Clinical characteristics and outcome of 60 pediatric patients with malignant melanoma registered with the German Pediatric Rare Tumor Registry (STEP) - Offenmüller, Sonja; Leiter, Ulrike; Bernbeck, Benedikt; Garbe, Claus; Eigentler, Thomas; Borkhardt, Arndt; Classen, Carl Friedrich; Corbacioglu, Selim; Dirksen, Uta; Ebetsberger-Dachs, Georg; Heinzerling, Lucie; Jorch, Norbert; et al. (Klinische Pädiatrie, 2017)
Background Malignant melanoma (MM) is a common malignancy in adults while it is rare in children. Thus, information on clinical behavior of pediatric MM is incomplete. Patients The German Pediatric Rare Tumor Registry (STEP) presents a prospective analysis of 60 childhood MM cases diagnosed between June 2006 and December 2014. Method Patients' ages ranged between 0 and 17 years at initial diagnosis (median age 9.6 years). Information on patient's and tumor characteristics was obtained by standardized documentation. Three-year overall survival (OS) and event-free survival (EFS) were estimated by the Kaplan-Meier test. Results Follow-up ranged from 0 to 116 months with a median of 36.5 months, however, univariate analysis was performed for 46 cases with a follow-up > 3 months, only. Cases with spitzoid histotype (40%) did not show a significantly different outcome compared to cases with non-spitzoid MM. Breslow thickness ≤ 2.00 mm was identified in 30% of the cases and 18% were Clark level I to III. Adjuvant therapy was used in 45% of cases. OS at 3 years was 100%, EFS 95.2%. Conclusion We present a series of cases with a high number of spitzoid malignant melanoma and advanced pediatric melanoma, but surprisingly good overall survival rates. Spitzoid and non-spitzoid MM do not differ in clinical behavior and survival.
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Clinical characteristics and therapy response in unresectable melanoma patients stage IIIB-IIID with in-transit and satellite metastases - Zaremba, Anne; Philip, Manuel; Hassel, Jessica C.; Glutsch, Valerie; Fiocco, Zeno; Loquai, Carmen; Rafei-Shamsabadi, David; Gutzmer, Ralf; Utikal, Jochen; Haferkamp, Sebastian; Reinhardt, Lydia; Kähler, Katharina C.; et al. (European Journal of Cancer, 2021)
Introduction: Cutaneous melanoma is notorious for the development of in-transit metastases (ITM). For unknown biological reasons, ITM remain the leading tumour manifestation without progression to distant sites in some patients. Methods: In total, 191 patients with initially unresectable stage III ITM and satellite metastases from 16 skin cancer centres were retrospectively evaluated for their tumour characteristics, survival and therapy response. Three groups according to disease kinetics (no distant progress, slow (>6 months) and fast (<6 months) distant progression) were analysed separately. Results: Median follow-up time was 30.5 (range 0.8–154.0) months from unresectable ITM. Progression to stage IV was observed in 56.5% of cases. Patients without distant metastasis were more often female, older (>70 years) and presented as stage III with lymph node or ITM at initial diagnosis in 45.7% of cases. Melanoma located on the leg had a significantly better overall survival (OS) from time of initial diagnosis compared to non-leg localised primaries (hazard ratio [HR] = 0.61, 95% confidence interval [CI] 0.40–0.91; p = 0.017), but not from diagnosis of unresectable stage III (HR = 0.67, 95% CI 0.45–1.02; p = 0.06). Forty percent of patients received local therapy for satellite and ITM. Overall response rate (ORR) to all local first-line treatments was 38%; disease control rate (DCR) was 49%. In total, 72.3% of patients received systemic therapy for unresectable stage IIIB-D. ORR for targeted therapy (n = 19) was highest with 63.2% and DCR was 84.2% compared to an ORR of 31.4% and a DCR of 54.3% in PD-1 treated patients (n = 70). Patients receiving PD-1 and intralesional talimogene laherparepvec (n = 12) had an ORR of 41.7% and a DCR of 75%. Conclusion: Patients with unresectable ITM and without distant progression are more often female, older, and have a primary on the leg. Response to PD-1 inhibitors in this cohort was lower than expected, but further investigation is required to elucidate the biology of ITM development and the interplay with the immune system.
CRIS-Team Scopus Importer:2021-07-23
Keywords: Immune checkpoint blockade; In-transit; Intralesional therapy; Melanoma; Prognosis; Satellite; Survival; Targeted therapy

Clinical characteristics and treatment modalities in uremic and non uremic calciphylaxis - a dermatological single-center experience - Yousuf, Sabine; Busch, Dorothee; Renner, Regina; Schliep, Stefan; Erfurt-Berge, Cornelia (Renal Failure, 2024)
Calciphylaxis (CP) is a serious, potentially life-threatening disease that presents with medial calcification of small-sized vessels and painful ischemic ulcerations. Although calciphylaxis is frequently seen in patients with end-stage kidney disease on dialysis (calcific uremic arteriolopathy, CUA), there are reported cases of nonuremic calciphylaxis (NUC), which often remain undiagnosed. We conducted a retrospective chart review at our dermatological hospital and evaluated data concerning the epidemiology, comorbidities, medication, laboratory abnormalities, and therapeutic approaches of 60 patients diagnosed with calciphylaxis between 01/2012 and 12/2022. We identified 21 patients diagnosed with NUC and 39 with kidney disease. The predilection sites of skin lesions were the lower legs in 88% (n = 53), followed by the thigh and gluteal regions in 7% (n = 4). Significant differences were identified in comorbidities, such as atrial fibrillation (p < 0.001) and hyperparathyroidism (p < 0.01) accounting for CUA patients. Medication with vitamin K antagonists (p < 0.001), phosphate binders (p < 0.001), and loop diuretics (p < 0.01) was found to be associated with the onset of calciphylaxis. Hyperphosphatemia (p < 0.001), increased parathyroid hormone (p < 0.01) and triglyceride levels (p < 0.01), hypoalbuminemia (p < 0.01) and decreased hemoglobin values (p < 0.001) in the CUA cohort were significantly different from those in the NUC group. All patients with CUA received systemic medication. In contrast, only 38% (n = 8) of patients with NUC received systemic treatment. Striking discrepancies in the treatment of both cohorts were detected. In particular, NUC remains a disease pattern that is still poorly understood and differs from CUA in several important parameters.
CRIS-Team Scopus Importer:2024-01-19
Keywords: calcific uremic arteriolopathy; Calciphylaxis; leg ulcer; nonuremic calciphylaxis

Clinical determinants of long-term survival in metastatic uveal melanoma - Koch, Elias; Petzold, Anne; Wessely, Anja; Dippel, Edgar; Erdmann, Michael; Heinzerling, Lucie; Hohberger, Bettina; Knorr, Harald; Leiter, Ulrike; Meier, Friedegund; Mohr, Peter; Rahimi, Farnaz; et al. (Cancer Immunology, Immunotherapy, 2021)
This study aimed to identify prognostic factors in patients with metastatic uveal melanoma (UM) that were associated with long-term survival in a real-world setting. A total of 94 patients with metastatic UM were included from German skin cancer centers and the German national skin cancer registry (ADOReg). Data were analyzed for the response to treatment, progression-free survival, and overall survival (OS). Prognostic factors were explored with univariate Cox regression, log-rank, and χ2-tests. Identified factors were subsequently validated after the population was divided into two cohorts of short-term survival (< 2 years OS, cohort A, n = 50) and long-term survival (> 2 years OS, cohort B, n = 44). A poor ECOG performance status (hazard ratio [HR] 2.0, 95% confidence interval [CI] 1.0–3.9) and elevated serum LDH (HR 2.0, 95% CI 1.0–3.8) were associated with a poor OS, whereas a good response to immune checkpoint blockade (ICB, p < 0.001), radiation therapy (p < 0.001), or liver-directed treatments (p = 0.01) were associated with a prolonged OS. Long-term survivors (cohort B) showed a higher median number of organs affected by metastasis (p < 0.001), while patients with liver metastases only were more common in cohort A (40% vs. 9%; p = 0.002). A partial response to ICB was observed in 16% (12/73), being 21% (8/38) for combined ICB, 17% (1/6) for single CTLA4 inhibition, and 10% (3/29) for single PD1 inhibition. One complete response occurred in cohort B with combined ICB. We conclude that the response to ICB and the presence of extrahepatic disease were favorable prognostic factors for long-term survival.
CRIS-Team Scopus Importer:2021-11-05
Keywords: Immune checkpoint blockade; Liver metastases; Liver-directed treatment; Long-term survival; Registry; Uveal melanoma

Clinical Experience Using a Monofilament Fiber Cleansing and Debriding Technology for Various Skin Conditions - Andriessen, Anneke Elizabeth; Wiegand, Cornelia; Eberlein, Thomas; Erfurt-Berge, Cornelia; Roes, Claas (Journal of Drugs in Dermatology, 2022)
Background: Gentle skin cleansing and exfoliation and the use of moisturizers as an adjunct to medical treatment should be part of the prevention, treatment, and maintenance of cutaneous conditions such as acne vulgaris (acne) psoriasis, and xerosis. A monofilament fiber debriding technology (MFDT) is used for effective, safe, and rapid skin cleansing and exfoliation and debris, slough, and biofilrn removal. The current review addresses the clinical experience using MFDT for various cutaneous conditions that require cleansing or exfoliation or both and how to combine it with medical treatment.
CRIS-Team WoS Importer:2022-12-09

Clinical impact of COVID-19 on patients with cancer treated with immune checkpoint inhibition - Rogiers, Aljosja; Da Silva, Ines Pires; Tentori, Chiara; Tondini, Carlo Alberto; Grimes, Joseph M.; Trager, Megan H.; Nahm, Sharon; Zubiri, Leyre; Manos, Michael; Bowling, Peter; Elkrief, Arielle; Papneja, Neha; et al. (Journal for ImmunoTherapy of Cancer, 2021)
Background Patients with cancer who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are more likely to develop severe illness and die compared with those without cancer. The impact of immune checkpoint inhibition (ICI) on the severity of COVID-19 illness is unknown. The aim of this study was to investigate whether ICI confers an additional risk for severe COVID-19 in patients with cancer. Methods We analyzed data from 110 patients with laboratory-confirmed SARS-CoV-2 while on treatment with ICI without chemotherapy in 19 hospitals in North America, Europe and Australia. The primary objective was to describe the clinical course and to identify factors associated with hospital and intensive care (ICU) admission and mortality. Findings Thirty-five (32%) patients were admitted to hospital and 18 (16%) died. All patients who died had advanced cancer, and only four were admitted to ICU. COVID-19 was the primary cause of death in 8 (7%) patients. Factors independently associated with an increased risk for hospital admission were ECOG ≥2 (OR 39.25, 95% CI 4.17 to 369.2, p=0.0013), treatment with combination ICI (OR 5.68, 95% CI 1.58 to 20.36, p=0.0273) and presence of COVID-19 symptoms (OR 5.30, 95% CI 1.57 to 17.89, p=0.0073). Seventy-six (73%) patients interrupted ICI due to SARS-CoV-2 infection, 43 (57%) of whom had resumed at data cut-off. Interpretation COVID-19-related mortality in the ICI-treated population does not appear to be higher than previously published mortality rates for patients with cancer. Inpatient mortality of patients with cancer treated with ICI was high in comparison with previously reported rates for hospitalized patients with cancer and was due to COVID-19 in almost half of the cases. We identified factors associated with adverse outcomes in ICI-treated patients with COVID-19.
CRIS-Team Scopus Importer:2021-02-05
Keywords: immunotherapy

Clinical Manifestation of Cutaneous Leishmaniasis Following a Mechanical Trauma - Busch, Dorothee; Bogdan, Christian; Erfurt-Berge, Cornelia (International Journal of Lower Extremity Wounds, 2020)
Unusual skin ulcers frequently represent a diagnostic challenge. When the most common disease entities such as arterial, venous or diabetic ulcers have been excluded, the question of further differential diagnoses and procedures arises. Other possible causes include chronic inflammatory diseases, neoplasia, self-inflicted wounds, primary infectious diseases and physical/chemical damage to the skin. To narrow down the differential diagnoses, a detailed history of the patient is essential, which also needs to include events further back in time.
CRIS-Team Scopus Importer:2020-11-13
Keywords: delayed diagnosis; leg ulcer; leishmaniasis; trauma

Clinical outcome of concomitant vs interrupted BRAF inhibitor therapy during radiotherapy in melanoma patients - Hecht, Markus; Meier, Friedegund; Zimmer, Lisa; Polat, Bulent; Loquai, Carmen; Weishaupt, Carsten; Forschner, Andrea; Gutzmer, Ralf; Utikal, Jochen S.; Goldinger, Simone M.; Geier, Michael; Hassel, Jessica C.; et al. (British Journal of Cancer, 2018)
This corrects the article DOI: 10.1038/bjc.2017.85.
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Clinical Prognostic Factors in metastatic Choroidal Melanoma - Koch, Elias; Petzold, Anne; Wessely, Anja; Dippel, E.; Erdmann, Michael; Heinzerling, L.; Hohberger, Bettina; Knorr, H.; Leiter-Stoppke, U.; Meier, F.; Mohr, P.; Rahimi, F.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Clinical-Scale Production of CAR-T Cells for the Treatment of Melanoma Patients by mRNA Transfection of a CSPG4-Specific CAR under Full GMP Compliance. - Wiesinger, Manuel; Maerz, Johannes; Kummer, Mirko; Schuler, Gerold; Dörrie, Jan; Schuler-Thurner, Beatrice; Schaft, Niels (Cancers, 2019)
Chimeric antigen receptor (CAR)-T cells already showed impressive clinical regressions in leukemia and lymphoma. However, the development of CAR-T cells against solid tumors lags behind. Here we present the clinical-scale production of CAR-T cells for the treatment of melanoma under full GMP compliance. In this approach a CAR, specific for chondroitin sulfate proteoglycan 4 (CSPG4) is intentionally transiently expressed by mRNA electroporation for safety reasons. The clinical-scale protocol was optimized for: (i) expansion of T cells, (ii) electroporation efficiency, (iii) viability, (iv) cryopreservation, and (v) potency. Four consistency runs resulted in CAR-T cells in clinically sufficient numbers, i.e., 2.4 x 10(9) CAR-expressing T cells, starting from 1.77x10(8)PBMCs, with an average expansion of 13.6x, an electroporation efficiency of 88.0% CAR-positive cells, a survival of 74.1% after electroporation, and a viability of 84% after cryopreservation. Purity was 98.7% CD3(+) cells, with 78.1% CD3(+)/CD8(+) T cells and with minor contaminations of 1.2% NK cells and 0.6% B cells. The resulting CAR-T cells were tested for cytolytic activity after cryopreservation and showed antigen-specific and very efficient lysis of tumor cells. Although our work is descriptive rather than investigative in nature, we expect that providing this clinically applicable protocol to generate sufficient numbers of mRNA-transfected CAR-T cells will help in moving the field of adoptive cell therapy of cancer forward.
CRIS-Team WoS Importer:2019-09-24

CLL-cell-mediated MDSC induction by exosomal miR-155 transfer is disrupted by vitamin D - Böttcher, Martin; Bruns, Heiko; Qorraj, M.; Fabri, M.; Jitschin, S.; Dindorf, J.; Busch, L.; Jitschin, R.; Mackensen, Andreas; Mougiakakos, Dimitrios (Leukemia, 2017)
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Cofactors and comorbidities of necrobiosis lipoidica: analysis of the German DRG data from 2012 - Jockenhoefer, Finja; Kroeger, Knut; Klode, Joachim; Renner, Regina; Dissemond, Joachim; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2016)
Necrobiosis lipoidica (NL) is a rare granulomatous inflammatory skin disease of unknown pathophysiology. Its potential association with diabetes mellitus is well known. Other relevant cofactors and comorbidities are subject to controversial debate.DRG (diagnosis-related groups) data of all inpatients with a coded primary or secondary diagnosis of NL treated at German hospitals in 2012 were evaluated.Data of 262 inpatient cases with the primary or secondary diagnosis of NL were analyzed. Women (63.4%; n = 166) were nearly twice as frequently affected as men (36.2%; n = 96). Most NL patients (14.8%) were in the age group between 50 and 55 years. Among comorbidities included in the metabolic syndrome complex, diabetes mellitus was the most common (34.4%; IDDM 20.6%, NIDDM 13.8%), while essential hypertension was observed in 9.2%, obesity in 4.6%, chronic heart failure in 4.1%, and dyslipidemias in 2.3% of cases. Leg ulcers were diagnosed in 7.3% of individuals; other venous disorders, in 5.7%.Our data analysis describes one of the largest compilations of patient cases with the diagnosis of NL worldwide. Besides the well-known association with diabetes mellitus, there are numerous other potentially relevant cofactors and comorbidities that should be considered in the diagnosis and management of NL patients.
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Combination therapies to improve DC-based treatment of melanoma - Seretis, A.; Cappellano, G.; Bellmann, L.; Schachtl-Riess, J.; Steindl, R.; Prokopi, N.; Ortner-Tobider, D.; Komenda, K.; Tripp, C.; Brinckerhoff, C. E.; Lühr, Jennifer; Amon, Lukas; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-11

