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.
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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)
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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

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

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 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

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 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.
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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).
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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.
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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)
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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)
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S2k guidelines for the therapy of pathological scars (hypertrophic scars and keloids) – Update 2020 - Nast, Alexander; Gauglitz, Gerd; Lorenz, Kerstin; Metelmann, Hans-Robert; Paasch, Uwe; Strnad, Vratislav; Weidmann, Michael; Werner, Ricardo Niklas; Bauerschmitz, Jürgen (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-10-16

S2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid: 2019 update - Schmidt, Enno; Sticherling, Michael; Sárdy, Miklós; Eming, Rüdiger; Goebeler, Matthias; Hertl, Michael; Hofmann, Silke C.; Hunzelmann, Nicolas; Kern, Johannes S.; Kramer, Harald; Nast, Alexander; Orzechowski, Hans Dieter; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-05-26

S2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid - Eming, Ruediger; Sticherling, Michael; Hofmann, Silke C.; Hunzelmann, Nicolas; Kern, Johannes S.; Kramer, Harald; Pfeiffer, Christiane; Schuster, Volker; Zillikens, Detlef; Goebeler, Matthias; Hertl, Michael; Nast, Alexander; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2015)
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S2k guidelines for the treatment of psoriasis in children and adolescents – Short version part 1 - Eisert, Lisa; Augustin, Matthias; Bach, Sabine; Dittmann, Martin; Eiler, Renate; Fölster-Holst, Regina; Gerdes, Sascha; Hamm, Henning; Höger, Peter; Horneff, Gerd; von Kiedrowski, Ralph; Philipp, Sandra; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2019)
The present guidelines are aimed at residents and board-certified physicians in the fields of dermatology, pediatrics, pediatric dermatology and pediatric rheumatology as well as policymakers and insurance funds. They were developed by dermatologists and pediatric dermatologists in collaboration with pediatric rheumatologists using a formal consensus process (S2k). The guidelines highlight topics such as disease severity, quality of life, treatment goals as well as problems associated with off-label drug therapy in children. Trigger factors and diagnostic aspects are discussed. The primary focus is on the various topical, systemic and UV-based treatment options available and includes recommendations for use and treatment algorithms. Other aspects addressed herein include vaccinations in children and adolescents with psoriasis as well as various disease subtypes such as guttate psoriasis, diaper psoriasis, pustular psoriasis and psoriatic arthritis. Finally, we also provide recommendations for imaging studies and the diagnostic workup to rule out tuberculosis prior to initiating systemic treatment. Note: This article constitutes part 1 of the Sk2 guidelines for the treatment of psoriasis in children and adolescents. Part 2 will be published in the next issue. It contains chapters on UV therapy, systemic treatment, tonsillectomy and antibiotics, vaccinations, guttate psoriasis, psoriatic arthritis, complementary medicine, as well as imaging studies and diagnostic workup to rule out tuberculosis prior to systemic treatment.
CRIS-Team Scopus Importer:2019-08-30

S2k guidelines for the treatment of psoriasis in children and adolescents - Short version part 2. - Eisert, Lisa; Augustin, Matthias; Bach, Sabine; Dittmann, Martin; Eiler, Renate; Foelster-Holst, Regina; Gerdes, Sascha; Hamm, Henning; Hoeger, Peter; Horneff, Gerd; Von Kiedrowski, Ralph; Philipp, Sandra; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2019)
The present guidelines are aimed at residents and board-certified physicians in the fields of dermatology, pediatrics, pediatric dermatology and pediatric rheumatology as well as policymakers and insurance funds. They were developed by dermatologists and pediatric dermatologists in collaboration with pediatric rheumatologists using a formal consensus process (S2k). The guidelines highlight topics such as disease severity, quality of life, treatment goals as well as problems associated with off-label drug therapy in children. Trigger factors and diagnostic aspects are discussed. The primary focus is on the various topical, systemic and UV-based treatment options available and includes recommendations for use and treatment algorithms. Other aspects addressed herein include vaccinations in children and adolescents with psoriasis as well as various disease subtypes such as guttate psoriasis, diaper psoriasis, pustular psoriasis and psoriatic arthritis. Finally, we also provide recommendations for imaging studies and the diagnostic workup to rule out tuberculosis prior to initiating systemic treatment. Note: This article constitutes part 2 of the Sk2 guidelines for the treatment of psoriasis in children and adolescents. Part 1 was published in last month's issue. It contained introductory remarks and addressed aspects of diagnosis and topical treatment.
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S2k-Leitlinie Therapie pathologischer Narben (hypertrophe Narben und Keloide) –Update 2020 - Nast, Alexander; Gauglitz, Gerd; Lorenz, Kerstin; Metelmann, Hans Robert; Paasch, Uwe; Strnad, Vratislav; Weidmann, Michael; Werner, Ricardo Niklas; Bauerschmitz, Jürgen (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-02-26

S2k-Leitlinie zur Diagnostik und Therapie des kutanen Lupus erythematodes – Teil 1: Klassifikation, Diagnostik, Prävention und Aktivitätsscores - Worm, Margitta; Zidane, Miriam; Eisert, Lisa; Fischer-Betz, Rebecca; Foeldvari, Ivan; Günther, Claudia; Iking-Konert, Christof; Kreuter, Alexander; Müller-Ladner, Ulf; Nast, Alexander; Ochsendorf, Falk; Schneider, Matthias; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-09-17

S2k-Leitlinie zur Therapie der Psoriasis bei Kindern und Jugendlichen – Kurzfassung Teil 1 - Eisert, Lisa; Augustin, Matthias; Bach, Sabine; Dittmann, Martin; Eiler, Renate; Fölster-Holst, Regina; Gerdes, Sascha; Hamm, Henning; Höger, Peter; Horneff, Gerd; von Kiedrowski, Ralph; Philipp, Sandra; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2019)
CRIS-Team Scopus Importer:2019-08-30

S2k-Leitlinie zur Therapie der Psoriasis bei Kindern und Jugendlichen - Kurzfassung Teil 2. - Eisert, Lisa; Augustin, Matthias; Bach, Sabine; Dittmann, Martin; Eiler, Renate; Fölster-Holst, Regina; Gerdes, Sascha; Hamm, Henning; Höger, Peter; Horneff, Gerd; von Kiedrowski, Ralph; Philipp, Sandra; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2019)
Diese Leitlinie richtet sich an Assistenz- und Fachärzte der Dermatologie, Pädiatrie, Kinderdermatologie und Kinderrheumatologie sowie an Kostenträger und politische Entscheidungsgremien. Die Leitlinie wurde im formellen Konsensusverfahren (S2k) von Dermatologen und Kinderdermatologen unter Einbindung von Kinderrheumatologen erstellt. Die Leitlinie stellt einen Überblick über Schweregrad, Lebensqualität und Therapieziele mit Erläuterung der Off-Label-Problematik im Kindesalter dar. Es werden Diagnosestellung und Triggerfaktoren erläutert. Der Schwerpunkt der Leitlinie liegt auf der Darstellung der verschiedenen topischen Therapien, UV-Therapien und systemischen Therapieoptionen mit Abbildung der Empfehlungen zur Anwendung der Therapien sowie Therapiealgorithmen. Darüber hinaus wird im Kontext auf Impfungen bei Psoriasis im Kindesalter sowie auf verschiedene Sonderformen wie Psoriasis guttata, Windelpsoriasis, Psoriasis pustulosa und Psoriasisarthritis eingegangen. Auch werden Empfehlungen zu Tuberkulosediagnostik und Röntgenuntersuchung vor Systemtherapie gegebe
EVALuna2:212833

S2k-Leitlinie zur Therapie des Pemphigus vulgaris/foliaceus und des bullösen Pemphigoids: 2019 Update - Schmidt, Enno; Sticherling, Michael; Sárdy, Miklós; Eming, Rüdiger; Goebeler, Matthias; Hertl, Michael; Hofmann, Silke C.; Hunzelmann, Nicolas; Kern, Johannes S.; Kramer, Harald; Nast, Alexander; Orzechowski, Hans Dieter; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-05-22

S3 guideline "actinic keratosis and cutaneous squamous cell carcinoma"- update 2023, part 1: treatment of actinic keratosis, actinic cheilitis, cutaneous squamous cell carcinoma in situ (Bowen's disease), occupational disease and structures of care - Heppt, Markus; Leiter, Ulrike; Steeb, Theresa; Alter, Mareike; Amaral, Teresa; Bauer, Andrea; Bechara, Falk G.; Becker, Jürgen C.; Breitbart, Eckhard W.; Breuninger, Helmut; Diepgen, Thomas; Dirschka, Thomas; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
Actinic keratosis (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline “actinic keratosis and cutaneous squamous cell carcinoma” was updated and expanded by the topics cutaneous squamous cell carcinoma in situ (Bowen's disease) and actinic cheilitis. The guideline is aimed at dermatologists, general practitioners, ear nose and throat specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings, as well as other medical specialties, policy makers and insurance funds involved in the diagnosis and treatment of patients with AK and cSCC. A separate guideline exists for patients and their relatives. In this part, we will address aspects relating to AK, actinic cheilitis, Bowen's disease, occupational disease and care structure
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S3 guideline „actinic keratosis and cutaneous squamous cell carcinoma“ – update 2023, part 2: epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention - Leiter, Ulrike; Heppt, Markus; Steeb, Theresa; Alter, Mareike; Amaral, Teresa; Bauer, Andrea; Bechara, Falk G.; Becker, Jürgen C.; Breitbart, Eckhard W.; Breuninger, Helmut; Diepgen, Thomas; Dirschka, Thomas; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
Actinic keratosis (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline “actinic keratosis and cutaneous squamous cell carcinoma” was updated and expanded by the topics cutaneous squamous cell carcinoma in situ (Bowen's disease) and actinic cheilitis. The guideline is aimed at dermatologists, general practitioners, ear nose and throat specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings, as well as other medical specialties, policy makers and insurance funds involved in the diagnosis and treatment of patients with AK and cSCC. A separate guideline exists for patients and their relatives. In this part, we will address aspects relating to epidemiology and etiology, diagnostics, surgical and systemic treatment of cutaneous squamous cell carcinoma (cSCC), surveillance and prevention.
CRIS-Team Scopus Importer:2023-11-17

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma (cSCC) - short version, part 2: epidemiology, surgical and systemic treatment of cSCC, follow-up, prevention and occupational disease - Leiter, Ulrike; Heppt, Markus; Steeb, Theresa; Amaral, Teresa; Bauer, Andrea; Becker, Juergen C.; Breitbart, Eckhardt; Breuninger, Helmut; Diepgen, Thomas; Dirschka, Thomas; Eigentler, Thomas; Flaig, Michael; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
Actinic keratoses (AKs) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guidelines for actinic keratosis and cutaneous squamous cell carcinoma were developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guidelines are aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AKs and cSCC. The guidelines are also aimed at affected patients, their relatives, policy makers and insurance funds. In the second part, we will address aspects relating to epidemiology, etiology, surgical and systemic treatment of cSCC, follow-up and disease prevention, and discuss AKs and cSCC in the context of occupational disease regulations.
CRIS-Team WoS Importer:2020-04-17

S3 guideline for actinic keratosis and cutaneous squamous cell carcinoma – short version, part 1: diagnosis, interventions for actinic keratoses, care structures and quality-of-care indicators - Heppt, Markus V.; Leiter, Ulrike; Steeb, Theresa; Amaral, Teresa; Bauer, Andrea; Becker, Jürgen C.; Breitbart, Eckhard; Breuninger, Helmut; Diepgen, Thomas; Dirschka, Thomas; Eigentler, Thomas; Flaig, Michael; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
Actinic keratoses (AK) are common lesions in light-skinned individuals that can potentially progress to cutaneous squamous cell carcinoma (cSCC). Both conditions may be associated with significant morbidity and constitute a major disease burden, especially among the elderly. To establish an evidence-based framework for clinical decision making, the guideline “actinic keratosis and cutaneous squamous cell carcinoma” was developed using the highest level of methodology (S3) according to regulations issued by the Association of Scientific Medical Societies in Germany (AWMF). The guideline is aimed at dermatologists, general practitioners, ENT specialists, surgeons, oncologists, radiologists and radiation oncologists in hospitals and office-based settings as well as other medical specialties involved in the diagnosis and treatment of patients with AK and cSCC. The guideline is also aimed at affected patients, their relatives, policy makers and insurance funds. In the first part, we will address aspects relating to diagnosis, interventions for AK, care structures and quality-of-care indicators.
CRIS-Team Scopus Importer:2020-03-17

