Importer:2023-05-12

Opposing functions of thymic stromal lymphopoietin-responsive basophils and dendritic cells in a mouse model of atopic dermatitis - Schwartz, Christian; Eberle, Jörg; Hoyler, Thomas; Diefenbach, Andreas; Lechmann, Matthias; Vöhringer, David (Journal of Allergy and Clinical Immunology, 2016)
EVALuna2:25878

Optimizing immune checkpoint blockade in metastatic uveal melanoma: exploring the association of overall survival and the occurrence of adverse events - Koch, Elias; Petzold, Anne; Dippel, Edgar; Erdmann, Michael; Gesierich, Anja; Gutzmer, Ralf; Hassel, Jessica C.; Haferkamp, Sebastian; Kähler, Katharina C.; Kreuzberg, Nicole; Leiter, Ulrike; Loquai, Carmen; et al. (Frontiers in Immunology, 2024)
Introduction: Despite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable. Methods: In this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57). Results: In the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively). Conclusions: This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens.
CRIS-Team Scopus Importer:2024-06-28
Keywords: adverse events; CTLA-4; immune checkpoint blockade; immune-related; PD-1; toxicity; uveal melanoma

Outcome of melanoma patients with elevated LDH treated with first-line targeted therapy or PD-1-based immune checkpoint inhibition - Knispel, Sarah; Gassenmaier, Maximilian; Menzies, Alexander M.; Loquai, Carmen; Johnson, Douglas B.; Franklin, Cindy; Gutzmer, Ralf; Hassel, Jessica C.; Weishaupt, Carsten; Eigentler, Thomas; Schilling, Bastian; Schummer, Patrick; et al. (European Journal of Cancer, 2021)
Background: Elevated lactate dehydrogenase (LDH) is a known predictive and prognostic factor for a poor outcome in patients with metastatic melanoma. It is unclear whether first-line targeted therapy (TT) or immune checkpoint inhibition (ICI) is more beneficial in melanoma patients with elevated LDH because prospective studies in this area are lacking. Methods: This multicentre retrospective cohort study was conducted at 25 melanoma centres worldwide to analyse progression-free survival (PFS) and overall survival (OS) among melanoma patients with elevated LDH. The role of confounders was addressed by using inverse probability of treatment weighting. Results: Among 173 BRAFV600-mutant patients, PFS at 12 months in the TT group was 22% compared with 52% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.6, 95% CI 0.4–1.0, p = 0.07) and 18% in the anti-PD-1 monotherapy group (HR 1.8, 95% CI 1.2–2.8, p = 0.003). Twelve months' OS was 48% in the TT group compared with 83% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.5, 95% CI 0.3–1.0, p = 0.03) and 50% in the anti-PD-1 monotherapy group (HR 1.2, 95% CI 0.8–2.0, p = 0.37). The ORR in the TT group was 63%, compared with 55% and 20% in the combined anti-PD-1 and anti-CTLA-4 and anti-PD-1 monotherapy group, respectively. Among 314 patients receiving ICI first-line, PFS at 12 months was 33% in the anti-PD-1 group versus 38% in the combined anti-PD-1 and anti-CTLA-4 group (HR 0.8, 95% CI 0.6–1.0; p = 0.07). OS at 12 months was 54% in the anti-PD-1 group versus 66% in the combined ICI group (HR 0.7, 95% CI 0.5–1.0; p = 0.03). The ORR was 30% in the anti-PD-1 monotherapy group and 43% in the combined anti-PD-1 and anti-CTLA-4 group. Results from multivariate analysis confirmed the absence of qualitative confounding. Conclusions: Among BRAF-mutant patients with elevated LDH, combined anti-PD-1 and anti-CTLA-4 blockade seems to be associated with prolonged OS compared with first-line TT. Among patients receiving ICI as a first-line treatment, OS appears to be longer for the combination of anti-PD-1 and anti-CTLA-4 than for anti-PD-1 alone.
CRIS-Team Scopus Importer:2021-03-26
Keywords: CTLA-4; Immune checkpoint inhibition; LDH; Melanoma; PD-1; Progression; Response; Survival; Targeted therapy

Outcome on 560 metastatic melanoma (MM) patients treated with pembrolizumab during the German Expanded Access Program (EAP) - Hassel, J.; Forschner, A.; Bluhm, L.; Heinzerling, Lucie; Zimmer, L.; Utikal, J.; Kaehler, K.; Schlaak, M.; Loquai, C.; Gutzmer, R.; Kieker, F.; Berking, C.; et al. (2016)
EVALuna2:33940

Overdiagnosis of melanoma – causes, consequences and solutions - 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)
Malignant melanoma is the skin tumor that causes most deaths in Germany. At an early stage, melanoma is well treatable, so early detection is essential. However, the skin cancer screening program in Germany has been criticized because although melanomas have been diagnosed more frequently since introduction of the program, the mortality from malignant melanoma has not decreased. This indicates that the observed increase in melanoma diagnoses be due to overdiagnosis, i.e. to the detection of lesions that would never have created serious health problems for the patients. One of the reasons is the challenging distinction between some benign and malignant lesions. In addition, there may be lesions that are biologically equivocal, and other lesions that are classified as malignant according to current criteria, but that grow so slowly that they would never have posed a threat to patient’s life. So far, these “indolent” melanomas cannot be identified reliably due to a lack of biomarkers. Moreover, the likelihood that an in-situ melanoma will progress to an invasive tumor still cannot be determined with any certainty. When benign lesions are diagnosed as melanoma, the consequences are unnecessary psychological and physical stress for the affected patients and incurred therapy costs. Vice versa, underdiagnoses in the sense of overlooked melanomas can adversely affect patients’ prognoses and may necessitate more intense therapies. Novel diagnostic options could reduce the number of over- and underdiagnoses and contribute to more objective diagnoses in borderline cases. One strategy that has yielded promising results in pilot studies is the use of artificial intelligence-based diagnostic tools. However, these applications still await translation into clinical and pathological routine.
CRIS-Team Scopus Importer:2020-09-04

Oxidative DNA damage in reconstituting T cells is associated with relapse and inferior survival after allo-SCT - Karl, Franziska; Liang, C.; Böttcher-Loschinski, R.; Stoll, Andrej; Flamann, Cindy; Richter, Silja; Lischer, Christopher; Völkl, Simon; Jacobs, Benedikt; Böttcher, M.; Jitschin, R.; Bruns, Heiko; et al. (Blood, 2023)
Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only curative treatment option for a number of hematologic malignancies. Its therapeutic potential relies on the potency of donor T cells to eliminate residual malignant cells, the so-called graft-versus-leukemia (GVL) effect. Disease relapse remains the most frequent treatment failure and is associated with poor outcome. Therefore, it is inevitable to decipher mechanisms that weaken GVL. In recent years, studies of tumor biology have revealed that metabolic remodeling of the micromilieu can critically regulate immune responses. Accumulation of reactive oxygen species leads to a metabolic condition known as oxidative stress, which can severely hamper T cells. Currently, only a few studies, mainly using preclinical models, have demonstrated the occurrence of oxidative stress after allo-SCTs. Therefore, we sought to investigate oxidative stress in a well-characterized group of patients who underwent allo-SCT and its impact on reconstituting T cells. We identified high concentrations of serum 8-hydroxydeoxyguanosine (8-OHdG) as an established biomarker for oxidative stress. 8-OHdG is one of the major products of DNA oxidation, which is normally rapidly removed. After allo-SCT, T cells accumulated oxidative DNA damage. High cellular 8-OHdG content (8-OHdGhi) was associated not only with signs of enhanced T-cell activation but also premature exhaustion. The inability of 8-OHdGhi T cells to efficiently target malignant cells or produce cytotoxic granzyme B and interferon gamma was associated with a significantly increased relapse risk and a shorter overall survival. Taken together, our novel findings could give reason to focus on bolstering DNA repair in reconstituting T cells as a means to improve GVL efficacy.
CRIS-Team Scopus Importer:2023-03-31

Palmitoylated Proteins on AML-Derived Extracellular Vesicles Promote Myeloid-Derived Suppressor Cell Differentiation via TLR2/Akt/mTOR Signaling - Tohumeken, Sehmus; Böttcher, Martin; Stoll, Andrej; Loschinski, Romy; Panagiotidis, Konstantinos; Braun, Martina; Saul, Domenica; Baur, Andreas; Bruns, Heiko; Mackensen, Andreas; Jitschin, Regina; Mougiakakos, Dimitrios; et al. (Cancer Research, 2020)
Acute myeloid leukemia (AML) represents the most common acute leukemia among adults. Despite recent progress in diagnosis and treatment, long-term outcome remains unsatisfactory. The success of allogeneic stem cell transplantation underscores the immunoresponsive nature of AML, creating the basis for further exploiting immunotherapies. However, emerging evidence suggests that AML, similar to other malignant entities, employs a variety of mechanisms to evade immunosurveillance. In light of this, T-cell inhibitory myeloid-derived suppressor cells (MDSC) are gaining interest as key facilitators of immunoescape. Accumulation of CD14(+) HLA-DRlow monocyticMDSCs has been described in newly diagnosed AML patients, and deciphering the underlying mechanisms could help to improve anti-AML immunity. Here, we report that conventional monocytes readily takeup AML-derived extracellular vesicles (EV) and subsequently undergo MDSC differentiation. They acquired an CD14(+)HLA-DRlow phenotype, expressed the immunomodulatory indoleamine-2,3-dioxygenase, and upregulated expression of genes characteristic for MDSCs, such as S100A8/9 and cEBP beta. The Akt/mTOR pathway played a critical role in the AML-EV-induced phenotypical and functional transition of monocytes. Generated MDSCs displayed a glycolytic switch, which rendered them more susceptible toward glycolytic inhibitors. Furthermore, palmitoylated proteins on the AML-EV surface activated Toll-like receptor 2 as the initiating event of Akt/mTOR-dependent induction of MDSC. Therefore, targeting protein palmitoylation in AML blasts could block MDSC accumulation to improve immune responses.
CRIS-Team WoS Importer:2020-09-25

Palmoplantar Pustular Psoriasis Is Associated with Missense Variants in CARD14, but Not with Loss-of-Function Mutations in IL36RN in European Patients - Moessner, Rotraut; Frambach, Yvonne; Wilsmann-Theis, Dagmar; Loehr, Sabine; Jacobi, Arnd; Weyergraf, Ansgar; Mueller, Michael; Philipp, Sandra; Renner, Regina; Traupe, Heiko; Burkhardt, Harald; Kingo, Kuelli; et al. (Journal of Investigative Dermatology, 2015)
EVALuna2:9269

PaM - Development and Validation of a palliative medical Integration Model for Melanoma - Bender-Säbelkampf, Sophia; Heckel, Maria; Ostgathe, Christoph; Berking, Carola; Heppt, Markus (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Panniculitis under successful targeted inhibition of the MAPK/ERK signaling pathway in a patient with BRAF V600E-mutated spindle cell oncocytoma of the pituitary gland - Sollfrank, Lukas; Lettmaier, Sebastian; Erdmann, Michael; Uslu, Ugur (Anticancer Research, 2019)
Background: Spindle cell oncocytoma (SCO) is a rare non-neuroendocrine neoplasm of the pituitary gland. In general, surgical excision and radiation therapy is performed. However, local recurrences are frequently seen, requiring repeated surgical and radio-oncological interventions. Thus, mutational analysis of the tumor and targeted therapy may represent a valuable therapy option in these patients. Case Report: A 38-year-old female patient with past medical history of 6 surgeries (two transsphenoidal and four transcranial), radiation therapy, and chemoradiation therapy due to several recurrences of a SCO, presented for follow-up imaging. MRI of the brain showed growth of a tumor in the right parasellar region consistent with a new local recurrence, which due to its size and location was considered to be not resectable. Molecular analysis of a previously surgically removed tumor showed a BRAF V600E mutation and thus, combined targeted inhibition of the MAPK/ERK signaling pathway using a BRAF inhibitor and a MEK inhibitor was started. Due to drug-induced panniculitis, MEK inhibitor had to be stopped and BRAF inhibitor only was continued, which was well tolerated by the patient. Subsequent imaging revealed tumor regression already four weeks after therapy initiation and no disease progression has been observed to date. Conclusion: A SCO patient with BRAF V600E mutation was successfully treated using targeted inhibition of the MAPK/ERK signaling pathway. Under therapy, tumor regression was observed and the patient has been free of progressive disease for more than two years now. Thus, mutational analysis and targeted inhibition may offer an effective treatment option for SCO patients, while potential side-effects to this therapy, like observed in our case, can occur and needs to be adequately treated.
CRIS-Team Scopus Importer:2019-07-12
Keywords: Adenoma; BRAF; Cobimetinib; Dabrafenib; MEK; Panniculitis; Pituicytoma; Targeted therapy; Trametinib; Vemurafenib

PARP inhibitors combined with ionizing radiation induce different effects in melanoma cells and healthy fibroblasts - Weigert, Verena; Jost, Tina; Hecht, Markus; Knippertz, Ilka; Heinzerling, Lucie; Fietkau, Rainer; Distel, Luitpold (BMC Cancer, 2020)
BACKGROUND: PARP inhibitors niraparib and talazoparib are FDA approved for special cases of breast cancer. PARP is an interesting repair protein which is frequently affected in cancer cells. We studied the combined action of talazoparib or niraparib with ionizing radiation in melanoma cells and healthy fibroblasts. METHODS: Homologous recombination (HR) status in six different melanoma cell lines and healthy fibroblasts was assessed. Cell cultures were treated with PARP inhibitors talazoparib or niraparib and ionizing radiation (IR). Apoptosis, necrosis and cell cycle distribution was analyzed via flow cytometry. Cell migration was studied by scratch assays. RESULTS: Studied melanoma cell cultures are HR deficient. Studied healthy fibroblasts are HR proficient. Talazoparib and niraparib have congruent effects within the same cell cultures. In all cell cultures, combined treatment increases cell death and G2/M arrest compared to IR. Combined treatment in melanoma cells distinctly increases G2/M arrest. Healthy fibroblasts are less affected by G2/M arrest. Treatment predominantly decelerates or does not modify migration. In two cell cultures migration is enhanced under the inhibitors. CONCLUSIONS: Although the two PARP inhibitors talazoparib and niraparib appear to be suitable for a combination treatment with ionizing radiation in our in vitro studies, a combination treatment cannot generally be recommended. There are clear interindividual differences in the effect of the inhibitors on different melanoma cells. Therefore, the effect on the cancer cells should be studied prior to a combination therapy. Since melanoma cells increase more strongly than fibroblasts in G2/M arrest, the fractional application of combined treatment should be further investigated.
CRIS-Team Scopus Importer:2020-08-28
Keywords: Cell cycle; Cell death; Homologous recombination; Ionizing radiation; Kinase inhibitor; PARP1/PARP2; Radiosensitivity

PASI <= 2 corresponds to PASI 90, irrespective of baseline severity: A post-hoc analysis of the PRIME-study - Reich, K.; Sieder, C.; Bachhuber, T.; Melzer, N.; Sticherling, Michael (2017)
EVALuna2:34343

Patch test informed consent form: position statement by European Academy of Dermatology and Venereology Task Force on Contact Dermatitis - Balato, A.; Scala, E.; Ayala, F.; Bauer, A.; Crepy, M. N.; Goncalo, M.; Johansen, J. Duus; John, S. M.; Rustemeyer, T.; Wagner, Nicola; Wilkinson, M.; Gimenez-Arnau, A. (Journal of the European Academy of Dermatology and Venereology, 2021)
Background To our knowledge, an international consensus is lacking regarding the development of an adequate informed consent form for a patch test (PT) and the information that should be included in such document. Objectives The aim of the study was to reach a consensus on the specific points that need to be addressed in a PT consent form. Methods A Delphi survey, comprising 2 rounds and 1 final discussion, was used to gather and analyse data, which was conducted over the Internet. Each statement that reached a consensus with the respondents (9 expert dermatologists from Europe) was defined as a median consensus score (MED) of >= 7 and agreement among panelists as an interquartile range (IQR) of <= 3. All study participants were members of the EADV task force on contact dermatitis. Results The expert panel addressed several topics that should be included in an informed consent form for a PT: introduction, preparation for PT, testing procedure, allowed activities, adverse events and additional authorizations. Conclusions Our results assess recommendations regarding points to be contained in an informed consent form for a PR. Future actions towards standardization and harmonization of this specific consent form are needed.
CRIS-Team WoS Importer:2021-07-30

Patch testing hydroperoxides of limonene and linalool in consecutive patients—Results of the IVDK 2018–2020 - Schubert, Steffen; Geier, Johannes; Brans, Richard; Heratizadeh, Annice; Kränke, Birger; Schnuch, Axel; Bauer, Andrea; Dickel, Heinrich; Buhl, Timo; Vieluf, Dieter; Wagner, Nicola; Worm, Margitta (Contact Dermatitis, 2023)
Background: Hydroperoxides of limonene (Lim-OOHs) and linalool (Lin-OOHs) are potent contact sensitizers. Objectives: To investigate the prevalence of positive patch test (PT) reactions to Lim-OOHs and Lin-OOHs in consecutive patients, their demographic factors and concomitant reactions. Methods: Between 7/2018 and 12/2020, Lim-OOHs 0.3% pet. and Lin-OOHs 1% pet. were patch tested in 5511 consecutive patients. We assessed PT reactivity and analysed data from patients with either positive or negative PTs to Lim-OOHs and Lin-OOHs. Results: Positive PT results to Lim-OOHs (n = 170, 3.1%) and Lin-OOHs (n = 483, 8.8%) were frequent. Most of the positive reactions were weak (LimOOHs n = 134/LinOOHs n = 429), and even more frequently, doubtful (n = 252/n = 578) or irritant reactions (n = 81/n = 178) were documented. PT reactivity to Lim-OOHs and Lin-OOHs was increased in patients with irritant reactions to sodium lauryl sulphate (SLS). The proportion of leg dermatitis and concomitant positive reactions to fragrances and essential oils was increased in patients with reactivity to these hydroperoxides. Conclusion: The observed reaction pattern suggests that both test preparations display an irritant potential with an increased risk of false positive reactions. Preparations should be chemically monitored in order to reduce irritancy. Mindful interpretation of PT results and aimed patch testing of lower concentrations is recommended.
CRIS-Team Scopus Importer:2023-05-26
Keywords: allergic contact dermatitis; autoxidation; fragrance; hydroperoxide; hydroperoxides of limonene; hydroperoxides of linalool; patch testing; sodium lauryl sulphate

Patch testing shellac in consecutive patients—Data of the Information Network of Departments of Dermatology (IVDK) 2021 - Schubert, Steffen; Worm, Margitta; Dickel, Heinrich; Wagner, Nicola; Brans, Richard; Schroder-Kraft, Claudia; Bauer, Andrea; Koch, Andre; Geier, Johannes (Contact Dermatitis, 2022)
CRIS-Team Scopus Importer:2022-10-21
Keywords: allergic contact dermatitis; cosmetics; epidemiology; patch test; shellac; tattoo

Patch test results with caine mix III and its three constituents in consecutive patients of the IVDK - Uter, Wolfgang; Worm, Margitta; Brans, Richard; Wagner, Nicola; Bauer, Andrea; Geier, Johannes (Contact Dermatitis, 2021)
CRIS-Team Scopus Importer:2021-01-29
Keywords: baseline series; benzocaine; caine mix III; cinchocaine (dibucaine); clinical epidemiology; contact allergy; RRID:SCR_001905; tetracaine

Pathogenetic Implications of BRAF Mutation Distribution in Stage IV Melanoma Patients - Baiter, Mirjam; Schuler, Gerold; Hartmann, Arndt; Schneider-Stock, Regine; Heinzerling, Lucie (Dermatology, 2015)
BRAF mutation frequencies in melanoma subtypes have clinical implications and offer pathogenetic clues.To characterize BRAF mutation status in melanoma of unknown primary (MUP) patients, in histological melanoma subtypes and by localization of primary tumors.In 179 patients with stage IV metastatic melanoma, BRAF mutation status, histological subtype and localization of primary (except for 29 MUP patients) were analyzed.BRAF mutations were found in 44.3%, of which 80.5% were BRAF V600E and 19.5% showed non-V600E BRAF mutations. BRAF mutation frequency depended on histological subtype (57.4% superficial spreading melanoma, 54.7% nodular melanoma, 11.1% mucosal melanoma, 28.6% acral lentiginous melanoma) and concerning non-V600E BRAF mutations on localization of primary. In MUP the BRAF mutation pattern resembled superficial spreading and nodular melanomas.BRAF mutation frequencies depend on histological subtype and localization of primary melanoma. Non-V600E BRAF mutations mostly occur in patients with primaries on 'head and neck' as well as 'trunk' but not on 'extremities'.
EVALuna2:6729

Patient Characteristics and Treatment Patterns in European Pediatric Patients with Psoriasis: A Real-World, Cross-Sectional Study - Sticherling, Michael; Mcpherson, Tess; Laguna, Raul De Lucas; Costanzo, Antonio; Reed, Catherine; Artime, Esther; Robert, Camille; Lucas, James; Schuster, Christopher; Mahe, Emmanuel (Dermatology and Therapy, 2022)
Introduction This study evaluated patient characteristics and treatment patterns according to weight in pediatric patients with psoriasis in a real-world setting. Methods Primary care and specialist physicians treating pediatric patients with psoriasis aged 6-17 years in five European countries were surveyed in the 2019-2020 Adelphi Real World Pediatric Psoriasis Disease Specific Programme. At least two patients with current or previous biologic use were included per physician. Patient characteristics and treatment patterns were analyzed overall and for patients weighing 25-50 kg or more than 50 kg. Results Data from 772 patients weighing 25-50 kg and 1147 weighing more than 50 kg were analyzed. Median age at diagnosis was significantly less in lighter than heavier patients (10.0 vs. 14.0 years; p < 0.001), as was median disease duration (2.2 vs. 3.0 years; p < 0.001). Topical treatments were prescribed in 59.0% of patients overall (70.3% of lighter and 51.4% of heavier patients; p < 0.001), and were used to treat mild rather than moderate-to-severe psoriasis. Conventional systemic use was low (10.8% of patients overall) and predominantly for moderate-to-severe psoriasis. In this biologic-enriched sample, most biologics (78.2%) were prescribed in older (> 13 years) patients. Biologic use increased with line of therapy (6.6% of first-line, 18.0% of second-line, 33.7% of third-line, 44.7% of fourth-line treatments). Conclusion Biologics are predominantly prescribed in older (> 13 years) and heavier (> 50 kg) patients, with little first- or second-line use. The low use of biologics in European pediatric patients with psoriasis may represent an unmet treatment need, as topical or conventional systemic agents remain the main treatment option for moderate or severe psoriasis in these patients through the treatment pathway.
CRIS-Team WoS Importer:2022-07-22

Patient-oriented Comparison of Systemic Therapies for Patients with advanced Melanoma - A multicenter Cross-sectional Study - Thiem, A.; Mashhadiakbar, P.; Hassel, J. C.; Grimmelmann, I.; Gutzmer, R.; Schlaak, M.; Heppt, Markus; Duecker, P.; Huening, S.; Schulmeyer, L.; Schilling, B.; Haferkamp, S.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Patient-oriented Comparison of Systems Therapies for advanced Melanoma: a multicenter Cross-Sectional Study - Thiem, A.; Mashhadiakbar, P.; Cussigh, Ch.; Hassel, J. C.; Grimmelmann, I.; Gutzmer, R.; Schlaak, M.; Heppt, Markus; Ducker, P.; Huning, S.; Schulmeyer, L.; Schilling, B.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-03

Patient Perception of Mobile Phone Apps for the Care and Prevention of Sexually Transmitted Diseases: Cross-Sectional Study - Jakob, Lena; Steeb, Theresa; Fiocco, Zeno; Pumnea, Teodora; Jakob, Sophia Nomi; Wessely, Anja; Rothenberger, Christoph Clemens; Brinker, Titus Josef; French, Lars Einar; Berking, Carola; Heppt, Markus (JMIR mHealth and uHealth, 2020)
BACKGROUND: In the emerging era of digitalization and electronic health, various health-related apps have been launched, including apps for sexually transmitted diseases. Until now, little has been known about how patients perceive the value of such apps. OBJECTIVE: To investigate patient's attitudes and awareness toward sexually transmitted disease-related apps in an outpatient sexually transmitted disease clinic setting. METHODS: A cross-sectional study was conducted at a dermatovenereological outpatient unit between April and July 2019. Patients completed a self-administered questionnaire on their perceptions of the popularity and usefulness of sexually transmitted disease-related apps. Descriptive analysis was performed with expression of categorical variables as frequencies and percentages. For continuous variables, the median, range, and interquartile range were indicated. Contingency tables and chi-square tests were used to investigate associations between sociodemographic data and items of the questionnaire. RESULTS: A total of 226 patients were surveyed (heterosexual: 137/193, 71.0%; homosexual: 44/193, 22.8%; bisexual: 12/193, 6.2%); 11.9% (27/225) had previously used health-related apps. Nearly half of the patients (97/214, 45.3%) specifically considered sexually transmitted disease-related apps useful, 47.8% (100/209) voted that they could supplement or support the consultation of a physician. Interestingly, only 35.1% (74/211) preferred a printed patient brochure on sexually transmitted diseases over downloading and using an app, but 64.0% (134/209) would download a sexually transmitted disease-related app recommended by their physician. General information regarding sexually transmitted diseases (93/167, 55.7%), evaluation of skin diseases based on photos or videos (78/167, 53.3%), information on the prevention of sexually transmitted diseases (76/167, 45.5%), mediation of nearby contact points or test sites (74/167, 44.3%), anonymous medical advice (69/167, 41.3%), and calculation of the risk of having a sexually transmitted disease (63/167, 37.3%) were rated as the most important features. Men were more likely than women to find sexually transmitted disease-related apps useful in general (P=.04; χ2=6.28) and to pay for such apps (P=.01; χ2=9.19). Patients aged <40 years would rather download an app recommended by their physician (P=.03; χ2=7.23), whereas patients aged >40 years preferred reading a patient brochure on sexually transmitted diseases (P=.02; χ2=8.14). CONCLUSIONS: This study demonstrated high general interest in the use of sexually transmitted disease-related apps in this sample of dermatovenereological outpatients. In particular, young age and male sex were significantly associated with a positive perception, underlining the high potential of apps in the prevention and early recognition of sexually transmitted diseases in this group. Future studies are warranted to validate these findings in other populations.
CRIS-Team Scopus Importer:2020-11-27
Keywords: health apps; mobile phone apps; sexually transmitted diseases; sexually transmitted infection

Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine - Grob, J. -J.; Amonkar, M. M.; Martin-Algarra, S.; Demidov, L. V.; Goodman, V.; Grotzinger, K.; Haney, P.; Kämpgen, Eckhart; Karaszewska, B.; Mauch, C.; Miller, W. H.; Millward, Michael; et al. (Annals of Oncology, 2014)
In a randomized phase III study (BREAK-3), dabrafenib showed prolonged progression-free survival (PFS) (median 5.1 versus 2.7 months; hazard ratio = 0.30; 95% confidence interval 0.18-0.53; P < 0.0001) compared with dacarbazine (DTIC) in patients with BRAF V600E metastatic melanoma. Assessing how these results are transformed into a real health benefit for patients is crucial.The EORTC QLQ-C30 questionnaire assessed quality of life (QoL) at baseline and follow-up visits.For DTIC, all functional dimensions except role dimension worsened from baseline at follow-up. For dabrafenib, all functionality dimensions remained stable relative to baseline or improved at week 6; mean change in seven symptom dimensions improved from baseline, with appetite loss, insomnia, nausea and vomiting, and pain showing the greatest improvement. In the DTIC arm, symptom dimensions were unchanged or worsened from baseline for all symptoms except pain (week 6), with the greatest exacerbations observed for fatigue and nausea and vomiting. Mixed-model-repeated measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements from baseline in favor of dabrafenib for emotional and social functioning, nausea and vomiting, appetite loss, diarrhea, fatigue, dyspnea, and insomnia at weeks 6 and/or 12. After crossing over to dabrafenib upon progression (n = 35), improvements in all QoL dimensions were evident after receiving dabrafenib for 6 (n = 31) to 12 (n = 25) weeks.This first reported QoL analysis for a BRAF inhibitor in metastatic melanoma demonstrates that the high tumor response rates and PFS superiority of dabrafenib over DTIC is not only a theoretical advantage, but also transforms in a rapid functional and symptomatic benefit for the patient.NCT01227889.
EVALuna2:19471

Patient preferences of German and Swiss melanoma patients with regard to life-threatening side effects in the context of adjuvant immunotherapy - a qualitative GerMelaTox-A substudy - Peters, W.; Maul, L. V.; Huning, S.; Hassel, J. C.; Heinzerling, Lucie; Loquai, C.; Gutzmer, R.; Sachse, M. M.; Blome, C.; Kah-Ler, K. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

Patient-reported Outcomes and Burden of Disease in Paediatric Patients with Psoriasis: Real-world Data from EU5 and US - Seyger, Marieke M.B.; Paller, Amy; Sticherling, Michael; Bachhuber, Teresa; Thomas, Nicolas; Hetherington, James; Lucas, James; Richardson, Craig; Augustin, Matthias (Acta Dermato-Venereologica, 2023)
CRIS-Team Scopus Importer:2023-04-28

Patient-reported outcomes and burden of disease in paediatric patients with psoriasis: real-world data from the EU5 and USA - Seyger, M.; Paller, A.; Sticherling, Michael; Bachhuber, T.; Fang, J.; Hetherington, J.; Lucas, J.; Meakin, S.; Richardson, C.; Augustin, M. (BRITISH JOURNAL OF DERMATOLOGY, 2022)
CRIS-Team WoS Importer:2022-01-14

Patients' and Physicians' Preferences for Systemic Psoriasis Treatments: A Nationwide Comparative Discrete Choice Experiment (PsoCompare) - Schaarschmidt, Marthe-Lisa; Herr, Raphael M.; Gutknecht, Mandy; Wroblewska, Katharina; Gerdes, Sascha; Sticherling, Michael; Augustin, Matthias; Peitsch, Wiebke K. (Acta Dermato-Venereologica, 2018)
Systemic antipsoriatic treatment options are increasing rapidly. The aim of this nationwide discrete choice experiment was to compare patients' (n = 222) and physicians' (n = 78) preferences for outcome and process attributes of systemic antipsoriatics using Relative Importance Scores (RIS). Both groups considered Psoriasis Area and Severity Index 90 (PASI 90) to be most important (RIS 21.4 and 20.8, respectively). Moreover, patients were highly concerned about mild and severe adverse events (RIS = 18.2 and 14.2), physicians about severe adverse events (RIS = 14.9) and cost (RIS = 13.8). Compared to physicians, patients worried more about mild adverse events and treatment location, but less about cost and frequency of laboratory tests. Physicians' preferences were influenced by work experience and percentage of biological prescriptions, patients' preferences by age, disease duration and severity. Older and less severely affected patients recruited via a patient organization focused more on safety, but less on efficacy and time until response than did patients from study centres. In conclusion, these differences in trade-offs should be integrated into a shared decision-making.
EVALuna2:34404

Patients Receiving Cytokine Inhibitors Have Low Prevalence of SARS-CoV-2 Infection - Simon, David; Tascilar, Koray; Krönke, Gerhard; Kleyer, Arnd; Zaiss, Mario; Heppt, Franz; Meder, Christine; Atreya, Raja; Klenske, Entcho; Dietrich, Peter; Abdullah, Abdullah; Kliem, Thorsten; et al. (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Patients with Chronic Urticaria need better Treatment: Results of the DERMLINE Online Survey - Hell, Katharina; Zink, Alexander; Schielein, Maximilian C.; Hacker, Elena; Romer, Katrin; Baeumer, Daniel; Wagner, Nicola (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-02-28

Patients with Chronic Urticaria Remain Largely Undertreated: Results from the DERMLINE Online Survey - Wagner, Nicola; Zink, Alexander; Hell, Katharina; Reinhardt, Maximilian; Romer, Katrin; Hillmann, Elena; Baeumer, Daniel; Schielein, Maximilian C. (Dermatology and Therapy, 2021)
Introduction Chronic urticaria (CU) is an unpredictable disease, with high disease burden and a significant negative impact on quality of life, especially in patients of working age. Many patients are undertreated, and there is poor awareness of strategies to manage patients with CU in the real-world setting. The current study aimed to gain a better understanding of CU from the patients' perspective, including the body areas most affected by wheals and angioedema, the disease burden and current use of the healthcare system. Methods A nationwide online survey was performed in Germany involving individuals who reported a diagnosis of CU and experienced symptoms within 3 months prior to inclusion. Results This self-report survey included 1037 participants (89.2% female), with a mean +/- standard deviation (SD) age of 33.4 +/- 11.0 years and a mean +/- SD disease duration of 10.0 +/- 9.4 years. On average, participants suffered from urticaria symptoms for 3.0 +/- 4.3 years before diagnosis. In 73% of participants, symptoms worsened due to external factors, with the majority specifying stress in their personal life or work-related stress as eliciting factors. Within the previous 3 months, 87.4 and 44.1% of participants experienced wheals and angioedema, respectively, at multiple body areas, and most (79.6%) participants had uncontrolled symptoms as measured with the Urticaria Control Test. Despite the high burden of disease, 60.3% of participants stated that they were not currently receiving treatment. The most commonly used therapies to treat CU were oral (72.8%) and non-prescription (43.3%) and prescription (47.3%) topical drugs, with 18.0% of the participants receiving injectable/infused drugs. Conclusion The majority of the participants responding to the survey reported that CU is not sufficiently controlled, thereby severely influencing a highly productive time in their life. The body areas most affected by wheals and angioedema are specified, based on data provided by a large group of affected participants. A greater awareness of disease burden and available treatment options is needed.
CRIS-Team WoS Importer:2021-05-14

PATIENTS WITH IMMUNE MEDIATED INFLAMMATORY DISEASES ARE OVERREPRESENTED IN LOW-FREQUENCY VIRAL SYMPTOM CLUSTERS - Tascilar, Koray; Simon, David; Krönke, Gerhard; Kleyer, Arnd; Ramming, Andreas; Atreya, Raja; Tenbusch, Matthias; Überla, Klaus; Berking, Carola; Sticherling, Michael; Neurath, Markus; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Patients with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of SARS-CoV-2 seroconversion - Simon, David; Tascilar, Koray; Krönke, Gerhard; Kleyer, Arnd; Zaiss, Mario; Heppt, Franz; Meder, Christine; Atreya, Raja; Klenske, Entcho; Dietrich, Peter; Abdullah, Abdullah; Kliem, Thorsten; et al. (Nature Communications, 2020)
Immune-mediated inflammatory diseases (IMIDs) of the joints, gut and skin are treated with inhibitors of inflammatory cytokines. These cytokines are involved in the pathogenesis of coronavirus disease 2019 (COVID-19). Investigating anti-SARS-CoV-2 antibody responses in IMIDs we observe a reduced incidence of SARS-CoV-2 seroconversion in IMID patients treated with cytokine inhibitors compared to patients receiving no such inhibitors and two healthy control populations, despite similar social exposure. Hence, cytokine inhibitors seem to at least partially protect from SARS-CoV-2 infection.
CRIS-Team Scopus Importer:2020-08-07

Patterns of care and follow-up care of patients with uveal melanoma in German-speaking countries: a multinational survey of the German Dermatologic Cooperative Oncology Group (DeCOG) - Steeb, Theresa; Wessely, Anja; Alter, Mareike; Bayerl, Christiane; Bender, Armin; Bruning, Guido; Dabrowski, Evelyn; Debus, Dirk; Devereux, Nina; Dippel, Edgar; Drexler, Konstantin; Dücker, Pia; et al. (Journal of Cancer Research and Clinical Oncology, 2020)
Purpose: Uveal melanoma (UM) is an orphan cancer of high unmet medical need. Current patterns of care and surveillance remain unclear as they are situated in an interdisciplinary setting. Methods: A questionnaire addressing the patterns of care and surveillance in the management of patients with uveal melanoma was distributed to 70 skin cancer centers in Austria, Germany and Switzerland. Frequency distributions of responses for each item of the questionnaire were calculated. Results: 44 of 70 (62.9%) skin cancer centers completed the questionnaire. Thirty-nine hospitals were located in Germany (88.6%), three in Switzerland (6.8%) and two in Austria (4.5%). The majority (68.2%) represented university hospitals. Most patients with metastatic disease were treated in certified skin cancer centers (70.7%, 29/41). Besides, the majority of patients with UM were referred to the respective skin cancer center by ophthalmologists (87.2%, 34/39). Treatment and organization of follow-up of patients varied across the different centers. 35.1% (14/37) of the centers stated to not perform any screening measures. Conclusion: Treatment patterns of patients with uveal melanoma in Germany, Austria and Switzerland remain extremely heterogeneous. A guideline for the treatment and surveillance is urgently needed.
CRIS-Team Scopus Importer:2020-11-27
Keywords: Background; Cross-sectional study; Follow-up; Ocular melanoma; Patterns of care; Surveillance; Treatment patterns; Uveal melanoma

People-centered care for psoriasis and urticaria: Are we overlooking Internet addiction while only considering patients and physician settings? - Schielein, Maximilian Christian; Tizek, Linda; Baeumer, Daniel; Hillmann, Elena; Romer, Katrin; Wagner, Nicola; Zink, Alexander (Journal of Dermatology, 2021)
Psoriasis and chronic urticaria (CU) are chronic skin diseases with a high impact on individuals’ life and mental health. Some studies indicate a high prevalence of Internet addiction and many affected individuals seem not to utilize healthcare, but rather search for health-related information online. The aims of the study were to assess Internet addiction as a potential comorbidity in both diseases as well as identify differences in healthcare utilization between individuals with psoriasis and CU. This cross-sectional study is based on self-reported data from individuals with psoriasis and CU living throughout Germany using the framework of an online survey from 12/2018 to 01/2019. Advertisements on Google and Facebook were used to address Internet users who searched online for information on psoriasis or CU. The study questionnaire comprised questions on demographics, current contact with physicians, and disease history as well as validated screening tools for well-being and Internet addiction. Overall, 1686 participants (74.0% female, 38.5% psoriasis) with a mean age of 36.9 ± 12.9 years were analyzed. Participants with CU were more likely female (89.2% vs 49.8%, P < 0.001) and not in medical care compared to participants with psoriasis (60.3% vs 45.9%, P < 0.001). Sixteen percent of the participants overall were screened positive for Internet addiction. Furthermore, not utilizing medical care showed a significant association with being screened positive for Internet addiction in participants with CU (adjusted odds ratio [aOR] = 1.49, 95% confidence interval [CI] 1.10–2.02), but not in those with psoriasis. The study revealed a high proportion of affected individuals not being in medical care and a high prevalence of Internet addiction, with individuals with CU not utilizing medical resources having a higher chance of being screened positive for Internet addiction. This underlines the approach of people-centered care and highlights its importance for further research.
CRIS-Team Scopus Importer:2021-01-15
Keywords: chronic skin diseases; depression; dermatology; epidemiology; Internet addiction; mental health; people-centered care

Perception of the coronavirus pandemic by patients with atopic dermatitis - Results from the TREATgermany registry - Helmert, Claudia; Siegels, Doreen; Haufe, Eva; Abraham, Susanne; Heratizadeh, Annice; Kleinheinz, Andreas; Harder, Inken; Schaekel, Knut; Effendy, Isaak; Wollenberg, Andreas; Sticherling, Michael; Stahl, Maren; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
Background TREATgermany, a registry for patients with moderate to severe atopic dermatitis (AD), established an additional questionnaire in spring 2020 to investigate the effects of the coronavirus pandemic on the daily life of patients with AD. Material and Methods A questionnaire was used to analyze general information regarding a patient's experience of the coronavirus pandemic and, using the Inventory of Life-Changing Events, the resulting personal burden. To analyze possible associations between disease severity (EASI score, oSCORAD, IGA, PGA, POEM), quality of life (DLQI) and personal burden, t-tests, analyses of variance and correlations were evaluated, controlled for sex and age. Results 58 % (n = 233) of the included 400 registry patients reported high burden scores caused by the coronavirus pandemic, regardless of an actual infection. Men showed significantly higher burden scores than women, and younger than older respondents (both P = 0.03). There were no differences in burden scores related to the physician's assessment of disease severity. However, patients with higher quality of life impairments and higher disease severity perceived the burden of the coronavirus pandemic as less severe (DLQI P = 0.019, PGA P = 0.044). Conclusions Our data show that registry patients considered the coronavirus pandemic as a life-changing event and perceived the burden differently. This should be taken into account in the treatment of patients with moderate to severe AD as well as in further studies.
CRIS-Team WoS Importer:2022-01-07

Peripheral PD-1+CD56+ T-cell frequencies correlate with outcome in stage IV melanoma under PD-1 blockade - Bochem, Jonas; Zelba, Henning; Amaral, Teresa; Spreuer, Janine; Soffel, Daniel; Eigentler, Thomas; Wagner, Nikolaus Benjamin; Uslu, Ugur; Terheyden, Patrick; Meier, Friedegund; Garbe, Claus; Pawelec, Graham; et al. (PLoS ONE, 2019)
Immune checkpoint blockade with anti-PD-1 antibodies is showing great promise for patients with metastatic melanoma and other malignancies, but despite good responses by some patients who achieve partial or complete regression, many others still do not respond. Here, we sought peripheral blood T-cell biomarker candidates predicting treatment outcome in 75 stage IV melanoma patients treated with anti-PD-1 antibodies. We investigated associations with clinical response, progression-free survival (PFS) and overall survival (OS). Univariate analysis of potential biological confounders and known biomarkers, and a multivariate model, was used to determine statistical independence of associations between candidate biomarkers and clinical outcomes. We found that a lower than median frequency of peripheral PD-1+CD56+ T-cells was associated with longer OS (p = 0.004), PFS (p = 0.041) and superior clinical benefit (p = 0.009). However, neither frequencies of CD56-CD4+ nor CD56-CD8+ T-cells, nor of the PD-1+ fraction within the CD4 or CD8 subsets was associated with clinical outcome. In a multivariate model with known confounders and biomarkers only the M-category (HR, 3.11; p = 0.007) and the frequency of PD-1+CD56+ T-cells (HR, 2.39; p = 0.028) were identified as independent predictive factors for clinical outcome under PD-1 blockade. Thus, a lower than median frequency of peripheral blood PD-1+CD56+ T-cells prior to starting anti-PD-1 checkpoint blockade is associated with superior clinical response, longer PFS and OS of stage IV melanoma patients.
CRIS-Team Scopus Importer:2019-08-27

Peristomal skin lesions – identifying patients at risk - Dietmaier, Louisa; Summa, Scarlett; Ronicke, Moritz; Erfurt-Berge, Cornelia (Zeitschrift für Gastroenterologie, 2024)
BACKGROUND AND OBJECTIVES: Diagnosis and therapy of peristomal skin lesions are challenging for the majority of therapists. Established diagnostic tools have not yet been validated. Our objective was to outline the spectrum of and to identify risk factors for skin lesions in ostomy patients. A focus was set on peristomal ulcerations and their differentiation as peristomal pyoderma gangrenosum. METHODS: In a retrospective analysis, frequency and character of peristomal skin lesions in patients presenting at two departments were analysed. Patients suffering from peristomal ulcerations were subjected to a more detailed analysis including application of the PARACELSUS score. RESULTS: A total of 565 patients with ostomy were analysed; 40.2% (n = 227) presented with peristomal skin lesions. Moisture-associated skin damage (27.9%) was the most common, while ulcerations (21.9%) and eczematous skin alterations (19.1%) were seen with comparable frequency. Peristomal pyoderma gangrenosum was diagnosed in 7.9% of all observed peristomal lesions. Among patients with inflammatory bowel disease (n = 98), peristomal ulcerations were the leading finding (35.7%), and pyoderma gangrenosum was more frequent in these patients (16.3%). CONCLUSIONS: It is necessary to assess and classify peristomal skin lesions. Further studies for the validation of different scores or the development of diagnostic tools are needed.
CRIS-Team Scopus Importer:2024-11-22

Persistence of the IgE repertoire in birch pollen allergy - Otte, Manuel; Mahler, Vera; Kerpes, Andrea; Pabst, Oliver; Vöhringer, David (Journal of Allergy and Clinical Immunology, 2016)
EVALuna2:19587

Persistent immune-related adverse events after cessation of checkpoint inhibitor therapy: Prevalence and impact on patients' health-related quality of life - Schulz, Thomas U.; Zierold, Sarah; Sachse, Michael M.; Pesch, Giulia; Tomsitz, Dirk; Schilbach, Katharina; Kähler, Katharina C.; French, Lars E.; Heinzerling, Lucie (European Journal of Cancer, 2022)
Background: Immune checkpoint inhibitors (ICIs) may induce persistent immune-related adverse events (irAEs). We investigated persistent irAEs and implications on patients' lives compared to non-ICI-induced autoimmune diseases (AIs). Methods: The multicentre, cross-sectional study comprised 200 patients with cancer ≥12 weeks after ICI cessation (ICI-patients) and 2705 patients with AIs (AI-patients), recruited in German outpatient clinics and support groups. The prevalence of persistent irAEs subdivided in long-term (12 weeks to <12 months) and chronic irAEs (≥12 months) since ICI discontinuation, health-related quality of life (HRQoL) using the EuroQol 5D-5L (EQ-Index/VAS score), and burden of autoimmune symptoms and respective therapies were assessed. Results: Long-term/chronic irAEs occurred in 51.9%/35.5% of outpatient ICI-patients, including arthralgia (16.7%/16.1%), myalgia (13.0%/14.0%), hypothyroidism (11.1%/10.8%), xerostomia (7.4%/8.6%), vitiligo (13.0%/7.5%) and hypophysitis (9.3%/7.5%). ICI-patients with long-term/chronic irAEs reported clinically significantly reduced HRQoL compared to ICI-patients without long-term/chronic irAEs (EQ-Index score: 0.767/0.752 versus 0.920/0.923, p < 0.001/0.001; EQ-VAS score: 52.2/52.0 versus 63.6/74.7, p =/< 0.040/0.001). Multiple linear regression analyses confirmed clinically significant reductions in HRQoL scores by chronic irAEs (EQ-Index/VAS score: −0.163/−23.4, p < 0.001/0.001). HRQoL, burden of autoimmune symptoms and burden of respective therapies in ICI-patients with chronic irAEs were similar to AI-patients with non-exacerbated AIs. Patients with chronic irAEs felt inadequately informed about side-effects compared to patients without chronic irAEs (p < 0.001). Conclusion: Persistent irAEs impose a significant burden on patients after ICI cessation. Especially in early tumour stages, risk-benefit ratios must be carefully evaluated, and patients need to be informed about potential long-term sequelae.
CRIS-Team Scopus Importer:2022-10-14
Keywords: Autoimmunity; Cancer survivors; Chronic immune-related adverse events (chronic irAEs); Health-related quality of life (HRQoL); Immune checkpoint inhibitors (ICIs); Immunotherapy; Long-term sequelae; Melanoma; Persistent toxicities; Prevalence

Personalized cancer immunotherapy using Systems Medicine approaches - Gupta, Shailendra K.; Jaitly, Tanushree; Schmitz, Ulf; Schuler, Gerold; Wolkenhauer, Olaf; Vera, Julio (Briefings in Bioinformatics, 2016)
The immune system is by definition multi-scale because it involves biochemical networks that regulate cell fates across cell boundaries, but also because immune cells communicate with each other by direct contact or through the secretion of local or systemic signals. Furthermore, tumor and immune cells communicate, and this interaction is affected by the tumor microenvironment. Altogether, the tumor-immunity interaction is a complex multi-scale biological system whose analysis requires a systemic view to succeed in developing efficient immunotherapies for cancer and immune-related diseases. In this review we discuss the necessity and the structure of a systems medicine approach for the design of anticancer immunotherapies. We support the idea that the approach must be a combination of algorithms and methods from bioinformatics and patient-data-driven mathematical models conceived to investigate the role of clinical interventions in the tumor-immunity interaction. For each step of the integrative approach proposed, we review the advancement with respect to the computational tools and methods available, but also successful case studies. We particularized our idea for the case of identifying novel tumor-associated antigens and therapeutic targets by integration of patient's immune and tumor profiling in case of aggressive melanoma.
EVALuna2:19569

PGAM5-MAVS interaction regulates TBK1/ IRF3 dependent antiviral responses - Yu, Yidong; Zielinska, Marta; Li, Wei; Bernkopf, Dominic; Heilingloh, Christiane; Neurath, Markus; Becker, Christoph (Scientific Reports, 2020)
Viral infections trigger host innate immune responses, characterized by the production of type-I interferons (IFN) including IFNβ. IFNβ induces cellular antiviral defense mechanisms and thereby contributes to pathogen clearance. Accumulating evidence suggests that mitochondria constitute a crucial platform for the induction of antiviral immunity. Here we demonstrate that the mitochondrial protein phosphoglycerate mutase family member 5 (PGAM5) is important for the antiviral cellular response. Following challenge of HeLa cells with the dsRNA-analog poly(I:C), PGAM5 oligomers and high levels of PGAM5 were found in mitochondrial aggregates. Using immunoprecipitation, a direct interaction of PGAM5 with the mitochondrial antiviral-signaling protein (MAVS) was demonstrated. In addition, PGAM5 deficient cells showed diminished expression of IFNβ and IFNβ target genes as compared to WT cells. Moreover, PGAM5 deficient mouse embryonic fibroblasts (MEFs) exhibited decreased phosphorylation levels of IRF3 and TBK1 when challenged with poly(I:C) intracellularly. Finally, PGAM5 deficient MEFs, upon infection with vesicular stomatitis virus (VSV), revealed diminished IFNβ expression and increased VSV replication. Collectively, our study highlights PGAM5 as an important regulator for IFNβ production mediated via the TBK1/IRF3 signaling pathway in response to viral infection.
CRIS-Team Scopus Importer:2020-06-02

Pharmacodynamic Effect of mTOR Inhibition-based Immunosuppressive Therapy on T- and B-cell Subsets After Renal Transplantation - Wei, Xinyi; Weber, Sabine; Yin, Decheng; Allabauer, Ida; Jobst-Schwan, Tilman; Wiesener, Michael; Schiffer, Mario; Dudziak, Diana; Lehmann, Christian; Wölfle, Joachim; Hörning, André (Transplantation Direct, 2024)
Background. The mammalian target of rapamycin inhibitor (mTORi) therapy after kidney transplantation is solely monitored pharmacokinetically, not necessarily reflecting PI3K-Akt-mTOR pathway blockade efficacy leading to potential under- or overimmunosuppression. Methods. In this cross-sectional study, phosphoflow cytometry was used to determine the efficacy of mTOR inhibition in peripheral T- and B-lymphocyte subsets by assessing p70S6 kinase (p70S6K) phosphorylation in renal transplant recipients upon treatment with a combination of either mTORi and calcineurin inhibitors (n = 18), or mTORi with mycophenolic acid (n = 9). Nine dialysis patients with end-stage renal disease and 17 healthy age-matched volunteers served as controls. Results. mTORi treatment reduced p70S6K phosphorylation in CD4+, CD8+ T, and CD19+ B cells compared with healthy controls (HCs). Subpopulation analysis of CD4+ T cells and CD19+ B cells revealed a significant reduction of p70S6K phosphorylation in CD4+CD45RA−CD25− Th cells (P < 0.05), CD24hiCD38hi transitional B cells (P < 0.001), CD24+CD38− memory B cells (P < 0.001), and CD24intCD38int-naive B cells (P < 0.05) upon mTORi treatment, whereas CD4+CD45RA−CD25++CD127− regulatory T cells and CD24−CD38hi plasmablasts were not affected. Compared with mTORi + mycophenolic acid therapy, mTORi + calcineurin inhibitor treatment exhibited an even stronger inhibition of p70S6K phosphorylation in CD4+CD45RA−CD25− Th cells and CD8+ T cells. However, trough levels of mTORi did not correlate with p70S6K phosphorylation. Conclusions. mTORi selectively inhibited p70S6K phosphorylation in select lymphocyte subtypes. Assessing p70S6K phosphorylation by phosphoflow cytometry may serve as an approach to understand cell subset specific effects of mTORi providing detailed pharmacodynamic information for individualizing immunosuppression.
CRIS-Team Scopus Importer:2024-07-19

Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-mutant Melanoma. - Schuler, Martin; Zimmer, Lisa; Kim, Kevin B.; Sosman, Jeffrey A.; Ascierto, Paolo A.; Postow, Michael A.; De Vos, Filip Y.F.L.; van Herpen, Carla M.L.; Carlino, Matteo S.; Johnson, Douglas B.; Berking, Carola; Reddy, Micaela B.; et al. (Clinical Cancer Research, 2022)
PURPOSE: Enhanced MAPK pathway signaling and cell-cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma and, as such, the regimen of the MEK inhibitor binimetinib and the selective CDK4/6 inhibitor ribociclib is a rational combination. PATIENTS AND METHODS: This is a phase Ib/II, open-label study of ribociclib + binimetinib in patients with NRAS-mutant melanoma (NCT01781572). Primary objectives were to estimate the MTD/recommended phase II dose (RP2D) of the combination (phase Ib) and to characterize combination antitumor activity at the RP2D (phase II). Tumor genomic characterization and pharmacokinetics/pharmacodynamics were also evaluated. RESULTS: Ten patients (16.4%) experienced dose-limiting toxicities in cycle 1 of phase Ib. Overall response rate in the phase II cohort (n = 41) for the selected RP2D (binimetinib 45 mg twice daily + ribociclib 200 mg once daily, 21 days on/7 days off) was 19.5% [8/41; 95% confidence interval (CI), 8.8-34.9]. The response rate was 32.5% (13/40; 95% CI, 20.1-48.0) in patients with NRAS mutation with concurrent alterations of CDKN2A, CDK4, or CCND1. Median progression-free survival was 3.7 months (95% CI, 3.5-5.6) and median overall survival was 11.3 months (95% CI, 9.3-14.2) for all patients. Common treatment-related toxicities included creatine phosphokinase elevation, rash, edema, anemia, nausea, diarrhea, and fatigue. Pharmacokinetics and safety were consistent with single-agent data, supporting a lack of drug-drug interaction. CONCLUSIONS: Ribociclib + binimetinib can be safely administered and is clinically active in patients with NRAS-mutant melanoma. Co-mutations of cell-cycle genes may define a population with greater likelihood of treatment benefit. See related commentary by Moschos, p. 2977.
EVALuna2:499725

Phase I dose-escalation and expansion study of intratumoral CV8102, a RNA-based TLR- nd RIG-1 agonist in patients with advanced solid tumors - Terheyden, P.; Weishaupt, C.; Heinzerling, Lucie; Klinkhardt, U.; Krauss, J.; Mohr, P.; Kiecker, F.; Becker, J. C.; Submitter, A. Daehling; Doener, F.; Heidenreich, R.; Scheel, B.; et al. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-08

Phase II DeCOG-study of ipilimumab in pretreated and treatment-naïve patients with metastatic uveal melanoma - Zimmer, Lisa; Vaubel, Julia; Mohr, Peter; Hauschild, Axel; Utikal, Jochen; Simon, Jan; Garbe, Claus; Herbst, Rudolf; Enk, Alexander; Kämpgen, Eckhart; Livingstone, Elisabeth; Bluhm, Leonie; et al. (PLoS ONE, 2015)
Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM.We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months.Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7-8.1), median progression-free survival 2.8 months (95% CI 2.5-2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3-4 events (36%). One drug-related death due to pancytopenia was observed.Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines.ClinicalTrials.gov NCT01355120.
EVALuna2:19596

Phenotype and risk factors of venom-induced anaphylaxis: a case-control study of the European Anaphylaxis Registry - Francuzik, Wojciech; Ruëff, Franziska; Bauer, Andrea; Bilò, Maria Beatrice; Cardona, Victoria; Christoff, George; Dölle-Bierke, Sabine; Ensina, Luis; Fernandes-Rivas, Montserat; Hawranek, Thomas; O'B Hourihane, Johnathan; Jakob, Thilo; et al. (Journal of Allergy and Clinical Immunology, 2020)
BACKGROUND: Venom-induced anaphylaxis is a common, potentially life-threatening hypersensitivity reaction associated with specific: 1) symptom profile, 2) cofactors, and 3) management. Identifying the differences in phenotypes of anaphylaxis is crucial for future management guidelines and the development of a personalized medicine approach. OBJECTIVE: This study aimed to evaluate the phenotype and risk factors of venom-induced anaphylaxis. METHODS: Using data from the European Anaphylaxis Registry (12874 cases) we identified 3612 patients with venom-induced anaphylaxis and analyzed these in comparison to sex- and age- matched anaphylaxis cases triggered by other elicitors (non-VIA n = 3605). RESULTS: Venom-induced anaphylaxis more frequently involved more than three organ systems and was associated with cardiovascular symptoms. The absence of skin symptoms during anaphylaxis correlated with baseline serum tryptase and was associated with an increased risk of a severe reaction. Intramuscular or intravenous epinephrine was administered significantly less often in venom-induced anaphylaxis, in particular in patients without prior history of anaphylaxis. Baseline serum tryptase within the upper normal range (8-11.5 ng-ml) was more frequently associated with severe anaphylaxis. CONCLUSION: Using a large cohort of VIA cases, we have validated that patients with intermediate baseline serum tryptase levels (8 - 11 ng/ml) and without skin involvement have higher risk of severe VIA. Patients receiving beta-blockers or ACE-I had a higher risk of developing severe cardiovascular symptoms (including cardiac arrest) in VIA and non-VIA cases. Patients undergoing VIA received epinephrine less frequently than non-VIA cases.
CRIS-Team Scopus Importer:2020-07-10
Keywords: anaphylaxis; beta-blockers; epinephrine (adrenaline); Hymenoptera; insect venom allergy

Phosphatase PTPN22 Regulates Dendritic Cell Homeostasis and cDC2 Dependent T Cell Responses - Purvis, Harriet A.; Clarke, Fiona; Montgomery, Anna B.; Colas, Chloe; Bibby, Jack A.; Cornish, Georgina H.; Dai, Xuezhi; Dudziak, Diana; Rawlings, David J.; Zamoyska, Rose; Guermonprez, Pierre; Cope, Andrew P. (Frontiers in Immunology, 2020)
Dendritic cells (DCs) are specialized antigen presenting cells that instruct T cell responses through sensing environmental and inflammatory danger signals. Maintaining the homeostasis of the multiple functionally distinct conventional dendritic cells (cDC) subsets that exist in vivo is crucial for regulating immune responses, with changes in numbers sufficient to break immune tolerance. Using Ptpn22-/- mice we demonstrate that the phosphatase PTPN22 is a highly selective, negative regulator of cDC2 homeostasis, preventing excessive population expansion from as early as 3 weeks of age. Mechanistically, PTPN22 mediates cDC2 homeostasis in a cell intrinsic manner by restricting cDC2 proliferation. A single nucleotide polymorphism, PTPN22R620W, is one of the strongest genetic risk factors for multiple autoantibody associated human autoimmune diseases. We demonstrate that cDC2 are also expanded in mice carrying the orthologous PTPN22619W mutation. As a consequence, cDC2 dependent CD4+ T cell proliferation and T follicular helper cell responses are increased. Collectively, our data demonstrate that PTPN22 controls cDC2 homeostasis, which in turn ensures appropriate cDC2-dependent T cell responses under antigenic challenge. Our findings provide a link between perturbations in DC development and susceptibility to a broad spectrum of PTPN22R620W associated human autoimmune diseases.
CRIS-Team Scopus Importer:2020-03-31
Keywords: autoimmunity; cDC2; dendritic cell; homeostasis; polymorphism; proliferation; PTPN22; T follicular helper cell

Photodynamic therapy 'to go' - a strengths, weaknesses, opportunities and threats analysis - Heppt, M. V.; Steeb, T.; Berking, Carola (Journal of the European Academy of Dermatology and Venereology, 2019)
EVALuna2:211758

Physician-reported Clinical Unmet Needs, Burden and Treatment Patterns of Paediatric Psoriasis Patients: A US and EU Real-world Evidence Study - Seyger, Marieke M.B.; Augustin, Matthias; Sticherling, Michael; Bachhuber, Teresa; Fang, Juanzhi; Hetherington, James; Lucas, James; Meakin, Sophie; Richardson, Craig; Paller, Amy S. (Acta Dermato-Venereologica, 2022)
This study is a retrospective analysis using data col-lected from the Adelphi Paediatric Psoriasis Disease-Specific Programme cross-sectional survey. Despite being treated for their psoriasis, a substantial proportion of paediatric patients presented with moderate (18.3%) or severe (1.3%) disease at sampling; 42.9% and 92.0% had a body surface area (BSA) of >10%, and 38.8% and 100.0% had a Psoriasis Area Severity Index (PASI) score >10, respectively. Overall, 69.9% of patients had only ever been treated with a topical therapy for their psoriasis. For patients with moderate or severe disease at sampling, 16.3% and 14.4% were currently receiving conventional systemics or biologic therapy, respectively. There is a clinical unmet need in this paediatric population; a considerable percen-tage of patients still experienced moderate or severe disease and persistent psoriasis symptoms, with nu-merous body areas affected. A significant proportion of patients were undertreated, which may explain the high burden of disease observed.
CRIS-Team Scopus Importer:2022-04-15
Keywords: clinical characteristics; paediatric psoriasis; point-in-time sur-vey; psoriasis; real-world; unmet needs

Pigmented lesions of the mucosa - Heppt, Markus; Heinzerling, Lucie (Die Dermatologie, 2022)
Background Pigmented lesions of the mucosa are a common reason to consult a dermatologist. They have heterogeneous etiologies and comprise a wide range of differential diagnoses. Both practitioners and patients are often uncertain about the malignancy of the lesions. Materials and methods Review and demonstration of the most common pigmentation disorders of the mucous membranes, including discussion of clinical findings and underlying causes. Results Pigmented mucosal lesions can be classified as either focal or multifocal-diffuse. Focal hyperpigmentation encompasses melanotic macules, nevi, deposition of exogenous materials or pigments, and oral melanoacanthoma. They are mostly benign but must be discerned from mucosal melanoma with an aggressive course and poor prognosis. Multifocal or diffuse hyperpigmentation may be drug-induced or indicative of an underlying medical condition. Importantly, as part of hereditary syndromes further diagnostic work-up is required. Conclusion Specific knowledge of the distribution and causes of pigmented mucosal lesions helps in clinical assessment between benign findings and those requiring further work-up and histologic clarification.
CRIS-Team WoS Importer:2022-09-09

Pivotal advance: Heme oxygenase 1 expression by human CD4+ T cells is not sufficient for their development of immunoregulatory capacity - Biburger, Markus; Theiner, Gabi; Schädle, Mirjam; Schuler, Gerold; Tiegs, Gisa (Journal of Leukocyte Biology, 2010)
HO-1 is the only inducible one of three isoenzymes that catalyzes the oxidative degradation of heme. HO-1 is inducible by various cellular stress factors and exerts cytoprotective and immunomodulatory effects. Recent publications demonstrated that HO-1 is constitutively expressed by CD4 CD25 T and induced in CD4 CD25 T cells upon FoxP3 transfection. Here, we investigated whether HO-1 was essential and sufficient for human T to exert immunosuppression in vitro. PGJ induced pronounced expression of HO-1 in CD4CD25 T cells without accompanying FoxP3 induction. Treatment of CD4CD25 T cells with PGJ decreased their proliferation, whereas the HO-1 inhibitor SnPP enhanced the proliferation of HO-1-expressing T, suggesting that HO-1 may modulate the proliferative capacity of T lymphocytes. HO-1 modulation by SnPP treatment of T or PGJ treatment of CD4CD25 T cells neither suppressed nor induced immune-modulatory function in these cells, respectively, as measured by responder-cell proliferation and/or IL-2 production. In summary, these data suggest that HO-1 expression by T might contribute to their typical reluctance to proliferate but does not account independently for their suppressive functions. © Society for Leukocyte Biology.
Keywords: CD4+CD25 + Tregs; Immune modulation; Proliferation; Regulatory T cells; Tolerance

Plasma-derived extracellular vesicles discriminate type-1 allergy subjects from non-allergic controls - Wagner, Nicola; Eberhardt, Martin; Vera, Julio; Cuomo, Federica; Blume, Katja; Galster, Silvia; Achenbach, Susanne; Laffert, Bernd; Kahlert, Helga; Schuler, Gerold; Berking, Carola; Baur, Andreas (World Allergy Organization Journal, 2021)
Background: Allergies are on the rise globally, with an enormous impact on affected individuals’ quality of life as well as health care resources. They cause a wide range of symptoms, from slightly inconvenient to potentially fatal immune reactions. While allergies have been described and classified phenomenologically, there is an unmet need for easily accessible biomarkers to stratify the severity of clinical symptoms. Furthermore, biomarkers marking the success of specific immunotherapy are urgently needed. Objectives: Plasma extracellular vesicles (pEV) play a role in coordinating the immune response and may be useful future biomarkers. A pilot study on differences in pEV content was carried out between patients with type I allergy, suffering from rhinoconjunctivitis with or without asthma, and voluntary non-allergic donors. Methods: We examined pEV from 38 individuals (22 patients with allergies and 16 controls) for 38 chemokines, cytokines, and soluble factors using high-throughput data mining approaches. Results: Patients with allergies had a distinct biomarker pattern, with 7 upregulated (TNF-alpha, IL-4, IL-5, IL-6, IL-17F, CCL2, and CCL17) and 3 downregulated immune mediators (IL-11, IL-27, and CCL20) in pEV compared to controls. This reduced set of 10 factors was able to discriminate controls and allergic patients better than the total array. Conclusions: The content of pEV showed potential as a target for biomarker research in allergies. Plasma EV, which are readily measurable via blood test, may come to play an important role in allergy diagnosis. In this proof-of-principle study, it could be shown that pEV's discriminate patients with allergies from controls. Further studies investigating whether the content of pEVs may predict the severity of allergic symptoms or even the induction of tolerance to allergens are needed.
CRIS-Team Scopus Importer:2021-10-08
Keywords: Allergy; Biomarkers; Extracellular vesicles-exosomes; Immune mediators; bioinformatics

Polysaccharides from European Black Elderberry Extract Enhance Dendritic Cell Mediated T Cell Immune Responses - Stich, Lena; Plattner, Stephan; McDougall, Gordon; Austin, Ceri; Steinkasserer, Alexander (International Journal of Molecular Sciences, 2022)
European black elderberry (Sambucus nigra L.) is a popular way to treat common colds or influenza infections. Mechanistically, this might be due to a direct antiviral effect or a stimulatory effect on the immune system of the host. Here, we evaluated the modulatory effects of black elderberry derived water extract (EC15) and its polysaccharide enriched fractions (CPS, BOUND, and UNBOUND) in comparison to a conventional alcoholic extract (EE25), regarding the phenotypical and functional properties of dendritic cells (DCs), which are essential cells to induce potent T cell responses. Interestingly, the water extract and its polysaccharide fractions potently induced DC maturation, while the ethanol extract did not. Moreover, the capacity to stimulate T cells by these matured DCs, as assessed using MLR assays, was statistically higher when induced by the water extracted fractions, compared to immature DCs. On the other hand, the ethanol extract EE25 did not induce T cell stimulation. Finally, the cytokine expression profiles of these DC—T cell cocultures were assessed and correlated well with increased T cell stimulation. Also, the expression of inflammatory cytokines, such as IL‐6, TNF‐α, and IFN‐γ was highly increased in the presence of the elderberry water extract EC15, and the polysaccharide enriched CPS, BOUND, and UNBOUND fractions, but not by EE25. Thus, from these data, we conclude that the polysaccharides present in water‐derived elderberry fractions induce potent immune‐modulatory effects, which represents the basis for a strong immune‐mediated response to viruses including influenza.
CRIS-Team Scopus Importer:2022-04-15
Keywords: dendritic cells; European black elderberry; polysaccharides; T cell stimulation

Pooled safety analysis from two phase III studies of secukinumab in paediatric patients with moderate-to-severe plaque psoriasis up to week 52 - Sticherling, Michael; Nikkels, A. F.; Hamza, A. M.; Kwong, P.; Ortmann, C. -E.; Papanastasiou, P.; Forrer, P.; Keefe, D. (BRITISH JOURNAL OF DERMATOLOGY, 2022)
CRIS-Team WoS Importer:2022-01-14

Poor Adherence to Self-Applied Topical Drug Treatment Is a Common Source of Low Lesion Clearance in Patients with Actinic Keratosis—A Cross-Sectional Study - Koch, Elias; Steeb, Theresa; Bender-Säbelkampf, Sophia; Busch, Dorothee; Feustel, Janina; Kaufmann, Matthias; Maronna, Andreas; Meder, Christine; Ronicke, Moritz; Toussaint, Frédéric; Wellein, Hedwig; Berking, Carola; et al. (Journal of Clinical Medicine, 2023)
Background: Many treatments for actinic keratosis (AK) have been proven efficient in clinical trials. However, patients with AK may still experience unsatisfactory therapeutic outcomes in clinical practice. Objectives: To investigate patient adherence to self-applied topical interventions for AK and to explore factors associated with adherence in a real-world setting. Methods: A cross-sectional study was conducted. Patients presenting with AK were asked to complete a self-administered questionnaire about their last topical AK treatment. Results: A total of 113 patients participated with a median age of 78.5 years (range 58–94). Fifty-four patients (47.8%) received topical diclofenac, ten (8.8%) imiquimod, nine (8%) 5-fluorouracil, nine (8%) 5-fluorouracil plus salicylic acid, and eight (7.1%) photodynamic therapy. The non-adherence rate was 46.9% (n = 53), and only 30.9% (n = 35) used the topical treatments according to the summary of product characteristics (SmPC). These subgroups were compared. Patients of the non-compliant group were significantly less informed about the application time of the specific topical intervention (p = 0.002) and adjusted the timeframe (p < 0.001) and application frequency of the therapy (p = 0.02) independently of their physician. Conversely, patients reporting a sufficient pre-treatment consultation (p = 0.019) generally complied with the SmPC compliance application. Conclusions: A thorough pre-treatment consultation can help to increase treatment adherence and ensure lesion clearance.
CRIS-Team Scopus Importer:2023-06-30
Keywords: actinic keratosis; adherence; compliance; consultation; topical treatment

Position paper of the Initiative Chronische Wunde (ICW) e. V. on the nomenclature of debridement in chronic wounds Positionspapier der Initiative Chronische Wunde (ICW) e. V. zur Nomenklatur des Débridements chronischer Wunden - Dissemond, Joachim; Bueltemann, Anke; Gerber, Veronika; Motzkus, Martin; Muenter, Karl Christian; Erfurt-Berge, Cornelia (Hautarzt, 2022)
The nomenclature used today in wound treatment varies widely across different disciplines and professions. Therefore, it is a mission of the professional association Initiative Chronische Wunde (ICW) e. V. to exactly and comprehensibly describe terms that were previously unclear. Therefore, the experts of the ICW defined in a consensus procedure debridement of chronic wounds as the removal of adherent, dead tissue, scabs or foreign bodies from wounds. There are various therapy options for this, which can be differentiated into autolytic, biosurgical, mechanical, osmotic, proteolytic/enzymatic and technical debridement. In the case of surgical debridement, a distinction is also made between sharp debridements that can usually be performed on an outpatient basis, such as minor surgical procedures, and surgical debridements with adequate anaesthesia in an operating theatre. Wound irrigation is defined by the ICW as the removal of non-adherent components on wounds with sterile solutions. Debridement and/or wound irrigation are often the first step in phase-appropriate modern wound treatment. Several methods are suitable for use in a combined or successive therapy. When deciding which therapeutic option to use, a number of individually different factors should be taken into account, depending on the patients to be treated but also on the therapists. The final individual decision for a method should be made together with the patient in each case and then adequately documented.
CRIS-Team Scopus Importer:2022-02-04
Keywords: Debridement; Pain; Wound healing; Wound irrigation; Wound therapy

Practical guidelines for the management of adverse events of the T cell engager bispecific tebentafusp - Hassel, Jessica C.; Berking, Carola; Forschner, Andrea; Gebhardt, Christoffer; Heinzerling, Lucie; Meier, Friedegund; Ochsenreither, Sebastian; Siveke, Jens; Hauschild, Axel; Schadendorf, Dirk (European Journal of Cancer, 2023)
Tebentafusp is a new T cell receptor bispecific fusion protein and the first approved treatment option for human leucocyte antigen-A*02:01 (HLA-A*02:01) metastatic uveal melanoma, with a proven benefit in overall survival versus the investigator's choice. As a first-in-class therapeutic option, this Immune mobilising monoclonal T cell receptor Against Cancer (ImmTAC) is associated with a new adverse event (AE) profile. Based on clinical experience, a national expert group discussed recommendations for tebentafusp treatment, focusing on AE management. Further topics included prerequisites for initiating tebentafusp treatment, appropriate treatment setting, and patient selection criteria. To provide guidance for treating physicians, the resulting recommendations are summarised including a model standard operating procedure for AE management. Patients in good clinical condition and with a low tumour burden are good candidates for tebentafusp treatment, particularly if treated as early as possible after the diagnosis of metastatic disease. The safety profile of tebentafusp is manageable and includes two major pathologies: cytokine release syndrome (CRS) and skin-related events. Postdose monitoring should thus focus on pyrexia and hypotension as the first symptoms of cytokine release. To minimise the risk of hypotension associated with CRS, patients should receive intravenous fluids before starting treatment. The monitoring of liver values is crucial, as patients may experience an increase in transaminases, which can even manifest as tumour lysis syndrome.
CRIS-Team Scopus Importer:2023-09-01
Keywords: Adverse event management; Bispecific; Cytokine release syndrome; Expert opinion; Immune mobilising monoclonal T cell receptor against cancer (ImmTAC); Skin toxicity; Tebentafusp; Treatment recommendation; Uveal melanoma

Preclinical evaluation of a combination of checkpoint blockade and dendritic cell vaccination against Merkel cell carcinoma - Sauerer, Tatjana; Gerer, K.; Hoyer, Stefanie; Erdmann, M.; Berking, Carola; Voll, R.; Schuler-Thurner, Beatrice; Schuler, Gerold; Schaft, Niels; Dörrie, Jan (EXPERIMENTAL DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-14

Preclinical evaluation of NF-κB-triggered dendritic cells expressing the viral oncogenic driver of Merkel cell carcinoma for therapeutic vaccination - Gerer, Kerstin F.; Erdmann, Michael; Hadrup, Sine R.; Lyngaa, Rikke; Martin, Lena-Marie; Voll, Reinhard E.; Schuler-Thurner, Beatrice; Schuler, Gerold; Schaft, Niels; Hoyer, Stefanie; Dörrie, Jan (Therapeutic Advances in Medical Oncology, 2017)
BACKGROUND: Merkel cell carcinoma (MCC) is a rare but very aggressive skin tumor that develops after integration of a truncated form of the large T-antigen (truncLT) of the Merkel cell polyomavirus (MCV) into the host's genome. Therapeutic vaccination with dendritic cells (DCs) loaded with tumor antigens is an active form of immunotherapy, which intends to direct the immune system towards tumors which express the respective vaccination antigens. METHODS: Cytokine-matured monocyte-derived DCs of healthy donors and MCC patients were electroporated with mRNA encoding the truncLT. To permit major histocompatibility complex (MHC) class II next to class I presentation, we used an RNA construct in which the antigen was fused to a DCLamp sequence in addition to the unmodified antigen. To further improve their immunogenicity, the DCs were additionally activated by co-transfection with the constitutively active nuclear factor (NF)-κB activator caIKK. These DCs were used to stimulate autologous CD8+ T-cells or a mixture of CD4+ and CD8+ T-cells. Then the percentage of T-cells, specific for the truncLT, was quantified by interferon (IFN)γ ELISpot assays. RESULTS: Both the truncLT and its DCLamp-fusion were detected within the DCs by flow cytometry, albeit the latter required blocking of the proteasome. The transfection with caIKK upregulated maturation markers and induced cytokine production. After 2-3 rounds of stimulation, the T-cells from 11 out of 13 healthy donors recognized the antigen. DCs without caIKK appeared in comparison less potent in inducing such responses. When using cells derived from MCC patients, we could induce responses for 3 out of 5 patients; however, here the caIKK-transfected DCs did not display their superiority. CONCLUSION: These results show that optimized DCs are able to induce MCV-antigen-specific T-cell responses. Therapeutic vaccination with such transfected DCs could direct the immune system against MCC.
EVALuna2:34320

Predicting the response of uveal melanoma to immunotherapy with MRI assessments - Moreira, Alvaro; Saake, Marc; Schuler, Gerold; Heinzerling, Lucie (CANCER IMMUNOLOGY RESEARCH, 2019)
CRIS-Team WoS Importer:2021-10-18

Predicting the response to anti-PD1 therapy in metastatic melanoma - Heinzerling, Lucie; Kirchberger, Michael Constantin; Walter, Lisa; Schuler, Gerold (TRANSLATIONAL CANCER RESEARCH, 2016)