Combined cytotoxic activity of an infectious, but non-replicative herpes simplex virus type 1 and plasmacytoid dendritic cells against tumour cells - Thomann, Sabrina; Boscheinen, Jan; Vogel, Karin; Knipe, David M.; Deluca, Neal; Gross, Stefanie; Schuler-Thurner, Beatrice; Schuster, Philipp; Schmidt, Barbara (Immunology, 2015)
Malignant melanoma is an aggressive tumour of the skin with increasing incidence, frequent metastasis and poor prognosis. At the same time, it is an immunogenic type of cancer with spontaneous regressions. Most recently, the tumoricidal effect of plasmacytoid dendritic cells (pDC) and their capacity to overcome the immunosuppressive tumour microenvironment are being investigated. In this respect, we studied the effect of the infectious, but replication-deficient, herpes simplex virus 1 (HSV-1) d106S vaccine strain, which lacks essential immediate early genes, in pDC co-cultures with 11 melanoma cell lines. We observed a strong cytotoxic activity, inducing apoptotic and necrotic cell death in most melanoma cell lines. The cytotoxic activity of HSV-1 d106S plus pDC was comparable to the levels of cytotoxicity induced by natural killer cells, but required only a fraction of cells with effector : target ratios of 1 : 20 (P < 0·05). The suppressive activity of cell-free supernatants derived from virus-stimulated pDC was significantly neutralized using antibodies against the interferon-? receptor (P < 0·05). In addition to type I interferons, TRAIL and granzyme B contributed to the inhibitory effect of HSV-1 d106S plus pDC to a minor extent. UV-irradiated viral stocks were significantly less active than infectious particles, both in the absence and presence of pDC (P < 0·05), indicating that residual activity of HSV-1 d106S is a major component and sensitizes the tumour cells to interferon-producing pDC. Three leukaemic cell lines were also susceptible to this treatment, suggesting a general anti-tumour effect. In conclusion, the potential of HSV-1 d106S for therapeutic vaccination should be further evaluated in patients suffering from different malignancies.
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Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions - Hassel, Jessica C.; Heinzerling, Lucie; Aberle, Jens; Baehr, Oliver; Eigentler, Thomas K.; Grimm, Marc-Oliver; Gruenwald, Victor; Leipe, Jan; Reinmuth, Niels; Tietze, Julia K.; Trojan, Joerg; Zimmer, Lisa; et al. (Cancer Treatment Reviews, 2017)
BACKGROUND: Combined immune checkpoint blockade (ICB) provides unprecedented efficacy gains in numerous cancer indications, with PD-1 inhibitor nivolumab plus CTLA-4 inhibitor ipilimumab in advanced melanoma as first-ever approved therapies for combined ICB. However, gains in efficacy must be balanced against a higher frequency and severity of adverse drug reactions (ADR). Because delays in diagnosis and management might result in symptom worsening and further complications, clinicians shall be well trained to identify ADR promptly and monitor patients adequately. This paper reviews safety data assessed by the European Medicines Agency for the anti-PD-1/CTLA-4 combination and provides a literature overview on published case reports for rare ADR with suspected potential underreporting. Incidences and kinetics of immune-related ADR are described. Recommendations for the evaluation and management of ADR are convened by an interdisciplinary expert panel focusing on rare but clinically important side effects arising from combined ICB. Pooled safety data from 1551 patients with advanced melanoma, treated either with 3mg/kg ipilimumab plus 1mg/kg nivolumab (N=407), or nivolumab alone (N=787), or ipilimumab alone (N=357) demonstrate that immune-related ADR occur more frequently for the combination, with a shorter time-to-onset, and tend to be more severe. The majority of events is reversible after systemic use of glucocorticoids, notably methylprednisolone or equivalents; in certain cases of long-lasting and refractory immune toxicities, non-steroidal immunosuppressants may be used, once ICB is interrupted or terminated. Combined ICB has considerable toxicities, therefore close monitoring and high experience in diagnosis and treatment of ADR is necessary.
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Combined immune checkpoint blockade for metastatic uveal melanoma: a retrospective, multi-center study - Heppt, Markus V.; Amaral, Teresa; Kähler, Katharina C.; Heinzerling, Lucie; Hassel, Jessica C.; Meissner, Markus; Kreuzberg, Nicole; Loquai, Carmen; Reinhardt, Lydia; Utikal, Jochen; Dabrowski, Evelyn; Gesierich, Anja; et al. (Journal for ImmunoTherapy of Cancer, 2019)
BACKGROUND: Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear. METHODS: Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression. RESULTS: The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5 months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0 months (range 7.0-65.0). The median PFS was 3.0 months (95% CI 2.4-3.6). The median OS was estimated to 16.1 months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p = 0.007). CONCLUSIONS: The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.
CRIS-Team Scopus Importer:2019-11-22
Keywords: Biomarker; Combined immune checkpoint blockade; Ipilimumab; Nivolumab; Uveal melanoma

Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients - Amaral, Teresa; Kiecker, Felix; Schaefer, Sarah; Stege, Henner; Kaehler, Katharina; Terheyden, Patrick; Gesierich, Anja; Gutzmer, Ralf; Haferkamp, Sebastian; Uttikal, Jochen; Berking, Carola; Rafei-Shamsabadi, David; et al. (Journal for ImmunoTherapy of Cancer, 2020)
BACKGROUND: Nivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM). However, in most of the clinical trials investigating immunotherapy in this subgroup, patients with symptomatic MBM and/or prior local brain radiotherapy were excluded. We studied the efficacy of nivolumab plus ipilimumab alone or in combination with local therapies regardless of treatment line in patients with asymptomatic and symptomatic MBM. METHODS: Patients with MBM treated with nivolumab plus ipilimumab in 23 German Skin Cancer Centers between April 2015 and October 2018 were investigated. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS. RESULTS: Three hundred and eighty patients were included in this study and 31% had symptomatic MBM (60/193 with data available) at the time of start nivolumab plus ipilimumab. The median follow-up was 18 months and the 2 years and 3 years OS rates were 41% and 30%, respectively. We identified the following independently significant prognostic factors for OS: elevated serum lactate dehydrogenase and protein S100B levels, number of MBM and Eastern Cooperative Oncology Group performance status. In these patients treated with checkpoint inhibition first-line or later, in the subgroup of patients with BRAFV600-mutated melanoma we found no differences in terms of OS when receiving first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (p=0.085). In BRAF wild-type patients treated with nivolumab plus ipilimumab in first-line or later there was also no difference in OS (p=0.996). Local therapy with stereotactic radiosurgery or surgery led to an improvement in OS compared with not receiving local therapy (p=0.009), regardless of the timepoint of the local therapy. Receiving combined immunotherapy for MBM in first-line or at a later time point made no difference in terms of OS in this study population (p=0.119). CONCLUSION: Immunotherapy with nivolumab plus ipilimumab, particularly in combination with stereotactic radiosurgery or surgery improves OS in asymptomatic and symptomatic MBM.
CRIS-Team Scopus Importer:2020-04-07
Keywords: immunology; oncology; radiotherapy; surgery

Combined low-dose ipilimumab and pembrolizumab after sequential ipilimumab and pembrolizumab failure in advanced melanoma - Kirchberger, Michael C.; Hauschild, Axel; Schuler, Gerold; Heinzerling, Lucie (European Journal of Cancer, 2016)
With the wide use of anti-PD-1 therapy, an increasing number of patients progress under treatment. Combined immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies induces higher response rates as first-line treatment in comparison to single-agent therapy, however, with substantial toxicity since the combination of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) induced 55% grade 3/4 treatment-related adverse events and treatment discontinuation rates of 39%. In this case series, we investigated the efficacy and toxicity of the combined immunotherapy with low-dose ipilimumab (1 mg/kg) plus pembrolizumab (2 mg/kg) in patients with metastatic melanoma with progressive disease under sequential monotherapy with both agents. All patients had received at least three lines of treatment, 78% of patients were M1c, and 67% had brain metastases. Stable disease was observed in 3 out of 9 patients with a median overall survival of 8 months after double checkpoint inhibition. No treatment-related grade 3/4 adverse events occurred, and none of the patients needed to discontinue the treatment due to toxicity. Further trials are needed to investigate combined immunotherapy as rescue treatment in heavily pretreated melanoma patients to find optimal dosage in regard to outcome and toxicity.
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Combining a CAR and a TCR to generate T cells expressing two additional receptors (TETARs) for melanoma immunotherapy - Uslu, Ugur; Gerer, K.; Hoyer, S.; Schuler, Gerold; Dörrie, Jan; Schaft, Niels (2016)
EVALuna2:19613

Combining a chimeric antigen receptor and a conventional T-cell receptor to generate T cells expressing two additional receptors (TETARs) for a multi-hit immunotherapy of melanoma. - Uslu, Ugur; Schuler, Gerold; Dörrie, Jan; Schaft, Niels (Experimental Dermatology, 2016)
The adoptive transfer of engineered T cells represents an important approach in immunotherapy of melanoma. However, relapse of the tumor can occur due to immune-escape mechanisms developed by the tumor cells, for example antigen loss, downregulation of the major histocompatibility complex presentation machinery and defects in antigen processing. To counteract these mechanisms, we combined a T-cell receptor and a chimeric antigen receptor, specific for different common melanoma antigens, gp100 (PMEL) and MCSP (HMW-MAA), to generate functional CD8(+) T cells expressing two additional receptors (TETARs) by electroporation of receptor-encoding mRNA. These TETARs produced cytokines and were lytic upon recognition of each of their cognate antigens, while no reciprocal inhibition of the receptors occurred. When stimulated with target cells, which express both antigens, an enhanced effect was suggested. The confirmation that chimeric antigen receptors and T-cell receptors can be functionally combined opens up new avenues in cancer immunotherapy, and the generation of TETARs helps by-passing major mechanisms by which tumor cells escape immune recognition.
EVALuna2:19624

Combining CNN-based histologic whole slide image analysis and patient data to improve skin cancer classification - Höhn, Julia; Krieghoff-Henning, Eva; Jutzi, Tanja B.; von Kalle, Christof; Utikal, Jochen S.; Meier, Friedegund; Gellrich, Frank F.; Hobelsberger, Sarah; Hauschild, Axel; Schlager, Justin G.; French, Lars; Heinzerling, Lucie; et al. (European Journal of Cancer, 2021)
Background: Clinicians and pathologists traditionally use patient data in addition to clinical examination to support their diagnoses. Objectives: We investigated whether a combination of histologic whole slides image (WSI) analysis based on convolutional neural networks (CNNs) and commonly available patient data (age, sex and anatomical site of the lesion) in a binary melanoma/nevus classification task could increase the performance compared with CNNs alone. Methods: We used 431 WSIs from two different laboratories and analysed the performance of classifiers that used the image or patient data individually or three common fusion techniques. Furthermore, we tested a naive combination of patient data and an image classifier: for cases interpreted as ‘uncertain’ (CNN output score <0.7), the decision of the CNN was replaced by the decision of the patient data classifier. Results: The CNN on its own achieved the best performance (mean ± standard deviation of five individual runs) with AUROC of 92.30% ± 0.23% and balanced accuracy of 83.17% ± 0.38%. While the classification performance was not significantly improved in general by any of the tested fusions, naive strategy of replacing the image classifier with the patient data classifier on slides with low output scores improved balanced accuracy to 86.72% ± 0.36%. Conclusion: In most cases, the CNN on its own was so accurate that patient data integration did not provide any benefit. However, incorporating patient data for lesions that were classified by the CNN with low ‘confidence’ improved balanced accuracy.
CRIS-Team Scopus Importer:2021-04-16
Keywords: Convolutional neural networks; Data fusion; Histologic whole slide images; Patient data; Skin cancer classification

COMBI-r: A Prospective, Non-Interventional Study of Dabrafenib Plus Trametinib in Unselected Patients with Unresectable or Metastatic BRAF V600-Mutant Melanoma - Berking, Carola; Livingstone, Elisabeth; Debus, Dirk; Loquai, Carmen; Weichenthal, Michael; Leiter, Ulrike; Kiecker, Felix; Mohr, Peter; Eigentler, Thomas K.; Remy, Janina; Schober, Katharina; Heppt, Markus; et al. (Cancers, 2023)
Combined BRAF/MEK-inhibition constitutes a relevant treatment option for BRAF-mutated advanced melanoma. The prospective, non-interventional COMBI-r study assessed the effectiveness and tolerability of the BRAF-inhibitor dabrafenib combined with the MEK-inhibitor trametinib in patients with advanced melanoma under routine clinical conditions. Progression-free survival (PFS) was the primary objective, and secondary objectives included overall survival (OS), disease control rate, duration of therapy, and the frequency and severity of adverse events. This study enrolled 472 patients at 55 German sites. The median PFS was 8.3 months (95%CI 7.1–9.3) and the median OS was 18.3 months (14.9–21.3), both tending to be longer in pre-treated patients. In the 147 patients with CNS metastases, PFS was similar in those requiring corticosteroids (probably representing symptomatic patients, 5.6 months (3.9–7.2)) compared with those not requiring corticosteroids (5.9 months (4.8–6.9)); however, OS was shorter in patients with brain metastases who received corticosteroids (7.8 (6.3–11.6)) compared to those who did not (11.9 months (9.6–19.5)). The integrated subjective assessment of tumor growth dynamics proved helpful to predict outcome: investigators’ upfront categorization correlated well with time-to-event outcomes. Taken together, COMBI-r mirrored PFS outcomes from other prospective, observational studies and confirmed efficacy and safety findings from the pivotal phase III COMBI-d/-v and COMBI-mb trials.
CRIS-Team Scopus Importer:2023-10-20
Keywords: BRAF mutation; brain metastases; dabrafenib; MAPK pathway; melanoma; trametinib; tumor dynamics

Common German language nomenclature for systemic sclerosis - Aringer, Martin; Mueller-Ladner, U.; Burkhardt, H.; Distler, Jörg; Distler, O.; Graninger, W. B.; Guenther, C.; Hunzelmann, N.; Kiener, H.; Sticherling, Michael; Sunderkoetter, C.; Walker, U. A.; et al. (Zeitschrift für Rheumatologie, 2015)
Large data bases and the projects arising from them have led to a much improved understanding of systemic sclerosis over the last decade. Serology has developed further so that more autoantibodies are available for routine testing. Capillary microscopy has become standard and relevant progress has also been made in therapy. Many diagnostic terms found in medical documentation do not adequately reflect this progress. The nomenclature is inconsistent and, therefore, confusing. The international classification of diseases (ICD) nomenclature is, from our point of view, also in need of improvement. This article aims to reestablish a common German language standard for systemic sclerosis, which reflects current knowledge and is suitable for implementation in the clinical routine.
EVALuna2:13102

Commonly used prophylactic vaccines as an alternative for synthetically produced TLR ligands to mature monocyte-derived dendritic cells - Schreibelt, Gerty; Benitez-Ribas, Daniel; Schuurhuis, Danita; Lambeck, Annechien J. A.; Van Hout-Kuijer, Maaike; Schaft, Niels; Punt, Cornelis J. A.; Figdor, Carl G.; Adema, Gosse J.; De Vries, I. Jolanda M. (Blood, 2010)
Currently dendritic cell (DC)-based vaccines are explored in clinical trials, predominantly in cancer patients. Murine studies showed that only maturation with Toll-like receptor (TLR) ligands generates mature DCs that produce interleukin-12 and promote optimal T-cell help. Unfortunately, the limited availability of clinicalgrade TLR ligands significantly hampers the translation of these findings into DC-based vaccines. Therefore, we explored 15 commonly used preventive vaccines as a possible source of TLR ligands. We have identified a cocktail of the vaccines BCG-SSI, Influvac, and Typhim that contains TLR ligands and is capable of optimally maturing DCs. These DCs (vaccine DCs) showed high expression of CD80, CD86, and CD83 and secreted interleukin-12. Although vaccine DCs exhibited an impaired migratory capacity, this could be restored by addition of prostaglandin E2 (PGE 2; vaccine PGE2 DCs). Vaccine PGE2 DCs are potent inducers of T-cell proliferation and induce Th1 polarization. In addition, vaccine PGE2 DCs are potent inducers of tumor antigen-specific CD8 + effector T cells. Finally, vaccine PGE2-induced DC maturation is compatible with different antigen-loading strategies, including RNA electroporation. These data thus identify a new clinical application for a mixture of commonly used preventive vaccines in the generation of Th1-inducing clinical-grade mature DCs. © 2010 by The American Society of Hematology.
CRIS-Team Scopus Importer:2021-10-01

Community effort endorsing multiscale modelling, multiscale data science and multiscale computing for systems medicine - Zanin, Massimiliano; Chorbev, Ivan; Stres, Blaz; Stalidzans, Egils; Vera, Julio; Tieri, Paolo; Castiglione, Filippo; Groen, Derek; Zheng, Huiru; Baumbach, Jan; Schmid, Johannes A.; Basilio, Jose; et al. (Briefings in Bioinformatics, 2019)
Systems medicine holds many promises, but has so far provided only a limited number of proofs of principle. To address this road block, possible barriers and challenges of translating systems medicine into clinical practice need to be identified and addressed. The members of the European Cooperation in Science and Technology (COST) Action CA15120 Open Multiscale Systems Medicine (OpenMultiMed) wish to engage the scientific community of systems medicine and multiscale modelling, data science and computing, to provide their feedback in a structured manner. This will result in follow-up white papers and open access resources to accelerate the clinical translation of systems medicine.
CRIS-Team WoS Importer:2019-08-09

Comorbidity and Therapeutic Approaches in Patients with Necrobiosis Lipoidica - Erfurt-Berge, Cornelia; Heusinger, Veronika; Reinboldt-Jockenhöfer, Finja; Dissemond, Joachim; Renner, Regina (Dermatology, 2021)
Background: Necrobiosis lipoidica (NL) is a rare granulomatous disorder of unknown aetiology. Randomized controlled studies are not available due to it being an orphan disease. Objectives: We evaluated patients in 2 dermatological centres to cluster data about epidemiology, the therapeutic approaches for NL, and their efficacy. Materials and Methods: Comorbidity and the efficacy of the applied treatment was assessed for 98 patients. Results: We identified 54% of patients with concomitant diabetes and 19% with thyroidal disorders. Topical steroids (85.7%) were predominantly used followed by calcineurin inhibitors (31%) and phototherapy (41.8%). Systemically, fumaric acid esters were more frequently applied (26.8%) than steroids (24.4%) and dapsone (24.4%). Steroids, compression therapy, calcineurin inhibitors, phototherapy, fumaric acid esters, and dapsone showed remarkable efficacy. Conclusion: Therapeutic options were chosen individually in accordance with the severity of NL and presence of ulceration. Topical calcineurin inhibitors, systemic application of fumaric acid esters, and dapsone represent effective alternatives to the use of steroids.
CRIS-Team Scopus Importer:2021-04-19

Comorbidity in chronic spontaneous urticaria Komorbidität bei chronisch spontaner Urtikaria - Wagner, Nicola; Staubach, P. (Allergologie, 2021)
Chronic spontaneous urticaria (CSU) is one of the most frequent dermatological diseases. Evaluating comorbidity in CSU patients, there is evidence, that disease burden is far more pronounced than supposed. Chronic inflammatory foci may trigger CSU. Autoimmune phenomena as well as metabolic disturbances with its low-grade inflammation may influence disease activity of CSU. Especially chronic inducible forms of urticaria, autoimmune and thyreoid diseases, bacterial infections as well as psychiatric comorbidities are frequently associated.
CRIS-Team Scopus Importer:2021-04-09
Keywords: Burden of disease; Chronic spontaneous urticaria; Comorbidity; Concomitant diseases

Comparative analysis of human dendritic cell subpopulations in steady state and inflammation - Heger, Lukas; Heidkamp, Gordon Frederik; Lehmann, Christian; Eissing, N.; Söder, Stephan; Hartmann, Arndt; Zenk, J.; Alexiou, Christoph; Schuler, Gerold; Purbojo, Ariawan; Cesnjevar, Robert; Nimmerjahn, Falk; et al. (2017)
EVALuna2:33136

Comparative analysis of human dendritic cell subpopulations in steady state and inflammation - Heger, Lukas; Heidkamp, Gordon Frederik; Lehmann, Christian; Söder, Stephan; Hartmann, Arndt; Alexiou, Christoph; Schuler, Gerold; Purbojo, Ariawan; Cesnjevar, Robert; Nimmerjahn, Falk; Dudziak, Diana (2018)
EVALuna2:34382