S3 guidelines: Epicutaneous patch testing with contact allergens and drugs – Short version, Part 1 - Mahler, Vera; Nast, Alexander; Bauer, Andrea; Becker, Detlef; Brasch, Jochen; Breuer, Kristine; Dickel, Heinrich; Drexler, Hans; Elsner, Peter; Geier, Johannes; John, Swen Malte; Kreft, Burkhard; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2019)
Epicutaneous patch testing is the diagnostic standard for the detection of allergic contact dermatitis. The present guidelines are aimed at residents and board-certified physicians in the fields of dermatology and allergology as well as other medical specialties involved in establishing the indication for patch testing and its execution in patients with contact dermatitis and other forms of delayed-type hypersensitivity. The target audience also includes other health care providers and insurance funds. Based on a systematic literature search and a formal consensus process (S3), the guidelines were developed by dermatologists in collaboration with pediatricians, occupational medicine physicians, nursing staff as well as patient representatives. The systematic methodological approach and appraisal of evidence upon which the recommendations are based are outlined in a separate method report that also contains evidence tables. The guidelines address general aspects of patch testing as well as medicolegal issues. The recommendations given relate to topics such as the indication for patch testing, informed patient consent, as well as the choice of test substances, test chambers and test site, duration of exposure, reading times and interpretation of test reactions. Furthermore, recommendations are provided with respect to endogenous and exogenous factors, specific patient groups (children, pregnant women, immunosuppressed individuals) as well as possible risks and adverse events associated with patch testing using contact allergens. Note: This publication is part 1 of the short version of the S3 guidelines for “Epicutaneous patch testing using contact allergens and drugs” (registry no. 013 – 018; date: March 20, 2019; valid until December 31, 2021). Part 2 of the short version will be published in the next issue. The long version of these guidelines can be accessed at www.awmf.org. The method report is available as online publication (https://www.awmf.org/leitlinien/detail/ll/013-018.html) and contains the evidence tables in its appendix.
CRIS-Team Scopus Importer:2019-10-29

S3-Leitlinie „Aktinische Keratose und Plattenepithelkarzinom der Haut“ – Kurzfassung, Teil 1: Diagnostik, Interventionen bei aktinischen Keratosen, Versorgungsstrukturen und Qualitätsindikatoren - Heppt, Markus V.; Leiter, Ulrike; Steeb, Theresa; Amaral, Teresa; Bauer, Andrea; Becker, Jürgen C.; Breitbart, Eckhard; Breuninger, Helmut; Diepgen, Thomas; Dirschka, Thomas; Eigentler, Thomas; Flaig, Michael; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
Aktinische Keratosen (AK) sind häufige Hautveränderungen bei hellhäutigen Menschen mit dem Potenzial, in ein kutanes Plattenepithelkarzinom (PEK) überzugehen. Beide Erkrankungen können mit erheblicher Morbidität verbunden sein und stellen eine große Krankheitslast insbesondere in der älteren Bevölkerung dar. Um eine evidenzbasierte, klinische Entscheidungsfindung zu unterstützen, wurde die Leitlinie “Aktinische Keratose und Plattenepithelkarzinom der Haut” auf der Methodikebene S3 nach dem Regelwerk der AWMF entwickelt. Die Leitlinie richtet sich dabei an Dermatologen, Allgemeinmediziner, HNO-Ärzte, Chirurgen, Onkologen, Radiologen und Strahlentherapeuten in Klinik und Praxis sowie an andere medizinische Fachgebiete, die sich mit der Diagnose und Behandlung von Patienten mit AK und PEK befassen. Die Leitlinie richtet sich auch an betroffene Patienten, deren Angehörige, politische Entscheidungsträger und Versicherungsgesellschaften. In diesem Teil behandeln wir die Themen Diagnostik, Interventionen bei AK, Versorgungsstrukturen und Qualitätsindikatoren.
CRIS-Team Scopus Importer:2020-03-17

S3-Leitlinie "Aktinische Keratose und Plattenepithelkarzinom der Haut" - Kurzfassung, Teil 2: Epidemiologie, chirurgische und systemische Therapie des Plattenepithelkarzinoms, Nachsorge, Pravention und Berufskrankheit - Leiter, Ulrike; Heppt, Markus V.; Steeb, Theresa; Amaral, Teresa; Bauer, Andrea; Becker, Juergen C.; Breitbart, Eckhardt; Breuninger, Helmut; Diepgen, Thomas; Dirschka, Thomas; Eigentler, Thomas; Flaig, Michael; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
Zusammenfassung Aktinische Keratosen (AK) sind haufige Hautveranderungen bei hellhautigen Menschen mit dem Potenzial, in ein kutanes Plattenepithelkarzinom (PEK) uberzugehen. Beide Erkrankungen konnen mit erheblicher Morbiditat verbunden sein und stellen eine gro ss e Krankheitslast insbesondere in der alteren Bevolkerung dar. Um eine evidenzbasierte, klinische Entscheidungsfindung zu unterstutzen, wurde die Leitlinie Aktinische Keratose und kutanes Plattenepithelkarzinom" auf der Methodikebene S3 nach dem Regelwerk der AWMF entwickelt. Die Leitlinie richtet sich dabei an Dermatologen, Allgemeinmediziner, HNO-Arzte, Chirurgen, Onkologen, Radiologen und Strahlentherapeuten in Klinik und Praxis sowie an andere medizinische Fachgebiete, die sich mit der Diagnose und Behandlung von Patienten mit AK und PEK befassen. Die Leitlinie richtet sich auch an betroffene Patienten, deren Angehorige, politische Entscheidungstrager und Versicherungsgesellschaften. In diesem Teil behandeln wir die Themen Epidemiologie, Atiologie, chirurgische und systemische Behandlung des PEK, Nachsorge des PEK, Pravention und Berufskrankheit durch AK und PEK.
CRIS-Team WoS Importer:2020-05-15

S3-Leitlinie “Aktinische Keratose und Plattenepithelkarzinom der Haut“ – Update 2023, Teil 1: Therapie der aktinischen Keratose, Morbus Bowen, Cheilitis actinica, berufsbedingte Erkrankung und Versorgungsstrukturen - Heppt, Markus; Leiter, Ulrike; Steeb, Theresa; Alter, Mareike; Amaral, Teresa; Bauer, Andrea; Bechara, Falk G.; Becker, Jürgen C.; Breitbart, Eckhard W.; Breuninger, Helmut; Diepgen, Thomas; Dirschka, Thomas; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
CRIS-Team Scopus Importer:2023-10-27

S3-Leitlinie: Durchführung des Epikutantests mit Kontaktallergenen und Arzneimitteln – Kurzfassung Teil 1 - Mahler, Vera; Nast, Alexander; Bauer, Andrea; Becker, Detlef; Brasch, Jochen; Breuer, Kristine; Dickel, Heinrich; Drexler, Hans; Elsner, Peter; Geier, Johannes; John, Swen Malte; Kreft, Burkhard; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2019)
CRIS-Team Scopus Importer:2019-10-29

S3-Leitlinie: Durchführung des Epikutantests mit Kontaktallergenen und Arzneimitteln - Kurzfassung Teil 2. - Mahler, Vera; Nast, Alexander; Bauer, Andrea; Becker, Detlef; Brasch, Jochen; Breuer, Kristine; Dickel, Heinrich; Drexler, Hans; Elsner, Peter; Geier, Johannes; John, Swen Malte; Kreft, Burkhard; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2019)
Zusammenfassung Der diagnostische Standard zum Nachweis einer bestehenden allergischen Kontaktdermatitis ist der Epikutantest. Die vorliegende Leitlinie richtet sich an Assistenz- und Facharzte der Dermatologie, Allergologie und Arzte weiterer Fachgruppen in Klinik und Praxis, die an der Indikationsstellung oder Durchfuhrung von Epikutantests bei Patienten mit Kontaktekzemen und weiteren Spattypallergien beteiligt sind, sowie Kooperationspartner der Arzteschaft (Fachberufe im Gesundheitswesen, Kostentrager). Die Leitlinie zur Durchfuhrung des Epikutantests mit Kontaktallergenen wurde auf der Basis einer systematischen Literatursuche zu definierten Schlusselfragen evidenzbasiert und im formellen Konsensusverfahren (S3) von Dermatologen unter Einbindung von Padiatern, Arbeitsmedizinern, Assistenzpersonal und Patientenvertretern erstellt. Bezuglich der methodischen und inhaltlichen Arbeit, auf denen die Empfehlungen basieren, wird auf Methodenbericht und Evidenztabellen verwiesen. Die Leitlinie stellt allgemeine Aspekte der Epikutantestung sowie medizinrechtliche Aspekte dar. Es werden Empfehlungen gegeben zur Indikationsstellung, Patientenaufklarung, Auswahl von Testsubstanzen und Kammersystemen, Expositionsort, -dauer und Ablesezeitpunkten, Interpretation von Testreaktionen, endogenen und exogenen Einflussfaktoren, Testung besonderer Personengruppen (Kinder, Schwangere, Immunsupprimierte) sowie Risiken und unerwunschten Nebenwirkungen bei der Durchfuhrung des Epikutantests mit Kontaktallergenen.
EVALuna2:280871

Safety and tolerability of a single infusion of autologous ex vivo expanded regulatory T cells in adults with ulcerative colitis (ER-TREG 01): protocol of a phase 1, open-label, fast-track dose-escalation clinical trial - Voskens, Caroline; Stoica, Diane; Roessner, Susanne; Vitali, Francesco; Zundler, Sebastian; Rosenberg, Marita; Wiesinger, Manuel; Wunder, Jutta; Siegmund, Britta; Schuler-Thurner, Beatrice; Schuler, Gerold; Berking, Carola; et al. (BMJ Open, 2021)
Introduction Accumulating evidence suggests that the adoptive transfer of ex vivo expanded regulatory T cells (Treg) may overcome colitogenic immune responses in patients with inflammatory bowel diseases. The objective of the ER-TREG 01 trial is to assess safety and tolerability of a single infusion of autologous ex vivo expanded Treg in adults with ulcerative colitis.
CRIS-Team WoS Importer:2021-12-24

Safety of topical interventions for the treatment of actinic keratosis - Koch, Elias; Wessely, Anja; Steeb, Theresa; Berking, Carola; Heppt, Markus (Expert Opinion on Drug Safety, 2021)
Introduction: Actinic keratosis (AK) are proliferations of atypical keratinocytes that may eventually progress to cutaneous squamous cell carcinoma. Therefore, AK requires consequent and early treatment. Areas covered: A variety of effective approaches is currently available for the clearance of AK. These interventions may be applied either in a lesion-directed or field-directed mode as AK can occur as single or multiple lesions. Field-directed approaches typically comprise topical drug-mediated interventions which aim at eliminating all visible lesions and also at clearing subclinical changes of the actinically damaged field. However, most treatment options are associated with local adverse events such as erythema, scaling, pain, and rarely with systemic symptoms. This expert review provides a comprehensive and up-to-date overview of the safety considerations of the commonly prescribed topical treatment agents cyclooxygenase inhibitors, 5-fluorouracil, imiquimod, ingenol mebutate, and photodynamic therapy. All these therapies have been proven efficient, yet they differ considerably regarding their safety profile. Expert opinion: In the future, safety concerns will relate to long-term and irreversible adverse drug events instead of application site reactions. In particular, the rate of treatment-associated non-melanoma skin cancers will increasingly come into focus and warrant investigation in postmarketing surveillance trials with a long-term follow-up.
CRIS-Team Scopus Importer:2021-08-06
Keywords: 5-fluorouracil; actinic keratosis; diclofenac; imiquimod; ingenol mebutate; photodynamic therapy

Sarcoidosis Under Dendritic Cell Vaccination Immunotherapy in Long-term Responding Patients with Metastatic Melanoma - Uslu, Ugur; Erdmann, Michael; Schliep, Stefan; Dörrie, Jan; Schaft, Niels; Schuler, Gerold; Schuler-Thurner, Beatrice (Anticancer Research, 2017)
Sarcoidosis, a chronic inflammatory disorder, results from increased immune responses. Its development can be triggered in patients under immunotherapy, as activation of the immune system in these patients is desired. Since 1997, 249 patients with metastasized cutaneous melanoma (stage III and IV, AJCC 2009) have been treated with dendritic cell (DC)-based vaccines at our hospital. Three out of these patients were diagnosed with sarcoidosis after or during long-term DC vaccination therapy (1.20%). Metastatic disease was initially suspected based on the radiographic manifestation of lung masses or bilateral hilar lymphadenopathy. Histological assessment, however, revealed the appropriate diagnosis. Interestingly, all three patients are long-term responders and have remained free of metastatic or progressive disease for over a period of at least 4 years. In summary, sarcoidosis can occur in patients with cancer who have benefited from DC-based therapeutic vaccination and thus, its development, even with substantial delay, may be associated with successful anticancer immunotherapy.
EVALuna2:34321

SARS-CoV-2 Transmission from Presymptomatic Meeting Attendee, Germany - Hijnen, Dirkjan; Marzano, Angelo Valerio; Eyerich, Kilian; Geurtsvankessel, Corine; Maria Gimenez-Arnau, Ana; Joly, Pascal; Vestergaard, Christian; Sticherling, Michael; Schmidt, Enno (Emerging Infectious Diseases, 2020)
During a meeting in Munich, Germany, a presymptomatic attendee with severe acute respiratory syndrome coronavirus 2 infected at least 11 of 13 other participants. Although 5 participants had no or mild symptoms, 6 had typical coronavirus disease, without dyspnea. Our findings suggest hand shaking and face-to-face contact as possible modes of transmission.
CRIS-Team WoS Importer:2020-08-07

SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases - Simon, David; Tascilar, Koray; Fagni, Filippo; Krönke, Gerhard; Kleyer, Arnd; Meder, Christine; Meder, Christine; Atreya, Raja; Leppkes, Moritz; Kremer, Andreas E.; Pachowsky, Milena; Schuch, Florian; et al. (Annals of the Rheumatic Diseases, 2021)
Objectives: To better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Methods: Patients and controls from a large COVID-19 study, with (1) no previous history of COVID-19, (2) negative baseline anti-SARS-CoV-2 IgG test and (3) SARS-CoV-2 vaccination at least 10 days before serum collection were measured for anti-SARS-CoV-2 IgG. Demographic, disease-specific and vaccination-specific data were recorded. Results: Vaccination responses from 84 patients with IMID and 182 controls were analysed. While all controls developed anti-SARS-CoV-2 IgG, five patients with IMID failed to develop a response (p=0.003). Moreover, 99.5% of controls but only 90.5% of patients with IMID developed neutralising antibody activity (p=0.0008). Overall responses were delayed and reduced in patients (mean (SD): 6.47 (3.14)) compared with controls (9.36 (1.85); p<0.001). Estimated marginal means (95% CI) adjusted for age, sex and time from first vaccination to sampling were 8.48 (8.12-8.85) for controls and 6.90 (6.45-7.35) for IMIDs. Significantly reduced vaccination responses pertained to untreated, conventionally and anticytokine treated patients with IMID. Conclusions: Immune responses against the SARS-CoV-2 are delayed and reduced in patients with IMID. This effect is based on the disease itself rather than concomitant treatment.
CRIS-Team Scopus Importer:2021-05-21
Keywords: biological therapy; COVID-19; epidemiology; vaccination

Schlusswort - Heinzerling, Lucie (Deutsches Ärzteblatt international, 2019)
CRIS-Team Scopus Importer:2019-06-25

SCLE manifestation after mRNA COVID-19 vaccination - Rechtien, Laura; Erfurt-Berge, Cornelia; Sticherling, Michael (Journal of the European Academy of Dermatology and Venereology, 2022)
CRIS-Team WoS Importer:2022-01-14

Scurvy : A rare differential diagnosis of rheumatic diseases - Hofheinz, K.; Ganzleben, Ingo; Schliep, S.; Wacker, J.; Schett, Georg; Manger, Bernhard (Zeitschrift für Rheumatologie, 2016)
In December 2014 a patient presented to our clinic with the clinical symptoms of vasculitis. However, treatment with glucocorticoids did not lead to any improvement; therefore, the differential diagnostics were extended to other indications and ultimately led to the diagnosis of scurvy.This article describes the clinical picture of scurvy and its relationship to rheumatic diseases based on a clinical case and additional information from the literature. Differences and similarities with important rheumatological disease symptoms are presented.Scurvy is a rare hypovitaminosis disease which can be manifested in different forms. In addition to vasculitis the symptoms can also resemble arthritis and hemarthrosis is a typical finding. These symptoms can be accompanied by unspecific manifestations, such as muscle pain and due to impaired collagen synthesis characteristic features, such as corkscrew hair can be observed. The causal therapy of scurvy is substitution of ascorbic acid.Scurvy is a rare differential diagnosis in the context of rheumatic diseases. The indications for scurvy can be a lack of response to immunosuppressive and immunomodulatory drugs as well as individual symptoms, such as corkscrew hair.
EVALuna2:2047

Secondary prevention measures in anaphylaxis patients: Data from the anaphylaxis registry - Kraft, Magdalena; Knop, Macarena Pia; Renaudin, Jean-Marie; Scherer Hofmeier, Kathrin; Pfoehler, Claudia; Bilo, Maria Beatrice; Lang, Roland; Treudler, Regina; Wagner, Nicola; Spindler, Thomas; Hourihane, Jonathan O'B; Maris, Ioana; et al. (Allergy, 2019)
Background Patients with a history of anaphylaxis are at risk of future anaphylactic reactions. Thus, secondary prevention measures are recommended for these patients to prevent or attenuate the next reaction. Methods Data from the Anaphylaxis Registry were analyzed to identify secondary prevention measures offered to patients who experienced anaphylaxis. Our analysis included 7788 cases from 10 European countries and Brazil. Results The secondary prevention measures offered varied across the elicitors. A remarkable discrepancy was observed between prevention measures offered in specialized allergy centers (84% of patients were prescribed adrenaline autoinjectors following EAACI guidelines) and outside the centers: Here, EAACI guideline adherence was only 37%. In the multivariate analysis, the elicitor of the reaction, age of the patient, mastocytosis as comorbidity, severity of the reaction, and reimbursement/availability of the autoinjector influence physician's decision to prescribe one. Conclusions Based on the low implementation of guidelines concerning secondary prevention measures outside of specialized allergy centers, our findings highlight the importance of these specialized centers and the requirement of better education for primary healthcare and emergency physicians.
CRIS-Team WoS Importer:2019-11-01

Secondary syphilis infection under treatment with ustekinumab - Uslu, Ugur; Heppt, Franz; Sticherling, Michael (Clinical and Experimental Dermatology, 2017)
EVALuna2:34342

Secukinumab 2-weekly vs. 4-weekly dosing in patients with plaque-type psoriasis: results from the randomized GAIN study - Reich, K.; Koerber, A.; Mrowietz, U.; Sticherling, Michael; Sieder, C.; Frueh, J.; Bachhuber, T. (British Journal of Dermatology, 2020)
Background: Secukinumab is a fully human monoclonal antibody that selectively neutralizes interleukin-17A and shows long-lasting efficacy and safety in plaque psoriasis. More evidence is required to optimize secukinumab dosing according to clinical response. Objectives: GAIN compared the efficacy and safety of secukinumab 300 mg every 2 weeks (q2w) with 300 mg every 4 weeks (q4w) in patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) but not PASI 90 after 16 weeks. Methods: In total, 772 patients with moderate-to-severe plaque psoriasis received secukinumab 300 mg subcutaneously at baseline and weeks 1, 2, 3 and 4, then q4w until week 16. At week 16, patients with PASI ≥ 75 to PASI < 90 were randomized 1: 1 to continue q4w dosing (n = 162) or switch to q2w (n = 163) to week 32. The primary endpoint was superiority of q2w to q4w dosing for PASI 90 response at week 32. Results: PASI 90 response at week 32 was numerically greater with secukinumab 300 mg q2w than with secukinumab 300 mg q4w in suboptimal responders, but this did not reach statistical significance (64·4% vs. 57·4%; odds ratio 0·64, 95% confidence interval 0·39–1·07; P = 0·087). Although the primary endpoint was not met, absolute PASI was significantly lower at week 32 in q2w vs. q4w patients (2·11 vs. 2·84, P = 0·024). Significantly more patients with q2w vs. q4w dosing showed minimal disease activity (Investigator’s Global Assessment score 0 or 1: 73·0% vs. 64·1%, P < 0·05) and improved quality of life (Dermatology Life Quality Index score 0 or 1: 58·9% vs. 50·6%, P < 0·05) at week 32. No new or unexpected safety signals arose. Conclusions: Most patients achieved PASI 90 response with secukinumab q4w. There was potential benefit of q2w dosing in some suboptimal responders. Continued q4w treatment can improve response even after 16 weeks.
CRIS-Team Scopus Importer:2020-12-04

Secukinumab in Pediatric Patients with Plaque Psoriasis: Pooled Safety Analysis from Two Phase 3 Randomized Clinical Trials - Sticherling, Michael; Nikkels, Arjen F.; Hamza, Ashraf M.; Kwong, Pearl; Szepietowski, Jacek C.; El Sayed, Mahira; Ghislain, Pierre Dominique; Khotko, Alkes A.; Patekar, Manmath; Ortmann, Christine Elke; Forrer, Pascal; Papanastasiou, Philemon; et al. (American Journal of Clinical Dermatology, 2023)
Background: Plaque psoriasis affects 1% of the pediatric population, negatively impacting quality of life. The efficacy and safety of secukinumab in pediatric patients with moderate to severe or severe chronic plaque psoriasis have been established in two pivotal phase 3 trials (open-label, NCT03668613; double-blind, NCT02471144). Objectives: The aims were to report the pooled safety of secukinumab up to 52 weeks from two studies in subgroups of pediatric patients stratified by age and bodyweight, and to present, alongside the pediatric data, the pooled safety data from four pivotal adult secukinumab trials. Methods: The safety of secukinumab was evaluated in subgroups of pediatric patients defined by age (6 to < 12 and 12 to < 18 years) and bodyweight (< 25 kg, 25 to < 50 kg, and ≥ 50 kg) in the pooled population. Patients received secukinumab low dose (LD; 75/75/150 mg), secukinumab high dose (HD; 75/150/300 mg), placebo, or etanercept (0.8 mg/kg). For safety analyses, data were pooled from the pediatric studies NCT03668613 and NCT02471144, and presented alongside the pooled data from four adult pivotal studies (NCT01365455, NCT01636687, NCT01358578, NCT01555125). Results: A total of 198 pediatric patients (overall exposure: 184.6 patient-years [PY]) and 1989 adult patients (1749.5 PY) receiving secukinumab up to week 52 were included in this analysis. At week 52, the incidence of adverse events (AEs) was lower in the lower age and bodyweight subgroups. The AEs reported within these subgroups were consistent with the overall AEs reported in this analysis. Overall, exposure-adjusted incidence rates for treatment-emergent AEs were lower in the secukinumab-treated pediatric pool (198.8/100 PY) compared with the etanercept (266.3/100 PY) and adult pools (256.1/100 PY). Up to 52 weeks, the incidence rates of the AEs in the secukinumab-treated patients in the 6 to < 12 years subgroup and 12 to < 18 years subgroup were 167.7/100 PY and 214.7/100 PY, respectively. Similarly, incidence rates of the AEs in the secukinumab-treated patients in the < 25 kg, 25 kg to < 50 kg, and ≥ 50 kg subgroups were 177.3/100 PY, 192.5/100 PY, and 206.8/100 PY, respectively. Nasopharyngitis was the most frequently reported AE in secukinumab-treated pediatric patients across age (< 12 years: 11.8/100 PY; ≥ 12 years: 42.4/100 PY) and bodyweight (< 25 kg: 22.8/100 PY; 25 kg to < 50 kg: 19.0/100 PY; ≥ 50 kg: 43.0/100 PY). Of the 198 secukinumab-treated pediatric patients, one reported nail Candida, one reported skin Candida, and two reported vulvovaginal Candida. Transient and mostly mild events of neutropenia were observed with secukinumab, none leading to study treatment discontinuation. No incidence of treatment-emergent anti-drug antibodies was reported in pediatric patients treated with secukinumab. Conclusions: Secukinumab was well tolerated in pediatric patients with moderate to severe and severe plaque psoriasis across age and bodyweight subgroups. The overall safety profile of secukinumab in pediatric patients was consistent with that of adult patients. ClinicalTrials.gov Identifier: NCT03668613 (Novartis Study Code CAIN457A2311, referred to as A2311), actual study start date: August 29, 2018; actual primary completion date: September 19, 2019; estimated study completion date: September 14, 2023. NCT02471144 (Novartis Study Code CAIN457A2310, referred to as A2310), study start date: September 29, 2015; primary completion date: December 13, 2018; estimated study completion date: March 31, 2023.
CRIS-Team Scopus Importer:2023-07-07

Secukinumab is superior to Fumaric Acid Esters in the Treatment of Patients with moderate to severe Plaque Psoriasis without previous Systemic Therapy for Improvement of Skin Symptoms: PASI and IGA mod. 2011-Results of the PRIME Study - Reich, K.; Mrowietz, U.; Augustin, M.; Thaci, D.; Kneidl, J.; Hentschke, C.; Simang, M.; Sieder, C.; Melzer, N.; Sticherling, Michael (2017)
EVALuna2:34358

Secukinumab is superior to Fumaric Acid Esters in the Treatment of Patients with moderate to severe Plaque Psoriasis without prior System Therapy with regard to compatibility-related Therapeutic Adherence: Safety Results of the PRIME Study - Mrowietz, U.; Augustin, M.; Thaci, D.; Reich, K.; Kneidl, J.; Hentschke, C.; Simang, M.; Sieder, C.; Melzer, N.; Sticherling, Michael (2017)
EVALuna2:34361

Secukinumab is superior to Fumaric Acid Esters in the Treatment of Patients with moderate to severe Plaque Psoriasis without prior System Therapy with respect to the Improvement of quality of life: DLQI and SF-36 Results of the PRIME Study - Augustin, M.; Thaci, D.; Reich, K.; Mrowietz, U.; Kneidl, J.; Hentschke, C.; Simang, M.; Sieder, C.; Melzer, N.; Sticherling, Michael (2017)
EVALuna2:34359

Secukinumab is superior to Fumaric Acid Esters in the Treatment of Patients with moderate to severe Plaque Psoriasis with without previous Systemic Therapy for Improvement of Nail Symptoms: NAPSI Results PRIME Study - Thaci, D.; Reich, K.; Mrowietz, U.; Augustin, M.; Kneidl, J.; Hentschke, C.; Simang, M.; Sieder, C.; Melzer, N.; Sticherling, Michael (2017)
EVALuna2:34360