Prediction of melanoma evolution in melanocytic nevi via artificial intelligence: A call for prospective data - Sondermann, Wiebke; Utikal, Jochen Sven; Enk, Alexander H.; Schadendorf, Dirk; Klode, Joachim; Hauschild, Axel; Weichenthal, Michael; French, Lars E.; Berking, Carola; Schilling, Bastian; Haferkamp, Sebastian; Fröhling, Stefan; et al. (European Journal of Cancer, 2019)
Recent research revealed the superiority of artificial intelligence over dermatologists to diagnose melanoma from images. However, 30–50% of all melanomas and more than half of those in young patients evolve from initially benign lesions. Despite its high relevance for melanoma screening, neither clinicians nor computers are yet able to reliably predict a nevus’ oncologic transformation. The cause of this lies in the static nature of lesion presentation in the current standard of care, both for clinicians and algorithms. The status quo makes it difficult to train algorithms (and clinicians) to precisely assess the likelihood of a benign skin lesion to transform into melanoma. In addition, it inhibits the precision of current algorithms since ‘evolution’ image features may not be part of their decision. The current literature reveals certain types of melanocytic nevi (i.e. ‘spitzoid’ or ‘dysplastic’ nevi) and criteria (i.e. visible vasculature) that, in general, appear to have a higher chance to transform into melanoma. However, owing to the cumulative nature of oncogenic mutations in melanoma, a more fine-grained early morphologic footprint is likely to be detectable by an algorithm. In this perspective article, the concept of melanoma prediction is further explored by the discussion of the evolution of melanoma, the concept for training of such a nevi classifier and the implications of early melanoma prediction for clinical practice. In conclusion, the authors believe that artificial intelligence trained on prospective image data could be transformative for skin cancer diagnostics by (a) predicting melanoma before it occurs (i.e. pre-in situ) and (b) further enhancing the accuracy of current melanoma classifiers. Necessary prospective images for this research are obtained via free mole-monitoring mobile apps.
CRIS-Team Scopus Importer:2019-08-13
Keywords: Artificial intelligence; Deep learning; Melanoma; Prediction; Skin cancer

Prediction of melanoma evolution in melanocytic nevi via artificial intelligence: A call for prospective data (vol 119, pg 30, 2019) - Sondermann, Wiebke; Utikal, Jochen Sven; Enk, Alexander H.; Schadendorf, Dirk; Klode, Joachim; Hauschild, Axel; Weichenthal, Michael; French, Lars E.; Berking, Carola; Schilling, Bastian; Haferkamp, Sebastian; Froehling, Stefan; et al. (European Journal of Cancer, 2019)
EVALuna2:212166

Predictive value of PD-L1 based on mRNA level in the treatment of stage IV melanoma with ipilimumab - Brueggemann, C.; Kirchberger, M. C.; Goldinger, S. M.; Weide, B.; Konrad, A.; Erdmann, M.; Schadendorf, D.; Croner, R. S.; Krahenbuhl, L.; Kaehler, K. C.; Hafner, C.; Leisgang, W.; et al. (Journal of Cancer Research and Clinical Oncology, 2017)
PD-L1 is established as a predictive marker for therapy of non-small cell lung cancer with pembrolizumab. Furthermore, PD-L1 positive melanoma has shown more favorable outcomes when treated with anti-PD1 antibodies and dacarbazine compared to PD-L1 negative melanoma. However, the role of PD-L1 expression with regard to response to checkpoint inhibition with anti-CTLA-4 is not clear, yet. In addition, the lack of standardization in the immunohistochemical assessment of PD-L1 makes the comparison of results difficult. In this study, we investigated the PD-L1 gene expression with a new fully automated technique via RT-PCR and correlated the findings with the response to the anti-CTLA-4 antibody ipilimumab.Within a retrospective multi-center trial, PD-L1 gene expression was evaluated in 78 melanoma patients in a total of 111 pre-treatment tumor samples from 6 skin cancer centers and analyzed with regard to response to ipilimumab. For meaningful statistical analysis, the cohort was enriched for responders with 30 responders and 48 non-responders. Gene expression was assessed by quantitative RT-PCR after extracting mRNA from formalin-fixed paraffin embedded tumor tissue and correlated with results from immunohistochemical (IHC) stainings.The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab. The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab.
EVALuna2:15289

Predictors of long-term survival of stage IV melanoma patients: a multicenter DeCOG study on 539 patients from the prospective skin cancer registry ADOREG - Placke, J. M.; Mohr, P.; Bluhm, L.; Kahler, K.; Weichenthal, M.; Meier, F.; Garzarolli, M.; Gutzmer, R.; Grimmelmann, I.; Utikal, J. S.; Pfohler, C.; Herbst, R.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

Predilection sites of pyoderma gangrenosum: Retrospective study of 170 clearly diagnosed patients - Moelleken, Maurice; Erfurt-Berge, Cornelia; Ronicke, Moritz; Busch, Dorothee; Hübner, Ursula Hertha; Hüsers, Jens; Przysucha, Mareike; Dissemond, Joachim (International Wound Journal, 2023)
Pyoderma gangrenosum (PG) is a non-infectious, neutrophilic dermatosis that was difficult to diagnose in clinical practice. Today, the PARACELSUS score is a validated tool for diagnostics. Based on this score, patients with clearly diagnosed PG were examined with regard to predilection sites. In this retrospective study, the data of patients from the University Hospitals of Essen and Erlangen were analysed in whom the diagnosis of PG could be clearly confirmed using the PARACELSUS score. A total of 170 patients, 49 men (29%) and 121 women (71%) with an average age at first manifestation of 55.5 years, could be included in the analysis. The predilection sites were identified as the lower legs in 80.6% of the patients and the extensor sides in 75.2%. Other localisations of PG were the thighs in 14.1%, mammae and abdomen in 10.0% each, back and gluteal in 7.1% each, feet in 5.9%, arms in 4.7%, genital in 3.5% and head in 2.9%. This retrospective study is the first to identify a collective of PG patients with the highest data quality using the PARACELSUS score. It could be shown that PG can basically occur on the entire integument. However, the predilection sites of PG, which have now been reliably identified for the first time, are the lower legs and in particular the extensor sides.
CRIS-Team Scopus Importer:2023-08-11
Keywords: chronic wounds; leg ulcer; PARACELSUS score; predilection sites; pyoderma gangrenosum

Preferences of German and Swiss melanoma patients for toxicities versus melanoma recurrence during adjuvant treatment (GERMELATOX-A-trial) - Kähler, Katharina C.; Hüning, S.; Nashan, D.; Meiss, F.; Rafei-Shamsabadi, D. A.; Rissmann, H.; Colapietro, C.; Livingstone, E.; Maul, L. V.; Heppt, Markus; Hassel, J. C.; Gutzmer, R.; et al. (Journal of Cancer Research and Clinical Oncology, 2023)
Purpose: Adjuvant treatment with immune checkpoint inhibitors like PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT) in high-risk melanoma patients demonstrate a significant improvement in disease-free survival (DFS). Due to specific side effects, the choice of treatment is very often driven by the risk for toxicity. This study addressed for the first time in a multicenter setting the attitudes and preferences of melanoma patients for adjuvant treatment with (c)ICI and TT. Methods: In this study (“GERMELATOX-A”), 136 low-risk melanoma patients from 11 skin cancer centers were asked to rate side effect scenarios typical for each (c)ICI and TT with mild-to-moderate or severe toxicity and melanoma recurrence leading to cancer death. We asked patients about the reduction in melanoma relapse and the survival increase at 5 years they would require to tolerate defined side-effects. Results: By VAS, patients on average valued melanoma relapse worse than all scenarios of side-effects during treatment with (c)ICI or TT. In case of severe side effects, patients required a 15% higher rate of DFS at 5 years for (c)ICI (80%) compared to TT (65%). For survival, patients required an increase of 5–10% for melanoma survival during (c)ICI (85%/80%) compared to TT (75%). Conclusion: Our study demonstrated a pronounced variation of patient preferences for toxicity and outcomes and a clear preference for TT. As adjuvant melanoma treatment with (c)ICI and TT will be increasingly implemented in earlier stages, precise knowledge of the patient perspective can be helpful for decision making.
CRIS-Team Scopus Importer:2023-09-08
Keywords: Adjuvant treatment; Melanoma; Patient preferences; Treatment toxicity

Preferences of German melanoma patients for interferon (IFN) ?-2b toxicities (the DeCOG "GERMELATOX survey") versus melanoma recurrence to quantify patients' relative values for adjuvant therapy - Kaehler, Katharina C.; Blome, Christine; Forschner, Andrea; Gutzmer, Ralf; Haalck, Thomas; Heinzerling, Lucie; Kornek, Thomas; Livingstone, Elisabeth; Loquai, Carmen; Maul, Lara Valeska; Lang, Berenice M.; Schadendorf, Dirk; et al. (Medicine, 2016)
Currently interferon alfa-2b (IFN?-2b) is an approved adjuvant drug for high-risk melanoma patients that leads to an improvement in disease-free survival (DFS). However, it is unclear whether it also impacts overall survival. Widespread use of adjuvant high-dose IFN? has been tempered by its significant toxicity and its limited efficacy. Current therapeutic strategies like immune checkpoint blockade or targeted therapy may also be useful in the adjuvant setting. Therefore, it is important to weigh the trade-offs between possible side effects and therapeutic benefit.We assessed patient utilities for health states associated with IFN therapy. Utilities are measures of preference for a specific health state on a scale of 0 (death) to 1 (perfect health).Utilities were determined for health states associated with adjuvant IFN among 130 German low-risk melanoma patients using the standard gamble technique. Four IFN?-2b toxicity scenarios and the following 3 posttreatment outcomes were assessed: disease-free health and melanoma recurrence (with or without previous use of IFN?-2b) resulting in cancer death. Patients were asked to trade-off the improvement in 5-year DFS and the IFN-related side effects.Utilities for melanoma recurrence (mean 0.60) were significantly lower than for all IFN?-2b toxicity scenarios (mean 0.81-0.90). Patients were willing to tolerate mild-to-moderate and severe toxicity for a 50% and 75% chance of 5-year DFS, respectively. Both utilities and threshold benefits were mostly independent from patient characteristics like gender, income, and social situation. Significant impact was only observed by age and previous personal experience with cancer.On average, German patients were willing to trade even severe IFN?-2b toxicity for reducing the rate of melanoma recurrence. This result points out the importance of a relapse-free survival for melanoma patients. The utilities measured in our study can be applied to decision-making processes in clinical trials of new adjuvant drugs.
EVALuna2:19621

Preferences of physicians for treatment-related toxicity vs. recurrence in melanoma (GERMELATOX-A): the doctors’ perspective - Kähler, Katharina C.; Gutzmer, Ralf; Angela, Yenny; Livingstone, Elisabeth; Lodde, Georg; Meiss, Frank; Rafei-Shamsabadi, David A.; Weyer-Fahlbusch, Sera S.; Nashan, Dorothée; Loquai, Carmen; Hassel, Jessica C.; Sachse, Michael M.M.; et al. (Journal of Cancer Research and Clinical Oncology, 2024)
Introduction: Adjuvant treatment with immune checkpoint inhibitors, such as PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT), has shown a significant improvement in disease-free survival (DFS) for high-risk melanoma patients. However, due to specific side effects, the choice of treatment is often influenced by the risk of toxicity. Therefore, the role of physicians in treatment decisions of patients is crucial. This study investigated for the first time in a multicenter setting the attitudes and preferences of dermatooncologists in Germany and Switzerland regarding adjuvant treatment with (c)ICI and TT. Methods: In the GERMELATOX-A study, 108 physicians (median age: 32 yrs, 67.6% female) from 11 skin cancer centers were surveyed to rate typical side effect scenarios of (c)ICI and TT treatments and then compared to patients’ ratings evaluated in a previous analysis from the same centers. The scenarios described mild-to-moderate or severe toxicity and included melanoma relapse leading to death. The physicians were asked about the level of side effects they would tolerate in exchange for a reduction in melanoma relapse and an increase in survival at 5 years. Results: The preferences of physicians and patients revealed significant differences regarding adjuvant melanoma treatment with (c)ICI and TT (p < 0.05). Compared to patients, physicians tend to value a melanoma relapse less severe, according to a visual analog scale. They were also less threatened by all scenarios of side effects during adjuvant treatment with (c)ICI or TT, compared to patients. Physicians required lower risk reductions for disease-free survival (DFS) and overall survival (OS) for both ICI and TT and their drug-related side effects to accept these treatments. In case of severe side effects, physicians required similar 5-year DFS rates for ICI and TT (60–65%), while patients needed a 15% improvement of 5-year DFS for ICI compared to TT (80%/65%). For survival, physicians expected an OS improvement of + 10% for all three treatment modalities, whereas patients required a higher increase: + 18–22% for ICI and + 15% for TT. Conclusion: Our study highlights the importance of understanding the patient’s perspective and a potential difference to the doctor’s view when making decisions about adjuvant melanoma treatment with (c)ICI and TT, especially as these treatments are increasingly being implemented in earlier stages.
CRIS-Team Scopus Importer:2024-05-24
Keywords: Adjuvant treatment; Melanoma; Physician preferences; Treatment toxicity

Pre-incubation of corneal donor tissue with sCD83 improves graft survival via the induction of alternatively activated macrophages and tolerogenic dendritic cells - Peckert-Maier, Katrin; Schoenberg, Alfrun; Wild, Andreas; Royzman, Dmytro; Braun, Gabriele; Stich, Lena; Hadrian, Karina; Tripal, Philipp; Cursiefen, Claus; Steinkasserer, Alexander; Zinser, Elisabeth; Bock, Felix (American Journal of Transplantation, 2021)
Immune responses reflect a complex interplay of cellular and extracellular components which define the microenvironment of a tissue. Therefore, factors that locally influence the microenvironment and re-establish tolerance might be beneficial to mitigate immune-mediated reactions, including the rejection of a transplant. In this study, we demonstrate that pre-incubation of donor tissue with the immune modulator soluble CD83 (sCD83) significantly improves graft survival using a high-risk corneal transplantation model. The induction of tolerogenic mechanisms in graft recipients was achieved by a significant upregulation of Tgfb, Foxp3, II27, and II10 in the transplant and an increase of regulatory dendritic cells (DCs), macrophages (M phi) and T cells (Tregs) in eye-draining lymph nodes. The presence of sCD83 during in vitro DC and M phi generation directed these cells toward a tolerogenic phenotype leading to reduced proliferation-stimulating activity in MLRs. Mechanistically, sCD83 induced a tolerogenic M phi and DC phenotype, which favors Treg induction and significantly increased transplant survival after adoptive cell transfer. Conclusively, pre-incubation of corneal grafts with sCD83 significantly prolongs graft survival by modulating recipient M phi and DCs toward tolerance and thereby establishing a tolerogenic microenvironment. This functional strategy of donor graft pre-treatment paves the way for new therapeutic options in the field of transplantation.
CRIS-Team WoS Importer:2021-10-01

Pre-incubation of corneal donor tissue with soluble CD83 improves graft survival via the induction of pro-resolving macrophages - Peckert-Maier, Katrin; Schoenberg, Alfrun; Wild, Andreas; Royzman, Dmytro; Braun, Gabriele; Hadrian, Karina; Tripal, Philipp; Cursiefen, Claus; Steinkasserer, Alexander; Zinser, Elisabeth; Bock, Felix (WOUND REPAIR AND REGENERATION, 2022)
CRIS-Team WoS Importer:2022-09-16

Presence of brain metastasis differentially impacts long-term survival after first-line therapy in melanoma depending on BRAF mutation status - Placke, Jan Malte; Rajcsanyi, Luisa Sophie; Herbst, Rudolf; Terheyden, Patrick; Utikal, Jochen; Pföhler, Claudia; Kreuter, Alexander; Mohr, Peter; Gutzmer, Ralf; Weichenthal, Michael; Meier, Friedegund; Berking, Carola; et al. (Frontiers in Immunology, 2025)
Background: Modern therapeutic strategies have significantly improved the prognosis of advanced melanoma patients. Predictive factors of therapy response include serum LDH; however, predictive markers for long-term survival are currently largely lacking. Patients and methods: Patients diagnosed with stage IV melanoma (AJCCv8) of cutaneous origin or unknown primary were identified from the prospective multicenter German Dermatologic Cooperative Oncology Group (DeCOG) skin cancer registry ADOREG. Baseline characteristics were compared between patient groups with short-term versus long-term survival. Statistical analysis included ROC analysis and multinomial regression analysis. Results: Of 3066 stage IV melanoma patients entered into the ADOREG between 05/2014 and 06/2021, 395 were identified for this study, of whom 301 (76.2%) survived ≤1 year, and 94 (23.8%) survived ≥5 years after stage IV diagnosis. The median follow-up time was 6 months (range 0-129 months). Regarding the baseline characteristics, only elevated serum LDH (P <0.001) was found to be independently predicting survival ≤1 year. Type of first-line therapy, immune checkpoint inhibition (ICI) versus BRAF/MEK targeted therapy (TT), was not predictive of long-term survival ≥5 years. For survival ≤1 year, the presence of brain metastases at treatment start was an independent predictor in BRAF-mutated patients regardless if they received TT (N=113; P=0<0.001) or ICI (N=69; P=0.015), but not in BRAF-wildtype patients who received ICI (N=161; P=0.47). Conclusions: Low serum LDH independently predicts long-term survival of stage IV melanoma patients in every subgroup of treatment type and BRAF status. Brain metastasis has a negative impact on long-term survival in BRAF-mutated, but not in BRAF-wildtype patients. Investigation of molecular features of brain metastases in BRAF-mutated vs. BRAF-wildtype melanomas may lead to new insights in tumor biology and may yield new therapeutic approaches.
CRIS-Team Scopus Importer:2025-03-14
Keywords: BRAF; brain metastases; immune checkpoint inhibitor (ICI); long-term survival; melanoma; targeted therapy

Prevalence and Determinants of Painful and Painless Neuropathy in Type 1 Diabetes Mellitus - Barbosa, Margarida; Saavedra, Ana; Oliveira, Sofia; Reis, Ligia; Rodrigues, Filipa; Severo, Milton; Sittl, Reinhard; Maier, Christoph; Carvalho, Davide M. (Frontiers in Endocrinology, 2019)
Aims: To evaluate (1) the prevalence of diabetic distal symmetrical sensory-motor polyneuropathy (DSPN) and painful DSPN among patients with type 1 diabetes mellitus (DM1) aged over 18 years and (2) the determinant factors of neuropathy and pain in those patients.
CRIS-Team WoS Importer:2019-07-16

Primary Biliary Cirrhosis and Granulomatous Hepatitis after Immune Checkpoint Blockade in Patients with Metastatic Melanoma: Report of 2 Cases and Literature Discussion - Ruini, Cristel; Haas, Carolin; Mastnik, Sebastian; Knott, Maximilian; French, Lars E.; Schlaak, Max; Berking, Carola (Journal of immunotherapy (Hagerstown, Md. : 1997), 2021)
Immune-related adverse events (irAEs) of immune checkpoint inhibitors can potentially affect every organ system, are sometimes challenging, and require a multidisciplinary approach. Most common irAEs are very well characterized, but some other such rare autoimmune liver diseases are probably underdiagnosed and less explored. We present here the case of a 69-year-old man with metastatic melanoma developing a severe primary biliary cirrhosis under pembrolizumab, and of a 52-year-old woman with metastatic melanoma with granulomatous hepatitis in the context of an immune-related multiorgan inflammatory reaction due to ipilimumab and nivolumab. Both cases were in part steroid refractory and required a complex diagnostic assessment and long-term therapeutic management. The liver biopsy was crucial for ensuring a correct diagnosis. Clinicians should be aware of rare liver diseases in the context of increased liver enzymes under immune checkpoint inhibitors, especially if not responding to corticosteroids. The primary diagnostic workup should localize the liver damage (biliary or parenchymal) and distinguish irAEs from other pathologic conditions such as metastasis, second benign and malignant tumors, viral hepatitis, and cholelithiasis. If in doubt, a liver biopsy should be performed. Early diagnosis and accurate assessment of hepatic adverse events is necessary for prompt and effective treatment, with reduction of inappropriate discontinuation of immunotherapy, morbidity, and mortality.
CRIS-Team Scopus Importer:2021-03-19
Keywords: granulomatous hepatitis; immune checkpoint blockade; metastatic melanoma; primary biliary cirrhosis

Primary cutaneous manifestation of systemically aggressive diffuse large B-cell lymphoma - Bender-Säbelkampf, Sophia; Spriewald, Bernd; Berking, Carola; Erdmann, Michael; Wagner, Nicola (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

PRI: Re-Analysis of a Public Mass Cytometry Dataset Reveals Patterns of Effective Tumor Treatments - Hoang, Yen; Gryzik, Stefanie; Hoppe, Ines; Rybak, Alexander; Schaedlich, Martin; Kadner, Isabelle; Walther, Dirk; Vera, Julio; Radbruch, Andreas; Groth, Detlef; Baumgart, Sabine; Baumgrass, Ria (Frontiers in Immunology, 2022)
Recently, mass cytometry has enabled quantification of up to 50 parameters for millions of cells per sample. It remains a challenge to analyze such high-dimensional data to exploit the richness of the inherent information, even though many valuable new analysis tools have already been developed. We propose a novel algorithm "pattern recognition of immune cells (PRI)" to tackle these high-dimensional protein combinations in the data. PRI is a tool for the analysis and visualization of cytometry data based on a three or more-parametric binning approach, feature engineering of bin properties of multivariate cell data, and a pseudo-multiparametric visualization. Using a publicly available mass cytometry dataset, we proved that reproducible feature engineering and intuitive understanding of the generated bin plots are helpful hallmarks for re-analysis with PRI. In the CD4(+)T cell population analyzed, PRI revealed two bin-plot patterns (CD90/CD44/CD86 and CD90/CD44/CD27) and 20 bin plot features for threshold-independent classification of mice concerning ineffective and effective tumor treatment. In addition, PRI mapped cell subsets regarding co-expression of the proliferation marker Ki67 with two major transcription factors and further delineated a specific Th1 cell subset. All these results demonstrate the added insights that can be obtained using the non-cluster-based tool PRI for re-analyses of high-dimensional cytometric data.
CRIS-Team WoS Importer:2022-06-03

Proactive Management with twice-a-week Use of topical Cal/BD Spray Foam Management extends the Effectiveness of the Treatment in Comparison to Reactive Management in Patients with Plaque Psoriasis - Stein-Gold, L.; Alonso-Llamazares, J.; Laws, P.; Perrussel, M.; Yamauchi, P.; Thoning, H.; Toxvaerd, C.; Sticherling, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-04-16

Prognosis of Patients With Primary Melanoma Stage I and II According to American Joint Committee on Cancer Version 8 Validated in Two Independent Cohorts: Implications for Adjuvant Treatment. - Garbe, Claus; Keim, Ulrike; Amaral, Teresa; Berking, Carola; Eigentler, Thomas K.; Flatz, Lukas; Gesierich, Anja; Leiter, Ulrike; Stadler, Rudolf; Sunderkötter, Cord; Tüting, Thomas; Utikal, Jochen; et al. (Journal of Clinical Oncology, 2022)
PURPOSE: The first randomized trial of adjuvant treatment with checkpoint inhibitor in stage II melanoma reported a significant reduction in risk of tumor recurrence. This study evaluates two independent data sets to further document survival probabilities for patients with primary stage I and II melanoma. PATIENTS AND METHODS: The Central Malignant Melanoma Registry (CMMR) in Germany evaluated 17,544 patients with a primary diagnosis of stage I and II melanoma from 2000 to 2015. The exploratory cohort consisted of 6,725 patients from the Center for Dermato-Oncology at the University of Tübingen, and the confirmatory cohort consisted of 10,819 patients from 11 other German centers. Survival outcomes were compared with published American Joint Committee on Cancer version 8 (AJCCv8) stage I and II survival data. RESULTS: For the two CMMR cohorts in stage IA compared with the AJCCv8 cohort, melanoma-specific survival rates at 10 years were 95.1%-95.6% versus 98%; 89.7%-90.9% versus 94% in stage IB; 80.7%-83.1% versus 88% in stage IIA; 72.0%-79.9% versus 82% in stage IIB; and 57.6%-64.7% versus 75% in stage IIC, respectively. Recurrence rates were approximately twice as high as melanoma-specific mortality rates in stages IA-IIA. CONCLUSION: The melanoma-specific survival rates in the two CMMR cohorts across stages I and II are less favorable than published in AJCCv8. This has important implications for the consideration of adjuvant treatment in this population.
EVALuna2:505688

Prognosis of Patients With Stage III Melanoma According to American Joint Committee on Cancer Version 8: A Reassessment on the Basis of 3 Independent Stage III Melanoma Cohorts - Garbe, Claus; Keim, Ulrike; Suciu, Stefan; Amaral, Teresa; Eigentler, Thomas K.; Gesierich, Anja; Hauschild, Axel; Heinzerling, Lucie; Kiecker, Felix; Schadendorf, Dirk; Stadler, Rudolf; Sunderkötter, Cord; et al. (Journal of Clinical Oncology, 2020)
PURPOSE: Three new therapies have been approved recently for the adjuvant treatment of stage III melanoma, substantially reducing the risk of tumor recurrences. This study evaluates 3 independent data sets to clarify the survival probabilities of patients with stage III melanoma. PATIENTS AND METHODS: The Central Malignant Melanoma Registry (CMMR) evaluated 1,553 patients with a primary diagnosis of stage III melanoma from 2000 to 2012. Studies from the European Organisation for Research and Treatment of Cancer (EORTC), of 573 patients in the observation arm of the 18991 study and 445 patients in the placebo arm of the 18071 study, were evaluated as reference cohorts. The survival outcomes were compared with the published American Joint Committee on Cancer version 8 (AJCCv8) stage III survival data. RESULTS: For the CMMR stage III cohort versus the AJCCv8 cohort, the melanoma-specific survival (MSS) rates at 5 years were 67% versus 77%, and at 10 years were 56% versus 69%, respectively. For stage IIIA, the MSS rates at 5 years were 80% versus 93%, and at 10 years were 71% versus 88%; for stage IIIB, the MSS rates at 5 years were 75% versus 83%, and at 10 years were 61% versus 77%. The MSS rates of the EORTC studies either overlapped with or were lower than, the CMMR data. CONCLUSION: The MSS rates in the CMMR and EORTC cohorts over the entire stage III are less favorable than those published in AJCCv8. This is particularly true for substages IIIA and IIIB.
CRIS-Team Scopus Importer:2020-08-14