Comparative Analysis of Radiomic Features and Gene Expression Profiles in Histopathology Data using Graph Neural Networks - Rivera Monroy, Luis; Rist, Leonhard; Eberhardt, Martin; Ostalecki, Christian; Bauer, Andreas; Vera, Julio; Breininger, Katharina; Maier, Andreas (Bildverarbeitung für die Medizin 2024, 2024)
This study leverages graph neural networks to integrate MELC data with Radiomic-extracted features for melanoma classification, focusing on cellwise analysis. It assesses the effectiveness of gene expression profiles and Radiomic features, revealing that Radiomic features, particularly when combined with UMAP for dimensionality reduction, significantly enhance classification performance. Notably, using Radiomics contributes to increased diagnostic accuracy and computational efficiency, as it allows for the extraction of critical data from fewer stains, thereby reducing operational costs. This methodology marks an advancement in computational dermatology for melanoma cell classification, setting the stage for future research and potential developments.<br

Comparative analysis of the phototoxicity induced by BRAF inhibitors and alleviation through antioxidants - Heppt, Markus V.; Clanner-Engelshofen, Benjamin M.; Marsela, Enklajd; Wessely, Anja; Kammerbauer, Claudia; Przybilla, Bernhard; French, Lars E.; Berking, Carola; Reinholz, Markus (Photodermatology Photoimmunology & Photomedicine, 2019)
BACKGROUND: Small molecules tackling mutated BRAF (BRAFi) are an important mainstay of targeted therapy in a variety of cancers including melanoma. Albeit commonly reported as side effect, the phototoxic potential of many BRAFi is poorly characterized. In this study, we evaluated the phototoxicity of 17 distinct agents and investigated whether BRAFi-induced phototoxicity can be alleviated by antioxidants. METHODS: The ultraviolet (UV) light absorbance of 17 BRAFi was determined. Their phototoxic potential was investigated independently with a reactive oxygen species (ROS) and the 3T3 neutral red uptake (NRU) assay in vitro. To test for a possible phototoxicity alleviation by antioxidants, vitamin C, vitamin E phosphate, trolox, and glutathione (GSH) were added to the 3T3 assay of selected inhibitors. RESULTS: The highest cumulative absorbance for both UVA and UVB was detected for vemurafenib. The formation of ROS was more pronounced for all compounds after irradiation with UVA than with UVB. In the 3T3 NRU assay, 8 agents were classified as phototoxic, including vemurafenib, dabrafenib, and encorafenib. There was a significant correlation between the formation of singlet oxygen (P = .026) and superoxide anion (P < .001) and the phototoxicity observed in the 3T3 NRU assay. The phototoxicity of vemurafenib was fully rescued in the 3T3 NRU assay after GSH was added at different concentrations. CONCLUSION: Our study confirms that most of the BRAF inhibitors exhibited a considerable phototoxic potential, predominantly after exposure to UVA. GSH may help treat and prevent the phototoxicity induced by vemurafenib.
EVALuna2:208521

Comparative efficacy analysis identifies immune checkpoint blockade as a new survival benchmark in advanced cutaneous squamous cell carcinoma - Petzold, Anne; Steeb, Theresa; Wessely, Anja; Schatton, Tobias; Berking, Carola; Heppt, Markus (European Journal of Cancer, 2022)
Background: Cutaneous squamous cell carcinoma is a common type of skin cancer that may progress to locally advanced or metastatic disease. Both disease stages are managed by a variety of treatment options, including immune checkpoint blockade (ICB), targeted therapy to epidermal growth factor, chemotherapy or treatment combinations. However, the comparative efficacy of such treatments is unclear. Methods: We performed a systematic literature search of Medline, Embase and Central to identify eligible studies reporting Kaplan–Meier curves or individual patient data for overall survival (OS) or progression-free survival (PFS). Kaplan–Meier curves were digitised using the “‘WebPlotDigitizer” program. Individual patient data was subsequently remodelled and pooled for distinct treatment groups. Results: Overall, 22 independent studies were included of which n = 927 patients were evaluable for PFS and n = 1054 for OS. ICB showed the highest median PFS (mPFS 9.9 months (95% CI: 8.1–19.9)) and median OS (mOS not reached (95% CI: 31.5 months-not reached)) compared to chemotherapy (mPFS 3.0 months (95% CI: 2.2–4.8), mOS 12.6 months (95% CI: 9.6–15.8)), targeted therapy to epidermal growth factor (mPFS 4.9 months (95% CI: 4.4–5.6), mOS 12.7 months (95% CI: 11.9–14.9)) and combination therapies without ICB (mPFS 9.1 months (95% CI: 8.0–12.1), mOS 18.1 months (95% CI: 16.3–22.8)). The survival benchmark with ICB after 26 months for metastatic squamous cell carcinoma was 70.8% (95% CI: 61.5%–81.5%) versus 37.9% (95% CI: 29.5%–48.8%) for the combination group and 17.1% (95% CI: 9.5%–30.8%) for chemotherapy. Conclusion: ICB is superior to other systemic treatments and sets a novel survival benchmark for advanced cutaneous squamous cell carcinoma.
CRIS-Team Scopus Importer:2022-06-17
Keywords: Cutaneous neoplasm; Cutaneous squamous cell carcinoma; Immune checkpoint blockade; Indirect comparison; Individual patient data; Overall survival; PD-1 therapy; Progression-free survival; Skin cancer

Comparative Efficacy and Safety of Tirbanibulin for Actinic Keratosis of the Face and Scalp in Europe: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials - Heppt, Markus; Dykukha, Igor; Graziadio, Sara; Salido-Vallejo, Rafael; Chapman-Rounds, Matt; Edwards, Mary (Journal of Clinical Medicine, 2022)
Actinic keratosis (AK) is a chronic skin condition that may progress to cutaneous squamous cell carcinoma. We conducted a systematic review of efficacy and safety for key treatments for AK of the face and scalp, including the novel 5-day tirbanibulin 1% ointment. MEDLINE, PubMed, Embase, Cochrane Library, clinical trial registries and regulatory body websites were searched. The review included 46 studies, of which 35 studies included interventions commonly used in Europe and were sufficiently homogenous to inform a Bayesian network meta-analysis of complete clearance against topical placebo or vehicle. The network meta-analysis revealed the following odds ratios and 95% credible intervals: cryosurgery 13.4 (6.2-30.3); diclofenac 3% 2.9 (1.9-4.3); fluorouracil 0.5% + salicylic acid 7.6 (4.6-13.5); fluorouracil 4% 30.3 (9.1-144.7); fluorouracil 5% 35.0 (10.2-164.4); imiquimod 3.75% 8.5 (3.5-22.4); imiquimod 5% 17.9 (9.1-36.6); ingenol mebutate 0.015% 12.5 (8.1-19.9); photodynamic therapy with aminolevulinic acid 24.1 (10.9-52.8); photodynamic therapy with methyl aminolevulinate 11.7 (6.0-21.9); tirbanibulin 1% 11.1 (6.2-20.9). Four sensitivity analyses, from studies assessing efficacy after one treatment cycle only, for <= 25 cm(2) treatment area, after 8 weeks post-treatment, and with single placebo/vehicle node confirmed the findings from the base case. Safety outcomes were assessed qualitatively. These results suggest that tirbanibulin 1% offers a novel treatment for AK, with a single short treatment period, favourable safety profile and efficacy, in line with existing topical treatments available in Europe.
CRIS-Team WoS Importer:2022-04-15

Comparative transcriptomics of immune checkpoint inhibitor myocarditis identifies guanylate binding protein 5 and 6 dysregulation - Finke, Daniel; Heckmann, Markus B.; Salatzki, Janek; Riffel, Johannes; Herpel, Esther; Heinzerling, Lucie; Meder, Benjamin; Voelkers, Mirko; Mueller, Oliver J.; Frey, Norbert; Katus, Hugo A.; Leuschner, Florian; et al. (Cancers, 2021)
Immune checkpoint inhibitors (ICIs) are revolutionizing cancer treatment. Nevertheless, their increasing use leads to an increase of immune-related adverse events (irAEs). Among them, ICI-associated myocarditis (ICIM) is a rare irAE with a high mortality rate. We aimed to characterize the transcriptional changes of ICIM myocardial biopsies and their possible implications. Patients suspected for ICIM were assessed in the cardio-oncology units of University Hospitals Heidelberg and Kiel. Via RNA sequencing of myocardial biopsies, we compared transcriptional changes of ICIM (n = 9) with samples from dilated cardiomyopathy (DCM, n = 11), virus-induced myocarditis (VIM, n = 5), and with samples of patients receiving ICIs without any evidence of myocarditis (n = 4). Patients with ICIM (n = 19) showed an inconsistent clinical presentation, e.g., asymptomatic elevation of cardiac biomarkers (hs-cTnT, NT-proBNP, CK), a drop in left ventricular ejection fraction, or late gadolinium enhancement in cMRI. We found 3784 upregulated genes in ICIM (FDR < 0.05). In the overrepresented pathway ‘response to interferon-gamma’, we found guanylate binding protein 5 and 6 (compared with VIM: GBP5 (log2 fc 3.21), GBP6 (log2 fc 5.37)) to be significantly increased in ICIM on RNA-and protein-level. We conclude that interferon-gamma and inflammasome-regulating proteins, such as GBP5, may be of unrecognized significance in the pathophysiology of ICIM.
CRIS-Team Scopus Importer:2021-06-04
Keywords: CD8; Comparative transcriptomics; CTLA4; ICI-associated myocarditis; ICIM; PD1; PDL-1; Virus myocarditis

COMPARISON OF BONE MICROSTRUCTURE OF PSORIATIC ARTHRITIS AND PSORIASIS PATIENTS - AN HR-PQCT STUDY OF ANABOLIC AND CATABOLIC BONE CHANGES - Simon, David; Faustini, F.; Englbrecht, Matthias; Kleyer, Arnd; Kocijan, R.; Haschka, J.; Figueiredo, C.; Kraus, S.; Hueber, Axel; Sticherling, Michael; Schett, Georg; Rech, Jürgen (2015)
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Comparison of guidelines for the management of patients with high-risk and advanced cutaneous squamous cell carcinoma - a systematic review - Heppt, M. V.; Steeb, T.; Berking, Carola; Nast, A. (Journal of the European Academy of Dermatology and Venereology, 2019)
The management of high-risk cutaneous squamous cell carcinoma (cSCC) can be a challenge as evidence from high quality clinical trials is rare. Guideline developers are challenged to provide practical and useful guidance for clinicians even in the absence of good evidence. In order to compare treatment recommendations for high-risk and advanced cSCC among national and international guidelines and to extract the most precise guidance provided, a systematic search was carried out in guideline databases Medline and Embase with a cutoff of 4 March 2019. Treatment recommendations for predefined clinical scenarios were extracted from selected guidelines and compared qualitatively. Five guidelines published from 2015 to 2018 were included. Excision of high-risk tumours with margin assessment was recommended in all guidelines. A safety margin of at least 6 mm was suggested in four guidelines. There was no clear recommendation to perform a sentinel lymph node biopsy in any guideline. Lymph node dissection was uniformly recommended in the presence of nodal disease. Treatment for metastatic cSCC was poorly characterized and restricted to the use of chemotherapy and epidermal growth factor receptor inhibitors. Recommendations for the management of high-risk and advanced cSCC were limited. We propose that guidelines should be updated to reflect recent advances in checkpoint blockade for metastatic cSCC.
EVALuna2:212853

Comparison of sedation with dexmedetomidine vs propofol during hysteroscopic surgery: Single-centre randomized controlled trial - Tanriverdi, Tugba Bingol; Koceroglu, Ikbal; Devrim, Sibel; Celik, Melek Gura (Journal of Clinical Pharmacy and Therapeutics, 2019)
What is known and objective The most appropriate sedative agent for conscious sedation in minor hysteroscopic surgeries is still unclear. Dexmedetomidine a sedative and analgesic agent, may be appropriate for outpatient procedures. The aim of our study was to compare the sedative, analgesic and hemodynamic effects of dexmedetomidine vs propofol in combination with fentanyl and midazolam in patients undergoing minor hysteroscopy surgery. Methods Sixty patients undergoing minor hysteroscopic surgery were randomized to receive either dexmedetomidine (n = 30) or propofol (n = 30) groups. Dexmedetomidine was infused at 1 mu g/kg for 10 minutes followed by a 0.7 mu g/kg/h maintenance infusion. Propofol was infused a bolus of 1.5 mg/kg followed by a 2.5 mg/kg/h maintenance infusion. Fentanyl 1.5 mcg/kg and midazolam 0.03 mg/kg were performed to all patients as premedication therapy before the hysteroscopic surgery. Post-operative pain score was assessed with visual analogue scale (VAS). Hemodynamic variables and Riker Sedation-Agitation Scale (SAS) scores were recorded for all patients. Results Mean arterial pressure and heart rate in the dexmedetomidine group were significantly lower than in propofol group, whereas SpO2 was similar between two groups. In addition, post-operative Riker SAS and VAS scores were significantly lower in dexmedetomidine group than in the propofol group. Bradycardia, hypotension and serious adverse events did not occur in any patients. What is new and conclusion Dexmedetomidine was associated with better analgesia and lower post-operative pain score than propofol in patients undergoing hysteroscopic surgery. However, arterial pressure and heart rate should be more closely monitored in patients received dexmedetomidine.
CRIS-Team WoS Importer:2019-03-20

Comparison of the Serum Tumor Markers S100 and Melanoma-inhibitory Activity (MIA) in the Monitoring of Patients with Metastatic Melanoma Receiving Vaccination Immunotherapy with Dendritic Cells - Uslu, Ugur; Schliep, Stefan; Schliep, Klaus; Erdmann, Michael; Koch, Hans-Uwe; Parsch, Hans; Rosenheinrich, Stina; Anzengruber, Doris; Boßerhoff, Anja Katrin; Schuler, Gerold; Schuler-Thurner, Beatrice (Anticancer Research, 2017)
In patients with melanoma, early dissemination via lymphatic and hematogenous routes is frequently seen. Thus, besides clinical follow-up examination and imaging, reliable melanoma-specific serological tumor markers are needed.We retrospectively compared two serum markers for melanoma, S100 and melanoma-inhibitory activity (MIA), for monitoring of patients with metastatic melanoma under either adjuvant or therapeutic vaccination immunotherapy with dendritic cells (DC). Serum was obtained from a total of 100 patients (28 patients in stage III and 72 patients in stage IV, according to the American Joint Committee on Cancer 2002) at regular intervals during therapy, accompanied by follow-up imaging.When relapse was detected, both markers often remained within normal range. In contrast, in patients with metastatic measurable disease receiving therapeutic and not adjuvant DC vaccination, an increase of both markers was a strong indicator for disease progression. When comparing both markers in the whole study population, MIA showed a superior sensitivity to detect disease progression.S100 and MIA are highly sensitive tumor markers for monitoring of patients with melanoma with current metastases, but less sensitive for monitoring of tumor-free patients. In the current study, MIA had a slightly superior sensitivity to detect progressive disease compared to S100 and seems to be more useful in monitoring of patients with metastatic melanoma receiving immunotherapy.
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Computational Approaches in microRNA Biology - Schmitz, Ulf; Gupta, Shailendra K.; Vera, Julio; Wolkenhauer, Olaf (Encyclopedia of Biomedical Engineering, Vol. 3, 2019)
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level by binding to mRNA targets and inducing translational repression or target degradation via the RNA-induced silencing complex. Since miRNAs were first identified, computational approaches have played an important role for understanding their biosynthesis, modes of target regulation, and interplay with other mechanisms of gene regulation. In this essay we discuss computational methodologies used in miRNA biology research. More specifically, we introduce concepts for the prediction of miRNAs and their target genes: miRNA structure prediction and miRNA expression profiling approaches, coupled with the functional characterization of miRNAs. We then review approaches used for modeling miRNA-mediated gene regulatory networks.<br
CRIS-Team WoS Importer:2020-03-27
Keywords: Mathematical modeling of miRNA regulation; microRNA; microRNA databases and web resources; microRNA gene prediction; microRNA target hubs; microRNA target prediction; Regulatory networks; Target regulation

Computational Biology of Non-Coding RNA Methods and Protocols Preface - Lai, Xin; Gupta, Shailendra K.; Vera, Julio (Methods in Molecular Biology, 2019)
CRIS-Team WoS Importer:2021-10-18

Computational decomposition reveals reshaping of the SARS‐CoV‐2–ACE2 interface among viral variants expressing the N501Y mutation - Socher, Eileen; Conrad, Marcus; Heger, Lukas; Paulsen, Friedrich; Sticht, Heinrich; Zunke, Friederike; Arnold, Philipp (Journal of Cellular Biochemistry, 2021)
Variants of concern of the SARS-CoV-2 virus with an asparagine-to-tyrosine substitution at position 501 (N501Y) in the receptor-binding domain (RBD) show enhanced infectivity compared to wild-type, resulting in an altered pandemic situation in affected areas. These SARS-Cov-2 variants comprise the two Alpha variants (B.1.1.7, United Kingdom and B.1.1.7 with the additional E484K mutation), the Beta variant (B.1.351, South Africa), and the Gamma variant (P.1, Brazil). Understanding the binding modalities between these viral variants and the host cell receptor ACE2 allows to depict changes, but also common motifs of virus–host cell interaction. The trimeric spike protein expressed at the viral surface contains the RBD that forms the molecular interface with ACE2. All the above-mentioned variants carry between one and three amino acid exchanges within the interface-forming region of the RBD, thereby altering the binding interface with ACE2. Using molecular dynamics (MD) simulations and decomposition of intermolecular contacts between the RBD and ACE2, we identified phenylalanine 486, glutamine 498, threonine 500, and tyrosine 505 as important interface-forming residues across viral variants. However, especially the N501Y exchange increased contact formation for this residue and also induced some local conformational changes. Comparing here, the in silico generated B.1.1.7 RBD–ACE2 complex with the now available experimentally solved structure reveals very similar behavior during MD simulation. We demonstrate, how computational methods can help to identify differences in conformation as well as contact formation for newly emerging viral variants. Altogether, we provide extensive data on all N501Y expressing SARS-CoV-2 variants of concern with respect to their interaction with ACE2 and how this induces reshaping of the RBD–ACE2 interface.