Secukinumab is superior to fumaric acid esters in treating patients with moderate-to-severe plaque psoriasis who are naive to systemic treatments: results from the randomized controlled PRIME trial - Sticherling, Michael; Mrowietz, U.; Augustin, M.; Thaci, D.; Melzer, N.; Hentschke, C.; Kneidl, J.; Sieder, C.; Reich, K. (British Journal of Dermatology, 2017)
BACKGROUND: Secukinumab is a fully human antibody that neutralizes interleukin-17A. It has significant efficacy and a favourable safety profile in moderate-to-severe plaque psoriasis and psoriatic arthritis. OBJECTIVES: To compare secukinumab with fumaric acid esters (FAEs) in a randomized controlled trial. METHODS: In this 24-week, randomized, open-label, multicentre study with blinded assessment, patients with moderate-to-severe plaque psoriasis, naive to systemic treatments, were randomized to receive secukinumab 300 mg subcutaneously or oral FAEs. The primary end point was ≥ 75% improvement from baseline Psoriasis Area and Severity Index score (PASI 75 response) at week 24, and missing patients were considered responders if they were responders at the time of dropout. RESULTS: In total 202 patients were randomized and 200 were treated with at least one dose. Outcomes at week 24 were available for 147 and imputed for 53 patients. Discontinuations were mostly due to adverse events, which occurred more frequently in the FAE group (1·9% vs. 33·0%). At week 24, significantly more patients receiving secukinumab compared with FAEs achieved PASI 75 response (89·5% vs. 33·7%, P < 0·001), PASI 90 response (81·0% vs. 28·4%, P < 0·001) and Dermatology Life Quality Index 0 or 1 response (71·4% vs. 25·3%, P < 0·001). CONCLUSIONS: Secukinumab demonstrated superior efficacy to FAEs in patients with psoriasis over a 24-week period.
EVALuna2:34340

Secukinumab leads to shifts from stage-based towards response-based disease clusters-comparative data from very early and established psoriatic arthritis - Kampylafka, Eleni; Tascilar, Koray; Lerchen, Veronika; Linz, Christina; Sokolova, Maria; Zekovic, Ana; Kleyer, Arnd; Simon, David; Rech, Jürgen; Sticherling, Michael; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2020)
Background: Limited information exists about the very early forms of psoriatic arthritis. In particular, differences and responsiveness of patient-reported outcomes (PROs) in very early as compared to established PsA have not been investigated to date. Methods: Cross-sectional and prospective longitudinal evaluation of PROs related to pain (VAS), physical function (HAQ-DI, SF-36 physical), mental function (SF-36 mental), impact of psoriatic skin (DLQI), joint (PsAID), and global disease (VAS) in two small prospective observational studies on secukinumab 300 mg over 6 months in very early disease patients (IVEPSA study, N = 20) and established PsA (PSARTROS study, N = 20). Cluster analysis was performed at baseline and 24-weeks of follow-up. Results: While responses in pain and physical activity-related PROs to secukinumab were more pronounced in established PsA than a very early disease, effects on PROs related to general health perception, as well as those related to emotional and mental well-being, were modified in a similar way in very early disease and established PsA. Cluster analysis based on global disease activity and PROs showed that baseline clusters reflected very early disease and established PsA, while after secukinumab treatment these clusters were abolished and new clusters based on differential responses to physically and mentally oriented PROs formed. Conclusions: Inhibition of IL-17A by secukinumab leads to comprehensive improvement of general health perception and mental well-being in very early and established PsA, while overall responses in pain and physical activity are more pronounced in established disease. Most importantly, treatment restructures the original patients' clusters based on disease stage and leads to the formation of new clusters that reflect their response in physical and mental-orientated PROs. Trial registration: NCT02483234, registered 26 June 2015, retrospectively registered.
CRIS-Team Scopus Importer:2020-10-02
Keywords: Cluster analysis; IL-17A; Psoriatic arthritis; Quality of life; Secukinumab

Secukinumab Treatment of moderate to severe Plaque Psoriasis in the clinical Routine Care: Baseline Data from the PROSPECT Study on Psoriasis Pre-treatment - Von Kiedrowski, R.; Korber, A.; Kraehn-Senftleben, G.; Sticherling, Michael; Lange, L.; Bachhuber, T.; Kasparek, T. R.; Augustin, M.; Thaci, D.; Amon, U. (2017)
EVALuna2:34357

Select Clr-g Expression on Activated Dendritic Cells Facilitates Cognate Interaction with a Minor Subset of Splenic NK Cells Expressing the Inhibitory Nkrp1g Receptor - Friede, Miriam E.; Leibelt, Stefan; Dudziak, Diana; Steinle, Alexander (Journal of Immunology, 2018)
Natural killer gene complex-encoded immunomodulatory C-type lectin-like receptors include members of the NKRP1 and C-type lectin-like 2 (CLEC2) gene families, which constitute genetically linked receptor-ligand pairs and are thought to allow for NK cell-mediated immunosurveillance of stressed or infected tissues. The mouse C-type lectin-like receptor Nkrp1g was previously shown to form several receptor-ligand pairs with the CLEC2 proteins Clr-d, Clr-f, and Clr-g, respectively. However, the physiological expression of Nkrp1g and its CLEC2 ligands as well as their functional relevance remained poorly understood. Recently, we demonstrated a gut-restricted expression of Clr-f on intestinal epithelial cells that is spatially matched by Nkrp1g on subsets of intraepithelial lymphocytes. In this study, we investigated expression and ligand interaction of Nkrp1g in the splenic compartment, and found an exclusive expression on a small subset of NK cells that upregulates Nkrp1g after cytokine exposure. Whereas transcripts of Clr-d and Clr-f are virtually absent from the spleen, Clr-g transcripts were abundantly detected throughout different leukocyte populations and hematopoietic cell lines. However, a newly generated anti-Clr-g mAb detected only residual Clr-g surface expression on splenic monocytes, whereas many hematopoietic cell lines brightly display Clr-g. Clr-g surface expression was strongly upregulated on splenic CD8α+ conventional dendritic cells (DCs) and plasmacytoid DCs upon TLR-mediated activation and detectable by Nkrp1g, which dampens NK cell effector functions upon Clr-g engagement. Hence, different to the intestinal tract, in the spleen, Nkrp1g is selectively expressed by a subset of NK cells, thereby potentially allowing for an inhibitory engagement with Clr-g-expressing activated DCs during immune responses.
EVALuna2:34802

Select hyperactivating NLRP3 ligands enhance the TH1-and TH17-inducing potential of human type 2 conventional dendritic cells - Hatscher, Lukas; Lehmann, Christian; Purbojo, Ariawan; Onderka, Constantin; Liang, Chunguang; Hartmann, Arndt; Cesnjevar, Robert; Bruns, Heiko; Gross, Olaf; Nimmerjahn, Falk; Burmazovic, Ivana Ivanovic; Kunz, Meik; et al. (Science Signaling, 2021)
The detection of microorganisms and danger signals by pattern recognition receptors on dendritic cells (DCs) and the consequent formation of inflammasomes are pivotal for initiating protective immune responses. Although the activation of inflammasomes leading to secretion of the cytokine IL-1 is typically accompanied by pyroptosis (an inflammatory form of lytic programmed cell death), some cells can survive and exist in a state of hyperactivation. Here, we found that the conventional type 2 DC (cDC2) subset is the major human DC subset that is transcriptionally and functionally poised for inflammasome formation and response without pyroptosis. When cDC2 were stimulated with ligands that relatively weakly activated the inflammasome, the cells did not enter pyroptosis but instead secreted IL-12 family cytokines and IL-1. These cytokines induced prominent T helper type 1 (TH1) and TH17 responses that were superior to those seen in response to Toll-like receptor (TLR) stimulation alone or to stronger, classical inflammasome ligands. These findings not only define the human cDC2 subpopulation as a prime target for the treatment of inflammasome-dependent inflammatory diseases but may also inform new approaches for adjuvant and vaccine development.
CRIS-Team Scopus Importer:2021-05-14
Keywords: Dendritic cells; cDC2; CD1c; inflammasome; hyperactivation; L18-MDP; T cell differentiation

Select hyperactivating NLRP3 ligands enhance the TH1-and TH17-inducing potential of human type 2 conventional dendritic cells - Heger, Lukas; Hatscher, Lukas; Lehmann, Christian; Purbojo, Ariawan; Onderka, Constantin; Liang, C.; Hartmann, Arndt; Cesnjevar, Robert; Bruns, Heiko; Gross, O.; Nimmerjahn, Falk; Ivanovic-Burmazovic, I.; et al. (EXPERIMENTAL DERMATOLOGY, 2022)
CRIS-Team WoS Importer:2022-03-04

Selection of adenovirus-specific and Epstein-Barr virus-specific T cells with major histocompatibility class I streptamers under Good Manufacturing Practice (GMP)-compliant conditions - Freimueller, Christine; Stemberger, Julia; Artwohl, Michaela; Germeroth, Lothar; Witt, Volker; Fischer, Gottfried; Tischer, Sabine; Eiz-Vesper, Britta; Knippertz, Ilka; Dörrie, Jan; Schaft, Niels; Lion, Thomas; et al. (Cytotherapy, 2015)
Despite antiviral drug therapies, human adenovirus (HAdV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections still contribute substantially to transplant-related death of patients after hematopoietic stem cell transplantation. Earlier clinical studies demonstrated successful adoptive transfer of magnetically selected CMV-specific T cells via removable, and thus Good Manufacturing Practice-compliant, major histocompatibility class I streptamers. Thus, the primary focus of the present study was the selection of HAdV-streptamer+ T cells, although in three experiments, EBV-streptamer+ T cells were also selected.Cells from leukaphereses of healthy donors were prepared in large (1-6 × 10(9)) and small (25 × 10(6)) cell batches. Whereas the larger batch was directly labeled with streptamers to select HAdV- and/or EBV-specific T cells (large-scale), the smaller batch was used to generate in vitro virus-specific T-cell lines before streptamer labeling for streptamer selection (small-scale). Isolation of HAdV- and/or EBV-specific T cells was performed with the use of the CliniMACS device.The purity of HAdV- and EBV-streptamer+ T cells among CD3+ cells, obtained from large-scale selection, was up to 6.7% and 44%, respectively. If HAdV- and EBV-streptamers were applied simultaneously, the purity of antigen-specific T cells reached up to 50.7%. A further increase in purity reaching up to 98% was achieved by small-scale selection of HAdV-specific T cells. All final products fulfilled the microbiological and chemical release criteria. Interferon-?-response indicating functional activity was seen in 6 of 9 HAdV and 2 of 3 EBV large-scale selections and in 2 of 3 HAdV small-scale selections.HAdV-streptamers were shown to be clinically feasible for few patients after the large-scale approach but for larger patient numbers if combined with EBV-streptamers or after the small-scale approach.
EVALuna2:19523

Semi-Automatic Cell Correspondence Analysis Using Iterative Point Cloud Registration - Chen, Shuqing; Gehrer, Simone; Kaliman, Sara; Ravikumar, Nishant; Becit, Abdurrahman; Aliee, Maryam; Dudziak, Diana; Merkel, Rudolf; Smith, Ana-Suncana; Maier, Andreas (Bildverarbeitung für die Medizin 2019. Informatik aktuell., 2019)

Senescence markers: Predictive for response to checkpoint inhibitors - Moreira, Alvaro; Gross, Stefanie; Kirchberger, Michael Constantin; Erdmann, Michael; Schuler, Gerold; Heinzerling, Lucie (International Journal of Cancer, 2019)
Recent studies suggest that the age-related remodeling of the immune system, known as immunosenescence, could impact the efficacy of immune checkpoint inhibitors in leukemia or nonsmall cell lung cancer. We investigated whether senescence markers can predict response to checkpoint inhibitor therapy in melanoma patients. The peripheral blood of patients with newly diagnosed, untreated metastatic melanoma was analyzed by flow cytometry to correlate the frequency of senescence markers with clinical response as measured by RECIST after 12 weeks of treatment with immune checkpoint inhibitors. The loss of surface markers CD27 and CD28 or the expression of Tim-3 and CD57 on T cells was associated with resistance to checkpoint inhibitor blockade, presenting these phenotypes as possible predictive biomarkers for checkpoint inhibitor therapy. Immunosenescence seems to impact on the response to checkpoint inhibitor therapy in melanoma patients. Thus, lymphocyte phenotyping for senescence markers, with the introduction of immunosenescence panels, could be predictive for checkpoint inhibitor response.
CRIS-Team Scopus Importer:2019-05-21
Keywords: biomarker; immune checkpoint inhibitors; immunosenescence; melanoma

Sensitive allele-specific real-time PCR test for mutations in BRAF codon V600 in skin melanoma - Pisareva, Ekaterina; Gutkina, Nadezhda; Kovalenko, Sergei; Kuehnapfel, Sarah; Hartmann, Arndt; Heinzerling, Lucie; Schneider-Stock, Regine; Lyubchenko, Lyudmila; Shamanin, Vladimir A. (Melanoma Research, 2014)
Mutations at BRAF codon V600 are used as predictive biomarkers for targeted therapy of skin melanoma. Here, a simple sensitive test to detect mutations of BRAF-V600 was developed using real-time PCR with allele-specific primers and TaqMan probes. Two versions of the test using sense and antisense allele-specific primers were designed and evaluated. The test detected 1% mutant allele V600E/K in 10 ng DNA standard made from wild-type human DNA spiked with BRAF-V600E or the V600K plasmid. The test was validated on clinical formalin-fixed paraffin-embedded samples of skin melanoma using pyrosequencing as a reference method. In the clinical samples, we detected the common mutation V600E, as well as the rare mutations V600K, V600E2 (codon GAA), V600E2 K601del, V600D-K601del, and V600R. In comparison with pyrosequencing, both versions of the test had 100% specificity with sensitivities of 97 and 86% for sense and antisense allele-specific primers, respectively. Using the PCR test with sense allele-specific primers, mutations in V600 were found in 33 of 51 Russian patients (64.7%) with cutaneous melanoma. This closed-tube real-time PCR test can be used as a simple and sensitive assay for mutations of BRAF-V600 in cutaneous melanoma.
EVALuna2:6621