Prognostic factors and outcomes in metastatic uveal melanoma treated with PD-1 or combined PD-1 / CTLA-4 inhibition - Heppt, M.; Heinzerling, Lucie; Kaehler, K.; Forschner, A.; Kirchberger, M.; Loquai, C.; Meissner, M.; Meier, F.; Terheyden, P.; Schell, B.; Herbst, R.; Goeppner, D.; et al. (2017)
EVALuna2:34329

Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition - Heppt, Markus V.; Heinzerling, Lucie; Kaehler, Katharina C.; Forschner, Andrea; Kirchberger, Michael C.; Loquai, Carmen; Meissner, Markus; Meier, Friedegund; Terheyden, Patrick; Schell, Beatrice; Herbst, Rudolf; Goeppner, Daniela; et al. (European Journal of Cancer, 2017)
BACKGROUND: Uveal melanoma (UM) is an ocular malignancy with high potential for metastatic spread. In contrast to cutaneous melanoma, immunotherapy has not yet shown convincing efficacy in patients with UM. Combined immune checkpoint blockade with checkpoint programmed cell death-1 (PD-1) and checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibition has not been systematically assessed for UM to date. PATIENTS AND METHODS: Patients with metastatic UM treated with either PD-1 inhibitor monotherapy or combined PD-1 inhibitor and ipilimumab (an anti-CTLA-4 monoclonal antibody) were included from 20 German skin cancer centres. Records from 96 cases were analysed for treatment outcomes. Clinical and blood parameters associated with overall survival (OS) or treatment response were identified with multivariate Cox regression and binary logistic regression. RESULTS: Eighty-six patients were treated with PD-1 inhibitors only (n = 54 for pembrolizumab, n = 32 for nivolumab) with a centrally confirmed response rate of 4.7%. Median OS was 14 months for pembrolizumab-treated and 10 months for nivolumab-treated patients (p = 0.765). Fifteen patients were treated with combined immune checkpoint blockade with partial response observed in two cases. Median OS was not reached in this group. Multivariate Cox regression identified Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.002), elevated serum levels of lactate dehydrogenase (LDH) (p = 0.002) and C-reactive protein (CRP) (p = 0.001), and a relative eosinophil count (REC) <1.5% (p = 0.002) as independent risk factors for poor survival. Patients with elevated CRP and LDH and a REC <1.5% were at highest risk for disease progression and death (p = 0.001). CONCLUSIONS: Blood markers predict survival in metastatic UM treated with immune checkpoint blockade. Normal serum levels of LDH and CRP and a high REC may help identify patients with better prognosis.
EVALuna2:34328

Prognostic factors and treatment outcomes in 444 patients with mucosal melanoma - Heppt, Markus V.; Roesch, Alexander; Weide, Benjamin; Gutzmer, Ralf; Meier, Friedegund; Loquai, Carmen; Kaehler, Katharina C.; Gesierich, Anja; Meissner, Markus; Von Bubnoff, Dagmar; Goeppner, Daniela; Schlaak, Max; et al. (European Journal of Cancer, 2017)
BACKGROUND: Mucosal melanoma (MM) is a rare but diverse cancer entity. Prognostic factors are not well established for Caucasians with MM. PATIENTS AND METHODS: We analysed the disease course of 444 patients from 15 German skin cancer centres. Disease progression was determined with the cumulative incidence function. Survival times were estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariate Cox regression analysis. RESULTS: Common anatomic sites of primary tumours were head and neck (MMHN, 37.2%), female genital tract (MMFG, 30.4%) and anorectal region (MMAN, 21.8%). MMAN patients showed the highest vertical tumour thickness (p = 0.001), had a more advanced nodal status (p = 0.014) and a higher percentage of metastatic disease (p = 0.001) at diagnosis. Mutations of NRAS (13.8%), KIT (8.6%) and BRAF (6.4%) were evenly distributed across all tumour site groups. Local relapses were observed in 32.4% and most commonly occurred in the MMHN group (p = 0.016). Male gender (p = 0.047), advanced tumour stage (p = 0.001), nodal disease (p = 0.001) and incomplete resection status (p = 0.001) were independent risk factors for disease progression. Overall survival (OS) was highest in the MMFG group (p = 0.030) and in patients without ulceration (p = 0.004). Multivariate risk factors for OS were M stage at diagnosis (p = 0.002) and incomplete resection of the primary tumour (p = 0.001). CONCLUSION: In this large series of MM patients in a European population, anorectal MM was associated with the poorest prognosis.
EVALuna2:34332

Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity - Gutzmer, Ralf; Koop, Anika; Meier, Friedegund; Hassel, Jessica C.; Terheyden, Patrick; Zimmer, Lisa; Heinzerling, Lucie; Ugurel, Selma; Pfoehler, Claudia; Gesierich, Anja; Livingstone, Elisabeth; Satzger, Imke; et al. (European Journal of Cancer, 2017)
AIM: Programmed cell death protein 1 (PD-1) inhibitors are a common treatment strategy for metastatic melanoma and other tumour entities. Clinical trials usually exclude patients with preexisting autoimmune diseases, thus experience with PD-1 inhibitor (PD-1i) in this patient population is limited. PATIENTS AND METHODS: Metastatic melanoma patients with preexisting autoimmune disorders or previous ipilimumab-triggered immune-related adverse events (irAE) undergoing treatment with PD-1i from seven German skin cancer centres were evaluated retrospectively with regard to flare of the preexisting autoimmunity and development of new, not preexisting irAE as well as response to PD-1i therapy. RESULTS: In total, 41 patients had either preexisting autoimmunity (n=19, group A, including two patients with additional ipilimumab-triggered autoimmune colitis) or ipilimumab-triggered irAE (n=22, group B). At PD-1i therapy initiation, six patients in group A and two patients in group B required immunosuppressive therapy. In group A, a flare of preexisting autoimmune disorders was seen in 42% of patients, new irAE in 16%. In group B, 4.5% of patients showed a flare of ipilimumab-triggered irAE and 23% new irAE. All flares of preexisting autoimmune disorders or irAE were managed by immunosuppressive and/or symptomatic therapy and did not require termination of PD-1i therapy. tumour responses (32% in group A and 45% in group B) were unrelated to occurrence of autoimmunity. CONCLUSION: While preexisting autoimmunity commonly showed a flare during PD-1i therapy, a flare of ipilimumab-triggered irAE was rare. Response rates were above 30% and unrelated to irAE. PD-1i therapy can be considered in patients with autoimmune disorders depending on severity and activity of autoimmunity.
EVALuna2:34334

Propagation of SARS-CoV-2 in a Closed Cell Culture Device: Potential GMP Compatible Production Platform for Live-Attenuated Vaccine Candidates under BSL-3 Conditions? - Klessing, Stephan; Peter, Antonia Sophia; Fraedrich, Kirsten; Wagner, Jannik; Kummer, Mirko; Deutschmann, Janina; Steininger, Philipp; Steibl, Hans Dieter; Überla, Klaus (Viruses, 2023)
Live-attenuated SARS-CoV-2 vaccines present themselves as a promising approach for the induction of broad mucosal immunity. However, for initial safety assessment in clinical trials, virus production requires conditions meeting Good Manufacturing Practice (GMP) standards while maintaining biosafety level 3 (BSL-3) requirements. Since facilities providing the necessary complex ventilation systems to meet both requirements are rare, we here describe a possibility to reproducibly propagate SARS-CoV-2 in the automated, closed cell culture device CliniMACS Prodigy® in a common BSL-3 laboratory. In this proof-of-concept study, we observed an approximately 300-fold amplification of SARS-CoV-2 under serum-free conditions with high lot-to-lot consistency in the infectious titers obtained. With the possibility to increase production capacity to up to 3000 doses per run, this study outlines a potential fast-track approach for the production of live-attenuated vaccine candidates based on highly pathogenic viruses under GMP-like conditions that may contribute to pandemic preparedness.
CRIS-Team Scopus Importer:2023-03-10
Keywords: CliniMACS Prodigy®; GMP; human challenge study; live-attenuated vaccines; SARS-CoV-2; virus propagation

Prospective multicenter study using artificial intelligence to improve dermoscopic melanoma diagnosis in patient care - Heinlein, Lukas; Maron, Roman C.; Hekler, Achim; Haggenmüller, Sarah; Wies, Christoph; Utikal, Jochen S.; Meier, Friedegund; Hobelsberger, Sarah; Gellrich, Frank F.; Sergon, Mildred; Hauschild, Axel; French, Lars E.; et al. (Communications Medicine, 2024)
Background: Early detection of melanoma, a potentially lethal type of skin cancer with high prevalence worldwide, improves patient prognosis. In retrospective studies, artificial intelligence (AI) has proven to be helpful for enhancing melanoma detection. However, there are few prospective studies confirming these promising results. Existing studies are limited by low sample sizes, too homogenous datasets, or lack of inclusion of rare melanoma subtypes, preventing a fair and thorough evaluation of AI and its generalizability, a crucial aspect for its application in the clinical setting. Methods: Therefore, we assessed “All Data are Ext” (ADAE), an established open-source ensemble algorithm for detecting melanomas, by comparing its diagnostic accuracy to that of dermatologists on a prospectively collected, external, heterogeneous test set comprising eight distinct hospitals, four different camera setups, rare melanoma subtypes, and special anatomical sites. We advanced the algorithm with real test-time augmentation (R-TTA, i.e., providing real photographs of lesions taken from multiple angles and averaging the predictions), and evaluated its generalization capabilities. Results: Overall, the AI shows higher balanced accuracy than dermatologists (0.798, 95% confidence interval (CI) 0.779–0.814 vs. 0.781, 95% CI 0.760–0.802; p = 4.0e−145), obtaining a higher sensitivity (0.921, 95% CI 0.900–0.942 vs. 0.734, 95% CI 0.701–0.770; p = 3.3e−165) at the cost of a lower specificity (0.673, 95% CI 0.641–0.702 vs. 0.828, 95% CI 0.804–0.852; p = 3.3e−165). Conclusion: As the algorithm exhibits a significant performance advantage on our heterogeneous dataset exclusively comprising melanoma-suspicious lesions, AI may offer the potential to support dermatologists, particularly in diagnosing challenging cases.
CRIS-Team Scopus Importer:2024-09-20

Prospective study in bullous pemphigoid: association of high serum anti-BP180 IgG levels with increased mortality and reduced Karnofsky score - Holtsche, M. M.; Goletz, S.; Van Beek, N.; Zillikens, Detlef; Benoit, S.; Harman, K.; Walton, S.; English, J.; Sticherling, Michael; Chapman, A.; Levell, N. J.; Groves, R.; et al. (British Journal of Dermatology, 2018)
BACKGROUND: Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the two hemidesmosomal proteins, BP180 (type XVII collagen) and BP230. The multicentre prospective BLISTER (Bullous Pemphigoid Steroids and Tetracyclines) trial randomized 253 patients with BP to compare the benefits and harms between initial treatment with doxycycline or prednisolone. OBJECTIVES: To analyse distinct autoantibody profiles for the prediction of the disease course in a well-characterized cohort of BP sera. METHODS: One hundred and forty-three patients of the BLISTER trial consented to participate in this serological study. Sera taken at baseline were analysed by (i) indirect immunofluorescence, (ii) anti-BP180 NC16A (16th noncollagenous domain) and anti-BP230 enzyme-linked immunosorbent assay and (iii) immunoblotting with various substrates. Results were then linked with clinical parameters including age, Karnofsky score, number of blisters, related adverse events and mortality. RESULTS: Disease activity correlated with immunoglobulin (Ig)G anti-BP180 levels but not with levels of anti-BP230 IgG and anti-BP180 IgE. High levels of both anti-BP180 IgG and anti-BP230 IgG were associated with a low Karnofsky score. The presence of anti-BP230 IgG was more frequent in older patients. Those with higher total IgE serum levels suffered from fewer adverse events. Higher IgG anti-BP180 levels were associated with an increased 1-year mortality rate. CONCLUSIONS: Analysis of the autoantibody profile is not only of diagnostic relevance but may also be helpful in predicting the course of the disease.
EVALuna2:34763

Proteasomes generate spliced epitopes by two different mechanisms and as efficiently as non-spliced epitopes - Ebstein, F.; Textoris-Taube, K.; Keller, C.; Golnik, R.; Vigneron, N.; Van Den Eynde, B. J.; Schuler-Thurner, Beatrice; Schadendorf, D.; Lorenz, F. K. M.; Uckert, W.; Urban, S.; Lehmann, A.; et al. (Scientific Reports, 2016)
Proteasome-catalyzed peptide splicing represents an additional catalytic activity of proteasomes contributing to the pool of MHC-class I-presented epitopes. We here biochemically and functionally characterized a new melanoma gp100 derived spliced epitope. We demonstrate that the gp100(mel)47-52/40-42 antigenic peptide is generated in vitro and in cellulo by a not yet described proteasomal condensation reaction. gp100(mel)47-52/40-42 generation is enhanced in the presence of the ?5i/LMP7 proteasome-subunit and elicits a peptide-specific CD8(+) T cell response. Importantly, we demonstrate that different gp100(mel)-derived spliced epitopes are generated and presented to CD8(+) T cells with efficacies comparable to non-spliced canonical tumor epitopes and that gp100(mel)-derived spliced epitopes trigger activation of CD8(+) T cells found in peripheral blood of half of the melanoma patients tested. Our data suggest that both transpeptidation and condensation reactions contribute to the frequent generation of spliced epitopes also in vivo and that their immune relevance may be comparable to non-spliced epitopes.
EVALuna2:19591

Proteomic Response of Human Umbilical Vein Endothelial Cells to Histamine Stimulation - Emirbayer, Pelin Esma; Sinha, Ankit; Ignatchenko, Vladimir; Hoyer, Stefanie; Dörrie, Jan; Schaft, Niels; Pischetsrieder, Monika; Kislinger, Thomas (Proteomics, 2017)
The histamine receptors (HRs) represent a subclass of G protein-coupled receptors (GPCRs) and comprise four subtypes. Due to their numerous physiological and pathological effects, HRs are popular drug targets for the treatment of allergic reactions or the regulation of gastric acid secretion. Hence, an understanding of the functional selectivity of HR ligands has gained importance. These ligands can bind to specific GPCRs and selectively activate defined pathways. Supporting the activation of a therapeutically necessary pathway without the activation of other signaling cascades can result in drugs with more specific activity and fewer side effects. To evaluate the cellular consequences resulting from receptor binding, comprehensive analyses of cellular protein alterations upon incubation with ligands are required. For this purpose, endothelial cells are treated with histamine, as the endogenous ligand of HRs, to obtain a global overview of its cellular effects. Quantitative proteomics and pathway analyses of histamine-treated and untreated cells reveal enrichment of the nuclear factor-B and tumor necrosis factor signaling pathways, cytokine-cytokine receptor interactions, complement and coagulation cascades, and acute inflammatory processes upon histamine treatment. This strategy offers the opportunity to monitor HR-mediated signaling in a multidimensional manner.
Keywords: histamine; label-free quantification; parallel reaction monitoring; secretome; Shotgun proteomics

Protocol for mapping the heterogeneous dendritic cell network across the murine tissue landscape via high-dimensional flow cytometry - Amon, Lukas; Seichter, Anna; Vurnek, Damir; Tchitashvili, Giorgi; Heß, Isabel; Heger, Lukas; Lehmann, Christian; Dudziak, Diana (STAR Protocols, 2024)
Dendritic cells (DCs) populate nearly all tissues and represent the central orchestrators of immunity. Here, we present a protocol for the mild but efficient preparation of single-cell suspensions from multiple murine tissues and the downstream analysis of the DC network via high-parameter flow cytometry. Additionally, we provide evaluation strategies that facilitate the stringent separation of the DC family from other myeloid cells, particularly macrophages and monocytes, and include an in-depth assessment of DC-intrinsic heterogeneity. For complete details on the use and execution of this protocol, please refer to Amon et al.1
CRIS-Team Scopus Importer:2024-07-19
Keywords: Cell Biology; Cell isolation; Flow Cytometry; Immunology; Single Cell

Pruritus in Psoriasis - Correlation to the Severity of the clinical appearance of the Skin? - Achterberg, Fritz Leonard; Kremer, Andreas; Sticherling, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Psoriasis and autoimmunity - Sticherling, Michael (Autoimmunity Reviews, 2016)
Psoriasis is one of the most common chronic inflammatory human skin diseases. Though clinically well characterized, the exact etiological and pathogenic mechanisms are still not known in detail. Current knowledge indicates distinct overlap to other inflammatory as well as autoimmune disorders. However, the one or more relevant autoantigens could not be characterized so-far. On the other side, several autoimmune diseases were shown to be associated with psoriasis. In addition, serological autoimmune phenomena, namely diverse circulating specific autoantibodies could be demonstrated in the past. A matter of current debate is if psoriasis is a primary autoimmune disease or secondarily evolving into autoimmunity as seen in other chronic inflammatory diseases. Related to this aspect is the concept of autoinflammation versus autoimmunity where psoriasis shares mechanisms of both entities. Though T-cells remain among the most important cellular players in the pathogenesis of psoriasis and current therapeutic strategies successfully target these cells or their products irrespective of these concepts, autoimmunity if relevant will add to the treatment armamentarium by using protective and prophylactic antigen-specific modalities.
EVALuna2:19626

Psoriasis as a Manifestation of an Immune Reconstitution in Two Patients with Hepatitis C Treated with Ledipasvir/Sofosbuvir - Heppt, Franz; Sticherling, Michael (Acta Dermato-Venereologica, 2017)
EVALuna2:34349

Psoriasis capitis and seborrhoic eczema of scalp diseases - Sticherling, Michael (Hautarzt, 2017)
The scalp may be affected by various diseases with equally varying manifestations. Erythema and scaling is often accompanied by agonizing itch. Scalp psoriasis and seborrheic eczema represent the most frequent diseases, which can be differentiated into classical cases; however, overlap and similarities are seen. Sharply demarcated erythematosquamous plaques across the natural hairline in psoriasis are opposed to blurred dark-red erythema and yellowish, greasy scales in seborrheic eczema. Whereas with the latter diffuse alopecia may frequently be found, hair loss is rarely seen in psoriasis and may also be related to therapeutic agents. Treatment is based on acuity as well as extent of disease and individual life quality aspects of the patients. It is mainly based on topical corticosteroids, combined with vitamin D derivatives in psoriasis and antimycotic agents in seborrheic eczema. In severe cases and widespread psoriatic disease, systemic treatment may be necessary, including the classic agents methotrexate, fumarates and ciclosporin as well as biologicals. Systemic treatment of seborrheic eczema is rarely necessary and resides on corticosteroids, antimycotic agents and vitamin A derivatives. In addition, intensive counseling of patients on the necessity of consequent and long-term treatment as well as use of mild skin care products is mandatory.
EVALuna2:34347

Psoriasis in children: a single center analysis - Heppt, Franz; Raap, J.; Sticherling, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Psoriasis in children: a single-centre analysis - Heppt, Franz; Raap, J.; Sticherling, Michael (2017)
EVALuna2:34339

Psoriasis in routine clinical care: Complete skin clearance rates with guselkumab increase through week 52-Results from the real-life PERSIST study - Hoffmann, Matthias; Sticherling, Michael; Korge, Bernhard; Mortazawi, Dariusch; Personke, Yvonne; Gomez, Mario; Wegner, Sven; Gerdes, Sascha (JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-08-27

Psoriasis - Occurrence and Reality: Disease of the Psoriasis Group - Leupolz, S.; Sticherling, Michael (2017)
EVALuna2:34353

Psoriasis Patients are still severely underserved: Results of the DERMLINE Online Survey - Hell, Katharina; Schielein, Maximilian C.; Romer, Katrin; Hacker, Elena; Baeumer, Daniel; Wagner, Nicola; Zink, Alexander (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-02-28

Psoriasis vulgaris as Manifestation of Immune Reconstitution in Patients with Hepatitis C under Treatment with Ledipasvir/Sofosbuvir - Heppt, Franz; Sticherling, Michael (2017)
EVALuna2:34350

Psoriatic arthritis epidemiology, comorbid disease profiles and risk factors: Results from a claims database analysis - Rech, Jürgen; Sticherling, Michael; Stoessel, Daniel; Biermann, Mona H.C.; Häberle, Benjamin M.; Reinhardt, Maximilian (Rheumatology Advances in Practice, 2020)
Objective. Psoriasis is a systemic inflammatory disease often accompanied by comorbidities, including metabolic syndrome, cardiovascular diseases and depression. Up to 41% of psoriasis patients develop psoriatic arthritis (PsA), making it one of the most relevant manifestations. A large health claims data set was analysed to determine the rate of PsA development in psoriasis patients. Furthermore, comorbid disease profiles of psoriasis patients with or without PsA were compared, and potential risk factors for the development of PsA were identified. Methods. This was a non-interventional, retrospective analysis of anonymized insurance health claims data using a subset of the Institute of Applied Health Research Berlin (InGef) database. The primary outcome was the prevalence and incidence of diagnosed PsA among psoriasis patients in Germany. Risk factors for the development of PsA in psoriasis patients were determined by conditional logistic regression analysis. Results. The cumulative percentage of patients with existing psoriasis developing concomitant PsA over 4 years was 3.44%, with a mean time to diagnosis of PsA of 1.5 years. Psoriasis patients diagnosed with acute rheumatism (odds ratio: 2.93, 95% CI=1.76, 4.86; P<0.001) or pain in unspecific joints (odds ratio: 1.74, 95% CI=1.01, 2.99; P=0.047) showed an increased risk for development of PsA later on. Interestingly, fewer than half of the patients with concomitant PsA consulted a rheumatologist. Conclusions. Unspecific arthritic symptoms are likely to precede PsA diagnoses and can develop soon after onset of psoriasis, with accumulating risk over time. There is a high unmet need for early rheumatological assessment of psoriasis patients.
CRIS-Team Scopus Importer:2020-12-04
Keywords: Comorbid disease; Epidemiology; Incidence; Insurance health claims data; PsA; Psoriasis; Risk factors

Psoriatic Arthritis - Epidemiology, Incidence Rate in Psoriasis Patients, Comorbidity Profiles and Risk Factor Analysis - Rech, Jürgen; Sticherling, Michael; Biermann, Mona; Haeberle, Benjamin; Reinhardt, Maximilian (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

Psychiatric disorders are common comorbidities in patients with chronic spontaneous or inducible urticaria in Germany - Weller, K.; Maurer, M.; Bauer, A.; Wedi, B.; Wagner, N.; Schliemann, S.; Baeumer, D.; Boehm, K.; Staubach, P. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

PU.1 controls fibroblast polarization and tissue fibrosis - Wohlfahrt, Thomas; Rauber, Simon; Uebe, Steffen; Luber, Markus; Soare, Alina; Ekici, Arif Bülent; Weber, Stefanie; Matei, Alexandru-Emil; Chen, Chih-Wei; Maier, Christiane; Karouzakis, Emmanuel; Kiener, Hans P.; et al. (Nature, 2019)
Fibroblasts are polymorphic cells with pleiotropic roles in organ morphogenesis, tissue homeostasis and immune responses. In fibrotic diseases, fibroblasts synthesize abundant amounts of extracellular matrix, which induces scarring and organ failure. By contrast, a hallmark feature of fibroblasts in arthritis is degradation of the extracellular matrix because of the release of metalloproteinases and degrading enzymes, and subsequent tissue destruction. The mechanisms that drive these functionally opposing pro-fibrotic and pro-inflammatory phenotypes of fibroblasts remain unknown. Here we identify the transcription factor PU.1 as an essential regulator of the pro-fibrotic gene expression program. The interplay between transcriptional and post-transcriptional mechanisms that normally control the expression of PU.1 expression is perturbed in various fibrotic diseases, resulting in the upregulation of PU.1, induction of fibrosis-associated gene sets and a phenotypic switch in extracellular matrix-producing pro-fibrotic fibroblasts. By contrast, pharmacological and genetic inactivation of PU.1 disrupts the fibrotic network and enables reprogramming of fibrotic fibroblasts into resting fibroblasts, leading to regression of fibrosis in several organs.
EVALuna2:35476

Purified complement C3b triggers phagocytosis and activation of human neutrophils via complement receptor 1 - Boero, Elena; Gorham, Ronald D.; Francis, Emmet A.; Brand, Jonathan; Teng, Lay Heng; Doorduijn, Dennis J.; Ruyken, Maartje; Muts, Remy M.; Lehmann, Christian; Verschoor, Admar; van Kessel, Kok P.M.; Heinrich, Volkmar; et al. (Scientific Reports, 2023)
The complement system provides vital immune protection against infectious agents by labeling them with complement fragments that enhance phagocytosis by immune cells. Many details of complement-mediated phagocytosis remain elusive, partly because it is difficult to study the role of individual complement proteins on target surfaces. Here, we employ serum-free methods to couple purified complement C3b onto E. coli bacteria and beads and then expose human neutrophils to these C3b-coated targets. We examine the neutrophil response using a combination of flow cytometry, confocal microscopy, luminometry, single-live-cell/single-target manipulation, and dynamic analysis of neutrophil spreading on opsonin-coated surfaces. We show that purified C3b can potently trigger phagocytosis and killing of bacterial cells via Complement receptor 1. Comparison of neutrophil phagocytosis of C3b- versus antibody-coated beads with single-bead/single-target analysis exposes a similar cell morphology during engulfment. However, bulk phagocytosis assays of C3b-beads combined with DNA-based quenching reveal that these are poorly internalized compared to their IgG1 counterparts. Similarly, neutrophils spread slower on C3b-coated compared to IgG-coated surfaces. These observations support the requirement of multiple stimulations for efficient C3b-mediated uptake. Together, our results establish the existence of a direct pathway of phagocytic uptake of C3b-coated targets and present methodologies to study this process.
CRIS-Team Scopus Importer:2023-01-20