Concealed complete response in melanoma patients under therapy with immune checkpoint inhibitors: two case reports - Schliep, Stefan; Agaimy, Abbas; Kiesewetter, Franklin; Schuler, Gerold; Heinzerling, Lucie; Cavallaro, Alexander Josef (Journal for ImmunoTherapy of Cancer, 2018)
BACKGROUND: The assessment of tumor size by RECIST using CT scans and MRIs is considered to be standard of care for staging cancer patients. Despite radiologic evidence of widespread disease, we document for the first time that patients were completely free of viable tumor. CASE PRESENTATION: Two patients with metastatic melanoma were treated with immune checkpoint inhibitors (ipilimumab/ nivolumab) and progressive metastases were detected on CT-scans performed shortly before histologic examinations. In both patients histologic assessment revealed a complete response with necrotic and scarred lesions free of tumor. One of the patients had started immunotherapy 20 months before with an initial partial response. CONCLUSIONS: This phenomenon of a concealed complete response can lead to overtreatment or unnecessary change in treatment. Thus, it is essential to raise awareness for it. Correct identification of responders to immune checkpoint inhibitor therapy is crucial to spare patients immune-mediated side effects and unnecessary as well as expensive treatment. Regression of metastases without decline in size, in these cases manifesting as complete responses, are probably more common than expected and identified to date. Until such responses can be readily identified by new imaging techniques, we recommend liberal biopsies for histologic assessment of progressive metastases in patients during and/or after immune checkpoint inhibitor therapy.
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Concurrent interaction of DCs with CD4(+) and CD8(+) T cells improves secondary CTL expansion: It takes three to tango. - Hoyer, Stefanie; Prommersberger, Sabrina; Pfeiffer, Isabell; Schuler-Thurner, Beatrice; Schuler, Gerold; Dörrie, Jan; Schaft, Niels (European Journal of Immunology, 2014)
T-cell help is essential for CTL-memory formation. Nevertheless, it is unclear whether the continuous presence of CD4(+) T-helper (Th) cells is required during dendritic cell (DC)/CD8(+) T-cell encounters, or whether a DC will remember the helper signal after the Th cell has departed. This question is relevant for the design of therapeutic cancer vaccines. Therefore, we investigated how human DCs need to interact with CD4(+) T cells to mediate efficient repetitive CTL expansion in vitro. We established an autologous antigen-specific in vitro system with monocyte-derived DCs, as these are primarily used for cancer vaccination. Contrary to common belief, a sequential interaction of licensed DCs with CD8(+) T cells barely improved CTL expansion. In sharp contrast, simultaneous encounter of Th cells and CTLs with the same DC during the first in vitro encounter is a prerequisite for optimal subsequent CTL expansion in our in vitro system. These data suggest that, in contrast to DC maturation, the activation of DCs by Th cells, which is necessary for optimal CTL stimulation, is transient. This knowledge has significant implications for the design of new and more effective DC-based vaccination strategies. Furthermore, our in vitro system could be a valuable tool for preclinical immunotherapeutical studies.
EVALuna2:19507

Consensus nomenclature for CD8(+) T cell phenotypes in cancer - Apetoh, Lionel; Smyth, Mark J.; Drake, Charles G.; Abastado, Jean-Pierre; Apte, Ron N.; Ayyoub, Maha; Blay, Jean-Yves; Bonneville, Marc; Butterfield, Lisa H.; Caignard, Anne; Castelli, Chiara; Cavallo, Federica; et al. (OncoImmunology, 2015)
Whereas preclinical investigations and clinical studies have established that CD8(+) T cells can profoundly affect cancer progression, the underlying mechanisms are still elusive. Challenging the prevalent view that the beneficial effect of CD8(+) T cells in cancer is solely attributable to their cytotoxic activity, several reports have indicated that the ability of CD8(+) T cells to promote tumor regression is dependent on their cytokine secretion profile and their ability to self-renew. Evidence has also shown that the tumor microenvironment can disarm CD8(+) T cell immunity, leading to the emergence of dysfunctional CD8(+) T cells. The existence of different types of CD8(+) T cells in cancer calls for a more precise definition of the CD8(+) T cell immune phenotypes in cancer and the abandonment of the generic terms "pro-tumor" and "antitumor." Based on recent studies investigating the functions of CD8(+) T cells in cancer, we here propose some guidelines to precisely define the functional states of CD8(+) T cells in cancer.
EVALuna2:19573

Contact allergy due to insulin pumps and glucose sensor systems Kontaktallergie auf Glukosemesssysteme und Insulinpumpen - Wagner, N.; Kamann, S.; Oppel, E. (Hautarzt, 2020)
The design and development of insulin pumps and various glucose sensor systems has an enormous impact on life quality of diabetic patients. Surveillance and therapy of diabetes has improved due to the new diabetic devices, which are affixed to the patients’ skin for several days. Since their introduction, irritant and allergic contact dermatitis have been frequently reported. Patients often acquire contact sensitization to isobornyl acrylate, N,N-dimethylacrylamide or formerly to 2‑ethyl-cyanoacrylate. These contact allergens were found in the patch, in the glue to affix the box on the patch or in the casing of the system itself. Development of contact allergy to substances of these systems may result in the need to abandon modern diabetic devices.
CRIS-Team Scopus Importer:2020-02-04
Keywords: Contact hypersensitivity; Glucose sensors; Insulin infusion systems; Insulin-dependent diabetes; Isobornyl acrylate

Contact allergy to medical devices - Wagner, Nicola (Allergo Journal, 2023)
Background: Medical devices are not subject to any legal obligation to declare ingredients. With an increasing number of available medical devices, increasing reports of contact allergies to these devices result in a more difficult, delayed or lack of diagnosis of the trigger. Methods: Elaborate chemical methods, such as gas chromatography–mass spectroscopy, were able to detect novel contact allergens in medical devices. Results: Diabetic patients requiring insulin benefit from sophisticated glucose sensor measurement systems and insulin pump systems, but are limited in their choices by the development of contact allergy. Potential contact allergens in medical adhesives, plasters, and wound dressings require extensive diagnostic testing. Contact allergic reactions to cardiac electronic implants are rare. The potential relevance of a contact allergic reaction to endoluminal stents to restenosis of the treated vascular territory is discussed. Contact dermatitis to medical gloves is usually due to the vulcanization accelerators. Mouth–nose protective or FFP2 mask-associated eczema is often irritant, very rarely allergic in origin. Conclusion: With continued development of medical devices, new contact allergens are introduced. The declaration of their ingredients is necessary for rapid diagnosis and future prevention.
CRIS-Team Scopus Importer:2023-11-17
Keywords: Adhesives; Allergy to diabetic devices; Contact dermatitis; Masks; Protective medical gloves

Contact sensitization to benzisothiazolinone: IVDK-data of the years 2002 to 2021. - Geier, Johannes; Brans, Richard; Weisshaar, Elke; Wagner, Nicola; Szliska, Christiane; Heratizadeh, Annice; Schubert, Steffen; Ivdk, (Contact Dermatitis, 2023)
BACKGROUND: Benzisothiazolinone (BIT; CAS no. 2634-33-5) is used as a biocide in various products, including water-based paints, metalworking fluids, and household products. In recent years, increasing sensitization rates have been observed in Europe. OBJECTIVE: To describe a time trend of sensitization to BIT, analyse concomitant reactions, and identify patients with increased risk of BIT sensitization. METHODS: Retrospective analysis of data from 26 739 patients patch tested with BIT, sodium salt, 0.1% petrolatum as part of several special test series within the Information Network of Departments of Dermatology (IVDK), 2002 to 2021. RESULTS: Positive reactions to BIT were noted in 771 patients (2.9%). Sensitization frequency varied over time and increased in recent years, peaking at 6.5% in 2020. Painters and metalworkers handling metalworking fluids, but not cleaners, had a significantly increased risk of BIT sensitization. From our data, there is no evidence of immunological cross-reactivity between BIT and other isothiazolinones. CONCLUSION: The increasing frequency of sensitization justifies adding BIT to the baseline series. More research on the clinical relevance of positive patch test reactions to BIT and the cause for the rising numbers of BIT sensitization is needed.
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Contact urticaria: Frequency, elicitors and cofactors in three cohorts (Information Network of Departments of Dermatology; Network of Anaphylaxis; and Department of Dermatology, University Hospital Erlangen, Germany) - Helene, S.; Dölle-Bierke, Sabine; Geier, Johannes; Kreft, Burkhard; Oppel, Eva; Pföhler, Claudia; Skudlik, Christoph; Worm, Margitta; Mahler, Vera (Contact Dermatitis, 2019)
Background: Contact urticaria (CU) is an infrequent, mostly occupational disease that may be life-threatening (CU syndrome stage 4). Objectives: To identify the current frequency, elicitors and cofactors of CU. Patients: Three cohorts were retrospectively analysed for CU: (a) patients from the Information Network of Departments of Dermatology (IVDK) database (2000-2014; n = 159 947); (b) patients from an allergy unit (Department of Dermatology, University Hospital Erlangen, 2000-2015; n = 4741); and (c) patients from the Anaphylaxis Registry (2007-2015: 6365 reported cases, including 2473 patients with Ring and Messmer grade III-IV reactions) for severe cases with skin/mucosal manifestations occurring at the workplace vs cases not occurring at the workplace (n = 68 vs n = 1821). Results: Four hundred and forty-eight CU patients (0.28%) were diagnosed in the IVDK cohort, and 16 (0.34%) (10 of immunological aetiology, and 6 of non-immunological aetiology) in the Erlangen cohort. The most frequent elicitors in the IVDK cohort were cosmetics, creams, sun protection agents (although these were less frequent in CU patients than in controls without CU; 26.8% vs 35.6%, P < 0.0001), and gloves (significantly more frequent in CU patients than in controls; 18.1% vs 6.5%, P < 0.0001). The most frequent elicitors in the Erlangen cohort were natural rubber latex and sorbic acid. Among the MOAHLFA index characteristics, in both cohorts occupational disease was more common in CU patients than in patients without CU. CU was significantly associated with allergic rhinitis and allergic asthma. Wet work was a relevant cofactor. In the Anaphylaxis Registry, 19 cases (0.3%) were identified with severe reactions including skin symptoms at the workplace linked to common occupational elicitors. Conclusions: CU is a rare occupational skin manifestation with a frequency of <0.4% in the examined patients; it may, however, progress to anaphylaxis. Preventive measures are important, and should take into account the identified elicitors and cofactors.
CRIS-Team Scopus Importer:2019-07-16
Keywords: anaphylaxis; atopic disease; cofactor; CU; elicitor; ICU; NICU; occupational skin disease

Contrary immediate effect of abatacept on skin and joint manifestations in psoriatic arthritis - Valor-Méndez, Larissa; Kleyer, Arnd; Schett, Georg; Manger, Bernhard; Sticherling, Michael (Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-11-05

Conventional and three-dimensional photography as a tool to map distribution patterns of in-transit melanoma metastases on the lower extremity - Müller, Kilian; Berking, Carola; Voskens, Caroline; Heppt, Markus; Heinzerling, Lucie; Koch, Elias; Kramer, Rafaela; Merkel, Susanne; Schuler-Thurner, Beatrice; Schellerer, Vera; Steeb, Theresa; Wessely, Anja; et al. (Frontiers in Medicine, 2023)
Background: In melanoma, in-transit metastases characteristically occur at the lower extremity along lymphatic vessels. Objectives: The objective of this study was to evaluate conventional or three-dimensional photography as a tool to analyze in-transit metastasis pattern of melanoma of the lower extremity. In addition, we assessed risk factors for the development of in-transit metastases in cutaneous melanoma. Methods: In this retrospective, monocentric study first we compared the clinical data of all evaluable patients with in-transit metastases of melanoma on the lower extremity (n = 94) with melanoma patients without recurrence of disease (n = 288). In addition, based on conventional (n = 24) and three-dimensional photography (n = 22), we defined the specific distribution patterns of the in-transit metastases on the lower extremity. Results: Using a multivariate analysis we identified nodular melanoma, tumor thickness, and ulceration as independent risk factors to develop in-transit metastases ITM (n = 94). In patients with melanoma on the lower leg (n = 31), in-transit metastases preferentially developed along anatomically predefined lymphatic pathways. In contrast when analyzing in-transit metastases of melanoma on the foot (n = 15) no clear pattern could be visualized. In addition, no difference in distance between in-transit metastases and primary melanoma on the foot compared to the lower leg was observed using three-dimensional photography (n = 22). Conclusion: A risk-adapted follow-up of melanoma patients to detect in-transit metastases can be applied by knowledge of the specific lymphatic drainage of the lower extremity. Our current analysis suggests a more complex lymphatic drainage of the foot.
CRIS-Team Scopus Importer:2023-02-10
Keywords: 3D photography; in-transit metastasis; lower extremity; lymphatic pathways; melanoma

Cooperative gene regulation by microRNA pairs and their identification using a computational workflow - Schmitz, Ulf; Lai, Xin; Winter, Felix; Wolkenhauer, Olaf; Vera González, Julio; Gupta, Shailendra K. (Nucleic Acids Research, 2014)
MicroRNAs (miRNAs) are an integral part of gene regulation at the post-transcriptional level. Recently, it has been shown that pairs of miRNAs can repress the translation of a target mRNA in a cooperative manner, which leads to an enhanced effectiveness and specificity in target repression. However, it remains unclear which miRNA pairs can synergize and which genes are target of cooperative miRNA regulation. In this paper, we present a computational workflow for the prediction and analysis of cooperating miRNAs and their mutual target genes, which we refer to as RNA triplexes. The workflow integrates methods of miRNA target prediction; triplex structure analysis; molecular dynamics simulations and mathematical modeling for a reliable prediction of functional RNA triplexes and target repression efficiency. In a case study we analyzed the human genome and identified several thousand targets of cooperative gene regulation. Our results suggest that miRNA cooperativity is a frequent mechanism for an enhanced target repression by pairs of miRNAs facilitating distinctive and fine-tuned target gene expression patterns. Human RNA triplexes predicted and characterized in this study are organized in a web resource at www.sbi.uni-rostock.de/triplexrna/.
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Corrigendum: Multiplicity of Mathematical Modeling Strategies to Search for Molecular and Cellular Insights into Bacteria Lung Infection - Cantone, Martina; Santos, Guido; Wentker, Pia; Lai, Xin; Vera, Julio (Frontiers in Physiology, 2017)
[This corrects the article on p. 645 in vol. 8, PMID: 28912729.].
EVALuna2:35402
Keywords: Systems biology; Systems medicine; ODE models; Stochastic modeling; Boolean network; Agent-based modeling; Mathematical modeling; Lung infection

Corrigendum to "Antibody-based immunotherapy of acyclovir resistant ocular herpes simplex virus infection" [Virology 512 (2017) 194-200] - Bauer, Dirk; Keller, Jessica; Alt, Mira; Schubert, Axel; Aufderhorst, Ulrich Wilhelm; Palapys, Vivien; Kasper, Maren; Heilingloh, Christiane; Dittmer, Ulf; Laffer, Bjoern; Eis-Huebinger, Anna Maria; Verjans, Georges M.; et al. (Virology, 2019)
EVALuna2:36334

Corrigendum to ‘Prediction of melanoma evolution in melanocytic nevi via artificial intelligence: A call for prospective data’ [Eur J Cancer, 119 (September 2019) Pages 30–34](S0959804919304095)(10.1016/j.ejca.2019.07.009) - 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)
Dr. Titus J. Brinker regrets that he originally forgot to disclose the following potential conflict of interest: Dr. Brinker owns a company that develops mobile apps (Smart Health Heidelberg GmbH, Handschuhsheimer Landstr. 9/1, 69120 Heidelberg). Dr. Brinker asked for this corrigendum himself for the reason that a paragraph of this perspective article discusses mole monitoring apps. No third party was involved in instructing this corrigendum. Dr. Brinker would like to apologise for any inconvenience caused.
CRIS-Team Scopus Importer:2019-12-03

Cost-effectiveness of Response-Adapted De-escalation of Immunotherapy in Advanced Melanoma - Cartun, Zachary; Kunz, Wolfgang G.; Heinzerling, Lucie; Tomsitz, Dirk; Guertler, Anne; Westphalen, C. Benedikt; Ricke, Jens; Weir, William; Unterrainer, Marcus; Mehrens, Dirk (JAMA Dermatology, 2022)
IMPORTANCE Combination immunotherapy with nivolumab and ipilimumab has markedly improved outcomes for patients with advanced melanoma. However, these therapies pose a considerable financial burden to both patients and the health care system. The ADAPT-IT trial demonstrated comparable progression-free and overall survival for patients with response-adapted ipilimumab discontinuation compared with standard of care (SOC).
CRIS-Team WoS Importer:2022-11-04

COVID-19 and immune-mediated inflammatory diseases: effect of disease and treatment on COVID-19 outcomes and vaccine responses - Fagni, Filippo; Simon, David; Tascilar, Koray; Schoenau, Verena; Sticherling, Michael; Neurath, Markus; Schett, Georg (The Lancet Rheumatology, 2021)
At the beginning of the COVID-19 pandemic, patients with immune-mediated inflammatory diseases were considered to be at high risk for SARS-CoV-2 infection and the development of severe COVID-19. Data collected over the past year, however, suggest that a diagnosis of inflammatory arthritis, psoriasis, or inflammatory bowel diseases does not increase risk for SARS-CoV-2 infection or severe COVID-19 compared with people without these diseases. Furthermore, substantial data suggest that certain medications frequently used in patients with immune-mediated inflammatory diseases, in particular cytokine inhibitors, might even lower the risk for severe COVID-19. Conversely, glucocorticoids and potentially B-cell-depleting treatments seem to worsen COVID-19 outcomes. Additionally, the first data on SARS-CoV-2 vaccination in patients with these diseases suggest that tolerability of vaccination in patients with immune-mediated inflammatory diseases is good, although the immune response to vaccination can be somewhat reduced in this patient group, particularly those taking methotrexate or CD20-targeted treatment.
CRIS-Team Scopus Importer:2021-10-01

COVID-19 and immunological regulations – from basic and translational aspects to clinical implications - Schoen, Michael P.; Berking, Carola; Biedermann, Tilo; Buhl, Timo; Erpenbeck, Luise; Eyerich, Kilian; Eyerich, Stefanie; Ghoreschi, Kamran; Goebeler, Matthias; Ludwig, Ralf J.; Schaekel, Knut; Schilling, Bastian; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
The COVID-19 pandemic caused by SARS-CoV-2 has far-reaching direct and indirect medical consequences. These include both the course and treatment of diseases. It is becoming increasingly clear that infections with SARS-CoV-2 can cause considerable immunological alterations, which particularly also affect pathogenetically and/or therapeutically relevant factors. Against this background we summarize here the current state of knowledge on the interaction of SARS-CoV-2/COVID-19 with mediators of the acute phase of inflammation (TNF, IL-1, IL-6), type 1 and type 17 immune responses (IL-12, IL-23, IL-17, IL-36), type 2 immune reactions (IL-4, IL-13, IL-5, IL-31, IgE), B-cell immunity, checkpoint regulators (PD-1, PD-L1, CTLA4), and orally druggable signaling pathways (JAK, PDE4, calcineurin). In addition, we discuss in this context non-specific immune modulation by glucocorticosteroids, methotrexate, antimalarial drugs, azathioprine, dapsone, mycophenolate mofetil and fumaric acid esters, as well as neutrophil granulocyte-mediated innate immune mechanisms. From these recent findings we derive possible implications for the therapeutic modulation of said immunological mechanisms in connection with SARS-CoV-2/COVID-19. Although, of course, the greatest care should be taken with patients with immunologically mediated diseases or immunomodulating therapies, it appears that many treatments can also be carried out during the COVID-19 pandemic; some even appear to alleviate COVID-19.
CRIS-Team Scopus Importer:2020-08-14