Sensitivity and specificity of standardised allergen extracts in skin prick test for diagnoses of IgE-mediated respiratory allergies - Wagner, Nicola; Rudert, Michael (Clinical and Translational Allergy, 2019)
Background: Skin prick tests (SPTs) are essential for the diagnosis of IgE-mediated allergy and are influenced by extract quality, biological potency and concentration of allergen.
CRIS-Team WoS Importer:2019-03-26

Sentinel Lymph Node Dissection in Head and Neck Melanoma has Prognostic Impact on Disease-Free and Overall Survival - Leiter, Ulrike; Eigentler, Thomas K.; Haefner, Hans-Martin; Krimmel, Michael; Uslu, Ugur; Keim, Ulrike; Weide, Benjamin; Breuninger, Helmut; Martus, Peter; Garbe, Claus (Annals of Surgical Oncology, 2015)
Sentinel lymph node biopsy (SLNB) plays an important role in the prognostic classification of melanoma and is now a standard staging procedure. However, due to the complex drainage pattern and the risk of site associated morbidity, the potential survival benefit of SLNB is controversial in head and neck (H&N) melanoma.Patients with primary H&N melanoma with a tumor thickness >=1.00 mm diagnosed in the Department of Dermatology, University of Tuebingen, Germany between 1991 and 2010 were included in this study. Regarding patterns of metastases, disease-free, and overall-survival, 259 patients with SLNB were compared retrospectively to 218 patients without SLNB.The detection of micrometastasis in SLN proved to be a significant prognostic factor in H&N patients [hazard ratio (HR) 3.69, p < 0.0001]. A significant improvement of recurrence-free survival (RFS, p = 0.011), regional lymph node metastasis-free survival (LFS, p = 0.007), and distant metastasis-free survival (DMSF, p = 0.015) was observed for patients with SLNB versus non-SLNB. Furthermore, a trend towards better overall survival (OS) was found (p = 0.053) for the SLNB group.SLNB improved prognostic outcome in H&N melanoma in terms of disease-free and distant metastases survival, reduced subsequent regional lymph node metastases, and showed a trend towards a better OS.
EVALuna2:19555

Sequence-dependent cross-resistance of combined radiotherapy plus BRAF(V600E) inhibition in melanoma - Shannan, B.; Matschke, J.; Chauvistre, H.; Vogel, F.; Klein, D.; Meier, F.; Westphal, D.; Bruns, J.; Rauschenberg, R.; Utikal, J.; Forschner, A.; Berking, C.; et al. (European Journal of Cancer, 2019)
Introduction: Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common. Methods & results: Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAF V600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor–pretreated compared with MAPK-inhibitor–naïve intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1B high cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death. Conclusion: The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.
CRIS-Team WoS Importer:2019-03-06
Keywords: Cross-resistance; JARID1B/KDM5B; Melanoma; Radiotherapy; Repopulation; Resistance; Slow-cycling cells; Targeted therapy; Therapy sequencing

Sequence-function analysis of three T cell receptors targeting the HIV-1 p17 - Mummert, Christiane; Hofmann, Christian; Hueckelhoven, Angela G.; Bergmann, Silke; Müller-Schmucker, Sandra; Harrer, Ellen G.; Dörrie, Jan; Schaft, Niels; Harrer, Thomas (2016)
EVALuna2:19635

Serial or Parallel Metastasis of Cutaneous Melanoma? A Study of the German Central Malignant Melanoma Registry - Gassenmaier, Maximilian; Eigentler, Thomas Kurt; Keim, Ulrike; Goebeler, Matthias; Fiedler, Eckhard; Schuler, Gerold; Leiter, Ulrike; Weide, Benjamin; Grischke, Eva-Maria; Martus, Peter; Garbe, Claus (Journal of Investigative Dermatology, 2017)
For more than a century the Halstedian hypothesis of contiguous metastasis from the primary tumor through the lymphatics to distant sites shaped lymph node surgery for melanoma. We challenge this dogma of serial metastatic dissemination. A single-center series of 2,299 patients with cutaneous metastatic melanoma was investigated to analyze overall survival and distant metastasis-free survival of stage IV patients with or without primary lymphatic metastasis. Results were then compared with those of 2,134 patients from three independent centers of the German Central Malignant Melanoma Registry. A multivariate binary logistic regression model was used to identify risk factors for the initial metastatic pathway. Distant metastasis-free survival (hazard ratio = 1.02; 95% confidence interval = 0.91-1.14; P = 0.76) and overall survival (HR = 1.09; 95% CI = 0.96-1.23; P = 0.177) did not differ between stage IV patients with primary hematogenous or primary lymphatic metastasis. Melanoma localization was the only significant risk factor for the initial metastatic pathway. These findings indicate that regional and distant metastases originate from the primary tumor itself in a rather parallel than serial fashion and could explain the lack of survival benefit associated with immediate complete lymph node dissection in sentinel lymph node-positive melanoma patients.
EVALuna2:34312

SERIO - Side Effect Registry Immuno-Oncology Side Effect Registry for rare, severe and complex Side Effects of Immunotherapy - Kramer, Rafaela; Mentzer, D.; Erdmann, M.; Knauss, S.; Broeckelmann, P. J.; Hassel, J. C.; Ugurel, S.; Pavel, Marianne Ellen; Nickel, Franziska; Landendinger, M.; Fuchs, Friederike; Meidenbauer, Norbert; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-09-11

Serio - Side Effect Registry in Immuno-Oncology - Koutzamanidis, Rafaela; Mentzer, Dirk; Knauss, Samuel; Broeckelmann, Paul J.; Hassel, Jessica Cecile; Ugurel-Becker, Selma; Pavel, Marianne Ellen; Nickel, Florian; Landendinger, Melanie; Fuchs, Florian; Meidenbauer, Norbert; Jefremow, Andre; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

Serositis in Association with System Therapy with Checkpoint Inhibitors - More frequent than thought? - An Evaluation of the SERIO Adverse Event Registry - Zierold, S.; Kramer, R.; Erdmann, Michael; Akcetin, S. L.; Maier, A. M.; Koenig, A.; Theurich, S.; French, L. E.; Heinzerling, Lucie (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Serum autoantibody reactivity in bullous pemphigoid is associated with neuropsychiatric disorders and the use of antidiabetics and antipsychotics: a large, prospective cohort study - Dikmen, H. O.; Yilmaz, K.; Benoit, S.; Bernard, P.; Drenovska, Kossara; Gerdes, S.; Glaeser, R.; Guenther, C.; Homey, B.; Horvath, O. N.; Huilaja, L.; Joly, P.; et al. (Journal of the European Academy of Dermatology and Venereology, 2022)
Background: Bullous pemphigoid (BP), the by far most frequent autoimmune blistering skin disease (AIBD), is immunopathologically characterized by autoantibodies against the two hemidesmosomal proteins BP180 (collagen type XVII) and BP230 (BPAG1 or dystonin). Several comorbidities and potentially disease-inducing medication have been described in BP, yet a systematic analysis of these clinically relevant findings and autoantibody reactivities has not been performed. Objective: To determine associations of autoantibody reactivities with comorbidities and concomitant medication. Methods: In this prospective multicenter study, 499 patients diagnosed with BP in 16 European referral centers were included. The relation between anti-BP180 NC16A and anti-BP230 IgG ELISA values at the time of diagnosis as well as comorbidities and concomitant medication collected by a standardized form were analysed. Results: An association between higher serum anti-BP180 reactivity and neuropsychiatric but not atopic and metabolic disorders was observed as well as with the use of insulin or antipsychotics but not with dipeptidyl peptidase-4 (DPP4) inhibitors, inhibitors of platelet aggregation and L-thyroxine. The use of DPP4 inhibitors was associated with less anti-BP180 and anti-BP230 reactivity compared with BP patients without these drugs. This finding was even more pronounced when compared with diabetic BP patients without DPP4 inhibitors. Associations between anti-BP180 and anti-BP230 reactivities were also found in patients using insulin and antipsychotics, respectively, compared with patients without this medication, but not for the use of inhibitors of platelet aggregation, and L-thyroxine. Conclusion: Taken together, these data imply a relation between autoantibody reactivities at the time of diagnosis and both neuropsychiatric comorbidities as well as distinct concomitant medication suggesting a link between the pathological immune mechanisms and clinical conditions that precede the clinically overt AIBD.
CRIS-Team Scopus Importer:2022-07-22

Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins - Sanmamed, Miguel F.; Carranza-Rua, Omar; Alfaro, Carlos; Onate, Carmen; Martin-Algarra, Salvador; Perez, Guiomar; Landazuri, Sara F.; Gonzalez, Alvaro; Gross, Stefanie; Rodriguez, Inmaculada; Munoz-Calleja, Cecilia; Rodriguez-Ruiz, Maria; et al. (Clinical Cancer Research, 2014)
Interleukin-8 (IL8) is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping protumoral vascularization and inflammation/immunity. We evaluated sequential levels of serum IL8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden.IL8 levels were monitored by sandwich ELISAs in cultured tumor cells supernatants, tumor-xenografted mice serum, and in samples from 126 patients with cancer. We correlated IL8 serum levels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis.IL8 concentrations correlated with the number of IL8-producing tumor cells in culture. In xenografted neoplasms, IL8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n = 16), renal cell carcinoma (RCC; n = 23), non-small cell lung cancer (NSCLC; n = 21), or hepatocellular carcinoma (HCC; n = 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n = 16; RCC, n = 23; HCC, n = 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n = 16) and immunomodulatory monoclonal antibodies (melanoma, n = 8). IL8 concentrations in urine (n = 18) were mainly elevated in tumors with direct contact with the urinary tract.IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance.
EVALuna2:19512

Serum levels of miR-320 family members are associated with clinical parameters and diagnosis in prostate cancer patients - Lieb, Verena; Weigelt, Katrin; Scheinost, Lena; Fischer, Kersten; Greither, Thomas; Marcou, Marios; Theil, Gerit; Klocker, Helmut; Holzhausen, Hans Juergen; Lai, Xin; Vera, Julio; Ekici, Arif Bülent; et al. (Oncotarget, 2018)
We studied the association of the serum levels of the microRNA family members miR-320a/-b/-c with clinico-pathological data to assess their applicability as diagnostic biomarker in prostate cancer (PCa) patients. The levels of miR-320a/-b/-c in 3 groups were evaluated by qRT-PCR (145 patients with PCa, 31 patients with benign prostatic hyperplasia (BPH) and 19 healthy controls). The levels of the three family members of miR-320 were directly correlated within each group (P < 0.001), but they differed significantly among the three groups (P < 0.001). The serum levels of the miR-320 family members were significantly increased in older patients compared to younger patients (≤ 66 years vs. > 66 years, P ≤ 0.001). In addition, the levels of all three miR-320 family members were significantly different in patients with low tumor stage compared with those with high tumor stage (miR-320a: P = 0.034; miR-320b: P = 0.006; miR-320c: P = 0.007) and in patients with low serum PSA compared with those with high serum PSA (≤ 4 ng vs. > 4 ng; miR-320a: P = 0.003; miR-320b: P = 0.003; miR-320c: P = 0.006). The levels of these miRNAs were inversely correlated with serum PSA levels. Detection in the serum samples of PCa patients with or without PSA relapse revealed higher levels of miR-320a/-b/-c in the group without PSA relapse before/after radical prostatectomy than in that with PCa relapse. In summary, the differences among the PCa/BPH/healthy control groups with respect to miR-320a/-b/-c levels in conjunction with higher levels in patients without a PSA relapse than in those with a relapse suggest the diagnostic potential of these miRNA-320 family members in PCa patients.
EVALuna2:35121

Short Peptide Vaccine Induces CD4+ T Helper Cells in Patients with Different Solid Cancers - Gross, Stefanie; Lennerz, Volker; Gallerani, Elisa; Mach, Nicolas; Boehm, Steffen; Hess, Dagmar; Von Boehmer, Lotta; Knuth, Alexander; Ochsenbein, Adrian; Gnad-Vogt, Ulrike; Forssmann, Ulf; Woelfel, Thomas; et al. (Cancer Immunology Research, 2016)
Previous cancer vaccination trials often aimed to activate CD8(+) cytotoxic T-cell (CTL) responses with short (8-10mer) peptides and targeted CD4(+) helper T cells (TH) with HLA class II-binding longer peptides (12-16 mer) that were derived from tumor antigens. Accordingly, a study of immunomonitoring focused on the detection of CTL responses to the short, and TH responses to the long, peptides. The possible induction of concurrent TH responses to short peptides was widely neglected. In a recent phase I vaccination trial, 53 patients with different solid cancers were vaccinated with EMD640744, a cocktail of five survivin-derived short (9- or 10-mer) peptides in Montanide ISA 51VG. We monitored 49 patients and found strong CD8(+) T-cell responses in 63% of the patients. In addition, we unexpectedly found CD4(+) TH cell responses against at least two of the five short peptides in 61% (23/38) of the patients analyzed. The two peptides were recognized by HLA-DP4- and HLA-DR-restricted TH1 cells. Some short peptide-reactive (sp)CD4 T cells showed high functional avidity. Here, we show that a short peptide vaccine is able to activate a specific CD4(+) T-cell repertoire in many patients, facilitating a strong combined CD4(+)/CD8(+) T-cell response.
EVALuna2:19595