Purple urine in a patient after recovery from a SARS-CoV-2 infection - Vetter, Marcel; Kaufmann, Matthias; Neurath, Markus; Kremer, Andreas (International Journal of Infectious Diseases, 2021)
CRIS-Team Scopus Importer:2021-04-02
Keywords: COVID-19; PUBS; Purple urine bag syndrome

Quality of life assessment in family members of patients with chronic wounds - Erfurt-Berge, Cornelia; Ronicke, Moritz; Richter-Schmidinger, Tanja; Walther, Felix; Renner, Regina (European Journal of Dermatology, 2019)
Familial caregivers are often directly involved in treatment of patients with chronic wounds, however, less is known about their personal impairment, and specific support is lacking for these important members of the therapeutic team regarding wound care. The aim of this study was to investigate the influence of wound care provided by family members on their quality of life, and to create a suitable questionnaire to describe the affected personal aspects. A five-part questionnaire, named ELWA, was created by the authors and answered by 30 familial caregivers of 30 respective patients with chronic leg ulcers. One third of the caregivers reported receiving no medical advice about detailed wound care at all. A lack of information regarding details of the disease correlated with personal strain. Additional costs, anxiety, frustration, and reduced spare-time activities were among the top-rated factors affecting quality of life of family members. The results from this newly created questionnaire point out the needs of familial caregivers of patients with chronic wounds and may help to establish individual support. Implementation of clinical treatment strategies is planned through multicentre application.
CRIS-Team Scopus Importer:2019-12-13
Keywords: chronic wounds; family member; leg ulcer; quality of life; wound care

Quality of life in patients with chronic wounds Lebensqualität bei Patienten mit chronischen Wunden - Erfurt-Berge, Cornelia; Renner, Regina (Hautarzt, 2020)
The quality of life of patients with chronic wounds is significantly reduced. Through pain, wound odor, and exudate, they experience limitations in various areas of their daily life. Pain can lead to reduced mobility, sleep disorders, or reduced food intake. Physical limitations caused by the wound itself, dependence on caregivers, and the financial burden are further influencing factors. At the same time, chronic wounds lead to changes in social life, withdrawal from friends and family, and a feeling of powerlessness over a patient’s own life. Pre-existing anxiety or a depressive disorder can further negatively influence the quality of life. There are various general and diagnosis-specific assessment tools for measuring the quality of life of patients with chronic wounds. Such a survey should be carried out regularly in the course of wound therapy. Especially at the beginning of treatment, it is important to identify limiting factors and to evaluate them regularly during wound therapy and to work out possible solutions together with the patient.
CRIS-Team Scopus Importer:2020-09-04
Keywords: Assessment tools; Interventions; Needs assessment; Pain; Physician-patient discussions

Quantitative and Qualitative Changes of Bone in Psoriasis and Psoriatic Arthritis Patients - Kocijan, Roland; Englbrecht, Matthias; Haschka, Judith; Simon, David; Kleyer, Arnd; Finzel, Stephanie; Kraus, Sebastian; Resch, Heinrich; Muschitz, Christian; Engelke, Klaus; Sticherling, Michael; Rech, Jürgen; et al. (Journal of Bone and Mineral Research, 2015)
Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by periarticular bone loss and new bone formation. Current data regarding systemic bone loss and bone mineral density (BMD) in PsA are conflicting. The aim of this study was to evaluate bone microstructure and volumetric BMD (vBMD) in patients with PsA and psoriasis. We performed HR-pQCT scans at the ultradistal and periarticular radius in 50 PsA patients, 30 psoriasis patients, and 70 healthy, age- and sex-related controls assessing trabecular bone volume (BV/TV), trabecular number (Tb.N), inhomogeneity of the trabecular network, cortical thickness (Ct.Th), and cortical porosity (Ct.Po), as well as vBMD. Trabecular BMD (Tb.BMD, p = 0.021, 12.0%), BV/TV (p = 0.020, -11.9%), and Tb.N (p = 0.035, 7.1%) were significantly decreased at the ultradistal radius and the periarticular radius in PsA patients compared to controls. In contrast, bone architecture of the ultradistal radius and periarticular radius was similar in patients with psoriasis and healthy controls. Duration of skin disease was associated with low BV/TV and Tb.N in patients with PsA. These data suggest that trabecular BMD and bone microstructure are decreased in PsA patients. The observation that duration of skin disease determines bone loss in PsA supports the concept of subclinical musculoskeletal disease in psoriasis patients. © 2015 American Society for Bone and Mineral Research.
EVALuna2:10104

Quercetin induces an immunoregulatory phenotype in maturing human dendritic cells - Michalski, Julia; Deinzer, Anja; Stich, Lena; Zinser, Elisabeth; Steinkasserer, Alexander; Knippertz, Ilka (Immunobiology, 2020)
The aryl hydrocarbon receptor (AhR) is an environmental sensor and ligand-activated transcription factor that is critically involved in the regulation of inflammatory responses and the induction of tolerance by modulating immune cells. As dendritic cells (DCs) express high AhR levels, they are efficient to induce immunomodulatory effects after being exposed to AhR-activating compounds derived from the environment or diet. To gain new insights into the molecular targets following AhR-activation in human monocyte-derived (mo)DCs, we investigated whether the natural AhR ligand quercetin or the synthetic ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) modulates the function of human moDCs regarding their capability to prime naïve T cells or to migrate. As only quercetin, but not TCDD, impaired T cell activation and migration of LPS-matured DCs (LPS-DCs), we analyzed the mode of action of quercetin on moDCs in more detail. Here, we found a specific down-regulation of the immunomodulatory molecule CD83 through the direct binding of the activated AhR to the CD83 promoter. Furthermore, treatment of LPS-DCs with quercetin resulted in a reduced production of the pro-inflammatory cytokine IL-12p70 and in an increased expression of the immunoregulatory molecules disabled adaptor protein (Dab) 2, immunoglobulin-like transcript (ILT)-3, ILT4, ILT5 as well as ectonucleotidases CD39 and CD73, thereby inducing a tolerogenic phenotype in quercetin-treated maturing DCs. Overall, these data demonstrate that quercetin represents a potent immunomodulatory agent to alter human DC phenotype and function, shifting the immune balance from inflammation to resolution.
CRIS-Team Scopus Importer:2020-03-10
Keywords: Aryl hydrocarbon receptor; Dendritic cells; Quercetin; Regulatory T cells; TCDD; Tolerance

Radiosensitization by BRAF inhibitor therapy-mechanism and frequency of toxicity in melanoma patients - Hecht, Markus; Zimmer, L.; Loquai, C.; Weishaupt, C.; Gutzmer, R.; Schuster, B.; Gleisner, S.; Schulze, B.; Goldinger, S. M.; Berking, C.; Forschner, A.; Clemens, P.; et al. (Annals of Oncology, 2015)
Recent evidence suggests that ionizing radiation may be associated with unexpected side-effects in melanoma patients treated with concomitant BRAF inhibitors. A large multicenter analysis was carried out to generate reliable safety data and elucidate the mechanism.A total of 161 melanoma patients from 11 European skin cancer centers were evaluated for acute and late toxicity, of whom 70 consecutive patients received 86 series of radiotherapy with concomitant BRAF inhibitor therapy. To further characterize and quantify a possible radiosensitization by BRAF inhibitors, blood samples of 35 melanoma patients were used for individual radiosensitivity testing by fluorescence in situ hybridization of chromosomal breaks after ex vivo irradiation.With radiotherapy and concomitant BRAF inhibitor therapy the rate of acute radiodermatitis >=2° was 36% and follicular cystic proliferation was seen in 13% of all radiotherapies. Non-skin toxicities included hearing disorders (4%) and dysphagia (2%). Following whole-brain radiotherapy, rates of radiodermatitis >=2° were 44% and 8% (P < 0.001) for patients with and without BRAF inhibitor therapy, respectively. Concomitant treatment with vemurafenib induced acute radiodermatitis >=2° more frequently than treatment with dabrafenib (40% versus 26%, P = 0.07). In line with these findings, analysis of chromosomal breaks ex vivo indicated significantly increased radiosensitivity for patients under vemurafenib (P = 0.004) and for patients switched from vemurafenib to dabrafenib (P = 0.002), but not for patients on dabrafenib only. No toxicities were reported after stereotactic treatment.Radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib.
EVALuna2:18285

Rapid development of bilateral necroses of the upper extremity - Kirchberger, Michael C.; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2017)
EVALuna2:35400

Rapid development of cutaneous melanoma metastases after herpes zoster infection in a radiotherapy field - Uslu, Ugur; Schliep, S.; Erdmann, M. (Clinical and Experimental Dermatology, 2018)
Click for the corresponding questions to this CME article.
EVALuna2:34807

Rapid Response of a multilocular metastatic Merkel Cell Carcinoma with an unclear Primarius to Avelumab - Bender-Säbelkampf, Sophia; Berking, Carola; Erdmann, M. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Rapid Response of locally distinct CD30 positive primary cutaneous anaplastic large T-Cell Lymphoma under Brentuximab Vedotin - Bender-Säbelkampf, Sophia; Berking, Carola; Erdmann, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Rasche Entwicklung bilateraler Nekrosen der oberen Extremität - Kirchberger, Michael C; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2017)
EVALuna2:35418

Rasches Ansprechen eines lokal ausgeprägten CD30-positiven primär kutanen anaplastisch-großzelligen T-Zell-Lymphoms unter Brentuximab-Vedotin - Bender-Säbelkampf, Sophia; Berking, Carola; Erdmann, Michael (Abstractband anlässlich des 31. Deutschen Hautkrebskongresses (ADO-Jahrestagung) 8.–11. September 2021, 2021)
CD30-Positivität gilt nicht nur als Indikator aktivierter Lymphozyten, sondern wird auch in der Lymphom-Entstehung diskutiert. Wir stellen den Fall einer 73-jährigen Landwirtin mit einer 2005 systemisch behandelten chronisch lymphatischen B-Zell-Leukämie (B-CLL) im Binet-Stadium B sowie mit einem neu aufgetretenen, rasch wachsenden, fazialen, CD30-positiven, primär kutanen anaplastisch-großzelligen T-Zell-Lymphom vor. An denselben Stellen waren vormals multiple Basalzell- und Plattenepithelkarzinome sowie ein primär kutanes B-Zell-Lymphom vom Keimzentrumstyp exzidiert worden. Histologisch zeigten sich nun plasmazytoide Zellen sowie teils großzellig blastär imponierende, CD30-positive Zellen. Bei immunhistologisch diagnostiziertem Lymphom der Haut ist die Abgrenzung eines primär kutanen gegenüber einem sekundär kutanen Lymphom im Rahmen der klinisch-pathologischen Korrelation inklusive bildgebender Verfahren zu treffen. Hierbei sind die fehlende Expression von ALK1, CD15 und EMA sowie die Histomorphologie mit häufig landkartenartiger Nekrose inmitten eines eosinophilenreichen Zellinfiltrats wichtige Indikatoren für ein primär kutanes CD30-positives primär kutanes anaplastisch-großzelliges T-Zell-Lymphom. In der Ausbreitungsdiagnostik mittels CT Hals-Thorax-Abdomen bestätigte sich die bereits im Rahmen der B-CLL bekannte Lymphadenopathie. Differentialblutbild sowie Blutausstrich verblieben bis auf die Leukämie-bedingte Lymphozytose unauffällig. Daher wurde von einer Knochenmarkspunktion und Lymphknotenbiopsie zum Ausschluss einer Richter-Transformation und dadurch ermöglichten kutanen T-Zell-Erkrankung abgesehen. Aufgrund der Befundausprägung sowie der bereits stattgehabten Chemotherapie im Rahmen der B-CLL entschieden wir uns für die Einleitung einer intravenösen, gewichtsadaptierten CD30-gerichteten-Antikörpertherapie mittels Brentuximab-Vedotin. Bereits nach dem 1. Zyklus kam es zu einer signifikanten Tumormassenreduktion sowie nach 6 Zyklen zu einer vollständigen Abheilung. Parallel zum klinischen Ansprechen fand sich ein hämatoonkologisch nicht behandlungsbedürftiger Anstieg der Leukozyten im Rahmen der B-CLL von 65.000 auf 115.000. Bemerkenswerterweise zeigte sich zudem ein präinterventionell histologisch gesichertes Basalzellkarzinom links retroaurikulär unter der onkologischen Systemtherapie gegen das kutane T-Zell-Lymphom klinisch regredient.<br

Rasches Ansprechen eines multilokulär metastasierten Merkelzellkarzinoms bei unklarem Primarius auf Avelumab - Bender-Säbelkampf, Sophia; Berking, Carola; Erdmann, Michael (Abstractband anlässlich des 31. Deutschen Hautkrebskongresses (ADO-Jahrestagung) 8.–11. September 2021, 2021)
Die seit 2017 zugelassene PD-L1-Antikörper-Therapie mit Avelumab zeigt beim metastasierten Merkelzellkarzinom eine objektive Ansprechrate von 62,1 % mit 13,8 % Vollremissionen und ein 5-Jahres-Überleben von 51 % bei lokaler, 35 % bei lymphonodaler und 14 % bei viszeraler Metastasierung. Wir stellen einen 84-jährigen Patienten mit innerhalb von 3 Monaten am Capillitium rasch wachsenden, multiplen, in Größe und Aussehen gleichartig imponierenden Hautmetastasen eines Merkelzellkarzinoms bei unklarem Primarius vor. In der Schnittbildgebung zeigten sich zusätzlich hepatische und ossäre Metastasen. Trotz initialer Bedenken seitens des betagten Patienten aufgrund bestehender Komorbiditäten wie chronischer Niereninsuffizienz Stadium III-IV, insulinpflichtigem Diabetes, koronarer Herzkrankheit sowie metabolischem Syndrom entschied er sich bei erhaltener Selbstständigkeit und einem ECOG-Status von 1 für die Systemtherapie mit Avelumab, die er gewichtsadaptiert alle 2 Wochen erhielt. Sowohl die Lokal- als auch Fernmetastasierung ergab im klinischen sowie radiologischen Verlauf ein rasches Ansprechen mit einer Vollremission nach 8 Gaben. Bei stark juckenden, erythematösen Papeln wurde ein bullöses Pemphigoid serologisch und (immun-)histologisch ausgeschlossen. Es zeigten sich irritierte ekzematoide Veränderungen, welches wir bei undulierenden renalen Retentionswerten im Rahmen der chronischen Niereninsuffizienz Stadium III-IV einordneten. Bei entsprechender topischer glukokortikoid-haltiger Therapie wurde die Systemtherapie bislang ohne autoimmunvermittelte Nebenwirkungen gut vertragen. Interessanterweise bildete sich zusätzlich die vorbekannte aktinische Feldkanzerisierung im Laufe der Immuntherapie weitestgehend zurück. Dies könnte theoretisch über beschriebene MHC-Klasse I-bindende Neoantigene bei aktinischen Keratosen und damit einhergehender T-Zell-Rezeptor-Erkennung erklärt werden. Schlussfolgerung: Auch im fortgeschrittenen Alter mit entsprechenden Komorbiditäten stellt die Immuncheckpoint-Blockade mit anti-PD-L1-Antikörpern eine Option mit hoher Erfolgsaussicht und guter Verträglichkeit beim fortgeschrittenen Merkelzellkarzinom auch bei unklarem Primarius dar.<br

Real-world analysis of dabrafenib plus trametinib in patients with BRAFV600-mutated melanoma brain metastases - Berking, Carola; Schadendorf, D.; Weichenthal, M.; Eigentler, T.; Mohr, P.; Schober, K.; Kiecker, F.; Loquai, C.; Debus, D.; Gutzmer, R.; Leiter-Stoeppke, U. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-10-30

Real-world clinical outcomes of pembrolizumab for advanced melanoma in the German ADOREG skin cancer registry - Mohr, P.; Scherrer, E.; Alar, V.; Assaf, C.; Beissert, S.; Berking, Carola; Eigentler, T.; Grimmelmann, I.; Gutzmer, R.; Haferkamp, S.; Hassel, J. C.; Hauschild, A.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

Real-world data on the effectiveness, safety and drug survival of dupilumab: an analysis from the TREATgermany registry - Stoelzl, Dora; Sander, Nicole; Heratizadeh, Annice; Haufe, Eva; Harder, Inken; Abraham, Susanne; Heinrich, Luise; Kleinheinz, Andreas; Wollenberg, Andreas; Weisshaar, Elke; Schaekel, Knut; Ertner, Konstantin; et al. (British Journal of Dermatology, 2022)
CRIS-Team Scopus Importer:2022-11-11

Real-world effectiveness of guselkumab in patients with psoriasis: Health-related quality of life and efficacy data from the noninterventional, prospective, German multicenter PERSIST trial - Gerdes, Sascha; Bräu, Beate; Hoffmann, Matthias; Korge, Bernhard; Mortazawi, Dariusch; Wiemers, Franca; Wegner, Sven; Personke, Yvonne; Gomez, Mario; Sticherling, Michael (Journal of Dermatology, 2021)
Psoriasis is a common, chronic inflammatory skin disorder negatively impacting health-related quality of life (HRQoL). Guselkumab, targeting interleukin-23 (IL-23), is an approved biologic therapy for psoriasis. PERSIST is an ongoing prospective, noninterventional, long-term, German multicenter study evaluating the effect of guselkumab on HRQoL, and its efficacy and safety in patients with moderate-to-severe psoriasis in a real-world setting. The primary endpoint is the proportion of patients with a Dermatology Life Quality Index (DLQI) score ≤ 1 at week 28. Of 303 patients enrolled and treated with guselkumab, mean age and disease duration were 49.7 and 21.0 years, respectively, and 51.2% (n = 155) of patients had received ≥1 prior biologic therapy. Mean baseline DLQI score was 13.7, and mean symptom and sign scores in the Psoriasis Symptoms and Signs Diary (PSSD) were 51.9 and 60.8, respectively. Baseline Psoriasis Area Severity Index (PASI) and body surface area (%) scores were 16.4 and 27.5. Following 28 weeks of guselkumab treatment, the mean DLQI score decreased to 2.8, and 56.8% of patients (n = 150) achieved DLQI ≤ 1. Mean PSSD symptom and sign scores also improved, decreasing to 12.5 and 15.9, respectively. At week 28, PASI 90 response was 55.3%; significant improvement was observed in patients with psoriasis in difficult-to-treat areas. Overall, analyses demonstrated that guselkumab was effective in the real-world setting, as measured by HRQoL and skin improvements, even in patients with a high burden of disease and those who have received multiple biologic therapies. No new safety signals were observed.
CRIS-Team Scopus Importer:2021-09-17
Keywords: anogenital; guselkumab; palmoplantar; psoriasis; quality of life; RWE; scalp

Real-world evidence from the non-interventional, prospective, German multicentre PERSIST study of patients with psoriasis after 1 year of treatment with guselkumab - Gerdes, S.; Asadullah, K.; Hoffmann, M.; Korge, B.; Mortazawi, D.; Wegner, S.; Personke, Y.; Gomez, M.; Sticherling, Michael (Journal of the European Academy of Dermatology and Venereology, 2022)
Background: PERSIST was a prospective, non-interventional, long-term, German multicentre study of patients with moderate-to-severe psoriasis receiving guselkumab, an approved monoclonal antibody that binds to the p19 subunit of interleukin (IL)-23, in a real-world setting. Objectives: Evaluation of the efficacy and safety of guselkumab, and its effect on health-related quality of life (HRQoL), in patients with moderate-to-severe psoriasis who have received 52 weeks of treatment. Methods: Patients (≥18 years old) were prescribed guselkumab as per routine clinical practice. End points assessed include Psoriasis Area and Severity Index (PASI), Physician's Global Assessment (PGA), target Nail Psoriasis Severity Index (NAPSI), and the Dermatology Life Quality Index (DLQI). Results: Overall, 303 patients were enrolled and treated with guselkumab. Mean disease duration was 21.0 years, and 77.2% and 51.2% of patients had received ≥1 prior conventional systemic or ≥1 prior biologic therapy, respectively. Mean PASI score decreased from 16.4 at baseline to 3.0 by Week (W) 28, and further decreased to 2.4 by W52, while the proportion of patients achieving an absolute PASI score of ≤1 increased from 1.3% at baseline, to 50.8% at W28 and to 58.4% by W52. PASI90 and PASI100 responses also showed marked improvements between W28 and W52, regardless of biologic treatment history. Clearance of psoriatic skin was observed in difficult-to-treat areas, with the percentage of patients achieving a PGA score ≤1 increasing between W28 and W52. Guselkumab improved HRQoL; mean DLQI score decreased from 13.7 at baseline to 2.8 by W28, and further decreased to 2.4 by W52. At W52, 64.6% of patients achieved a DLQI score ≤1. The cumulative probability of drug survival was 92.4% at W52. Conclusions: Guselkumab is efficacious and well tolerated regardless of previous biologic therapies, comorbidities or psoriasis manifestation in difficult-to-treat areas. No new safety signals were observed.
CRIS-Team Scopus Importer:2022-06-03

Real world experience in low-dose ipilimumab in combination with PD-1 blockade in advanced melanoma patients - Kirchberger, Michael Constantin; Moreira, Alvaro; Erdmann, Michael; Schuler, Gerold; Heinzerling, Lucie (Oncotarget, 2018)
Dual immune-checkpoint blockade with the anti-PD-1 antibody nivolumab (1 mg/kg) and standard-dose ipilimumab (3 mg/kg) is the mainstay of immunotherapy in advanced melanoma and it is approved since 2016. However, severe side effects (grade 3/4) occur in up to 60% of the patients. Recently, clinical trials have shown similar anti-tumor activity with a more favorable toxicity profile in patients treated with low-dose ipilimumab (1 mg/kg) and standard-dose pembrolizumab (2 mg/kg). In this study we report on the real-world experience of this dosing regime in advanced melanoma patients not eligible for clinical trials. A total of 33 patients with metastatic melanoma (24 with cutaneous and 9 with uveal melanoma) were assessed, retrospectively. Brain metastases were present in 33% of the patients and lactate dehydrogenase was elevated in 70%. Overall response rates were 38% and 0% in cutaneous melanoma and uveal melanoma respectively. Median overall survival was not reached in cutaneous melanoma and was 18 months in uveal melanoma. In 18% of the patients at least one treatment-related severe adverse event was observed. Our observation that the combination of standard dose pembrolizumab and low-dose ipilimumab has a favorable toxicity profile yet anti-tumor activity comparable to the approved standard-dose combination regime in advanced patients not suitable for enrollment in clinical trials is encouraging.
EVALuna2:34415

Real-world management of patients with complete response under immune-checkpoint inhibition for advanced melanoma - Reitmajer, Markus; Livingstone, Elisabeth; Thoms, Kai Martin; Heppt, Markus; Meiss, Frank; Gesierich, Anja; Drexler, Konstantin; Heinzerling, Lucie; Meier, Friedegund; Menzer, Christian; Schlaak, Max; Zimmer, Lisa; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2025)
Background: Up to now, the optimal duration of immune checkpoint inhibitors (ICI) has not been evaluated in prospective studies. However, current clinical practice requires decisions to be made regarding the duration of ICI in complete responders. Material and Methods: A survey was sent to 80 DeCOG skin cancer centers to assess how decisions are made on treatment duration of ICI in melanoma after having reached complete response, and staging intervals after ICI discontinuation. All responses received by March 10, 2024 (51 centers) were included. Results: The duration of ICI after having achieved complete remission varies between centers from three to 36 months. In total, 66% of the DeCOG centers continue treatment for up to 6 months, after having achieved complete remission (CR) with ICI. In the first year after discontinuation of ICI, most centers perform staging intervals (CT/MRI) every 3 months. More than 60% of centers continue staging at least once per year even in the 4th and 5th year after discontinuation. Conclusions: There are significant differences between the centers regarding staging intervals and duration of ICI upon CR. Prospective studies are necessary to determine the optimal time point of ICI discontinuation and follow-up.
CRIS-Team Scopus Importer:2025-01-31
Keywords: Advanced Melanoma; follow-up; immune checkpoint inhibitor (ICI); pause; PET/CT; surveillance; treatment discontinuation

Real-world outcomes using PD-1 antibodies and BRAF plus MEK inhibitors for adjuvant melanoma treatment from 39 skin cancer centers in Germany, Austria and Switzerland - Schumann, Katharina; Mauch, Cornelia; Klespe, Kai-Christian; Loquai, Carmen; Nikfarjam, Ulrike; Schlaak, Max; Akcetin, Larissa; Koelblinger, Peter; Hoellwerth, Magdalena; Meissner, Markus; Mengi, Guelcin; Braun, Andreas Dominik; et al. (Journal of the European Academy of Dermatology and Venereology, 2022)
BackgroundProgrammed death-1 (PD-1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high-risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real-world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland. MethodsMulticenter, retrospective study investigating stage III-IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12-month recurrence-free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear-regression machine learning model to assess the risk of early melanoma recurrence. ResultsIn total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD-1 therapies (n = 1003). Twelve-month RFS for anti PD-1 and BRAF + MEK inhibitor-treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335-2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD-1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow-up of 17 months. Data indicates that anti PD-1 treated patients who develop immune-related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443-0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD-1 treatment (p > 0.05). In both, anti PD-1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12-month RFS and 12-month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials. ConclusionsDespite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk.
CRIS-Team WoS Importer:2023-01-20