COVID-19 and implications for dermatological and allergological diseases - Buhl, Timo; Beissert, Stefan; Gaffal, Evelyn; Goebeler, Matthias; Hertl, Michael; Mauch, Cornelia; Reich, Kristian; Schmidt, Enno; Schoen, Michael P.; Sticherling, Michael; Sunderkoetter, Cord; Traidl-Hoffmann, Claudia; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
COVID-19, caused by the coronavirus SARS-CoV-2, has become pandemic. A further level of complexity opens up as soon as we look at diseases whose pathogenesis and therapy involve different immunological signaling pathways, which are potentially affected by COVID-19. Medical treatments must often be reassessed and questioned in connection with this infection. This article summarizes the current knowledge of COVID-19 in the light of major dermatological and allergological diseases. It identifies medical areas lacking sufficient data and draws conclusions for the management of our patients during the pandemic. We focus on common chronic inflammatory skin diseases with complex immunological pathogenesis: psoriasis, eczema including atopic dermatitis, type I allergies, autoimmune blistering and inflammatory connective tissue diseases, vasculitis, and skin cancers. Since several other inflammatory skin diseases display related or comparable immunological reactions, clustering of the various inflammatory dermatoses into different disease patterns may help with therapeutic decisions. Thus, following these patterns of skin inflammation, our review may supply treatment recommendations and thoughtful considerations for disease management even beyond the most frequent diseases discussed here.
CRIS-Team Scopus Importer:2020-08-07

COVID-19: risk for cytokine targeting in chronic inflammatory diseases? - Schett, Georg; Sticherling, Michael; Neurath, Markus (Nature Reviews Immunology, 2020)
CRIS-Team Scopus Importer:2020-04-28

COVID-19 und Auswirkungen auf dermatologische und allergologische Erkrankungen - Buhl, Timo; Beissert, Stefan; Gaffal, Evelyn; Goebeler, Matthias; Hertl, Michael; Mauch, Cornelia; Reich, Kristian; Schmidt, Enno; Schön, Michael P.; Sticherling, Michael; Sunderkötter, Cord; Traidl-Hoffmann, Claudia; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-08-28

COVID-19 und Immunregulation – von grundlegenden und translationalen Aspekten zu klinischen Implikationen - Schön, Michael P.; Berking, Carola; Biedermann, Tilo; Buhl, Timo; Erpenbeck, Luise; Eyerich, Kilian; Eyerich, Stefanie; Ghoreschi, Kamran; Goebeler, Matthias; Ludwig, Ralf J.; Schäkel, Knut; Schilling, Bastian; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-08-28

C-reactive protein as an early marker of immune-related adverse events - Abolhassani, Amir-Reza; Schuler, Gerold; Kirchberger, Michael Constantin; Heinzerling, Lucie (Journal of Cancer Research and Clinical Oncology, 2019)
Purpose Immune checkpoint inhibitors (ICIs) are effective against a wide variety of cancers. However, they also induce a plethora of unique immune-related adverse events (irAEs). Since for many organ systems symptoms can be unspecific, differential diagnosis with progression of disease or infection may be difficult. C-reactive protein (CRP) has been suggested as a marker for infection. The purpose of this study was to evaluate the diagnostic value of CRP in differentiating infectious causes from autoimmune side effects induced by ICIs. Methods In order to investigate the role of CRP in irAEs, we screened our patient data base. Only events with full infectious workup were included. In total 88 events of irAEs in 37 melanoma patients were analyzed. CRP levels before and during irAEs were evaluated. Statistical analyses were conducted using the Chi-square test for categorical variables. Results At the onset of irAE, CRP rose in 93% of cases to a mean of 52.7 mg/L (CI 35.1-70.3) from 8.4 mg/L at baseline (normal < 5 mg/L) (P < 0.0001). Other causes of CRP elevation including infectious diseases were excluded, and procalcitonin (PCT) levels were normal in 92% of events. Importantly, in 42% of cases CRP elevations preceded clinical symptoms. Conclusion CRP elevation can predict the onset of irAEs in patients treated with ICIs in the absence of infectious disease.
CRIS-Team WoS Importer:2019-10-04

c-Rel is a cell cycle modulator in human melanoma cells - Priebe, Marie K.; Dewert, Nadin; Amschler, Katharina; Erpenbeck, Luise; Heinzerling, Lucie; Schoen, Michael P.; Seitz, Cornelia S.; Lorenz, Verena N. (Experimental Dermatology, 2019)
Melanoma progression and resistance to therapy are associated with faulty regulation of signalling molecules including the central transcription factor NF-kappa B. Increased expression of the c-Rel subunit of NF-kappa B has been described in progressing melanoma, though mechanistic implications of this upregulation remain unclear. To elucidate the functional role of c-Rel in melanoma biology, we have assessed its expression in human melanoma as well as in melanoma cell lines. Suppression of c-Rel expression in four melanoma cell lines resulted in reduced growth and altered cell cycle regulation, namely G2/M and polyploid phase induction. Moreover, mitotic spindle morphology was profoundly altered in three of the cell lines with a predominance of monopolar structures. These findings suggest that c-Rel is involved in G2/M phase regulation, prevention of polyploidy and, consequently, chromosomal stability. Our results highlight a novel tumor-promoting function of c-Rel in human melanoma cells through governing cell cycle regulation.
CRIS-Team WoS Importer:2019-02-21

Crusted Nodules on the Lower Left Arm in a Traveller Returning from South America: A Quiz. Furuncular myiasis - Uslu, Ugur; Erdmann, Michael; Schliep, Stefan; Sticherling, Michael (Acta Dermato-Venereologica, 2018)
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Cryopreservation impairs 3-D migration and cytotoxicity of natural killer cells - Mark, Christoph; Czerwinski, Tina; Roessner, Susanne; Mainka, Astrid; Hörsch, Franziska; Heublein, Lucas; Winterl, Alexander; Sanokowski, Sebastian; Richter, Sebastian; Bauer, Nina; Angelini, Thomas E.; Schuler, Gerold; et al. (Nature Communications, 2020)
Natural killer (NK) cells are important effector cells in the immune response to cancer. Clinical trials on adoptively transferred NK cells in patients with solid tumors, however, have thus far been unsuccessful. As NK cells need to pass stringent safety evaluation tests before clinical use, the cells are cryopreserved to bridge the necessary evaluation time. Standard degranulation and chromium release cytotoxicity assays confirm the ability of cryopreserved NK cells to kill target cells. Here, we report that tumor cells embedded in a 3-dimensional collagen gel, however, are killed by cryopreserved NK cells at a 5.6-fold lower rate compared to fresh NK cells. This difference is mainly caused by a 6-fold decrease in the fraction of motile NK cells after cryopreservation. These findings may explain the persistent failure of NK cell therapy in patients with solid tumors and highlight the crucial role of a 3-D environment for testing NK cell function.
CRIS-Team Scopus Importer:2020-10-23

Cryopreservation reduces the Ability to migrate and the Cytotoxicity of natural Killer Cells in 3D: Possible Effects on cellular Immunotherapy - Mark, Christoph; Czerwinksi, T.; Roessner, S.; Mainka, Astrid; Hoersch, F.; Heublein, L.; Winterl, Alexander; Sanokowski, Sebastian; Richter, S.; Bauer, N.; Angelini, T.; Schuler, Gerold; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-09-11

Crystal Structure of the Extracellular Domain of the Human Dendritic Cell Surface Marker CD83 - Heilingloh, Christiane; Klingl, Stefan; Egerer-Sieber, Claudia; Schmid, Benedikt; Weiler, Sigrid; Mühl-Zürbes, Petra; Hofmann, Jörg; Stump, Joachim; Sticht, Heinrich; Kummer, Mirko; Steinkasserer, Alexander; Muller, Yves (Journal of Molecular Biology, 2017)
Keywords: homotypic interactions; immune co-stimulation and -suppression; structure–function relationships; V-set Ig-domain; X-ray crystallography

CSPG4 as Target for CAR-T-Cell Therapy of Various Tumor Entities-Merits and Challenges. - Harrer, Dennis; Dörrie, Jan; Schaft, Niels (International Journal of Molecular Sciences, 2019)
Targeting cancer cells using chimeric-antigen-receptor (CAR-)T cells has propelled adoptive T-cell therapy (ATT) to the next level. A plentitude of durable complete responses using CD19-specific CAR-T cells in patients suffering from various lymphoid malignancies resulted in the approval by the food and drug administration (FDA) of CD19-directed CAR-T cells for the treatment of acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). A substantial portion of this success in hematological malignancies can be traced back to the beneficial properties of the target antigen CD19, which combines a universal presence on target cells with no detectable expression on indispensable host cells. Hence, to replicate response rates achieved in ALL and DLBCL in the realm of solid tumors, where ideal target antigens are scant and CAR-T cells are still lagging behind expectations, the quest for appropriate target antigens represents a crucial task to expedite the next steps in the evolution of CAR-T-cell therapy. In this review, we want to highlight the potential of chondroitin sulfate proteoglycan 4 (CSPG4) as a CAR-target antigen for a variety of different cancer entities. In particular, we discuss merits and challenges associated with CSPG4-CAR-T cells for the ATT of melanoma, leukemia, glioblastoma, and triple-negative breast cancer.
CRIS-Team Scopus Importer:2019-12-10
Keywords: CAR-T cell; CSPG4; Glioblastoma; Leukemia; Melanoma; Target antigen; Triple-negative breast cancer

CSPG4-Specific CAR T Cells for High-Risk Childhood B Cell Precursor Leukemia - Harrer, Dennis C.; Schuler, Gerold; Dörrie, Jan; Schaft, Niels (International Journal of Molecular Sciences, 2019)
The advent of CD19-specific chimeric antigen receptor (CAR) T cells has proven to be a powerful asset in the arsenal of cancer immunotherapy of acute lymphoblastic leukemia and certain B cell lymphomas. However, a sizable portion of patients treated with CD19-CAR T cells relapse with CD19-negative cancer cells, necessitating the quest for back-up antigens. Chondroitin sulfate proteoglycan 4 (CSPG4) expression has been reported on leukemic blasts bearing the ill-fated MLL 11q23 rearrangement. We aimed at exploring the use of CSPG4-specific CAR T cells against mixed-lineage leukemia (MLL)-rearranged leukemic blasts, using the precursor B cell leukemia cell line KOPN8 (MLL-MLLT1 translocation) as a model. First, we confirmed CSPG4 expression on KOPN8 cells. Bulk T cells electroporated with mRNA encoding a CSPG4-specific CAR upregulated activation markers and secreted the Th1 cytokines TNF and IFNγ in an antigen-specific manner upon co-culture with KOPN8 cells. More importantly, CSPG4-specific CAR T cells evinced specific degranulation towards KOPN8 cells and specifically lysed KOPN8 target cells in chromium lysis experiments. CSPG4 is a well-established CAR target in cutaneous melanoma. Here, we provide proof-of-principle data for the use of CSPG4-specific CAR T cells against MLL-translocated leukemias.
CRIS-Team Scopus Importer:2019-07-09
Keywords: back-up target antigen; CAR T cells; CSPG4; high-risk childhood B cell precursor leukemia; MLL-translocated leukemias

Curatopes Melanoma: A Database of Predicted T-cell Epitopes from Overly Expressed Proteins in Metastatic Cutaneous Melanoma. - Lischer, Christopher; Eberhardt, Martin; Jaitly, Tanushree; Schinzel, Cornelia; Schaft, Niels; Dörrie, Jan; Schuler, Gerold; Vera González, Julio (Cancer Research, 2019)
Therapeutic anticancer vaccination has been adapted as an immunotherapy in several solid tumors. However, the selection of promising candidates from the total quantity of possible epitopes poses a challenge to clinicians and bioinformaticians alike, and very few epitopes have been tested in experimental or clinical settings to validate their efficacy. Here, we present a comprehensive database of predicted nonmutated peptide epitopes derived from genes that are overly expressed in a group of 32 melanoma biopsies compared with healthy tissues and that were filtered against expression in a curated list of survival-critical tissues. We hypothesize that these "self-tolerant" epitopes have two desirable properties: they do not depend on mutations, being immediately applicable to a large patient collective, and they potentially cause fewer autoimmune reactions. To support epitope selection, we provide an aggregated score of expected therapeutic efficiency as a shortlist mechanism. The database has applications in facilitating epitope selection and trial design and is freely accessible at https://www.curatopes.com. SIGNIFICANCE: A database is presented that predicts and scores antitumor T-cell epitopes, with a focus on tolerability and avoidance of severe autoimmunity, offering a supplementary epitope set for further investigation in immunotherapy.
CRIS-Team Scopus Importer:2019-10-22

Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy - Hofmann, Lars; Forschner, Andrea; Loquai, Carmen; Goldinger, Simone M.; Zimmer, Lisa; Ugurel, Selma; Schmidgen, Maria I.; Gutzmer, Ralf; Utikal, Jochen S.; Goeppner, Daniela; Hassel, Jessica C.; Meier, Friedegund; et al. (European Journal of Cancer, 2016)
Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential.In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis.Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
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Cutaneous squamous cell carcinoma: state of the art, perspectives and unmet needs - Heppt, Markus; Leiter, Ulrike (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
Squamous cell carcinoma of the skin (cSCC) is one of the most common cancers of the Caucasian population and accounts for 20% of all cutaneous tumors. An S3 guideline from the German Guideline Program in Oncology has been available since 2019 and was updated in 2022. The diagnosis of cSCC is based on clinical examination. Excision and histological confirmation are required for clinically suspicious lesions to allow for prognostic assessment and correct treatment. The treatment of first choice is excision with complete histological assessment of the surgical margins. Adjuvant radiation therapy may be considered if there is a high risk of recurrence. The immune checkpoint inhibitor cemiplimab is approved and recommended as the treatment of first choice for locally advanced or metastatic cSCC in Europe. If contraindications are present, chemotherapy, EGFR inhibitors, or palliative radiation therapy may be used. Surveillance should be performed in a risk-stratified manner and includes a dermatological control supplemented by sonography examinations in high-risk patients. Much research is still needed for solid organ transplant patients, concomitant hematologic diseases, and cSCC showing primary or acquired resistance to immunotherapies. Current developments include new drug combinations, intralesional therapies alone or in combination with immune checkpoint inhibitors, and neoadjuvant approaches.
CRIS-Team Scopus Importer:2023-04-21
Keywords: cutaneous; immune checkpoint inhibitor; management; skin; squamous cell carcinoma; treatment

Cu, Zn doped borate bioactive glasses: antibacterial efficacy and dose-dependent in vitro modulation of murine dendritic cells - Schuhladen, Katharina; Stich, Lena; Schmidt, Jochen; Steinkasserer, Alexander; Boccaccini, Aldo R.; Zinser, Elisabeth (Biomaterials Science, 2020)
Among emerging biomaterials, bioactive glasses (BGs) are being widely explored for various applications in tissue engineering. However, the effects of BGs (in particular BG ionic dissolution products) on immune cells and specifically on dendritic cells (DCs), which are the most potent antigen-presenting cells of the immune system, have not been previously investigated in detail. Such interactions between BGs and DCs must be assessed as a novel biocompatibility criterion for biomaterials, since, with the increased application possibilities of BGs, the modulation of the immune system may induce potential complications and undesired side effects. Indeed, the effects of BG exposure on specific immune cells are not well understood. Thus, in this study we investigated, for the first time, the effect of borate BGs doped with biologically active ions on specific immune cells, such as DCs and we further investigated the antibacterial properties of these borate BGs. The compositions of the borate BGs (B3) were based on the well-known 13-93 (silicate) composition by replacing silica with boron trioxide and by adding copper (3 wt%) and/or zinc (1 wt%). By performing an agar diffusion test, the antibacterial effect depending on the compositions of the borate BGs could be proved. Furthermore we found a dose-dependent immune modulation of DCs after treatment with borate BGs, especially when the borate BGs contained Zn and/or Cu. Depending on the ion concentration and the rise in pH, the phenotype and function of DCs were modified. While at low doses B3 and Zn-doped B3 BGs had no impact on DC viability, Cu containing BGs strongly affected cell viability. Furthermore, the surface expression of DC-specific activation markers, such as the major histocompatibility complex (MHC)-II, CD86 and CD80, was modulated. In addition, also DC mediated T-cell proliferation was remarkably reduced when treated with high doses of B3-Cu and B3-Cu-Zn BGs. Interestingly, the release of inflammatory cytokines increased after incubation with B3 and B3-Zn BGs compared to mock-treated DCs. Considering the essential role of DCs in the modulation and regulation of immune responses, these findings provide first evidence of phenotypic and functional consequences regarding the exposure of DCs to BGs in vitro.
CRIS-Team Scopus Importer:2020-04-28

CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation - Fu, Jian; Lehmann, Christian; Wang, Xinning; Wahlbuhl, Mandy; Allabauer, Ida; Wilde, Benjamin; Amon, Lukas; Dolff, Sebastian; Cesnjevar, Robert; Kribben, Andreas; Wölfle, Joachim; Rascher, Wolfgang; et al. (Scientific Reports, 2021)
Allograft-specific regulatory T cells (Treg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive Treg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific Treg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for Treg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3+ T cell infiltrated, higher Treg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated Treg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase Treg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment.
CRIS-Team Scopus Importer:2021-12-24

CXCR4-SDF1 alpha Blockade Reduces the Severity of Murine Heart Allograft Rejection - Fu, J.; Wahlbuhl, Mandy; Wang, X.; Wilde, B.; Jing, L.; Kribben, A.; Hoyer, P.; Lehmann, C. H. K.; Dudziak, Diana; Witzke, O.; Hoerning, A. (2017)
EVALuna2:34369

Dangerous mimikry - cutaneous tumours appearing as ulcus cruris - Scheerer, Cora; Tsoupis, Helene; Erfurt-Berge, Cornelia (Deutsche Medizinische Wochenschrift, 2016)
We report on a 83-year-old female patient which suffered from a chronic ulcer of the right leg for several years. She has been treated with standard wound dressings under the diagnosis of an ulcer due to chronic venous insufficiency.A first biopsy showed a lower leg dermatitis and dermatosclerosis due to the chronic venous insufficiency. Not till a second biopsy was taken in the course of the disease, a sqamous cell carcinoma could be diagnosed. Staging procedures showed no metastases.A wide excision including parts of tendon and bone was necessary. Finally a myocutaneous latissimus-dorsi-flap in combination with split skin graft was performed. A sentinel-node-biopsy was negative.Differential diagnoses of chronic wounds on lower legs are diverse and are often missed in clinical routine. Typical causes like chronic venous insufficiency, peripheral arterial occlusive disease or diabetes are found via basic diagnostics, rare diagnoses like the existence of ulcerated skin tumors are often found with a delay which leads to a poor prognosis for these patients. Besides pre-existing tumors also a secondary malignant transformation can be observed, for example towards a squamous skin cancer from an originally vascular long-lasting leg ulcer. In case of recalcitrant leg ulcers despite exhausting all therapeutic options a histological investigation of a tissue sample should be performed and an initially diagnosed cause for the chronic wound has to be scrutinized.
EVALuna2:19625

Das kutane Plattenepithelkarzinom: Aktueller Stand, Perspektiven und offene Fragen - Heppt, Markus; Leiter, Ulrike (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
CRIS-Team Scopus Importer:2023-04-28
Keywords: cutaneous; Diagnostik; Immuncheckpoint-Inhibitor; immune checkpoint inhibitor; kutanes Plattenepithelkarzinom; Management; management; skin; squamous cell carcinoma; Therapie; treatment