Side effect management during immune checkpoint blockade using CTLA-4 and PD-1 antibodies for metastatic melanoma - an update - Kaehler, Katharina C.; Hassel, Jessica C.; Heinzerling, Lucie; Loquai, Carmen; Thoms, Kai-Martin; Ugurel, Selma; Zimmer, Lisa; Gutzmer, Ralf (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CTLA-4 and PD-1 play a key role in tumor-induced downregulation of lymphocytic immune responses. Immune checkpoint inhibitors have been shown to alter the immune response to various cancer types. Anti-CTLA-4 and anti-PD-1 antibodies affect the interaction between tumor, antigen-presenting cells and T lymphocytes. Clinical studies of the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab have provided evidence of their positive effects on overall survival in melanoma patients. Combined treatment using ipilimumab and nivolumab has been shown to achieve five-year survival rates of 52 %. Such enhancement of the immune response is inevitably associated with adverse events. Knowledge of the spectrum of side effects is essential, both in terms of prevention and management. Adverse events include colitis, dermatitis, hypophysitis, thyroiditis, hepatitis and other, less common autoimmune phenomena. In recent years, considerable progress has been made in the detection and treatment of the aforementioned immune-related adverse events. However, early diagnosis of rare neurological or cardiac side effects, which may be associated with increased mortality, frequently pose a challenge. The present update highlights our current understanding as well as new insights into the spectrum of side effects associated with checkpoint inhibitors and their management.
CRIS-Team WoS Importer:2020-06-16

Siglec-15 on osteoclasts is crucial for bone erosion in serum-Transfer arthritis - Korn, Marina; Schmitt, Heike; Angermüller, Sieglinde; Chambers, David; Seeling, Michaela; Lux, Uwe; Brey, Stefanie; Royzman, Dmytro; Bruckner, Christin; Popp, Vanessa; Percivalle, Elena; Bäuerle, Tobias; et al. (Journal of Immunology, 2020)
Siglec-15 is a conserved sialic acid binding Ig-like lectin, which is expressed on osteoclasts. Deficiency of Siglec-15 leads to an impaired osteoclast development, resulting in a mild osteopetrotic phenotype. The role of Siglec-15 in arthritis is still largely unclear. To address this, we generated Siglec-15 knockout mice and analyzed them in a mouse arthritis model.We could show that Siglec-15 is directly involved in pathologic bone erosion in the K/BxN serum-Transfer arthritis model. Histological analyses of joint destruction provided evidence for a significant reduction in bone erosion area and osteoclast numbers in Siglec-152/2 mice, whereas the inflammation area and cartilage destruction was comparable to wild-Type mice. Thus, Siglec-15 on osteoclasts has a crucial function for bone erosion during arthritis. In addition, we generated a new monoclonal anti Siglec-15 Ab to clarify its expression pattern on immune cells. Whereas this Ab demonstrated an almost exclusive Siglec-15 expression on murine osteoclasts and hardly any other expression on various other immune cell types, human Siglec-15 was more broadly expressed on human myeloid cells, including human osteoclasts. Taken together, our findings show a role of Siglec-15 as a regulator of pathologic bone resorption in arthritis and highlight its potential as a target for future therapies, as Siglec-15 blocking Abs are available.
CRIS-Team Scopus Importer:2020-11-20

Siglec-H-Deficient Mice Show Enhanced Type I IFN Responses, but Do Not Develop Autoimmunity After Influenza or LCMV Infections - Szumilas, Nadine; Corneth, Odilia B.J.; Lehmann, Christian; Schmitt, Heike; Cunz, Svenia; Cullen, Jolie G.; Chu, Talyn; Marosán, Anita; Mócsai, Attila; Benes, Vladimir; Zehn, Dietmar; Dudziak, Diana; et al. (Frontiers in Immunology, 2021)
Siglec-H is a DAP12-associated receptor on plasmacytoid dendritic cells (pDCs) and microglia. Siglec-H inhibits TLR9-induced IFN-α production by pDCs. Previously, it was found that Siglec-H-deficient mice develop a lupus-like severe autoimmune disease after persistent murine cytomegalovirus (mCMV) infection. This was due to enhanced type I interferon responses, including IFN-α. Here we examined, whether other virus infections can also induce autoimmunity in Siglec-H-deficient mice. To this end we infected Siglec-H-deficient mice with influenza virus or with Lymphocytic Choriomeningitis virus (LCMV) clone 13. With both types of viruses we did not observe induction of autoimmune disease in Siglec-H-deficient mice. This can be explained by the fact that both types of viruses are ssRNA viruses that engage TLR7, rather than TLR9. Also, Influenza causes an acute infection that is rapidly cleared and the chronicity of LCMV clone 13 may not be sufficient and may rather suppress pDC functions. Siglec-H inhibited exclusively TLR-9 driven type I interferon responses, but did not affect type II or type III interferon production by pDCs. Siglec-H-deficient pDCs showed impaired Hck expression, which is a Src-family kinase expressed in myeloid cells, and downmodulation of the chemokine receptor CCR9, that has important functions for pDCs. Accordingly, Siglec-H-deficient pDCs showed impaired migration towards the CCR9 ligand CCL25. Furthermore, autoimmune-related genes such as Klk1 and DNase1l3 are downregulated in Siglec-H-deficient pDCs as well. From these findings we conclude that Siglec-H controls TLR-9-dependent, but not TLR-7 dependent inflammatory responses after virus infections and regulates chemokine responsiveness of pDCs.
CRIS-Team Scopus Importer:2021-09-17
Keywords: Interferon-alpha; plasmacytoid dendritic cells; Siglec; SLE; TLR9

Significant differences in patients with a complete insufficiency of the great versus small saphenous vein - Pochec, Katarzyna; Mühlberger, Dominic; Hummel, Thomas; Stücker, Markus; Reich-Schupke, Stefanie (Phlebology, 2019)
Objectives: Most studies on diagnostics and therapy of saphenous veins focus on great saphenous vein or sum up great and small saphenous vein. This study compares patients with an insufficiency of the great saphenous vein versus small saphenous vein. Methods: Prospective study including 50 patients with untreated insufficiency of the great saphenous vein or small saphenous vein, respectively. Patients got a standardised phlebological examination and filled a vein-specific life quality questionnaire (SQOR-V). Results: Great saphenous vein patients were significantly younger (p = 0.001), had more visible varicose veins (p < 0.001), a higher Venous Clinical Severity Score (p = 0.002) and had more symptoms, especially at midday (p = 0.0030) and evening (p = 0.078). They had significantly more concerns about worsening of their varicose veins (p = 0.009) and a vein disease in family members (p = 0.005). Conclusion: Great saphenous vein patients have more and sooner symptoms than small saphenous vein patients. This study discusses if the difference in symptoms is related to the difference in tributaries and a therapy of the tributaries is able to reduce the symptoms.
CRIS-Team Scopus Importer:2019-08-02
Keywords: Chronic venous insufficiency; tributaries; varicose veins; vein therapy; venous symptoms

Silencing β1,2-xylosyltransferase in Transgenic Tomato Fruits Reveals xylose as Constitutive Component of Ige-Binding Epitopes. - Sonnewald, Uwe; Kogel, Karl-Heinz; Pabst, Martin; Paulus, Kathrin; Altmann, Friedrich; Mahler, Vera (Frontiers in Plant Science, 2011)
Complex plant N-glycans containing β1,2-xylose and core α1,3-fucose are regarded as the major class of the so-called "carbohydrate cross-reactive determinants" reactive with IgE antibodies in sera of many allergic patients, but their clinical relevance is still under debate. Plant glycosyltransferases, β1,2-xylosyltransferase (XylT), and core α1,3-fucosyltransferase (FucT) are responsible for the transfer of β1,2-linked xylose and core α1,3-linked fucose residues to N-glycans of glycoproteins, respectively. To test the clinical relevance of β1,2-xylose-containing epitopes, expression of the tomato β1,2-xylosyltransferase was down-regulated by RNA interference (RNAi) in transgenic plants. Fruits harvested from these transgenic plants were analyzed for accumulation of XylT mRNA, abundance of β1,2-xylose epitopes and their allergenic potential. Based on quantitative real-time PCR analysis XylT mRNA levels were reduced up to 10-fold in independent transgenic lines as compared to untransformed control, whereas no xylosylated N-glycans could be revealed by MS analysis. Immunoblotting using anti-xylose-specific IgG antibodies revealed a strong reduction of β1,2-xylose-containing epitopes. Incubating protein extracts from untransformed controls and XylT_RNAi plants with sera from tomato allergic patients showed a patient-specific reduction in IgE-binding, indicating a reduced allergenic potential of XylT_RNAi tomato fruits, in vitro. To elucidate the clinical relevance of β1,2-xylose-containing complex N-glycans skin prick tests were performed demonstrating a reduced responsiveness of tomato allergic patients, in vivo. This study provides strong evidence for the clinical relevance of β1,2-xylose-containing epitopes in vivo.
Keywords: beta 1; 2-xylosyltransferase; RNA interference; tomato allergy; N-glycosylation; CCDs

Similar Impact of Psoriatic Arthritis and Rheumatoid Arthritis on Objective and Subjective Parameters of Hand Function - Liphardt, Anna-Maria; Manger, Eva; Liehr, Sonja; Bieniek, Lisa Maria; Kleyer, Arnd; Simon, David; Tascilar, Koray; Sticherling, Michael; Rech, Jürgen; Schett, Georg; Hueber, Axel (ACR Open Rheumatology, 2020)
ObjectiveThe objective of this study was to compare the impact of psoriatic disease (psoriatic arthritis [PsA] and psoriasis) and rheumatoid arthritis (RA) on objective and subjective parameters of hand function.
CRIS-Team WoS Importer:2021-07-16

Similar Impact of Psoriatic Arthritis and Rheumatoid Arthritis on Objective and Subjective Parameters of Hand Function - Liphardt, Anna-Maria; Manger, Eva; Liehr, Sonja; Bieniek, Lisa; Kleyer, Arnd; Simon, David; Tascilar, Koray; Sticherling, Michael; Rech, Jürgen; Schett, Georg; Hueber, Axel (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Simultaneous quantification of bone erosions and enthesiophytes in the joints of patients with psoriasis or psoriatic arthritis - effects of age and disease duration - Simon, David; Kleyer, Arnd; Faustini, Francesca; Englbrecht, Matthias; Haschka, Judith; Berlin, Andreas; Kraus, Sebastian; Hueber, Axel; Kocijan, Roland; Sticherling, Michael; Rech, Jürgen; Schett, Georg (Arthritis Research & Therapy, 2018)
BACKGROUND: Comprehensive simultaneous quantification of bone erosion and enthesiophytes in the joints of patients with psoriatic arthritis (PsA) has not been performed. Herein, we aimed to compare the extent of bone erosion and enthesiophytes in patients with PsA, psoriasis (PSO) and healthy controls, assess the influence of age and disease duration on the development of erosions and enthesiophytes and define their impact on physical function. METHODS: Patients with PsA or with PSO and controls were analysed by high-resolution peripheral quantitative computed tomography (HR-pQCT). The extent of bone erosions and enthesiophytes was assessed and plotted according to different categories of age, duration of PSO and duration of PsA, respectively. In addition, demographic and disease-specific data, including physical function (health assessment questionnaire) were collected. RESULTS: A total of 203 patients were analysed; 101 had PsA, 55 had PSO and 47 were healthy individuals. Patients with PsA had significantly more and larger erosions (p = 0.002/p = 0.003) and enthesiophytes (p < 0.001) compared to patients with PSO and healthy controls. Patients with PSO and healthy controls did not differ in erosions, while enthesiophytes were more frequent in patients with PSO than in healthy controls. Bone erosions, but not enthesiophytes, showed strong age-dependency in all three groups. In contrast, enthesiophytes were mostly influenced by the duration of PSO and PsA and, in contrast to bone erosions, were associated with poorer physical function. CONCLUSIONS: Bone erosions are age-dependent, enhanced in PsA and increase with disease duration. Enthesiophytes are less age-dependent, are enhanced in both PSO and PsA and strongly influenced by disease duration. Enthesiophytes impact physical function in PsA suggesting the need for early therapeutic interventions to prevent damage.
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Single-cell Transcriptome Analysis and clonal Kinetics in a Patient after CD19.CAR-T Cell Therapy - Lischer, Christopher; Eisenhauer, Nina; Aigner, Michael; Jacobs, Benedikt; Schletter, M.; Gebhard, C.; Rehli, M.; Bruns, Heiko; Müller, Fabian; Mackensen, Andreas; Vera González, Julio; Völkl, Simon (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