Real-World Therapy with Pembrolizumab: Outcomes and Surrogate Endpoints for Predicting Survival in Advanced Melanoma Patients in Germany - Mohr, Peter; Scherrer, Emilie; Assaf, Chalid; Bender, Marc; Berking, Carola; Chandwani, Sheenu; Eigentler, Thomas; Grimmelmann, Imke; Gutzmer, Ralf; Haferkamp, Sebastian; Hassel, Jessica C.; Hauschild, Axel; et al. (Cancers, 2022)
Knowledge on the real-world characteristics and outcomes of pembrolizumab-treated advanced melanoma patients in Germany and on the value of different real-world endpoints as surrogates for overall survival (OS) is limited. A sample of 664 pembrolizumab-treated patients with advanced melanoma from the German registry ADOReg was used. We examined OS, real-world progression-free survival (rwPFS), real-world time to next treatment (rwTtNT), and real-world time on treatment (rwToT). Spearman’s rank and iterative multiple imputation (IMI)-based correlation coefficients were computed between the OS and the rwPFS, rwTtNT, and rwToT and reported for the first line of therapy and the overall sample. The median OS was 30.5 (95%CI 25.0–35.4) months, the rwPFS was 3.9 months (95%CI 3.5–4.9), the rwTtNT was 10.7 months (95%CI 9.0–12.9), and the rwToT was 6.2 months (95%CI 5.1–6.8). The rwTtNT showed the highest correlation with the OS based on the IMI (rIMI = 0.83), Spearman rank correlations (rs = 0.74), followed by the rwToT (rIMI = 0.74 and rs = 0.65) and rwPFS (rIMI = 0.69 and rs = 0.56). The estimates for the outcomes and correlations were similar for the overall sample and those in first-line therapy. The median OS was higher compared to recent real-world studies, supporting the effectiveness of pembrolizumab in regular clinical practice. The rwTtNT may be a valuable OS surrogate, considering the highest correlation was observed with the OS among the investigated real-world endpoints.
CRIS-Team Scopus Importer:2022-04-15
Keywords: advanced melanoma; overall survival (OS); pembrolizumab; real-world evidence; surrogate endpoint; time to next treatment (rwTtNT)

Recent developments in topical wound therapy: impact of antimicrobiological changes and rebalancing the wound milieu - Renner, Regina; Erfurt-Berge, Cornelia (BioMed Research International, 2014)
Wound therapy improves every year by developing new wound treatment options or by advancing already existing wound materials, for example, adding self-releasing analgesic drugs or growth factors to wound dressings, or by binding and inactivating excessive proteases. Also new dressing materials based on silk fibers and enhanced methods to reduce bacterial burden, for example, cold argon plasma, might help to fasten wound healing.
EVALuna2:19478

Re-challenge von BRAF/MEK Inhibitoren bei Langzeit-Überlebendem - Horbrügger, M.; Bender-Säbelkampf, Sophia; Tüting, Thomas; Alter, Mareike (Abstractband anlässlich des 29. Deutschen Hautkrebskongresses (ADO–Jahrestagung), 2019)
Das Vorhandensein einer BRAF Mutation bei ca. 40–50 % der kutanen Melanome bietet dem behandelnden Arzt und dem Patienten eine weitere Therapieoption mit oftmals überraschend gutem Ansprechen. Wir berichten über einen 62-jährigen Patienten, welcher sich seit 8 Jahren in unserer Behandlung befindet. Die Primärexzision eines nodulären Melanoms an der rechten Flanke und die negative Sentinellymphknotenbiopsie erfolgte im September 2011. Im Juni 2013 zeigte eine CT-gestützte Punktion Lymphknotenmetastasen iliakal rechts. Nach einer radikalen operativen Lymphknotendissektion und dem dennoch postoperativ lokalen Progress, leiteten wir im September 2013 die zielgerichtete Therapie mit Vemurafenib ein. Auf Grund von Unverträglichkeiten wurde die Therapie im Verlauf auf Dabrafenib und Trametinib umgestellt. Unter beiden zielgerichteten Therapien zeigte sich ein sehr gutes Ansprechen, so dass wir nach ca. 5 Jahren Vollremission in Absprache mit dem Patienten eine Therapiepause wagten. Im 3-monatigen Verlauf zeigten sich im Staging neue pulmonale, hepatische, peritoneale und kutane Metastasen. Nach Diskussion im Tumorboard und Abwägung der Therapieoptionen leiteten wir die erneute zielgerichtete Therapie mit Dabrafenib und Trametinib ein. Im kurzfristigen Verlauf kam es erneut zur Regredienz aller bekannten Metastasierungen. Wie bereits in großen multizentrischen retrospektiven Studien gezeigt werden konnte, zeigen 43 % der Patienten ein erneutes Ansprechen auf die zielgerichtete Therapie nach Pausieren (Valpione et al., 2018). Es konnte sogar gezeigt werden, dass Patienten trotz vorherigem Progress unter der zielgerichteten Therapie mit BRAFi auf eine Rechallenge ansprechen. Bekanntlich sprechen nicht alle Patienten vergleichbar gut auf die Therapie an. Der Patient zeigte initial eine niedrige Metastasenlast und eine normwertige LDH. Das Rechallenge bietet somit im klinischen Alltag eine weitere gute Option für den Patienten.<br

Recurrent shock and pulmonary edema due to acetazolamide medication after cataract surgery - Zimmermann, S.; Achenbach, Susanne; Wolf, M.; Janka, Rolf Matthias; Marwan, M.; Mahler, V. (Heart & Lung, 2014)
We report a patient with recurrent shock and transient non-cardiogenic pulmonary edema within a period of two months - every time occurring after cataract surgery and a single oral dose of standard post-operative medication with acetazolamide.Records of the intensive care unit, review of the literature.This case demonstrates a rare but severe side effect of acetazolamide. We also present a review of the literature to raise the awareness of health care providers for this special form of non-cardiogenic pulmonary edema.
EVALuna2:11868

Redirecting T cells to ewing's sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection - Lehner, Manfred; Goetz, Gabriel; Proff, Julia; Schaft, Niels; Dörrie, Jan; Full, Florian; Enßer, Armin; Muller, Yves; Cerwenka, Adelheid; Abken, Hinrich; Parolini, Ornella; Ambros, Peter F.; et al. (PLoS ONE, 2012)
We explored the possibility to target Ewing's sarcoma family of tumors (ESFT) by redirecting T cells. To this aim, we considered NKG2D-ligands (NKG2D-Ls) as possible target antigens. Detailed analysis of the expression of MICA, MICB, ULBP-1, -2, and -3 in fourteen ESFT cell lines revealed consistent expression of at least one NKG2D-L. Thus, for redirecting T cells, we fused a CD3ζ/CD28-derived signaling domain to the ectodomain of NKG2D, however, opposite transmembrane orientation of this signaling domain and NKG2D required inverse orientation fusion of either of them. We hypothesized that the particularly located C-terminus of the NKG2D ectodomain should allow reengineering of the membrane anchoring from a native N-terminal to an artificial C-terminal linkage. Indeed, the resulting chimeric NKG2D receptor (chNKG2D) was functional and efficiently mediated ESFT cell death triggered by activated T cells. Notably, ESFT cells with even low NKG2D-L expression were killed by CD8 pos and also CD4 pos cells. Both, mRNA transfection and lentiviral transduction resulted in high level surface expression of chNKG2D. However, upon target-cell recognition receptor surface levels were maintained by tranfected RNA only during the first couple of hours after transfection. Later, target-cell contact resulted in strong and irreversible receptor down-modulation, whereas lentivirally mediated expression of chNKG2D remained constant under these conditions. Together, our study defines NKG2D-Ls as targets for a CAR-mediated T cell based immunotherapy of ESFT. A comparison of two different methods of gene transfer reveals strong differences in the susceptibility to ligand-induced receptor down-modulation with possible implications for the applicability of RNA transfection. © 2012 Lehner et al.
CRIS-Team Scopus Importer:2021-10-01

Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. - Pfeifle, René; Rothe, Tobias; Ipseiz, Natacha; Scherer, Hans U.; Culemann, Stephan; Harre, Ulrike; Ackermann, Jochen; Seefried, Martina; Kleyer, Arnd; Uderhardt, Stefan; Haugg, Benjamin; Huebert, Axel J.; et al. (Nature Immunology, 2017)
The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the TH17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, TH17 cells regulated the expression of β-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-TH17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotoleranc

Reinvigoration of innate and adaptive immunity via therapeutic cellular vaccine for patients with AML - Fujii, Shin-Ichiro; Kawamata, Toyotaka; Shimizu, Kanako; Nakabayashi, Jun; Yamasaki, Satoru; Iyoda, Tomonori; Shinga, Jun; Nakazato, Hiroshi; Sanpei, An; Kawamura, Masami; Ueda, Shogo; Dörrie, Jan; et al. (Molecular Therapy: Oncolytics, 2022)
Strategies integrating activation of innate and adaptive immu-nity against cancer are desired. We established a novel plat-form, Wilms' tumor antigen 1 (WT1)-expressing artificial adjuvant vector cells (aAVC-WT1), linking invariant natural killer T (iNKT)-mediated dendritic cell activation to T cell im-munity. Here, we report the first-in-human application of aAVC-WT1 in nine patients with relapsed and refractory acute myelogenous leukemia. No dose-limiting toxicities were observed, whereas activation of iNKT and/or NK cells was observed in all patients. Five patients experienced objective leukemic regression, which correlated with WT1-specific T cell responses. Paired single-cell RNA and T cell receptor (TCR) sequencing demonstrated effector CD8+ T cell clones in the bone marrow. Some bone marrow CD8+ T cells under-went transition from pre-existing precursor exhausted T cells to functional T cells or emerged as newly activated T cells, some of which were maintained long term. These demonstrate the feasibility and safety of aAVC-WT1 therapy and the capac-ity of this platform to activate both innate and adaptive immu-nity in humans.
CRIS-Team WoS Importer:2023-01-27

Reply: Intra-patient heterogeneity of BRAF mutation status: fact or fiction? - Heinzerling, Lucie; Schuler, Gerold; Hartmann, Arndt; Schneider-Stock, Regine (British Journal of Cancer, 2014)
EVALuna2:6657

Reporting Quality of Studies Developing and Validating Melanoma Prediction Models: An Assessment Based on the TRIPOD Statement - Kaiser, Isabelle; Diehl, Katharina; Heppt, Markus; Mathes, Sonja; Pfahlberg, Annette Bettina; Steeb, Theresa; Uter, Wolfgang; Gefeller, Olaf (Healthcare, 2022)
Transparent and accurate reporting is essential to evaluate the validity and applicability of risk prediction models. Our aim was to evaluate the reporting quality of studies developing and validating risk prediction models for melanoma according to the TRIPOD (Transparent Reporting of a multivariate prediction model for Individual Prognosis Or Diagnosis) checklist. We included studies that were identified by a recent systematic review and updated the literature search to ensure that our TRIPOD rating included all relevant studies. Six reviewers assessed compliance with all 37 TRIPOD components for each study using the published “TRIPOD Adherence Assessment Form”. We further examined a potential temporal effect of the reporting quality. Altogether 42 studies were assessed including 35 studies reporting the development of a prediction model and seven studies reporting both development and validation. The median adherence to TRIPOD was 57% (range 29% to 78%). Study components that were least likely to be fully reported were related to model specification, title and abstract. Although the reporting quality has slightly increased over the past 35 years, there is still much room for improvement. Adherence to reporting guidelines such as TRIPOD in the publication of study results must be adopted as a matter of course to achieve a sufficient level of reporting quality necessary to foster the use of the prediction models in applications.
CRIS-Team Scopus Importer:2022-02-04
Keywords: Melanoma; Prediction models; reporting quality; TRIPOD

Reproducibility of mRNA-Based Testing of ESR1, PGR, ERBB2, and MKI67 Expression in Invasive Breast Cancer-A Europe-Wide External Quality Assessment - Erber, Ramona; Hartmann, Arndt; Fasching, Peter; Rübner, Matthias; Stöhr, Robert; Beckmann, Matthias; Zentgraf, Miriam; Popp, Verena; Weidler, Jodi; Simon, Iris; Becker, Steffi; Hübner, Hanna; et al. (Cancers, 2021)
Simple Summary Four biomarkers [estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2], are used to stratify breast cancer (BC) into subtypes predictive of therapy response. In a Europe-wide external quality assessment, we compared performance of an mRNA-based method [Xpert(R) Breast Cancer STRAT4 (CE-IVD)] for determining ESR1, PGR, ERBB2, and MKI67 expression against the gold standard [immunohistochemistry (IHC)/HER2 in situ hybridization (ISH)]. The coordinating center (CC) and five European laboratories tested ten breast cancer samples. STRAT4 binary (positive or negative) results of each marker were compared with the gold standard. ESR1 and ERBB2 mRNA results were concordant with IHC/ISH in all single analyses. In contrast, PGR and MKI67 results were discordant in a few cases, which had STRAT4 expression values close to assay cut-offs and immunohistochemically presented heterogeneous low positive PgR and heterogeneous Ki-67. STRAT4 assay may be a reproducible method. However, cases with expression values close to cut-offs should be carefully reviewed. Estrogen receptor (ER), progesterone receptor (PgR), Ki-67, and HER2 immunohistochemistry (IHC) together with HER2 in situ hybridization (ISH) are utilized to classify invasive breast cancer (IBC) into predictive molecular subtypes. As IHC evaluation may be hampered by analytical errors, gene expression assays could offer a reliable alternative. In this first Europe-wide external quality assessment (EQA) study, we investigated performance of mRNA-based Xpert(R) Breast Cancer STRAT4 (CE-IVD) in five European laboratories. The cohort comprised ten pre-therapy IBC core biopsies diagnosed in the coordinating center (CC). STRAT4 binary (positive or negative) mRNA results of each marker (ESR1, PGR, ERBB2, MKI67) were compared with the gold standard IHC/ISH performed by the CC. Sensitivity, specificity, and accuracy of ESR1 and ERBB2 mRNA were 100% for all samples. In contrast, PGR expression was falsely negative for one case by two sites and MKI67 falsely negative for two cases (respectively by four and one sites). These cases had STRAT4 expression values close to assay cut-offs and immunohistochemically presented heterogeneous low positive PgR and heterogeneous Ki-67. Our EQA shows that STRAT4 mRNA assay may be a reproducible method to evaluate ER, PgR, HER2, and Ki-67 status. However, cases with expression values close to assay cut-offs should be carefully reviewed.
CRIS-Team WoS Importer:2021-10-08

Residual homing of alpha 4 beta 7-expressing beta 1(+)PI16(+) regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab - Becker, Emily; Dedden, Mark; Gall, Christine; Wiendl, Maximilian; Ekici, Arif Bülent; Schulz-Kuhnt, Anja; Schweda, Anna; Bosch-Voskens, Caroline; Hegazy, Ahmed; Vitali, Francesco; Atreya, Raja; Müller, Tanja; et al. (Gut, 2021)
Objective The anti-alpha 4 beta 7 integrin antibody vedolizumab is administered at a fixed dose for the treatment of IBDs. This leads to a wide range of serum concentrations in patients and previous studies had suggested that highest exposure levels are associated with suboptimal clinical response. We aimed to determine the mechanisms underlying these non-linear exposure-efficacy characteristics of vedolizumab. Design We characterised over 500 samples from more than 300 subjects. We studied the binding of vedolizumab to T cells and investigated the functional consequences for dynamic adhesion, transmigration, gut homing and free binding sites in vivo. Employing single-cell RNA sequencing, we characterised alpha 4 beta 7 integrin-expressing T cell populations 'resistant' to vedolizumab and validated our findings in vitro and in samples from vedolizumab-treated patients with IBD. We also correlated our findings with a post-hoc analysis of the Gemini II and III studies. Results Regulatory T (T-Reg) cells exhibited a right-shifted vedolizumab binding profile compared with effector T (T-Eff) cells. Consistently, in a certain concentration range, the residual adhesion, transmigration, homing of and availability of functional alpha 4 beta 7 on T-Reg cells in vivo was higher than that of/on T-Eff cells. We identified a vedolizumab-'resistant' alpha 4 beta 7-expressing beta 1(+)PI16(+) T-Reg cell subset with pronounced regulatory properties as the substrate for this effect. Our observations correlated with exposure-efficacy data from Gemini II and III trials. Conclusion Completely blocking T-Eff cell trafficking with vedolizumab, while simultaneously permitting residual homing of powerful T-Reg cells in an optimal 'therapeutic window' based on target exposure levels might be a strategy to optimise treatment outcomes in patients with IBD.
CRIS-Team WoS Importer:2021-12-10

Resolution of synovitis and arrest of catabolic and anabolic bone changes in patients with psoriatic arthritis by IL-17A blockade with secukinumab: results from the prospective PSARTROS study - Kampylafka, Eleni; D'Oliveira, Isabelle; Linz, Christina; Lerchen, Veronika; Stemmler, Fabian; Simon, David; Englbrecht, Matthias; Sticherling, Michael; Rech, Juergen; Kleyer, Arnd; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2018)
BACKGROUND: Although the effects of interleukin-17A (IL-17A) inhibition on the signs and symptoms of psoriatic arthritis (PsA) are well defined, little is known about its impact of local inflammatory and structural changes in the joints. The PSARTROS study was designed to elucidate the effects of IL-17A inhibition on inflammation and bone changes in joints affected by PsA. METHODS: This was a prospective open-label study in 20 patients with active PsA receiving 24 weeks of treatment with the IL-17A inhibitor secukinumab. Magnetic resonance imaging (MRI), power Doppler ultrasound (PDUS), and high-resolution peripheral quantitative computer tomography (HR-pQCT) of the hands were performed at baseline and after 24 weeks to assess synovitis, periarticular inflammation, bone erosion, enthesiophyte formation, and bone structure. Demographic and clinical measures of joint disease (DAPSA and DAS28-ESR), skin disease (PASI and BSA), and composite measures (minimal disease activity, or MDA) were also recorded. RESULTS: Treatment with secukinumab led to significant improvement of signs and symptoms of PsA; 46% reached MDA and 52% DAPSA low disease activity. MRI synovitis (P = 0.034) and signal in PDUS (P = 0.030) significantly decreased after 24 weeks of treatment. Bone erosions in MRI and HR-pQCT and enthesiophytes in the HR-pQCT did not show any progression, and structural integrity and functional bone strength remained stable. CONCLUSIONS: IL-17 inhibition by secukinumab over 24 weeks led to a significant decrease of synovial inflammation and no progression of catabolic and anabolic bone changes in the joints of patients with PsA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02483234 , June 26, 2015; retrospectively registered.
EVALuna2:34447

Response to First-Line Treatment with Immune-Checkpoint Inhibitors in Patients with Advanced Cutaneous Squamous Cell Carcinoma: A Multicenter, Retrospective Analysis from the German ADOReg Registry - Haist, Maximilian; Stege, Henner; Lang, Berenice Mareen; Tsochataridou, Aikaterini; Salzmann, Martin; Mohr, Peter; Schadendorf, Dirk; Ugurel, Selma; Placke, Jan Malte; Weichenthal, Michael; Gutzmer, Ralf; Leiter, Ulrike; et al. (Cancers, 2022)
Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates.
CRIS-Team Scopus Importer:2022-12-02
Keywords: advanced cutaneous squamous cell carcinoma; cemiplimab; checkpoint inhibitor therapy; immunosuppression; real-world data; response durability

Response to letter entitled: ‘Re: Hematological immune related adverse events after treatment with immune checkpoint inhibitors’ - Heinzerling, Lucie; La Rosée, Paul; Gutzmer, Ralf; Kramer, Rafaela; Keller-Stanislawski, Brigitte; Zierold, Sarah; Mentzer, Dirk (European Journal of Cancer, 2021)
CRIS-Team Scopus Importer:2021-07-30

Results of isolated limb perfusion for metastasized malignant melanoma - Schellerer, Vera; Frenger, Johannes; Merkel, Susanne; Göhl, Jonas; Kersting, Stephan; Grützmann, Robert; Erdmann, Michael; Förtsch, Thomas (Surgical Oncology-Oxford, 2021)
Background and objectives: Locoregional metastases are typical biological manifestations of advanced malignant melanomas. Treatment with hyperthermic isolated limb perfusion (HILP) should be considered in affected patients. In the present study, we have analyzed the results of HILPs performed in our department. Patients and methods: Eighty patients with locoregional metastases of the extremities received HILP at the Department of Surgery between January 2007 and December 2016. The mean follow-up was 38 months. Results: The study included 50 men and 30 women (mean age: 63 years). The median time between melanoma diagnosis and HILP was 25 months (range: 1–219 months). HILP was performed in curative (n = 45) and palliative (n = 35) intention. Seventy-five patients received a drug combination of melphalan/dactinomycin and five patients received a drug combination of melphalan/tumor necrosis factor-alpha. Remission rates were determined in 72 of 80 patients (90%) as follows: partial response n = 28, complete response n = 25, no response n = 19. Of the 25 patients with complete response, 13 patients developed a new tumor manifestation during follow-up (locoregional recurrences n = 4; distant metastases n = 3; both n = 6). The median overall survival rate was 33 months. Tumor stage influenced the survival rate significantly (p = 0.001). Patients with complete response showed a significantly better overall survival than patients with partial or no response (p = 0.016). Conclusion: HILP is an effective therapeutic option in patients with locoregional metastases. This procedure carries a certain risk of side effects and adverse events but overall results in good response rates. Therefore, HILP should be offered to selected patients based on an individual discussion, considering their health status and oncological prognosis.
CRIS-Team Scopus Importer:2021-05-21
Keywords: Hyperthermic isolated limb perfusion; In-transit metastases; Malignant melanoma; Recurrence; Survival

Retrospective analysis of autoimmune bullous diseases in Middle Franconia - Sollfrank, Lukas; Schönfelder, Valerie; Sticherling, Michael (Frontiers in Immunology, 2023)
Introduction: Autoimmune bullous diseases (AIBDs) are a group of rare cutaneous disorders affecting cornified skin and mucous membranes. They are characterized by tense or flaccid blistering and erosions due to autoantibodies against desmosomal and hemidesmosomal structural proteins of the skin. This group of disorders can be divided into those of pemphigoid and those of pemphigus diseases. If left untreated, these autoimmune diseases can cause serious or even life-threatening complications such as loss of fluid, superinfections or impaired food intake. Due to modern standardized serological assays, the diagnosis of AIBDs can usually be confirmed in combination with their clinical appearance. Whereas for a long time corticosteroids were the major players in the treatment of these diseases, with the approval of rituximab and other immunosuppressive agents, the therapy has increasingly improved. Methods: In this study, we aimed to investigate epidemiologic and clinical features as well as diagnostics and therapy of bullous autoimmune diseases in Middle Franconia, a governorate within the German federal state of Bavaria. Patients diagnosed or treated because of a AIBDs between 01.04.2013 and 31.03.2019 at the dermatological department of the university hospital Erlangen were included in this retrospective study (n = 242). Patients were either diagnosed for the first time (n=176) or the diagnosis has been confirmed (n=66) at the department. The respective incidence was calculated among the 176 subjects who had been diagnosed at the center in this period. Data was taken from patient records and analyzed with Microsoft® Excel. The evaluation included the diagnoses of pemphigus vulgaris (PV), pemphigus foliaceus (PF), bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), linear IgA dermatosis (LAD), epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (DH). Results: This study shows that the incidence of each AIBDs in Middle Franconia is low and comparable (PV, PF, LAD, EBA) or lower (BP, MMP, DH) than in other studies and regions. BP is the most common newly diagnosed AIBD in Middle Franconia. Discussion: Due to the chronic and sometimes severe course of AIBDs, repeated in-house treatments are often necessary. To date, mainly topically and systemically applied corticosteroids in combination with immunomodulators are used as first-line therapy.
CRIS-Team Scopus Importer:2023-11-03
Keywords: autoimmune bullous dermatoses; bullous dermatoses; bullous pemphigod; epidemiology; pemphigoid diseases; pemphigus diseases

Retrospective interactive rigid fusion of 18F-FDG-PET and CT: Additional diagnostic information in melanoma patients - Römer, Wolfgang; Nömayr, Anton; Greess, Holger; Fiedler, Ekkehard; Platsch, Günter; Schuler-Thurner, Beatrice; Pfahlberg, Annette; Hothorn, Torsten; Schuler, Gerold; Hornegger, Joachim; Bautz, Werner; Kuwert, Torsten (Nuklearmedizin-Nuclear Medicine, 2006)
Aim: This study investigates whether interactive rigid fusion of routine PET and CT data improves localization, detection and characterization of lesions compared to separate reading. For this purpose, routine PET and CT scans of patients with metastases from malignant melanoma were used. Patients, methods: In 34 patients with histologically confirmed malignant melanoma, FDG-PET and spiral CT were performed using clinical standard protocols. For all of these patients, gold standard was available. Clinical and radiological follow-up identified 82 lesions as definitely pathological. Two board-certified nuclear medicine physicians and two board-certified radiologists analyzed PET and CT images independently from each other. For each patient up to 32 anatomical regions (24 lymph node regions, 8 extranodular regions) were systematically classified. Discordant areas were interactively analyzed in manually and rigidly registered images using a commercially available fusion tool. No side-by-side reading was performed. Results: Image fusion disclosed that the evaluation of the PET images alone led to a mislocalization in 26 of 91 focally FDG enhancing lesions. The overall sensitivities of PET, CT, and image fusion were 85, 88, and 94%, respectively; the overall specificities of PET, CT and image fusion were 98, 95 and 100%, respectively. Image fusion exhibited statistically significant higher specificity values as compared with CT. Ten definitely malignant sites were false-negative in CT, but could be detected by PET. On the other hand, twelve metastases were false-negative in PET, but could be detected by CT. These included two lesions, which had a clear correlate on the PET image when the fused images were evaluated. On the whole, registration of the PET and CT images yielded additional diagnostic information in 44% of the definitely malignant lesions. Conclusion: Retrospective image fusion of independently obtained PET and CT data is particularly valuable in exactly lodizing foci of abnormal FDG uptake and improves the detection of metastases of malignant melanoma. © 2006 Schattauer GmbH.