Dataset of a retrospective multicenter cohort study on characteristics of immune checkpoint inhibitor-induced encephalitis and comparison with HSV-1 and anti-LGI1 encephalitis - Müller-Jensen, Leonie; Zierold, Sarah; Versluis, Judith M.; Boehmerle, Wolfgang; Huehnchen, Petra; Endres, Matthias; Mohr, Raphael; Compter, Annette; Blank, Christian U.; Hagenacker, Tim; Meier, Friedegund; Reinhardt, Lydia; et al. (Data in Brief, 2022)
Over the past decade, cancer immunotherapy with immune checkpoint inhibitors (ICIs) has significantly improved the outcome of many malignancies. However, with the broad use of ICIs, neurological immune related adverse events (irAE) are increasingly recognized. ICI-induced encephalitis (ICI-iE) is a particularly severe irAE, often leading to treatment termination, long-term sequalae or death. Despite its high morbidity and mortality, data on clinical features and diagnostic criteria are limited. We aimed to define clinical, radiologic and laboratory characteristics of ICI-iE and identify factors that discriminate it from anti-leucine-rich glioma-inactivated (anti-LGI)-1 encephalitis and herpes simplex virus (HSV)-1 encephalitis – two alternative causes of encephalitis – to increase the awareness of ICI-iE and improve its diagnosis and management. To that end, we retrospectively collected 30 cases of ICI-iE that were reported to the Side Effect Registry Immuno-Oncology (SERIO) and 46 cases of anti-LGI1 encephalitis or herpes simplex virus (HSV)-1 encephalitis that presented to a large German neurological referral center (Charité Universitätsmedizin Berlin) between January 2015 and September 2021. Signs and symptoms, imaging and electroencephalogram features, laboratory findings and outcome measures were assessed using standardized case report forms as well as patients’ medical records and compared between the groups. The data reported here represents the largest primary cohort of patients with ICI-iE to date and the first comparison with other types of encephalitis. As all three disorders – ICI-iE, HSV-1 encephalitis and anti-LGI1 encephalitis – are rare neurological entities, this dataset can be used as a reference in future clinical studies on ICI-induced neurotoxicity, neurological autoimmune disorders, and central nervous system infections.
CRIS-Team Scopus Importer:2022-10-21
Keywords: Anti-LGI1 encephalitis; Cancer; Encephalitis; Herpetic encephalitis; Immune related adverse events; Immunotherapy; Neurotoxicity

DC subset-specific induction of T cell responses upon antigen uptake via Fc. receptors in vivo - Lehmann, Christian; Baranska, Anna; Heidkamp, Gordon Frederik; Heger, Lukas; Neubert, Kirsten; Lühr, Jennifer; Hofmann, Andrea; Reimer, Katharina; Brueckner, Christin; Beck, Simone; Seeling, Michaela; Kießling, Melissa; et al. (EUROPEAN JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

DC subset-specific induction of T cell responses upon antigen uptake via Fcγ receptors in vivo. - Lehmann, Christian; Baranska, Anna; Heidkamp, Gordon Frederik; Heger, Lukas; Neubert, Kirsten; Luehr, Jennifer J.; Hoffmann, Alana; Reimer, Katharina; Brückner, Christin; Beck, Simone; Seeling, Michaela; Kießling, Melissa; et al. (Journal of Experimental Medicine, 2017)
Dendritic cells (DCs) are efficient antigen-presenting cells equipped with various cell surface receptors for the direct or indirect recognition of pathogenic microorganisms. Interestingly, not much is known about the specific expression pattern and function of the individual activating and inhibitory Fcγ receptors (FcγRs) on splenic DC subsets in vivo and how they contribute to the initiation of T cell responses. By targeting antigens to select activating and the inhibitory FcγR in vivo, we show that antigen uptake under steady-state conditions results in a short-term expansion of antigen-specific T cells, whereas under inflammatory conditions especially, the activating FcγRIV is able to induce superior CD4(+) and CD8(+) T cell responses. Of note, this effect was independent of FcγR intrinsic activating signaling pathways. Moreover, despite the expression of FcγRIV on both conventional splenic DC subsets, the induction of CD8(+) T cell responses was largely dependent on CD11c(+)CD8(+) DCs, whereas CD11c(+)CD8(-) DCs were critical for priming CD4(+) T cell responses.

Decision Conflicts in Clinical Care during COVID-19: A Multi-Perspective Inquiry. - Haier, Joerg; Beller, Johannes; Adorjan, Kristina; Bleich, Stefan; De Greck, Moritz; Griesinger, Frank; Heppt, Markus; Hurlemann, Rene; Mees, Soeren Torge; Philipsen, Alexandra; Rohde, Gernot; Schilling, Georgia; et al. (Healthcare, 2022)
Background: The early COVID-19-pandemic was characterized by changes in decision making, decision-relevant value systems and the related perception of decisional uncertainties and conflicts resulting in decisional burden and stress. The vulnerability of clinical care professionals to these decisional dilemmas has not been characterized yet. Methods: A cross-sectional questionnaire study (540 patients, 322 physicians and 369 nurses in 11 institutions throughout Germany) was carried out. The inclusion criterion was active involvement in clinical treatment or decision making in oncology or psychiatry during the first year of COVID-19. The questionnaires covered five decision dimensions (conflicts and uncertainty, resources, risk perception, perception of consequences for clinical processes, and the perception of consequences for patients). Data analysis was performed using ANOVA, Pearson rank correlations, and the Chi²-test, and for inferential analysis, nominal logistic regression and tree classification were conducted. Results: Professionals reported changes in clinical management (27.5%) and a higher workload (29.2%), resulting in decisional uncertainty (19.2%) and decisional conflicts (22.7%), with significant differences between professional groups (p < 0.005), including anxiety, depression, loneliness and stress in professional subgroups (p < 0.001). Nominal regression analysis targeting “Decisional Uncertainty” provided a highly significant prediction model (LQ p < 0.001) containing eight variables, and the analysis for “Decisional Conflicts” included six items. The classification rates were 64.4% and 92.7%, respectively. Tree analysis confirmed three levels of determinants. Conclusions: Decisional uncertainty and conflicts during the COVID-19 pandemic were independent of the actual pandemic load. Vulnerable professional groups for the perception of a high number of decisional dilemmas were characterized by individual perception and the psychological framework. Coping and management strategies should target vulnerability, enable the handling of the individual perception of decisional dilemmas and ensure information availability and specific support for younger professionals.
EVALuna2:510807

Decitabine-Mediated Upregulation of CSPG4 in Ovarian Carcinoma Cells Enables Targeting by CSPG4-Specific CAR-T Cells - Harrer, Dennis Christoph; Schenkel, Charlotte; Berking, Carola; Herr, Wolfgang; Abken, Hinrich; Dörrie, Jan; Schaft, Niels (Cancers, 2022)
Simple Summary Cancer therapy by specifically redirected T cells has revolutionized the field of oncology. However, the repertoire of targetable antigens is small. Here, we use the FDA-approved drug decitabine to upregulate the surface antigen CSPG4 on CSPG4-negative ovarian carcinoma cells. By optimizing decitabine dosing, we converted more than 50% of treated ovarian carcinoma cells to CSPG4-positive cells. Importantly, CSPG4 is a very well-established target antigen in melanoma, and we could previously demonstrate that T cells engineered to target CSPG4 could reliably kill CSPG4-positive melanoma cells. Using CSPG4-specific T cells, we demonstrate CSPG4-directed killing of decitabine-treated ovarian carcinoma cells, thereby adding CSPG4 to the repertoire of target antigens for ovarian cancer. The addition of CAR-T cells to the armamentarium of immunotherapy revigorated the field of oncology by inducing long-lasting remissions in patients with relapsing/refractory hematological malignancies. Nevertheless, in the lion's share of patients diagnosed with solid tumors, CAR-T-cell therapy so far failed to demonstrate satisfactory anti-tumor activity. A crucial cause of resistance against the antigen-specific attack of CAR-T cells is predicated on the primary or secondary absence of suitable target antigens. Thus, the necessity to create a broad repertoire of different target antigens is vital. We aimed to evaluate the potential of the well-established melanoma antigen chondroitin sulfate proteoglycan 4 (CSPG4) as an inducible antigen in ovarian cancer cells, using CSPG4-negative SKOV-3 ovarian cancer cells as a model. Based on the hypomethylating activity of the FDA-approved drug decitabine, we refined a protocol to upregulate CSPG4 in the majority of decitabine-treated SKOV-3 cells. CSPG4-specific CAR-T cells generated by mRNA-electroporation showed CSPG4-directed cytokine secretion and cytotoxicity towards decitabine-treated SKOV-3. Another ovarian cancer cell line (Caov-3) and the neoplastic cell line 293T behaved similar. In aggregate, we generated proof-of-concept data paving the way for the further exploration of CSPG4 as an inducible antigen for CAR-T cells in ovarian cancer.
CRIS-Team WoS Importer:2022-11-11

Decreased numbers of regulatory T cells are associated with human atherosclerotic lesion vulnerability and inversely correlate with infiltrated mature dendritic cells - Dietel, Barbara; Cicha, Iwona; Voskens, Caroline; Verhoeven, Eric; Achenbach, Stephan; Garlichs, Christoph (Atherosclerosis, 2013)
Purpose: Mature dendritic cells (DCs) play a crucial role in the inflammatory process within atherosclerotic lesions by stimulation of effector T cells, which can contribute to plaque instability. Interactions between DCs and regulatory T cells (Treg), which regulate immune response by attenuating acute inflammation, are postulated to be involved in the pathogenesis of autoimmune diseases. We investigated a possible correlation between infiltrated DCs and Treg in human atherosclerotic plaques. Methods: Cross-sections of 40 human carotid endarterectomy specimens were classified into groups of stable and vulnerable plaques using Trichrome staining. Immunohistochemical staining of plaques was used to detect infiltrated total (S100) and mature DCs (fascin, DC-LAMP, CD83), Treg (CD3, Foxp3), and to analyze the inflammatory state of the plaques (CD3, COX-2, CD68). In addition, RNA was isolated from plaque specimens and quantitative real-time PCR was performed to analyze transcription rates of DC markers (CD11c, CD209, HLA-DR), maturation markers (CD80, CD83, CD86), Treg-associated genes (CTLA-4, Foxp3) and of pro- and anti-inflammatory cytokines (TGFβ-family, IL-10, IFN-γ, IL-17α, IL-6). Migration assays and adhesion experiments were performed, to investigate the effects of Treg on mature DCs invitro. Results: As compared with stable plaques, vulnerable lesions were characterized by increased numbers of COX-2-expressing cells and T lymphocytes, indicating an enhanced inflammatory process. In vulnerable plaques, numbers of total and mature DCs were significantly higher in the inflammatory plaque shoulder, whereas the numbers of Treg were decreased compared to stable plaques. This inverse correlation and the association of the observed infiltration rates with plaque stability, were confirmed by PCR analyses, showing increased transcription levels of DC-specific markers, decreased mRNA expression of Treg-associated genes and decreased anti-inflammatory cytokines in vulnerable atherosclerotic plaques. In vitro, pre-incubation of mature DCs with Treg resulted in decreased DC migration and inhibited the adhesion of DCs to endothelial cells under non-uniform shear stress. Conclusions: The results of our study provide novel insights in the direct interaction of mature DCs and Treg in plaque inflammation and stability. © 2013 Elsevier Ireland Ltd.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Atherosclerosis; Carotid plaques; Dendritic cells; Immunologic tolerance; Regulatory T cells

Dedifferentiated and Undifferentiated Melanomas: Report of 35 New Cases with Literature Review and Proposal of Diagnostic Criteria - Agaimy, Abbas; Stöhr, Robert; Hornung, Annkathrin; Popp, Judith; Erdmann, Michael; Heinzerling, Lucie; Hartmann, Arndt (American Journal of Surgical Pathology, 2021)
Dedifferentiated melanoma (DM) and undifferentiated melanoma (UM) is defined as a primary or metastatic melanoma showing transition between conventional and undifferentiated components (DM) or lacking histologic and immunophenotypic features of melanoma altogether (UM). The latter is impossible to verify as melanoma by conventional diagnostic tools alone. We herein describe our experience with 35 unpublished cases to expand on their morphologic, phenotypic, and genotypic spectrum, along with a review of 50 previously reported cases (total: 85) to establish the diagnostic criteria. By definition, the dedifferentiated/undifferentiated component lacked expression of 5 routinely used melanoma markers (S100, SOX10, Melan-A, HMB45, Pan-melanoma). Initial diagnoses (known in 66 cases) were undifferentiated/unclassified pleomorphic sarcoma (n=30), unclassified epithelioid malignancy (n=7), pleomorphic rhabdomyosarcoma (n=5), other specific sarcoma types (n=6), poorly differentiated carcinoma (n=2), collision tumor (n=2), atypical fibroxanthoma (n=2), and reactive osteochondromatous lesion (n=1). In only 11 cases (16.6%) was a diagnosis of melanoma considered. Three main categories were identified: The largest group (n=56) comprised patients with a history of verified previous melanoma who presented with metastatic DM or UM. Axillary or inguinal lymph nodes, soft tissue, bone, and lung were mainly affected. A melanoma-compatible mutation was detected in 35 of 48 (73%) evaluable cases: BRAF (n=20; 40.8%), and NRAS (n=15; 30.6%). The second group (n=15) had clinicopathologic features similar to group 1, but a melanoma history was lacking. Axillary lymph nodes (n=6) was the major site in this group followed by the lung, soft tissue, and multiple site involvement. For this group, NRAS mutation was much more frequent (n=9; 60%) than BRAF (n=3; 20%) and NF1 (n=1; 6.6%). The third category (n=14) comprised primary DM (12) or UM (2). A melanoma-compatible mutation was detected in only 7 cases: BRAF (n=2), NF1 (n=2), NRAS (n=2), and KIT exon 11 (n=1). This extended follow-up study highlights the high phenotypic plasticity of DM/UM and indicates significant underrecognition of this aggressive disease among general surgical pathologists. The major clues to the diagnosis of DM and UM are: (1) presence of minimal differentiated clone in DM, (2) earlier history of melanoma, (3) undifferentiated histology that does not fit any defined entity, (4) locations at sites that are unusual for undifferentiated/unclassified pleomorphic sarcoma (axilla, inguinal, neck, digestive system, etc.), (5) unusual multifocal disease typical of melanoma spread, (6) detection of a melanoma-compatible gene mutation, and (7) absence of another genuine primary (eg, anaplastic carcinoma) in other organs.
CRIS-Team Scopus Importer:2021-02-05
Keywords: BRAF; chondrosarcoma; dedifferentiated melanoma; giant cell tumor; KIT; NRAS; osteosarcoma; pleomorphic sarcoma; rhabdomyosarcoma; undifferentiated melanoma

Deep learning approach to predict sentinel lymph node status directly from routine histology of primary melanoma tumours - Brinker, Titus J.; Kiehl, Lennard; Schmitt, Max; Jutzi, Tanja B.; Krieghoff-Henning, Eva I.; Krahl, Dieter; Kutzner, Heinz; Gholam, Patrick; Haferkamp, Sebastian; Klode, Joachim; Schadendorf, Dirk; Hekler, Achim; et al. (European Journal of Cancer, 2021)
Aim: Sentinel lymph node status is a central prognostic factor for melanomas. However, the surgical excision involves some risks for affected patients. In this study, we therefore aimed to develop a digital biomarker that can predict lymph node metastasis non-invasively from digitised H&E slides of primary melanoma tumours. Methods: A total of 415 H&E slides from primary melanoma tumours with known sentinel node (SN) status from three German university hospitals and one private pathological practice were digitised (150 SN positive/265 SN negative). Two hundred ninety-one slides were used to train artificial neural networks (ANNs). The remaining 124 slides were used to test the ability of the ANNs to predict sentinel status. ANNs were trained and/or tested on data sets that were matched or not matched between SN-positive and SN-negative cases for patient age, ulceration, and tumour thickness, factors that are known to correlate with lymph node status. Results: The best accuracy was achieved by an ANN that was trained and tested on unmatched cases (61.8% ± 0.2%) area under the receiver operating characteristic (AUROC). In contrast, ANNs that were trained and/or tested on matched cases achieved (55.0% ± 3.5%) AUROC or less. Conclusion: Our results indicate that the image classifier can predict lymph node status to some, albeit so far not clinically relevant, extent. It may do so by mostly detecting equivalents of factors on histological slides that are already known to correlate with lymph node status. Our results provide a basis for future research with larger data cohorts.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Artificial intelligence; Biomarkers; Histology; Lymph node biopsy; Machine learning; Melanoma; Neural network model; Pathology; Sentinel; Skin cancer

Deepnapsi: Deep Learning for Nail Psoriasis Prediction - Folle, Lukas; Fenzl, Pauline; Fagni, Filippo; Thies, Mareike; Christlein, Vincent; Meder, Christine; Sticherling, Michael; Simon, David; Schett, Georg; Maier, Andreas; Kleyer, Arnd (Proceedings - International Symposium on Biomedical Imaging, 2023)
Nail psoriasis is a frequent condition that is associated with a severe course of rheumatic diseases. Thus, it may be used to adapt the therapy of patients according to the change of nail psoriasis. The nail psoriasis severity index (NAPSI) was developed to measure this condition. Nevertheless, there is a lack of application for the NAPSI, as its use in the clinic is too time-consuming. In this work, we propose the use of advancements in deep learning in a new domain by recording, annotating, and predicting the NAPSI based on photographs of the hand and term our approach DeepNAPSI. This allows not just the automated recording of the NAPSI in the clinic, but also patient self-assessment from home. Our method achieved an area-under-receiver-operator-characteristic curve (AUROC) of 0.83 and 0.86 for macro and micro averaging, respectively, and a mean absolute error of 0.55.
CRIS-Team Scopus Importer:2023-10-06
Keywords: Deep Learning; Mobile device; Nail psoriasis; Precision medicine

DeepNAPSI multi-reader nail psoriasis prediction using deep learning - Folle, Lukas; Fenzl, Pauline; Fagni, Filippo; Thies, Mareike; Christlein, Vincent; Meder, Christine; Simon, David; Minnopoulou, Ioanna; Sticherling, Michael; Schett, Georg; Maier, Andreas; Kleyer, Arnd (Nature Scientific Reports, 2023)
Nail psoriasis occurs in about every second psoriasis patient. Both, finger and toe nails can be affected and also severely destroyed. Furthermore, nail psoriasis is associated with a more severe course of the disease and the development of psoriatic arthritis. User independent quantification of nail psoriasis, however, is challenging due to the heterogeneous involvement of matrix and nail bed. For this purpose, the nail psoriasis severity index (NAPSI) has been developed. Experts grade pathological changes of each nail of the patient leading to a maximum score of 80 for all nails of the hands. Application in clinical practice, however, is not feasible due to the time-intensive manual grading process especially if more nails are involved. In this work we aimed to automatically quantify the modified NAPSI (mNAPSI) of patients using neuronal networks retrospectively. First, we performed photographs of the hands of patients with psoriasis, psoriatic arthritis, and rheumatoid arthritis. In a second step, we collected and annotated the mNAPSI scores of 1154 nail photos. Followingly, we extracted each nail automatically using an automatic key-point-detection system. The agreement among the three readers with a Cronbach’s alpha of 94% was very high. With the nail images individually available, we trained a transformer-based neural network (BEiT) to predict the mNAPSI score. The network reached a good performance with an area-under-receiver-operator-curve of 88% and an area-under precision-recall-curve (PR-AUC) of 63%. We could compare the results with the human annotations and achieved a very high positive Pearson correlation of 90% by aggregating the predictions of the network on the test set to the patient-level. Lastly, we provided open access to the whole system enabling the use of the mNAPSI in clinical practice.

Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells - Gradtke, Ann-Christine; Mentrup, Torben; Lehmann, Christian; Cabrera-Cabrera, Florencia; Desel, Christine; Okakpu, Darian; Assmann, Maike; Dalpke, Alexander; Schaible, Ulrich E.; Dudziak, Diana; Schroder, Bernd (Journal of Immunology, 2021)
Signal peptide peptidase-like 2a (SPPL2a) is an aspartyl intramembrane protease essential for degradation of the invariant chain CD74. In humans, absence of SPPL2a leads to Mendelian susceptibility to mycobacterial disease, which is attributed to a loss of the dendritic cell (DC) subset conventional DC2. In this study, we confirm depletion of conventional DC2 in lymphatic tissues of SPPL2a(-/-) mice and demonstrate dependence on CD74 using SPPL2a(-/-) CD74(-1-) mice. Upon contact with mycobacteria, SPPL2a(-/-) bone marrow-derived DCs show enhanced secretion of IL-1 beta, whereas production of IL-10 and IFN-beta is reduced. These effects correlated with modulated responses upon selective stimulation of the pattern recognition receptors TLR4 and Dectin-1. In SPPL2a(-/-) bone marrow-derived DCs, Dectin-1 is redistributed to endosomal compartments. Thus, SPPL2a deficiency alters pattern recognition receptor pathways in a CD74-dependent way, shifting the balance from anti- to proinflammatory cytokines in antimycobacterial responses. We propose that in addition to the DC reduction, this altered DC functionality contributes to Mendelian susceptibility to mycobacterial disease upon SPPL2a deficiency.
CRIS-Team WoS Importer:2021-01-15

Definition, aims, and implementation of GA2LEN/HAEi Angioedema Centers of Reference and Excellence - Maurer, Marcus; Aberer, Werner; Agondi, Rosana; Al-Ahmad, Mona; Al-Nesf, Maryam Ali; Ansotegui, Ignacio; Arnaout, Rand; Arruda, Luisa Karla; Asero, Riccardo; Aygören-Pürsü, Emel; Banerji, Aleena; Bauer, Andrea; et al. (Allergy, 2020)
CRIS-Team Scopus Importer:2020-05-12
Keywords: angioedema; center; excellence; management; urticaria

Delay in antibiotic therapy results in fatal disease outcome in murine pneumococcal pneumonia - Berger, Sarah; Goekeri, Cengiz; Gupta, Shishir K.; Vera, Julio; Dietert, Kristina; Behrendt, Ulrike; Lienau, Jasmin; Wienhold, Sandra-Maria; Gruber, Achim D.; Suttorp, Norbert; Witzenrath, Martin; Nouailles, Geraldine (Critical Care, 2018)
BACKGROUND: Community-acquired pneumonia (CAP) remains a major cause of death worldwide. Mechanisms underlying the detrimental outcome despite adequate antibiotic therapy and comorbidity management are still not fully understood. METHODS: To model timely versus delayed antibiotic therapy in patients, mice with pneumococcal pneumonia received ampicillin twice a day starting early (24 h) or late (48 h) after infection. Clinical readouts and local and systemic inflammatory mediators after early and late antibiotic intervention were examined. RESULTS: Early antibiotic intervention rescued mice, limited clinical symptoms and restored fitness, whereas delayed therapy resulted in high mortality rates. Recruitment of innate immune cells remained unaffected by antibiotic therapy. However, both early and late antibiotic intervention dampened local levels of inflammatory mediators in the alveolar spaces. Early treatment protected from barrier breakdown, and reduced levels of vascular endothelial growth factor (VEGF) and perivascular and alveolar edema formation. In contrast, at 48 h post infection, increased pulmonary leakage was apparent and not reversed by late antibiotic treatment. Concurrently, levels of VEGF remained high and no beneficial effect on edema formation was evident despite therapy. Moreover, early but not late treatment protected mice from a vast systemic inflammatory response. CONCLUSIONS: Our data show that only early antibiotic therapy, administered prior to breakdown of the alveolar-capillary barrier and systemic inflammation, led to restored fitness and rescued mice from fatal streptococcal pneumonia. The findings highlight the importance of identifying CAP patients prior to lung barrier failure and systemic inflammation and of handling CAP as a medical emergency.
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Dendritic cells are involved in the resolution of inflammation by IVIg in arthritis - Lehmann, Christian; Amon, Lukas; Seichter, A.; Brückner, Christin; Altmann, Leon; Heger, Lukas; Heger, L.; Ravetch, J. V.; Nimmerjahn, Falk; Dudziak, Diana (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Dendritic Cells Control Regulatory T Cell Function Required for Maintenance of Intestinal Tissue Homeostasis - Hilpert, Cornelia; Sitte, Selina; Arnold, Harald; Lehmann, Christian; Dudziak, Diana; Mattner, Jochen; Vöhringer, David (Journal of Immunology, 2019)
Dendritic cells (DCs) together with regulatory T cells (Tregs) are essential mediators of immune homeostasis. Disruption of function or frequency of either cell type can lead to fatal autoimmunity. We previously described that mice constitutively lacking DCs (∆DC) develop autoimmunity characterized by reduced body weight, autoantibodies, and pronounced intestinal inflammation. In this study, we show that lack of DCs leads to an altered gene expression profile in peripheral but not thymic Tregs with increased expression of inhibitory receptors. The suppressive function of Tregs from ΔDC mice was impaired in T cell cocultures. In a model of transfer colitis, Tregs from ∆DC mice were only functional in the presence of DCs in recipient mice. Lack of MHC class II on DCs also resulted in upregulation of inhibitory receptors on Tregs, reduced body weight, and elevated serum IgA levels. Further analysis of the IgA response revealed an expansion of IgA+ germinal center B cells and plasma cells in mesenteric lymph nodes and more IgA-coated commensal bacteria in feces of ∆DC mice. Thus, we show a critical role for DCs to establish intestinal homeostasis by regulating Treg function for prevention of spontaneous inflammation.
CRIS-Team Scopus Importer:2019-11-29

Dermatological Moulages in Germany- Comparison of Two Representative Collections - Sticherling, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Dermatological Quality of Life and Neurodermatitis: Results from the German Neurodermatitis Registry TREATgermany - Helmert, C.; Haufe, E.; Abraham, S.; Heratizadeh, A.; Harder, I.; Kleinheinz, A.; Wollenberg, A.; Wiemers, F.; Weisshaar, E.; Augustin, M.; Zink, A.; Von Kiedrowski, R.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-04-16

Dermatology Part 2: Ichthyoses and Psoriasis - Sticherling, Michael (Handbook of Experimental Pharmacology, 2020)
Acute and chronic inflammatory skin diseases are frequent in childhood and may be hereditary or acquired. In this context, ichthyosis is rather a symptom than a defined disease as scaling is accompanying a number of disorders and is mostly consequence of a disrupted skin barrier. Ichthyosis is the basic pathogenic trait of atopic dermatitis but on the other side describes a group of rare hereditary diseases. These may only affect the skin or comprise several internal symptoms as well. Psoriasis is another scaling inflammatory skin disease with classical sharply demarcated erythematosquamous plaques and with a distinct immunogenetic background. It comprises several clinical subsets, some of which are characteristic for children and demanding in both diagnostics and therapy. Comorbid diseases point towards a systemic inflammatory response and require ample, often systemic treatment. Both ichthyosis and psoriasis may be topically treated including emollients with and without humectants as well as active agents like corticosteroids, vitamin D derivatives, and calcineurin inhibitors. In moderate to severe diseases, systemic treatment should be applied using methotrexate, ciclosporin, fumarates, or biologics. Their use should be critically discussed yet if necessary and indicated be applied to avoid chronic physical and psychological damage to the affected children.
EVALuna2:212856

Dermatomyositis- a rare, but important Disease between Dermatology and Internal Medicine - Sell, S.; Sticherling, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Design and Implementation of an ETL-Process to Transfer Wound-Related Data into a Standardized Common Data Model - Przysucha, Mareike; Hüsers, Jens; Liberman, Daniil; Kersten, Oliver; Schlüter, Aphrodite; Fraas, Sebastian; Busch, Dorothee; Moelleken, Maurice; Erfurt-Berge, Cornelia; Dissemond, Joachim; Hübner, Ursula (German Medical Data Sciences 2023 – Science. Close to People., 2023)
For observational studies, which are relevant especially for chronic conditions like chronic wounds, the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) offers a standardized database schema. In this study an ETL process for the transition of wound related data was developed. After understanding the data in general and mapping the relevant codes to concepts available in OMOP, the ETL process was implemented. In a first step, a generic algorithm to convert data to a csv format was implemented in Java. The resulting csv file was then processed within KNIME to be loaded into an OMOP CDM conformant database. During the whole ETL process, HL7 FHIR CodeSystem and ConceptMap resources were used for coding and mapping. First clinical test cases to retrieve data were successfully processed as an example to demonstrate the feasibility and usefulness. They concerned wound size at the first visit and the main issues of patients in the wound quality of life questionnaire (n = 24). In general, the ETL process worked well, yet some challenges arose, like post coordinated SNOMED codes or conditions, which might occur more than once.
CRIS-Team Scopus Importer:2023-09-22
Keywords: ETL Process; OMOP CDM; Wound Care

Despite large choice of effective therapies: Individuals with psoriasis still seem undertreated - Pilz, Anna Caroline; Zink, Alexander; Schielein, Maximilian C.; Hell, Katharina; Romer, Katrin; Hillmann, Elena; Baumer, Daniel; Reinhardt, Maximilian; Wagner, Nicola (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
Background and objectives Due to the development of new anti-psoriatic drugs in combination with improved structures for implementation throughout Germany, the medical care of psoriasis patients has markedly improved. In this study we investigated the real-life utilization of the health care system and identified reasons for dissatisfaction in affected individuals.
CRIS-Team WoS Importer:2021-05-21

Detecting long-range interactions between migrating cells - Metzner, C.; Hörsch, F.; Mark, Christoph; Czerwinski, Tina; Winterl, Alexander; Voskens, Caroline; Fabry, Ben (Scientific Reports, 2021)
Chemotaxis enables cells to systematically approach distant targets that emit a diffusible guiding substance. However, the visual observation of an encounter between a cell and a target does not necessarily indicate the presence of a chemotactic approach mechanism, as even a blindly migrating cell can come across a target by chance. To distinguish between the chemotactic approach and blind migration, we present an objective method that is based on the analysis of time-lapse recorded cell migration trajectories: For each movement step of a cell relative to the position of a potential target, we compute a p value that quantifies the likelihood of the movement direction under the null-hypothesis of blind migration. The resulting distribution of p values, pooled over all recorded cell trajectories, is then compared to an ensemble of reference distributions in which the positions of targets are randomized. First, we validate our method with simulated data, demonstrating that it reliably detects the presence or absence of remote cell-cell interactions. In a second step, we apply the method to data from three-dimensional collagen gels, interspersed with highly migratory natural killer (NK) cells that were derived from two different human donors. We find for one of the donors an attractive interaction between the NK cells, pointing to a cooperative behavior of these immune cells. When adding nearly stationary K562 tumor cells to the system, we find a repulsive interaction between K562 and NK cells for one of the donors. By contrast, we find attractive interactions between NK cells and an IL-15-secreting variant of K562 tumor cells. We therefore speculate that NK cells find wild-type tumor cells only by chance, but are programmed to leave a target quickly after a close encounter. We provide a freely available Python implementation of our p value method that can serve as a general tool for detecting long-range interactions in collective systems of self-driven agents.
CRIS-Team Scopus Importer:2021-08-06

Detection and Analysis of Critical Dynamic Properties of Oligodendrocyte Differentiation - Nikolov, Svetoslav G.; Wolkenhauer, Olaf; Nenov, Momchil; Vera González, Julio (Mathematics, 2022)
In this paper, we derive a four-dimensional ordinary differential equation (ODE) model representing the main interactions between Sox9, Sox10, Olig2 and several miRNAs, which drive the process of (olygodendrocyte) differentiation. We utilize the Lyapunov-Andronov theory to analyze its dynamical properties. Our results indicated that the strength of external signaling (morphogenic gradients shh and bmp), and the transcription rate of mOlig2 explain the existence of stable and unstable (sustained oscillations) behavior in the system. Possible biological implications are discussed.
CRIS-Team WoS Importer:2022-09-09

Detection and Assessment of epidermotropic, pigmented Melanoma Metastases under Therapy using 3D Whole-Body Photography - Erdmann, M.; Toussaint, Frédéric; Hornung, Annkathrin; Heinzerling, Lucie; Berking, Carola; Schliep, S. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-09-11

Detection and Characterization of Circulating Tumor Cells in Patients with Merkel Cell Carcinoma - Riethdorf, Sabine; Hildebrandt, Lina; Heinzerling, Lucie; Heitzer, Ellen; Fischer, Nicole; Bergmann, Sonja; Mauermann, Oliver; Waldispuehl-Geigl, Julie; Coith, Cornelia; Schoen, Gerhard; Peine, Sven; Schuler, Gerold; et al. (Clinical Chemistry, 2019)
BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with increasing incidence and high mortality rates. MCC has recently become the subject of immune checkpoint therapy, but reliable biomarkers for estimating prognosis, risk stratification, and prediction of response are missing.
CRIS-Team WoS Importer:2019-03-15

Development and evaluation of a digital education tool for medical students in wound care - Schlupeck, Mischa; Stubner, Birgit; Erfurt-Berge, Cornelia (International Wound Journal, 2020)
The aim of this study was to develop and evaluate an interactive, video-enhanced, and case-based online course for medical students. We chose a case about wound care since this topic is still underrepresented in the medical curriculum. First, instructional videos were created to teach practical skills in wound care. These were implemented into a case-based online course, using the online learning platform ILIAS. In a comparative initial and final survey, numbers of users were assessed, content and structure of the course, as well as the thematic interest of the students and self-assessed gain of competence, were evaluated. Since the summer of 2019, 310 students have successfully completed the course. The survey data showed a high participation rate and a positive response regarding the content as well as the structural concept. Most of the students rated the content within the course as useful for their future medical work (86.1%) and the gain of knowledge superior to a traditional lecture (69.4%). Self-assessments of video-mediated skills showed a significant increase in subjectively perceived competence. The online course is an efficient way to reach many students by the small use of resources. It resembles an option to arouse growing interest in wound care in medical students.
CRIS-Team Scopus Importer:2020-09-25
Keywords: digital education; health care; medical students; practical skills; wound care

Development and evaluation of an interprofessional teaching concept for modern wound management - Bergendahl, Lukas; Werner, Felix; Schmidt, Anita; Ronicke, Moritz; Renner, Regina; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
Background and objectives: The aim of the present study was to establish and evaluate a new interprofessional teaching concept on the topic of wound management. Methods: After determining the status quo using a survey among medical students, we developed a new teaching concept that included a 150-minute course aimed at providing students with the opportunity to gain hands-on wound management skills. This interprofessional course was offered at the existing ‘SkillsLab’ teaching facility. The participants’ subjective level of knowledge was assessed by questionnaire before and after the course. Results: Our survey among 190 medical students showed them to be very interested in gaining practical experience in the field of wound management. To date, 120 participants (54.8 % medical students; 45.2 % nursing students) have attended this new interprofessional course, which has been equally well received by both medical and nursing students. For all specific topics (diagnosis, treatment, use of wound dressings, debridement), course participation was associated with a significant increase in knowledge. Conclusion: Given its relevance in clinical practice, it is important for medical students to learn about the various aspects associated with the care of patients with chronic wounds. By offering new teaching concepts, dermatology in particular is well suited to help students gain a better understanding of the challenges related to wound management and to improve their practical skills. Wound management is an ideal topic for interprofessional learning.
CRIS-Team Scopus Importer:2020-09-11

Development of a digital Teaching Project on the Topic of "Immunooncology" - Kaufmann, Matthias; Berking, Carola; French, L. E.; Meyerolbersleben, Marion; Reinholz, M.; Steeb, Theresa; Heppt, Markus (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Development of brain metastases and survival outcomes upon first-line systemic therapy in BRAF mutant and BRAF wildtype melanoma patients: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG - Franklin, C.; Mohr, P.; Meier, F.; Weichenthal, M.; Grimmel-Mann, I.; Gutzmer, R.; Utikal, J. S.; Terheyden, P.; Herbst, R.; Haferkamp, S.; Pfohler, C.; Leiter-Stoppke, U.; et al. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

Development of combination therapy to delay resistance in BRAF-inhibitor treated melanoma - Seretis, A.; Cappellano, G.; Bellmann, L.; Hornsteiner, F.; Tripp, C. H.; Ortner-Tobider, D.; Mullins, D. W.; Amon, Lukas; Lehmann, Christian; Dudziak, Diana; Stoitzner, P. (EXPERIMENTAL DERMATOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-14

Differences in Stakeholders' Perception of the Impact of COVID-19 on Clinical Care and Decision-Making - Haier, Joerg; Beller, Johannes; Adorjan, Kristina; Bleich, Stefan; De Greck, Moritz; Griesinger, Frank; Heppt, Markus; Hurlemann, Rene; Mees, Soeren Torge; Philipsen, Alexandra; Rohde, Gernot; Schilling, Georgia; et al. (Cancers, 2022)
Simple Summary Pandemics induce many changes in clinical management. The consequences and extent of these changes are perceived in an individual manner and differ between various stakeholder groups. Using a cross-sectional questionnaire in 11 German institutions we evaluated the different perceptions of related risks and decision-making processes. All the investigated groups share concerns about the impact of the COVID-19 pandemic on healthcare management and clinical processes, but to very different extent. Their perception is dissociated in projection towards other stakeholders. Specific awareness should avoid this dissociation that potentially results in impaired shared decision-making. Background: Pandemics are related to changes in clinical management. Factors that are associated with individual perceptions of related risks and decision-making processes focused on prevention and vaccination, but perceptions of other healthcare consequences are less investigated. Different perceptions of patients, nurses, and physicians on consequences regarding clinical management, decisional criteria, and burden were compared. Study Design: Cross-sectional OnCoVID questionnaire studies. Methods: Data that involved 1231 patients, physicians, and nurses from 11 German institutions that were actively involved in clinical treatment or decision-making in oncology or psychiatry were collected. Multivariate statistical approaches were used to analyze the stakeholder comparisons. Results: A total of 29.2% of professionals reported extensive changes in workload. Professionals in psychiatry returned severe impact of pandemic on all major aspects of their clinical care, but less changes were reported in oncology (p < 0.001). Both patient groups reported much lower recognition of treatment modifications and consequences for their own care. Decisional and pandemic burden was intensively attributed from professionals towards patients, but less in the opposite direction. Conclusions: All of the groups share concerns about the impact of the COVID-19 pandemic on healthcare management and clinical processes, but to very different extent. The perception of changes is dissociated in projection towards other stakeholders. Specific awareness should avoid the dissociated impact perception between patients and professionals potentially resulting in impaired shared decision-making.
CRIS-Team WoS Importer:2022-09-16