Single-Molecule RNA Sequencing Reveals IFN gamma-Induced Differential Expression of Immune Escape Genes in Merkel Cell Polyomavirus-Positive MCC Cell Lines - Sauerer, Tatjana; Lischer, Christopher; Weich, Adrian; Berking, Carola; Vera, Julio; Dörrie, Jan (Frontiers in Microbiology, 2021)
Merkel cell carcinoma (MCC) is a rare and highly aggressive cancer, which is mainly caused by genomic integration of the Merkel cell polyomavirus and subsequent expression of a truncated form of its large T antigen. The resulting primary tumor is known to be immunogenic and under constant pressure to escape immune surveillance. Because interferon gamma (IFN gamma), a key player of immune response, is secreted by many immune effector cells and has been shown to exert both anti-tumoral and pro-tumoral effects, we studied the transcriptomic response of MCC cells to IFN gamma. In particular, immune modulatory effects that may help the tumor evade immune surveillance were of high interest to our investigation. The effect of IFN gamma treatment on the transcriptomic program of three MCC cell lines (WaGa, MKL-1, and MKL-2) was analyzed using single-molecule sequencing via the Oxford Nanopore platform. A significant differential expression of several genes was detected across all three cell lines. Subsequent pathway analysis and manual annotation showed a clear upregulation of genes involved in the immune escape of tumor due to IFN gamma treatment. The analysis of selected genes on protein level underlined our sequencing results. These findings contribute to a better understanding of immune escape of MCC and may help in clinical treatment of MCC patients. Furthermore, we demonstrate that single-molecule sequencing can be used to assess characteristics of large eukaryotic transcriptomes and thus contribute to a broader access to sequencing data in the community due to its low cost of entry.
CRIS-Team WoS Importer:2022-01-28

Sinus Pericranii - Heppt, Franz; Meder, Christine; Wagner, Nicola (Deutsches Ärzteblatt international, 2020)
CRIS-Team WoS Importer:2020-05-05

siRNA Electroporation to Modulate Autophagy in Herpes Simplex Virus Type 1-Infected Monocyte-Derived Dendritic Cells - Düthorn, Alexandra; Turan, Aykut; Drassner, Christina; Muehl-Zurbes, Petra; Heilingloh, Christiane; Steinkasserer, Alexander; Grosche, Linda (Journal of Visualized Experiments, 2019)
Herpes simplex virus type-1 (HSV-1) induces autophagy in both, immature dendritic cells (iDCs) as well as mature dendritic cells (mDCs), whereas autophagic flux is only observed in iDCs. To gain mechanistic insights, we developed efficient strategies to interfere with HSV-1-induced autophagic turnover. An inhibitor-based strategy, to modulate HSV-1-induced autophagy, constitutes the first choice, since it is an easy and fast method. To circumvent potential unspecific off-target effects of such compounds, we developed an alternative siRNA-based strategy, to modulate autophagic turnover in iDCs upon HSV-1 infection. Indeed, electroporation of iDCs with FIP200-specific siRNA prior to HSV-1 infection is a very specific and successful method to ablate FIP200 protein expression and thereby to inhibit autophagic flux. Both presented methods result in the efficient inhibition of HSV-1-induced autophagic turnover in iDCs, whereby the siRNA-based technique is more target specific. An additional siRNA-based approach was developed to selectively silence the protein expression of KIF1 B and KIF2A, facilitating autophagic turnover upon HSV-1 infection in mDCs. In conclusion, the technique of siRNA electroporation represents a promising strategy, to selectively ablate the expression of distinct proteins and to analyze their influence upon an HSV-1 infection.
CRIS-Team WoS Importer:2019-11-15

Sister-Mary-Joseph-Knoten der Brust – Beschreibung einer neuen Entität? - Popp, Judith; Heppt, Markus; Berking, Carola; Heppt, Franz (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-04-23

Six-Color Confocal Immunofluorescence Microscopy with 4-Laser Lines - Heger, Lukas; Lühr, Jennifer J.; Amon, Lukas; Smith, Ana-Suncana; Eissing, Nathalie; Dudziak, Diana (Methods in Molecular Biology, 2021)
Confocal immunofluorescence microscopy is an advanced imaging technique routinely applied in the laboratory and clinics. Histological analyses are performed from tissue material. In general, a single fluorochrome per laser is employed, limiting simultaneous analysis to four antigens in one staining with a conventional 4-laser line microscope. Here, we describe a protocol for combining fluorochromes with the same excitation but different emission properties that allows for the analysis of six different antigens in confocal immunofluorescence microscopy with a conventional 4-laser line microscope. The proposed multiplexed method permits the identification and characterization of complex cell populations in rare tissue material.
CRIS-Team Scopus Importer:2021-10-01
Keywords: DC; Dendritic cells; Fluorochrome; Histology; Multicolor imaging; Tissue

Skin and Soft Tissue Infections Caused by Mycobacterium chelonae: More Common Than Expected? - Uslu, Ugur; Boehm, Olga; Heppt, Franz; Sticherling, Michael (Acta Dermato-Venereologica, 2019)
Mycobacterium chelonae is a rapidly growing non-tuberculous mycobacterium, which causes infections of the human skin and soft tissue. Despite an increasing incidence of such infections, patients are often misdiagnosed. We report here 5 patients with cutaneous and/or soft tissue infection due to M. chelonae who were diagnosed and treated at our centre. Two of the 5 patients were on immunosuppressive treatment. While clinical presentations differed in each patient, all had a long history of skin lesions. In addition to careful history-taking, tissue biopsies were obtained for mycobacterial culture and histopathological examination. Culture-directed antibiotic therapy was initiated, which resulted in a slow, but continuous, healing of the lesions. In summary, M. chelonae infections are still relatively rare, but should be considered in both immunocompromised and immunocompetent patients with prolonged skin lesions resistant to standard antibiotic treatment. For diagnosis, tissue analysis for mycobacterial culture and histopathological examination, and once diagnosed, adequate antibiotic treatment, is needed.
CRIS-Team WoS Importer:2019-09-10

Skin lesions may be misleading for final diagnosis – a case of delayed diagnosis and therapy - Meder, Christine; Sticherling, Michael (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
CRIS-Team Scopus Importer:2023-06-09
Keywords: bacterial infections; T cell; virus

Skin symptoms as diagnostic clue for autoinflammatory diseases - Moreira, Alvaro; Torres, Barbara; Peruzzo, Juliano; Mota, Alberto; Eyerich, Kilian; Ring, Johannes (Anais Brasileiros De Dermatologia, 2017)
Autoinflammatory disorders are immune-mediated diseases with increased production of inflammatory cytokines and absence of detectable autoantibodies. They course with recurrent episodes of systemic inflammation and fever is the most common symptom. Cutaneous manifestations are prevalent and important to diagnosis and early treatment of the syndromes. The purpose of this review is to emphasize to dermatologists the skin symptoms present in these syndromes in order to provide their early diagnosis.
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Sklerosierende Hauterkrankungen - Sticherling, Michael (Internist, 2019)
Sclerosing skin manifestations are more a symptom than a diagnosis and must therefore be meticulously clarified. Systemic scleroderma as a multiorgan disease must be distinguished from localized scleroderma or morphea because in addition to a different clinical picture they have a different prognosis and necessitate other therapeutic procedures. Rare sclerosing skin diseases with implications for internal medicine are eosinophilic fasciitis, Buschke’s scleredema adultorum, scleromyxedema and nephrogenic systemic fibrosis.
CRIS-Team Scopus Importer:2019-08-02
Keywords: Mixed connective tissue disease; Morphea; Scleredema adultorum; Scleromyxedema; Systemic scleroderma

Soluble CD83 ameliorates experimental colitis in mice - Eckhardt, Jenny; Kreiser, Simon; Döbbeler, Marina; Nicolette, C.; Debenedette, M. A.; Tcherepanova, I. Y.; Ostalecki, Christian; Pommer, A. J.; Becker, Christoph; Günther, Claudia; Zinser, E.; Mak, T. W.; et al. (Mucosal Immunology, 2014)
The physiological balance between pro- and anti-inflammatory processes is dysregulated in inflammatory bowel diseases (IBD) as in Crohn's disease and ulcerative colitis. Conventional therapy uses anti-inflammatory and immunosuppressive corticosteroids to treat acute-phase symptoms. However, low remission rate and strong side effects of these therapies are not satisfying. Thus, there is a high medical need for new therapeutic strategies. Soluble CD83, the extracellular domain of the transmembrane CD83 molecule, has been reported to have interesting therapeutic and immunosuppressive properties by suppressing dendritic cell (DC)-mediated T-cell activation and inducing tolerogenic DCs. However, the expression and function of CD83 in IBD is still unknown. Here, we show that CD83 expression is upregulated by different leukocyte populations in a chemical-induced murine colitis model. Furthermore, in this study the potential of sCD83 to modulate colitis using an experimental murine colitis model was investigated. Strikingly, sCD83 ameliorated the clinical disease symptoms, drastically reduced mortality, and strongly decreased inflammatory cytokine expression in mesenteric lymph nodes and colon. The infiltration of macrophages and granulocytes into colonic tissues was vigorously inhibited. Mechanistically, we could show that sCD83-induced expression of indolamine 2,3-dioxygenase is essential for its protective effects.
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Soluble CD83 improves and accelerates wound healing by the induction of pro-resolving macrophages - Royzman, Dmytro; Peckert-Maier, Katrin; Stich, Lena; König, Christina; Wild, Andreas; Tauchi, Miyuki; Ostalecki, Christian; Kiesewetter, Franklin; Seyferth, Stefan; Lee, Geoffrey; Eming, Sabine A.; Fuchs, Maximilian; et al. (Frontiers in Immunology, 2022)
To facilitate the recovery process of chronic and hard-to-heal wounds novel pro-resolving treatment options are urgently needed. We investigated the pro-regenerative properties of soluble CD83 (sCD83) on cutaneous wound healing, where sCD83 accelerated wound healing not only after systemic but also after topical application, which is of high therapeutic interest. Cytokine profile analyses revealed an initial upregulation of inflammatory mediators such as TNFα and IL-1β, followed by a switch towards pro-resolving factors, including YM-1 and IL-10, both expressed by tissue repair macrophages. These cells are known to mediate resolution of inflammation and stimulate wound healing processes by secretion of growth factors such as epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), which promote vascularization as well as fibroblast and keratinocyte differentiation. In conclusion, we have found strong wound healing capacities of sCD83 beyond the previously described role in transplantation and autoimmunity. This makes sCD83 a promising candidate for the treatment of chronic- and hard-to-heal wounds.
CRIS-Team Scopus Importer:2022-10-28
Keywords: CD83; macrophages; stem cells; therapy; tissue regeneration; wound healing

Soluble CD83 inhibits skin inflammation to chemical sensitizers - Mihatsch, P.; Boyd, P.; Krzyzak, Lena; Lechmann, Matthias; Nicolas, J.; Mahler, Vera; Steinkasserer, Alexander; Vocanson, Marc (2016)
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Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14(+) Monocytes - Horvatinovich, Joe M.; Grogan, Elizabeth W.; Norris, Marcus; Steinkasserer, Alexander; Lemos, Henrique; Mellor, Andrew L.; Tcherepanova, Irina Y.; Nicolette, Charles A.; Debenedette, Mark A. (Journal of Immunology, 2017)
The transmembrane protein CD83, expressed on APCs, B cells, and T cells, can be expressed as a soluble form generated by alternative splice variants and/or by shedding. Soluble CD83 (sCD83) was shown to be involved in negatively regulating the immune response. sCD83 inhibits T cell proliferation in vitro, supports allograft survival in vivo, prevents corneal transplant rejection, and attenuates the progression and severity of autoimmune diseases and experimental colitis. Although sCD83 binds to human PBMCs, the specific molecules that bind sCD83 have not been identified. In this article, we identify myeloid differentiation factor-2 (MD-2), the coreceptor within the TLR4/MD-2 receptor complex, as the high-affinity sCD83 binding partner. TLR4/MD-2 mediates proinflammatory signal delivery following recognition of bacterial LPSs. However, altering TLR4 signaling can attenuate the proinflammatory cascade, leading to LPS tolerance. Our data show that binding of sCD83 to MD-2 alters this signaling cascade by rapidly degrading IL-1R-associated kinase-1, leading to induction of the anti-inflammatory mediators IDO, IL-10, and PGE2 in a COX-2-dependent manner. sCD83 inhibited T cell proliferation, blocked IL-2 secretion, and rendered T cells unresponsive to further downstream differentiation signals mediated by IL-2. Therefore, we propose the tolerogenic mechanism of action of sCD83 to be dependent on initial interaction with APCs, altering early cytokine signal pathways and leading to T cell unresponsiveness.
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Soluble CD83 modulates human-monocyte-derived macrophages toward alternative phenotype, function, and metabolism. - Peckert-Maier, Katrin; Wild, Andreas; Sprißler, Laura; Fuchs, Maximilian; Beck, Philipp; Auger, Jean-Philippe; Sinner, Pia; Strack, Astrid; Mühl-Zürbes, Petra; Ramadan, Ntilek; Kunz, Meik; Krönke, Gerhard; et al. (Frontiers in Immunology, 2023)
Alterations in macrophage (Mφ) polarization, function, and metabolic signature can foster development of chronic diseases, such as autoimmunity or fibrotic tissue remodeling. Thus, identification of novel therapeutic agents that modulate human Mφ biology is crucial for treatment of such conditions. Herein, we demonstrate that the soluble CD83 (sCD83) protein induces pro-resolving features in human monocyte-derived Mφ biology. We show that sCD83 strikingly increases the expression of inhibitory molecules including ILT-2 (immunoglobulin-like transcript 2), ILT-4, ILT-5, and CD163, whereas activation markers, such as MHC-II and MSR-1, were significantly downregulated. This goes along with a decreased capacity to stimulate alloreactive T cells in mixed lymphocyte reaction (MLR) assays. Bulk RNA sequencing and pathway analyses revealed that sCD83 downregulates pathways associated with pro-inflammatory, classically activated Mφ (CAM) differentiation including HIF-1A, IL-6, and cytokine storm, whereas pathways related to alternative Mφ activation and liver X receptor were significantly induced. By using the LXR pathway antagonist GSK2033, we show that transcription of specific genes (e.g., PPARG, ABCA1, ABCG1, CD36) induced by sCD83 is dependent on LXR activation. In summary, we herein reveal for the first time mechanistic insights into the modulation of human Mφ biology by sCD83, which is a further crucial preclinical study for the establishment of sCD83 as a new therapeutical agent to treat inflammatory conditions.
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Soluble CD83 promotes cutaneous wound healing in an IDO-and beta-catenindependent manner - Royzman, Dmytro; Peckert-Maier, K.; Stich, L.; Wild, Andreas; Ostalecki, C.; Kiesewetter, Franklin; Seyferth, Stefan; Lee, Geoffrey; Eming, S. A.; Berking, Carola; Zinser, Elisabeth; Steinkasserer, Alexander (EXPERIMENTAL DERMATOLOGY, 2022)
CRIS-Team WoS Importer:2022-03-04