Rhinophyma-Like Cutaneous Leishmaniasis due to Leishmania aethiopica Treated Successfully with Liposomal Amphotericin B - Kirchberger, Michael Constantin; Schliep, Stefan; Bogdan, Christian (American Journal of Tropical Medicine and Hygiene, 2019)
CRIS-Team WoS Importer:2019-03-20

Risk Factors for Regional and Systemic Metastases in Patients with Sentinel Lymph Node-negative Melanoma - Erdmann, Michael; Sigler, Dominic; Uslu, Ugur; Göhl, Jonas; Grützmann, Robert; Schuler, Gerold; Schellerer, Vera (Anticancer Research, 2018)
BACKGROUND: Sentinel lymph node status is a strong prognostic factor in melanoma. However, up to 21% of sentinel lymph node-negative patients develop locoregional and distant metastases during follow-up. AIM: To analyze risk factors for locoregional and distant metastasis in patients with sentinel lymph node-negative melanoma. PATIENTS AND METHODS: A total of 545 patients underwent sentinel lymph node biopsy (SNB) between 2005 and 2013 at our hospital. Data for 449 patients with a negative SNB were analyzed regarding risk factors and development of metastases. Follow-up was performed until 2016. RESULTS: A total of 72 SNB-negative patients developed metastases, including 25 (34.7%) distant and 47 (63.3%) locoregional metastases. Locoregional metastases occurred earlier compared to distant metastases (with a mean of 24.2 and 23.5 months for regional lymph node and cutaneous metastases, respectively, vs. 31.4 months for distant metastases). Patients with metastases despite negative SNB had a greater tumor thickness (p=0.001), a higher rate of nodular melanoma (p=0.001), ulceration (p<0.001), and were older (p=0.05) compared to SNB-negative patients without subsequent metastases. Out of SNB-negative patients, 16% developed metastases. CONCLUSION: Close clinical follow-up including sonography of the draining lymph node region is mandatory for melanoma patients regardless of SNB status.
EVALuna2:203619

Risk Factors for Relapse after Intentional Discontinuation of Immune Checkpoint Inhibitors in Melanoma Patients - Persa, Oana D.; Schatton, Kerstin; Rübben, Albert; Berking, Carola; Erdmann, Michael; Schlaak, Max; Mauch, Cornelia; Steeb, Theresa (Journal of Immunotherapy, 2021)
Immune checkpoint inhibitors (ICIs) have tremendously changed the therapeutic landscape of melanoma since they are associated with a durable response, allowing for intentional discontinuation of therapy after complete or partial remission. However, a subset of patients develops a relapse after cessation of ICI treatment and may not respond to reinduction of ICIs. The aim of the present study was to identify risk factors for relapse after intentional discontinuation of ICI therapy. Patients with intentional discontinuation of ICI therapy for metastatic or unresectable melanoma from 5 German university hospitals were analyzed retrospectively. Clinicopathologic and follow-up data of 87 patients were collected and analyzed by univariate and multivariate Cox proportional-hazards models. The following parameters were associated with relapse after cessation of ICI treatment in the univariate Cox regression analysis: concurrent radiotherapy and ICI, best overall response, and presence of brain metastases. Duration of treatment, type of primary tumor, body mass index, programmed-death ligand 1 expression, and lactate dehydrogenase levels did not significantly influence the risk for relapse. In the multivariate analysis, partial remission [hazard ratio 4.217 (95% confidence interval: 1.424-12.49), P=0.009] and stable disease [3.327 (1.204-9.19), P=0.02] were associated with a significant decrease in progression-free survival compared with complete remission. Concurrent radiotherapy and ICI [3.619 (1.288-10.168), P=0.015] are additional independent risk factors for decreased progression-free survival upon ICI discontinuation, whereas the presence of brain metastasis did not reach statistical significance on multivariate analysis.
CRIS-Team Scopus Importer:2021-06-25
Keywords: checkpoint inhibitor therapy; melanoma; nivolumab; pembrolizumab; radiotherapy

Risk factors for systemic reactions in typical cold urticaria: Results from the COLD-CE study - Bizjak, Mojca; Kosnik, Mitja; Dinevski, Dejan; Thomsen, Simon Francis; Fomina, Daria; Borzova, Elena; Kulthanan, Kanokvalai; Meshkova, Raisa; Ahsan, Dalia Melina; Al-Ahmad, Mona; Altrichter, Sabine; Bauer, Andrea; et al. (Allergy, 2021)
Background Cold urticaria (ColdU), that is, the occurrence of wheals or angioedema in response to cold exposure, is classified into typical and atypical forms. The diagnosis of typical ColdU relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). We aimed to determine risk factors for ColdA in typical ColdU. Methods An international, cross-sectional study COLD-CE was carried out at 32 urticaria centers of reference and excellence (UCAREs). Detailed history was taken and CST with an ice cube and/or TempTest(R) performed. ColdA was defined as an acute cold-induced involvement of the skin and/or visible mucosal tissue and at least one of: cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms. Results Of 551 ColdU patients, 75% (n = 412) had a positive CST and ColdA occurred in 37% (n = 151) of the latter. Cold-induced generalized wheals, angioedema, acral swelling, oropharyngeal/laryngeal symptoms, and itch of earlobes were identified as signs/symptoms of severe disease. ColdA was most commonly provoked by complete cold water immersion and ColdA caused by cold air was more common in countries with a warmer climate. Ten percent (n = 40) of typical ColdU patients had a concomitant chronic spontaneous urticaria (CSU). They had a lower frequency of ColdA than those without CSU (4% vs. 39%, p = .003). We identified the following risk factors for cardiovascular manifestations: previous systemic reaction to a Hymenoptera sting, angioedema, oropharyngeal/laryngeal symptoms, and itchy earlobes. Conclusion ColdA is common in typical ColdU. High-risk patients require education about their condition and how to use an adrenaline autoinjector.
CRIS-Team WoS Importer:2021-12-31

Risk prediction models for melanoma: A systematic review on the heterogeneity in model development and validation - Kaiser, Isabelle; Pfahlberg, Annette Bettina; Uter, Wolfgang; Heppt, Markus; Veierød, Marit B.; Gefeller, Olaf (International Journal of Environmental Research and Public Health, 2020)
The rising incidence of cutaneous melanoma over the past few decades has prompted substantial efforts to develop risk prediction models identifying people at high risk of developing melanoma to facilitate targeted screening programs. We review these models, regarding study characteristics, differences in risk factor selection and assessment, evaluation, and validation methods. Our systematic literature search revealed 40 studies comprising 46 different risk prediction models eligible for the review. Altogether, 35 different risk factors were part of the models with nevi being the most common one (n = 35, 78%); little consistency in other risk factors was observed. Results of an internal validation were reported for less than half of the studies (n = 18, 45%), and only 6 performed external validation. In terms of model performance, 29 studies assessed the discriminative ability of their models; other performance measures, e.g., regarding calibration or clinical usefulness, were rarely reported. Due to the substantial heterogeneity in risk factor selection and assessment as well as methodologic aspects of model development, direct comparisons between models are hardly possible. Uniform methodologic standards for the development and validation of risk prediction models for melanoma and reporting standards for the accompanying publications are necessary and need to be obligatory for that reason.
CRIS-Team Scopus Importer:2020-11-06
Keywords: Melanoma; Risk prediction; Statistical models; Validation

RNA sequencing of collecting duct renal cell carcinoma suggests an interaction between miRNA and target genes and a predominance of deregulated solute carrier genes - Wach, Sven; Taubert, Helge; Weigelt, Katrin; Hase, Nora; Köhn, Marcel; Misiak, Danny; Hüttelmaier, Stefan; Stöhr, Christine G.; Kahlmeyer, Andreas; Haller, Florian; Vera, Julio; Hartmann, Arndt; et al. (Cancers, 2020)
Collecting duct carcinoma (CDC) is a rare renal cell carcinoma subtype with a very poor prognosis. There have been only a few studies on gene expression analysis in CDCs. We compared the gene expression profiles of two CDC cases with those of eight normal tissues of renal cell carcinoma patients. At a threshold of |log2fold-change| ≥ 1, 3349 genes were upregulated and 1947 genes were downregulated in CDCs compared to the normal samples. Pathway analysis of the deregulated genes revealed that cancer pathways and cell cycle pathways were most prominent in CDCs. The most upregulated gene was keratin 17, and the most downregulated gene was cubilin. Among the most downregulated genes were four solute carrier genes (SLC3A1, SLC9A3, SLC26A7, and SLC47A1). The strongest negative correlations between miRNAs and mRNAs were found between the downregulated miR-374b-5p and its upregulated target genes HIST1H3B, HK2, and SLC7A11 and between upregulated miR-26b-5p and its downregulated target genes PPARGC1A, ALDH6A1, and MARC2. An upregulation of HK2 and a downregulation of PPARGC1A, ALDH6A1, and MARC2 were observed at the protein level. Survival analysis of the cancer genome atlas (TCGA) dataset showed for the first time that low gene expression of MARC2, cubilin, and SLC47A1 and high gene expression of KRT17 are associated with poor overall survival in clear cell renal cell carcinoma patients. Altogether, we identified dysregulated protein-coding genes, potential miRNA-target interactions, and prognostic markers that could be associated with CDC.
CRIS-Team Scopus Importer:2020-01-10
Keywords: Collecting duct carcinoma; RNA sequencing; Solute carrier proteins

RNA-transfection of gamma/delta T cells with a chimeric antigen receptor or an alpha/ss T-cell receptor: a safer alternative to genetically engineered alpha/ss T cells for the immunotherapy of melanoma - Harrer, D.; Simon, B.; Fujii, S. I.; Kanako, S.; Uslu, Ugur; Schuler, Gerold; Gerer, K. F.; Hoyer, S.; Dörrie, Jan; Schaft, Niels (2017)
EVALuna2:34308

RNA-transfection of γ/δ T cells with a chimeric antigen receptor or an α/β T-cell receptor: a safer alternative to genetically engineered α/β T cells for the immunotherapy of melanoma - Harrer, Dennis C.; Simon, Bianca; Fujii, Shin-Ichiro; Shimizu, Kanako; Uslu, Ugur; Schuler, Gerold; Gerer, Kerstin F.; Hoyer, Stefanie; Dörrie, Jan; Schaft, Niels (BMC Cancer, 2017)
BACKGROUND: Adoptive T-cell therapy relying on conventional T cells transduced with T-cell receptors (TCRs) or chimeric antigen receptors (CARs) has caused substantial tumor regression in several clinical trials. However, genetically engineered T cells have been associated with serious side-effects due to off-target toxicities and massive cytokine release. To obviate these concerns, we established a protocol adaptable to GMP to expand and transiently transfect γ/δ T cells with mRNA. METHODS: PBMC from healthy donors were stimulated using zoledronic-acid or OKT3 to expand γ/δ T cells and bulk T cells, respectively. Additionally, CD8+ T cells and γ/δ T cells were MACS-isolated from PBMC and expanded with OKT3. Next, these four populations were electroporated with RNA encoding a gp100/HLA-A2-specific TCR or a CAR specific for MCSP. Thereafter, receptor expression, antigen-specific cytokine secretion, specific cytotoxicity, and killing of the endogenous γ/δ T cell-target Daudi were analyzed. RESULTS: Using zoledronic-acid in average 6 million of γ/δ T cells with a purity of 85% were generated from one million PBMC. MACS-isolation and OKT3-mediated expansion of γ/δ T cells yielded approximately ten times less cells. OKT3-expanded and CD8+ MACS-isolated conventional T cells behaved correspondingly similar. All employed T cells were efficiently transfected with the TCR or the CAR. Upon respective stimulation, γ/δ T cells produced IFNγ and TNF, but little IL-2 and the zoledronic-acid expanded T cells exceeded MACS-γ/δ T cells in antigen-specific cytokine secretion. While the cytokine production of γ/δ T cells was in general lower than that of conventional T cells, specific cytotoxicity against melanoma cell lines was similar. In contrast to OKT3-expanded and MACS-CD8+ T cells, mock-electroporated γ/δ T cells also lysed tumor cells reflecting the γ/δ T cell-intrinsic anti-tumor activity. After transfection, γ/δ T cells were still able to kill MHC-deficient Daudi cells. CONCLUSION: We present a protocol adaptable to GMP for the expansion of γ/δ T cells and their subsequent RNA-transfection with tumor-specific TCRs or CARs. Given the transient receptor expression, the reduced cytokine release, and the equivalent cytotoxicity, these γ/δ T cells may represent a safer complementation to genetically engineered conventional T cells in the immunotherapy of melanoma (Exper Dermatol 26: 157, 2017, J Investig Dermatol 136: A173, 2016).
EVALuna2:34316

Robustness of convolutional neural networks in recognition of pigmented skin lesions - Maron, Roman C.; Haggenmüller, Sarah; von Kalle, Christof; Utikal, Jochen S.; Meier, Friedegund; Gellrich, Frank F.; Hauschild, Axel; French, Lars E.; Schlaak, Max; Ghoreschi, Kamran; Kutzner, Heinz; Heppt, Markus; et al. (European Journal of Cancer, 2021)
Background: A basic requirement for artificial intelligence (AI)–based image analysis systems, which are to be integrated into clinical practice, is a high robustness. Minor changes in how those images are acquired, for example, during routine skin cancer screening, should not change the diagnosis of such assistance systems. Objective: To quantify to what extent minor image perturbations affect the convolutional neural network (CNN)–mediated skin lesion classification and to evaluate three possible solutions for this problem (additional data augmentation, test-time augmentation, anti-aliasing). Methods: We trained three commonly used CNN architectures to differentiate between dermoscopic melanoma and nevus images. Subsequently, their performance and susceptibility to minor changes (‘brittleness’) was tested on two distinct test sets with multiple images per lesion. For the first set, image changes, such as rotations or zooms, were generated artificially. The second set contained natural changes that stemmed from multiple photographs taken of the same lesions. Results: All architectures exhibited brittleness on the artificial and natural test set. The three reviewed methods were able to decrease brittleness to varying degrees while still maintaining performance. The observed improvement was greater for the artificial than for the natural test set, where enhancements were minor. Conclusions: Minor image changes, relatively inconspicuous for humans, can have an effect on the robustness of CNNs differentiating skin lesions. By the methods tested here, this effect can be reduced, but not fully eliminated. Thus, further research to sustain the performance of AI classifiers is needed to facilitate the translation of such systems into the clinic.
CRIS-Team Scopus Importer:2021-01-22
Keywords: Artificial intelligence; Deep learning; Dermatology; Machine learning; Melanoma; Neural networks; Nevus; Skin neoplasms

Role of L-Particles during Herpes Simplex Virus Infection - Heilingloh, Christiane; Krawczyk, Adalbert (Frontiers in Microbiology, 2017)
Infection of eukaryotic cells with α-herpesviruses results in the formation and secretion of infectious heavy particles (virions; H-particles) and non-infectious light particles (L-particles). Herpes simplex virus type 1 (HSV-1) H-particles consist of a genome-containing capsid surrounded by tegument proteins and a glycoprotein-rich lipid bilayer. Non-infectious L-particles are composed mainly of envelope and tegument proteins and are devoid of capsids and viral DNA. L-particles were first described in the early nineties and from then on investigated for their formation and role during virus infection. The development and secretion of L-particles occur simultaneously to the assembly of complete viral particles. HSV-1 L-particles are assembled by budding of condensed tegument into Golgi-delivered vesicles and are capable of delivering their functional content to non-infected cells. Thereby, HSV-1 L-particles contribute to viral pathogenesis within the infected host by enhancing virion infectivity and providing immune evasion functions. In this review we discuss the emergence of HSV-1 L-particles during virus replication and their biological functions described thus far.
EVALuna2:35398

Role of Nuclear Factor (Erythroid-Derived 2)-Like 2 Signaling for Effects of Fumaric Acid Esters on Dendritic Cells - Hammer, Anna; Waschbisch, Anne; Knippertz, Ilka; Zinser, Elisabeth; Berg, Johannes; Joerg, Stefanie; Kuhbandner, Kristina; David, Christina; Pi, Jingbo; Bayas, Antonios; Lee, De-Hyung; Haghikia, Aiden; et al. (Frontiers in Immunology, 2017)
To date, the intracellular signaling pathways involved in dendritic cell (DC) function are poorly understood. The antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been shown to affect maturation, function, and subsequent DC-mediated T cell responses of murine and human DCs. In experimental autoimmune encephalomyelitis (EAE), as prototype animal model for a T helper cell-mediated autoimmune disease, antigen presentation, cytokine production, and costimulation by DCs play a major role. We explore the role of Nrf2 in DC function, and DC-mediated T cell responses during T cell-mediated autoimmunity of the central nervous system using genetic ablation and pharmacological activation in mice and men to corroborate our data in a translational setting. In murine and human DCs, monomethyl fumarate induced Nrf2 signaling inhibits DC maturation and DC-mediated T cell proliferation by reducing inflammatory cytokine production and expression of costimulatory molecules. In contrast, Nrf2-deficient DCs generate more activated T helper cells (Th1/Th17) but fewer regulatory T cells and foster T cell proliferation. Transfer of DCs with Nrf2 activation during active EAE reduces disease severity and T cell infiltration. Our data demonstrate that Nrf2 signaling modulates autoimmunity in murine and human systems via inhibiting DC maturation and function thus shedding further light on the mechanism of action of antioxidative stress pathways in antigen-presenting cells.
EVALuna2:22557

Rough hypercuboid based supervised clustering of miRNAs - Paul, Sushmita; Vera González, Julio (Molecular Biosystems, 2015)
The microRNAs are small, endogenous non-coding RNAs found in plants, animals, and some viruses, which function in RNA silencing and post-transcriptional regulation of gene expression. It is suggested by various genome-wide studies that a substantial fraction of miRNA genes is likely to form clusters. The coherent expression of the miRNA clusters can then be used to classify samples according to the clinical outcome. In this regard, a new clustering algorithm, termed as rough hypercuboid based supervised attribute clustering (RH-SAC), is proposed to find such groups of miRNAs. The proposed algorithm is based on the theory of rough set, which directly incorporates the information of sample categories into the miRNA clustering process, generating a supervised clustering algorithm for miRNAs. The effectiveness of the new approach is demonstrated on several publicly available miRNA expression data sets using support vector machine. The so-called B.632+ bootstrap error estimate is used to minimize the variability and biasedness of the derived results. The association of the miRNA clusters to various biological pathways is also shown by doing pathway enrichment analysis.
EVALuna2:19519

S100A8 BUT NOT S100A9 LEVEL IS RELATED TO THE EXTENT OF EROSIVE BONE DAMAGE IN PSORIATIC ARTHRITIS PATIENTS - Simon, David; Nas, K.; Faustini, F.; Kleyer, Arnd; Haschka, J.; Englbrecht, Matthias; Hueber, Axel; Kocijan, R.; Sticherling, Michael; Schett, Georg; Rech, Jürgen (2016)
EVALuna2:13430

S1-guideline atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) - Helbig, Doris; Ziemer, Mirjana; Dippel, Edgar; Erdmann, Michael; Hillen, Uwe; Leiter, Ulrike; Mentzel, Thomas; Osterhoff, Georg; Ugurel, Selma; Utikal, Jochen; von Bubnoff, Dagmar; Weishaupt, Carsten; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are rare cutaneous neoplasms representing histomorphological, genetic as well as epigenetic variants of a disease spectrum. Both tumors typically manifest as nonspecific, often ulcerated, skin- to flesh-colored nodules in chronically sun-damaged skin of elderly male patients. AFX is a rather well demarcated, often rapidly growing tumor. PDS tumors are poorly circumscribed and are characterized by aggressive infiltrative growth. Fast as well as slow growth behavior has been reported for both tumors. Histologically, both are composed of spindle-shaped and epithelioid tumor cells with pleomorphic nuclei as well as atypical multinucleated giant cells. Atypical mitoses are common. In contrast to AFX, PDS involves relevant parts of the subcutis and shows areas of tumor necrosis and/or perineural infiltration. Due to the poorly differentiated nature of AFX/PDS (Grade 3), histopathologically similar cutaneous sarcomas, undifferentiated carcinomas, melanomas and other diseases have to be excluded by immunohistochemical analysis. The treatment of choice is micrographically controlled surgery. In cases of AFX, a cure can be assumed after complete excision. Local recurrence rates are low as long as PDS tumors are surgically removed with a safety margin of 2 cm. Metastasis is rare and mostly associated with very thick or incompletely excised tumors; it mainly affects the skin and lymph nodes. Distant metastasis is even more rare. No approved and effective systemic therapy has been established.
CRIS-Team Scopus Importer:2022-02-25

S1-guideline cutaneous and subcutaneous leiomyosarcoma - Helbig, Doris; Dippel, Edgar; Erdmann, Michael; Frisman, Alexander; Kage, Paula; Leiter, Ulrike; Mentzel, Thomas; Seidel, Clemens; Weishaupt, Carsten; Ziemer, Mirjana; Ugurel, Selma (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
Superficial leiomyosarcomas (LMS) are rare skin cancers (2–3% of cutaneous sarcomas) that originate from dermally located hair follicle muscles, dartos or areolar muscles (cutaneous/dermal LMS), or from vascular muscle cells of the subcutaneous adipose tissue (subcutaneous LMS). These superficial LMS are distinct from LMS of the deep soft tissues. Leiomyosarcomas are typically localized at the lower extremities, trunk or capillitium, and present as painful, erythematous to brownish nodules. Diagnosis is made by histopathology. The treatment of choice for primary LMS is complete (R0) microscopically controlled excision, with safety margins of 1 cm in dermal LMS, and 2 cm in subcutaneous LMS, if possible. Non-resectable or metastatic LMS require individual treatment decisions. After R0 resection with 1 cm safety margins, the local recurrence rate of dermal LMS is very low, and metastasis is very rare. Subcutaneous LMS, very large, or incompletely excised LMS recur and metastasize more frequently. For this reason, clinical follow-up examinations are recommended every six months for cutaneous LMS, and every three months for subcutaneous LMS within the first two years (in subcutaneous LMS including locoregional lymph node sonography). Imaging such as CT/MRI is indicated only in primary tumors with special features, recurrences, or already metastasized tumors.
CRIS-Team Scopus Importer:2023-04-21

S1-Leitlinie dermales und subkutanes Leiomyosarkom - Helbig, Doris; Dippel, Edgar; Erdmann, Michael; Frisman, Alexander; Kage, Paula; Leiter, Ulrike; Mentzel, Thomas; Seidel, Clemens; Weishaupt, Carsten; Ziemer, Mirjana; Ugurel, Selma (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
CRIS-Team Scopus Importer:2023-05-26

S1-Leitlinie Diagnostik und Therapie der Livedovaskulopathie - Schiffmann, Marie Luise; Dissemond, Joachim; Erfurt-Berge, Cornelia; Hafner, Jürg; Itzlinger-Monshi, Babak Alexander; Jungkunz, Hans Wilfried; Kahle, Birgit; Kreuter, Alexander; Scharffetter-Kochanek, Karin; Lutze, Stine; Rappersberger, Klemens; Schneider, Stefan Werner; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-12-03

S2k guideline: Diagnosis and management of cutaneous lupus erythematosus - Part 1: Classification, diagnosis, prevention, activity scores - Worm, Margitta; Zidane, Miriam; Eisert, Lisa; Fischer-Betz, Rebecca; Foeldvari, Ivan; Guenther, Claudia; Iking-Konert, Christof; Kreuter, Alexander; Mueller-Ladner, Ulf; Nast, Alexander; Ochsendorf, Falk; Schneider, Matthias; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team WoS Importer:2021-08-27

S2k guideline: Diagnosis and management of cutaneous lupus erythematosus – Part 2: Therapy, risk factors and other special topics - Worm, Margitta; Zidane, Miriam; Eisert, Lisa; Fischer-Betz, Rebecca; Foeldvari, Ivan; Gunther, Claudia; Iking-Konert, Christof; Kreuter, Alexander; Muller-Ladner, Ulf; Nast, Alexander; Ochsendorf, Falk; Schneider, Matthias; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-08-13

S2k Guideline for the diagnosis and treatment of mucous membrane pemphigoid - Hofmann, Silke C.; Gunther, Claudia; Bockle, Barbara C.; Didona, Dario; Ehrchen, Jan; Gaskins, Matthew; Geerling, Gerd; Glaser, Regine; Hadaschik, Eva; Hampl, Monika; Habkamp, Pia; Jackowski, Jochen; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
Mucous membrane pemphigoid (MMP) is a pemphigoid disease with predominant mucous membrane involvement. It mainly affects the mucous membranes of the mouth, eyes, nose and pharynx, but also the larynx, trachea, esophagus, genital and perianal regions. The manifestation of the disease covers a wide spectrum from gingival erythema and single oral lesions to severe tracheal strictures that obstruct breathing and conjunctival scarring with marked visual impairment and, not infrequently, blindness. In addition to a clinical picture of predominant mucosal involvement, diagnosis is based on direct immunofluorescence of a peri-lesional biopsy and serology. The main target antigen is BP180 (collagen XVII), and reactivity with laminin 332 is associated with malignancy in approximately 25 % of MMP patients. The treatment of MMP is challenging. On the one hand, due to the involvement of different mucous membranes, good interdisciplinary cooperation is required; on the other hand, due to the rarity of the disease, no randomized controlled clinical trials are available. The aim of this guideline is to present the clinical picture, including severity and scoring systems, and to give guidance for diagnosing and treating this complex disease. In MMP, interdisciplinary cooperation plays an essential role as well as the prompt diagnosis and initiation of adequate therapy in order to avoid irreversible damage to the mucous membranes with serious complications.
CRIS-Team WoS Importer:2022-11-25

S2k guideline for the diagnosis of pemphigus vulgaris/foliaceus and bullous pemphigoid - Schmidt, Enno; Goebeler, Matthias; Hertl, Michael; Sardy, Miklos; Sitaru, Cassian; Eming, Ruediger; Hofmann, Silke C.; Hunzelmann, Nicolas; Kern, Johannes S.; Kramer, Harald; Orzechowski, Hans-Dieter; Pfeiffer, Christiane; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2015)
EVALuna2:19565