Soluble CD83 Triggers Resolution of Arthritis and Sustained Inflammation Control in IDO Dependent Manner - Royzman, Dmytro; Andrev, Darja; Stich, Lena; Rauh, Manfred; Bäuerle, Tobias; Ellmann, Stephan; Boon, Louis; Kindermann, Markus; Peckert, Katrin; Bozec, Aline; Schett, Georg; Steinkasserer, Alexander; et al. (Frontiers in Immunology, 2019)
Interference with autoimmune-mediated cytokine production is a key yet poorly developed approach to treat autoimmune and inflammatory diseases such as rheumatoid arthritis. Herein, we show that soluble CD83 (sCD83) enhances the resolution of autoimmune antigen-induced arthritis (AIA) by strongly reducing the expression levels of cytokines such as IL-17A, IFN gamma, IL-6, and TNF alpha within the joints. Noteworthy, also the expression of RANKL, osteoclast differentiation, and joint destruction was significantly inhibited by sCD83. In addition, osteoclasts which were cultured in the presence of synovial T cells, derived from sCD83 treated AIA mice, showed a strongly reduced number of multinuclear large osteoclasts compared to mock controls. Enhanced resolution of arthritis by sCD83 was mechanistically based on IDO, since inhibition of IDO by 1-methyltryptophan completely abrogated sCD83 effects on AIA. Blocking experiments, using anti-TGF-beta antibodies further revealed that also TGF-beta is mechanistically involved in the sCD83 induced reduction of bone destruction and cartilage damage as well as enhanced resolution of inflammation. Resolution of arthritis was associated with increased numbers of regulatory T cells, which are induced in a sCD83-IDO-TGF-beta dependent manner. Taken together, sCD83 represents an interesting approach for downregulating cytokine production, inducing regulatory T cells and inducing resolution of autoimmune arthritis.
CRIS-Team WoS Importer:2019-04-12

Sonnenschutz, Stahl, Strahl, Salbe und Systemtherapie - Berking, Carola; Szeimies, R. M. (Hautarzt, 2020)
CRIS-Team Scopus Importer:2020-08-07

SOX10-based drug repurposing identifies novel therapeutic targets in uveal melanoma - Wessely, A.; Kammerbauer, C.; Lischer, Christopher; Weich, A.; Vera, Julio; Berking, Carola; Heppt, Markus (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

Späte Diagnose einer subkutanen Dirofilariose nach einem Mückenstich in Deutschland - Uslu, Ugur; Jahn, Julia; Erdmann, Michael (Journal der Deutschen Dermatologischen Gesellschaft, 2017)
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Spätfolgen nach Immuntherapie: Immunvermittelte Nebenwirkungen von Checkpointinhibitoren - Duong, Sophie L.; Zierold, Sarah; Kramer, Rafaela; Reincke, Martin; Kerl-French, Katrin; Boehmerle, Wolfgang; Pavel, Marianne Ellen; Weckbach, Ludwig; French, Lars E.; Knauss, Samuel; Heinzerling, Lucie (Onkologe, 2021)
Background: Immune checkpoint inhibitors (ICIs) are potent immunotherapeutic agents for many tumor entities. However, ICIs can induce immune-related adverse events (irAE) that can potentially affect any organ system, causing life-changing sequelae or even death. These irAEs can occur months after termination of immunotherapy and long-term effects may persist for years after finishing therapy. Due to expanding clinical indications for ICIs including therapy in earlier tumor stages, the risk–benefit analysis needs to take into account these long-term side effects. Objectives: The sequelae of ICI therapy are reviewed and the international online registry Side Effect Registry Immuno-Oncology (SERIO) for the unified collection and characterization of irAEs is introduced. Materials and methods: We analyzed data from SERIO and performed a selective literature search in the databases PubMed, Cochrane Central Register of Controlled Trials and Google Scholar to characterize, analyze and summarize long-term sequelae of irAE induced by ICI therapy. Results: The most commonly observed irAEs with long-term sequelae involve the skin (leucotrichia, melanoma-associated hypopigmentation) and endocrine irAEs (thyroiditis, hypophysitis, adrenalitis and diabetes). While the former is especially stigmatizing, endocrine irAEs usually require long-term hormone substitution. Neurologic and cardiologic irAEs are relatively rare, but they are associated with severe complications leading to increased morbidity and mortality. Conclusions: Until now, prospective data about long-term consequences of irAEs are lacking. The SERIO registry addresses this need as irAEs are collected to enable long-term follow-up and optimized management.
CRIS-Team Scopus Importer:2021-05-21
Keywords: Benefit-risk assessment; Data collection; Hypopigmentation; Neoplasms; Registries

Spatial, structural and density determinants of DC:T cell interaction under immunostimulatory conditions - Vurnek, D.; Amon, Lukas; Buttazzo, L.; Lehmann, C.; Zaburdaev, Vasily; Dudziak, Diana (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Specific dermatoses of pregnancy - Ambros-Rudolph, C. M.; Sticherling, Michael (Hautarzt, 2017)
The specific dermatoses of pregnancy represent a heterogeneous group of inflammatory skin diseases related to pregnancy and/or the postpartum period. A clinically relevant classification has been well established over the past 10 years and includes pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy, and atopic eruption of pregnancy. The hallmark of all four entities is severe pruritus that is accompanied by characteristic skin changes. While some of these dermatoses are distressing only to the mother because of pruritus, others may be associated with significant fetal risks. Early diagnosis and prompt treatment are therefore essential. In this review, we discuss in detail pemphigoid gestationis, polymorphic and atopic eruptions of pregnancy whereas intrahepatic cholestasis of pregnancy is discussed in a separate article (Kremer A, Ständer S, DOI 10.1007/s00105-016-3923-y ). Furthermore, we present a helpful algorithm for diagnosis and management of pruritus in pregnancy.
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Specific phenotype and function of CD56-expressing innate immune cell subsets in human thymus - Gerstner, Stephanie; Köhler, Wolfgang; Heidkamp, Gordon Frederik; Purbojo, Ariawan; Uchida, Shizuka; Ekici, Arif Bülent; Heger, Lukas; Luetke-Eversloh, Merlin; Schubert, Ralf; Bader, Peter; Klingebiel, Thomas; Koehl, Ulrike; et al. (Journal of Leukocyte Biology, 2016)
Whereas innate immune cells, such as NK and innate lymphoid cells (ILCs), have been characterized in different human tissues, knowledge on the thymic CD56-expressing cell subsets is limited. In this study, the rare subpopulations of thymic CD56(+)CD3(-) cells from samples of >100 patients have been successfully analyzed. The results revealed fundamental differences between thymic and peripheral blood (PB) CD56(+)CD3(-) cells. Thymic tissues lacked immunoregulatory CD56(high)CD16(dim) NK cells but showed two Eomes(+)CD56(dim) subsets on which common NK cell markers were significantly altered. CD56(dim)CD16(high) cells expressed high amounts of NKG2A, NKG2D, and CD27 with low CD57. Conversely, CD56(dim)CD16(dim) cells displayed high CD127 but low expression of KIR, NKG2D, and natural cytotoxicity receptors (NCRs). Thymic CD56(+)CD3(-) cells were able to gain cytotoxicity but were especially immunoregulatory cells, producing a broad range of cytokines. Finally, one population of thymic CD56(+) cells resembled conventional NK cells, whereas the other represented a novel, noncanonical NK subset.
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Spectrum of peristomal Dermatoses - Dietmaier, Louisa; Summa, S.; Erfurt-Berge, Cornelia (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-04-16

Spontaneous regression rates of actinic keratosis: a systematic review and pooled analysis of randomized controlled trials. - Steeb, Theresa; Petzold, Anne; Hornung, Annkathrin; Wessely, Anja; Berking, Carola; Heppt, Markus (Scientific Reports, 2022)
Actinic keratosis (AK) are precancerous lesions of the skin which may progress to invasive squamous cell carcinoma. However, single lesions may also persist or even regress and heal spontaneously. Until now, evidence on the natural course of AK including spontaneous regression is limited. We aimed to synthesize regression rates of AK. We performed a systematic literature research in Medline, Embase, and CENTRAL for eligible trials until 3rd March 2020. Spontaneous regression rates were pooled using a random-effects model to calculate pooled proportions of participant-specific and lesion-specific complete clearance rates reported for the placebo arms of randomized controlled trials. Subgroup analyses were performed to dissect differences according to the type of placebo, immunocompetence of the participants, and localization of the lesions. Data from 38 records was included. The pooled participant-specific clearance rate was 8% (95% CI 6-10%, I2 = 71%) while the lesion-specific clearance rate was 23% (95% CI 16-31%, I2 = 97%). The highest participant- and lesion-specific clearance rates were achieved 12 weeks after the end of treatment (12% and 33%, respectively). Subgroup analysis revealed participant- as well as lesion-specific clearance rates of 0% for organ transplant recipients (OTR). We conclude that only a few participants achieve complete regression of their AK without any active treatment. Besides, the results underline that lesion clearance without active treatment is unlikely in OTR. Thus, early and consequent treatment of AK is recommended. Special attention should be paid when treating AK of OTR.
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Squamous cell carcinomas in chronic venous leg ulcers. Data of the German Marjolin Registry and review - Reich-Schupke, Stefanie; Doerler, Martin; Wollina, Uwe; Dissemond, Joachim; Horn, Thomas; Stroelin, Anke; Stuecker, Markus; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2015)
Background: Secondary squamous cell carcinoma (SCC) is a rare complication of chronic venous leg ulcers. So far, little is known about its pathophysiology and clinical behavior. Initiated by the working group "Wound Healing" (AGW) of the German Society of Dermatology (DDG), it is the objective of the current Marjolin registry to collect cases of SCC arising in venous ulcers, in order to evaluate diagnostic characteristics. Patients and Methods: All members of the AGW received questionnaires inquiring about basic patient data, ulcer characteristics, and therapy conducted. Results: From 2010 to 2013, 30 patients (20 women, 10 men) from six tertiary wound care centers were registered. Mean age was 76.17 years. The average duration of venous leg ulcers prior to SCC diagnosis was 15.93 years. Suspicious wound characteristics primarily included: pain (n = 3), therapy resistance (n = 27), and fetor (n = 12) as well as clinical appearance (n = 10) with atypical morphology, nodular wound bed, and hypergranulation. Conclusions: Atypical morphology or changes in appearance as well as therapy resistance despite optimal care (6-12 weeks) should prompt physicians to take spindle-shaped, if necessary multiple and serial, biopsies. Primary risk factors for malignant transformation include patient age and ulcer duration.
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Stability and activity of MCSP-specific chimeric antigen receptors (CARs) depend on the scFv antigen-binding domain and the protein backbone - Krug, Christian; Birkholz, Katrin; Paulus, Alexander; Schwenkert, Michael; Schmidt, Patrick; Hoffmann, Nicole; Hombach, Andreas; Fey, Georg; Abken, Hinrich; Schuler, Gerold; Schuler-Thurner, Beatrice; Dörrie, Jan; et al. (Cancer Immunology Immunotherapy, 2015)
Chimeric antigen receptor (CAR)-modified T cells emerged as effective tools in the immunotherapy of cancer but can produce severe on-target off-tissue toxicities. This risk can conceivably be overcome, at least partially, by transient transfection. The design of CARs, however, has so far not been optimized for use in non-permanent T cell modification. Here we compared the performance of T cells modified with three different first- and second-generation CARs, each specific for MCSP (HMW-MAA) which is commonly expressed by melanoma cells. Upon RNA transfer, the expression of all receptors was limited in time. The second-generation CARs, which combined CD28-CD3ζ signaling, were expressed at higher levels and more prolonged than first-generation CARs with CD3ζ only. The CD28 domain increased the cytokine production, but had only an indirect effect on the lytic capacity, by prolonging the CAR expression. Especially for the second-generation CARs, the scFv clearly impacted the level and duration of CAR expression and the T cell performance. Thus, we identified a CAR high in both expression and anti-tumor cell reactivity. T cells transfected with this CAR increased the mean survival time of mice after challenge with melanoma cells. To facilitate clinical application, this CAR was used to redirect T cells from late-stage melanoma patients by RNA transfection. These T cells mediated effective antigen-specific tumor cell lysis and release of pro-inflammatory cytokines, even after cryoconservation of the transfected T cells. Taken together, the analysis identified a CAR with superior anti-melanoma performance after RNA transfer which is a promising candidate for clinical exploration.
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