Differential effects of ?4?7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo - Fischer, Anika; Zundler, Sebastian; Atreya, Raja; Rath, Timo; Voskens, Caroline; Hirschmann, Simon; Lopez Posadas, Rocío; Watson, Alastair; Becker, Christoph; Schuler, Gerold; Neufert, Clemens; Atreya, Imke; et al. (Gut, 2016)
Gut homing of lymphocytes via adhesion molecules has recently emerged as new target for therapy in IBDs. We aimed to analyse the in vivo homing of effector (Teff) and regulatory (Treg) T cells to the inflamed gut via ?4?7 and G protein receptor GPR15.We assessed the expression of homing receptors on T cells in peripheral blood and inflamed mucosa. We studied the migration pattern and homing of Teff and Treg cells to the inflamed gut using intravital confocal microscopy and FACS in a humanised mouse model in dextran sodium sulfate-treated NSG (NOD.Cg-Prkdcscid-Il2rgtm1Wjl/SzJ) mice.Expression of GPR15 and ?4?7 was significantly increased on Treg rather than Teff cells in peripheral blood of patients with UC as compared with Crohn's disease and controls. In vivo analysis in a humanised mouse model showed augmented gut homing of UC Treg cells as compared with controls. Moreover, suppression of UC (but not control) Teff and Treg cell homing was noted upon treatment with the ?4?7 antibody vedolizumab. In contrast, siRNA blockade of GPR15 had only effects on homing of Teff cells but did not affect Treg homing in UC. Clinical vedolizumab treatment was associated with marked expansion of UC Treg cells in peripheral blood.?4?7 rather than GPR15 is crucial for increased colonic homing of UC Treg cells in vivo, while both receptors control UC Teff cell homing. Vedolizumab treatment impairs homing of UC Treg cells leading to their accumulation in peripheral blood with subsequent suppression of systemic Teff cell expansion.
EVALuna2:2173

Differential expression of toll like receptors and antibiotic peptides by human keratinocytes - Heusinger, Juliane; Herter-Kermann, T.; Sticherling, Michael (2019)
EVALuna2:212072

Differential Modulation of Dendritic Cell Biology by Endogenous and Exogenous Aryl Hydrocarbon Receptor Ligands - Sadeghi Shermeh, Atefeh; Royzman, Dmytro; Kuhnt, Christine; Draßner, Christina; Stich, Lena; Steinkasserer, Alexander; Knippertz, Ilka; Wild, Andreas (International Journal of Molecular Sciences, 2023)
The aryl hydrocarbon receptor (AhR) is a decisive regulatory ligand-dependent transcription factor. It binds highly diverse ligands, which can be categorized as either endogenous or exogenous. Ligand binding activates AhR, which can adjust inflammatory responses by modulating immune cells such as dendritic cells (DCs). However, how different AhR ligand classes impact the phenotype and function of human monocyte-derived DCs (hMoDCs) has not been extensively studied in a comparative manner. We, therefore, tested the effect of the representative compounds Benzo(a)pyrene (BP), 6-formylindolo[3,2-b]carbazole (FICZ), and Indoxyl 3-sulfate (I3S) on DC biology. Thereby, we reveal that BP significantly induces a tolerogenic response in lipopolysaccharide-matured DCs, which is not apparent to the same extent when using FICZ or I3S. While all three ligand classes activate AhR-dependent pathways, BP especially induces the expression of negative immune regulators, and subsequently strongly subverts the T cell stimulatory capacity of DCs. Using the CRISPR/Cas9 strategy we also prove that the regulatory effect of BP is strictly AhR-dependent. These findings imply that AhR ligands contribute differently to DC responses and incite further studies to uncover the mechanisms and molecules which are involved in the induction of different phenotypes and functions in DCs upon AhR activation.
CRIS-Team Scopus Importer:2023-05-26
Keywords: aryl hydrocarbon receptor; dendritic cells; endogenous ligands; exogenous ligands

Different phenotypes of drug-induced anaphylaxis-Data from the European Anaphylaxis Registry - Hanschmann, Theresa; Francuzik, Wojciech; Doelle-Bierke, Sabine; Hofmeier, Kathrin Scherer; Grabenhenrich, Linus; Rueff, Franziska; Renaudin, Jean-Marie; Pfoehler, Claudia; Treudler, Regina; Bilo, M. Beatrice; Lang, Roland; Ensina, Luis Felipe; et al. (Allergy, 2022)
BackgroundDrugs are a frequent cause of severe anaphylactic reactions. Here, we analyze a large dataset on drug induced anaphylaxis regarding elicitors, risk factors, symptoms, and treatment. MethodsData from the European Anaphylaxis Registry (2007-2019) with 1815 reported cases of drug-induced anaphylaxis were studied accordingly. ResultsDrugs are the third most frequent cause of anaphylaxis reported in the Anaphylaxis Registry. Among the eliciting groups of drugs analgesics and antibiotics were far most often reported. Female and senior patients were more frequently affected, while the number of children with DIA was low. DIA patients had symptoms affecting the skin and mucous membranes (n = 1525, 84.02%), the respiratory (n = 1300, 71.63%), the cardiovascular (n = 1251, 68.93%) and the gastrointestinal system (n = 549, 30.25%). Drugs caused significant more severe reactions, occurred more often in medical facilities and led to increased hospitalization rates in comparison to food and insect venom induced anaphylaxis. Adrenaline was used more often in patients with DIA than in anaphylaxis due to other causes. Patients with skin symptoms received more antihistamines and corticosteroids in the acute treatment, while gastrointestinal symptoms led to less adrenaline use. ConclusionThe study contributes to a better understanding of DIA, with a large number of cases from Europe supporting previous data, e.g., analgesics and antibiotics being the most frequent culprits for DIA. Female gender and higher age are relevant risk factors and despite clear recommendations, the emergency treatment of DIA is not administered according to the guidelines.
CRIS-Team WoS Importer:2023-01-20

Digital and innovative teaching in dermatology Practically oriented teaching online - Wittbecker, L. M.; Pham, C.; Wohlgemuth, L. K.; Hoang, M. A.; Bandholz, T. C.; Schuh, S.; Gihl, J.; Erfurt-Berge, Cornelia; Glaeser, R.; Welzel, J. (Die Dermatologie, 2022)
Background Due to the corona pandemic and also to the new competence-oriented catalogue of learning objectives in medicine and the master plan for medical studies 2020, the development of digital and practical teaching concepts has experienced a great increase in importance. Aim of the work As a result of this development, it was an important task to establish this combination and incorporate it into the curricular teaching process. Material and methods The "Toolkit dermatology" was established, which was sent to a total of more than 650 students at German university dermatology clinics. Using educational films, the students were able to practice their skills. In a further development, the toolkit was combined with classroom lectures and the students were asked to evaluate the toolkit online. Results The vast majority of students (95-100%) clearly stated that the toolkit helped them to develop their practical skills. Some of them were in fact motivated to complete a clinical traineeship/practical tertial year in dermatology (21-88%). The combination of toolkit and subsequent classroom teaching was also rated very positively (82.2%), as this hybrid mode of teaching provided a better understanding. Discussion Digital teaching formats as part of the concept of blended learning, i.e. the combination of virtual and analogue teaching formats, are becoming increasingly more important. Solutions for the disadvantages, such as the lack of real interaction and suitable examination formats, still remain to be found; however, the toolkit project demonstrates that hands-on and digital teaching can lead to high student motivation as well as a high educational standard.
CRIS-Team WoS Importer:2022-10-21

Direct delivery of antigens to dendritic cells via antibodies specific for endocytic receptors as a promising strategy for future therapies - Lehmann, Christian; Heger, Lukas; Heidkamp, Gordon Frederik; Baranska, Anna; Lühr, Jennifer; Hoffmann, Alana; Dudziak, Diana (Vaccines, 2016)
Dendritic cells (DCs) are the most potent professional antigen presenting cells and are therefore indispensable for the control of immunity. The technique of antibody mediated antigen targeting to DC subsets has been the basis of intense research for more than a decade. Many murine studies have utilized this approach of antigen delivery to various kinds of endocytic receptors of DCs both in vitro and in vivo. Today, it is widely accepted that different DC subsets are important for the induction of select immune responses. Nevertheless, many questions still remain to be answered, such as the actual influence of the targeted receptor on the initiation of the immune response to the delivered antigen. Further efforts to better understand the induction of antigen-specific immune responses will support the transfer of this knowledge into novel treatment strategies for human diseases. In this review, we will discuss the state-of-the-art aspects of the basic principles of antibody mediated antigen targeting approaches. A table will also provide a broad overview of the latest studies using antigen targeting including addressed DC subset, targeted receptors, outcome, and applied coupling techniques.
Created from Fastlane, Scopus look-up
Keywords: Antigen targeting; Antigen targeting antibodies; Cancer; CLR; DC; DCIR; DEC205; Dendritic cell subsets; moDC; Vaccine

DISEASE INTERCEPTION IN PSORIASIS PATIENTS WITH SUBCLINICAL JOINT INFLAMMATION BY INTERLEUKIN 17 INHIBITION WITH SECUKINUMAB - DATA FROM A PROSPECTIVE OPEN LABEL STUDY - Kamoylafka, E.; Oliveira, I. D.; Linz, C.; Lerchen, V.; Englbrecht, Matthias; Simon, David; Sticherling, Michael; Rech, Jürgen; Kleyer, Arnd; Schett, Georg; Hueber, Axel (2018)
EVALuna2:34789

Disease interception with interleukin-17 inhibition in high-risk psoriasis patients with subclinical joint inflammation - Data from the prospective IVEPSA study - Kampylafka, Eleni; Simon, David; D'Oliveira, Isabelle; Linz, Christina; Lerchen, Veronika; Englbrecht, Matthias; Rech, Jürgen; Kleyer, Arnd; Sticherling, Michael; Schett, Georg; Hueber, Axel (Arthritis Research & Therapy, 2019)
Background: A specific subset of psoriasis patients is characterized by subclinical inflammatory changes. These patients frequently present with arthralgia and have a higher risk to develop psoriatic arthritis (PsA). We hypothesized that IL-17A inhibition in this subset of patients can intercept the link between skin and joint disease and resolves pain and inflammatory changes. Methods: Psoriasis, but no PsA, patients were included in the open prospective exploratory Interception in very early PsA (IVEPSA) study. Patients had to have nail or scalp involvement or a high psoriasis area severity index (PASI) (> 6) as well as inflammatory or erosive changes in MRI or CT. Patients received treatment with the anti-interleukin (IL)-17A antibody secukinumab over 24 weeks. Clinical assessments of skin and joint disease were done at baseline and after 12 and 24 weeks, MRI and CT at baseline and after 24 weeks. Results: Twenty patients were included, 85% of them reporting arthralgia and 40% had tender joints at the examination. Eighty-three percent had at least one inflammatory lesion in the MRI, most of them synovitis/enthesitis. Skin disease (PASI: p < 0.002; BSA: p < 0.003) and arthralgia (VAS pain: p < 0.003) significantly improved after 24 weeks. Total PsAMRIS (p = 0.005) and synovitis subscore (p = 0.008) also significantly improved. Erosions and enthesiophytes did not progress, while bone mass in the distal radius significantly (p = 0.020) increased after 24 weeks. Conclusions: These data suggest that very early disease interception in PsA is possible leading to a comprehensive decline in skin symptoms, pain, and subclinical inflammation. IVEPSA therefore provides rationale for future early interventions with the concept to prevent the onset of PsA in high-risk individuals. Trial registration: Trial registry name PSARTROS; trial registry number: NCT02483234; June 26, 2015.
CRIS-Team Scopus Importer:2019-08-06
Keywords: Interleukin-17; Magnetic resonance imaging; Psoriasis; Psoriatic arthritis

Dissecting the IFN gamma-mediated transcriptomic alterations in Merkel cell carcinoma cell lines using Nanopore sequencing - Sauerer, Tatjana; Lischer, Christopher; Berking, Carola; Vera González, Julio; Dörrie, Jan (EXPERIMENTAL DERMATOLOGY, 2022)
CRIS-Team WoS Importer:2022-03-04

Disseminated Pustules in a 3 Year Old Boy - Grosch, Ella; Koeceroglu, M.; Schliep, S.; Kiesewetter, Franklin; Sticherling, Michael; Voskens, C. J. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases - Wopperer, Florian; Knaup, Karl; Stanzick, Kira J.; Schneider, Karen; Jobst-Schwan, Tilman; Ekici, Arif Bülent; Uebe, Steffen; Wenzel, Andrea; Schliep, Stefan; Schürfeld, Carsten; Seitz, Randolf; Bernhardt, Wanja; et al. (Kidney International, 2022)
Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is caused by mutations in one of at least five genes and leads to kidney failure usually in mid adulthood. Throughout the literature, variable numbers of families have been reported, where no mutation can be found and therefore termed ADTKD-not otherwise specified. Here, we aim to clarify the genetic cause of their diseases in our ADTKD registry. Sequencing for all known ADTKD genes was performed, followed by SNaPshot minisequencing for the dupC (an additional cytosine within a stretch of seven cytosines) mutation of MUC1. A virtual panel containing 560 genes reported in the context of kidney disease (nephrome) and exome sequencing were then analyzed sequentially. Variants were validated and tested for segregation. In 29 of the 45 registry families, mutations in known ADTKD genes were found, mostly in MUC1. Sixteen families could then be termed ADTKD-not otherwise specified, of which nine showed diagnostic variants in the nephrome (four in COL4A5, two in INF2 and one each in COL4A4, PAX2, SALL1 and PKD2). In the other seven families, exome sequencing analysis yielded potential disease associated variants in novel candidate genes for ADTKD; evaluated by database analyses and genome-wide association studies. For the great majority of our ADTKD registry we were able to reach a molecular genetic diagnosis. However, a small number of families are indeed affected by diseases classically described as a glomerular entity. Thus, incomplete clinical phenotyping and atypical clinical presentation may have led to the classification of ADTKD. The identified novel candidate genes by exome sequencing will require further functional validation.
CRIS-Team Scopus Importer:2022-07-15
Keywords: ADTKD; Alport syndrome; exome; MITKD; MUC1; UMOD

DIVERSITY OF CD4(+) BLOOD T-CELL CLONALITY PREDICTS LONGER SURVIVAL WITH CTLA4 OR PD-1 CHECKPOINT INHIBITION IN ADVANCED MELANOMA - Arakawa, A.; Vollmer, S.; Tietze, J.; Galinski, A.; Heppt, Markus; Berking, Carola; Prinz, J. C. (JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2021)
CRIS-Team WoS Importer:2021-12-03

Do B-Cells play a Role in Patients with Psoriasis? - Banki, Simon; Heusinger, Juliane; Herter-Kermann, T.; Sticherling, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-04-16

Documentation of psoriasis in routine care – expert consensus on a German data set - Otten, Marina; Mrowietz, Ulrich; Von Kiedrowski, Ralph Michael; Otto, Ramona; Altenburg, Andreas; Aschoff, Roland; Beissert, Stefan; Beiteke, Ulrike; Bonnekoh, Bernd; Hoffmann, Matthias; Koerber, Andreas; Maassen, Dirk; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
Background and objectives: Documenting patient data in psoriasis clinical practice can improve care, but standardized and transparent documentation is rare. The current project aimed to develop a data set for the documentation of psoriasis in daily practice. Material and methods: In four online Delphi rounds and one in-person meeting, 27 psoriasis experts allocated variables to a standard, an optimal and an optional data set. Most of the questions were standardized. Open questions were included to allow for the provision of reasons and to enlarge the data sets. Furthermore, in the in-person meeting we considered a) patients’ attitudes and b) dermatologists’ information on the current usage and acceptability in Germany. Results: The consensus approach resulted in a data set with 69 variables. The standard data set includes 20, the optimal data set 31 and the optional data set 18 variables. In summary, the data set can mainly be grouped into master data, general status and medical history data, medical history of psoriasis, status of psoriasis, diagnostics and comorbidity, therapies and patient-reported outcomes. Conclusions: The consensus recommendation of a standard, an optimal and an optional data set for routine care of psoriasis intends to be a decision-making aid and an orientation for both daily practice and further development of documentation systems.
CRIS-Team Scopus Importer:2021-10-22

Does In-transit-Metastasis in lower Extremity Melanoma Patients correlate with anatomical Lymphatic Drainage Pathways? - Müller, Kilian; Schellerer, Vera; Berking, Carola; Erdmann, Michael (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Does Subjectively Perceived Loss Of Hand Function Sufficiently Represent Ultrasonography-Detected Synovitis And Tenosynovitis In Patients With Psoriasis And Psoriatic Arthritis? - Coppers, Birte; Bayat, Sara; Elie-Tino, Godonou; Valor-Mendez, Larissa; Fagni, Filippo; Corte, Giulia; Tascilar, Koray; Hueber, Axel; Schönau, Verena; Sticherling, Michael; Schett, Georg; Kleyer, Arnd; et al. (poster, European Alliance of Association for Rheumatology (EULAR) Congress, 2023)

Dokumentation der Psoriasis in der Routineversorgung – Expertenkonsens zu einem deutschen Datensatz - Otten, Marina; Mrowietz, Ulrich; von Kiedrowski, Ralph Michael; Otto, Ramona; Altenburg, Andreas; Aschoff, Roland; Beissert, Stefan; Beiteke, Ulrike; Bonnekoh, Bernd; Hoffmann, Matthias; Körber, Andreas; Maaßen, Dirk; et al. (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-10-29
Keywords: Datensatz; Delphi; Dokumentation; klinische Praxis; Patientenbeteiligung; Psoriasis

Do Patients with Lower Limb Melanoma have an increased Risk of a "false negative" Sentinel Node Biopsy? - Braun, L.; Schellerer, Vera; Schuler, Gerold; Goeol, J.; Erdmann, M. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Doxycycline versus Prednisolone for the initial Treatment of bullous Pemphigoids: a pragmatic prospective randomized Study - Schmidt, E.; Benoit, S.; Ehrchen, J.; Glaeser, R.; Guenther, C.; Steinbrink, K.; Sticherling, Michael; Van Beek, N.; Wojnarowska, F.; Kirtschig, G.; Mason, J.; Godec, T.; et al. (2017)
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Drei Generationen Leiden: Cryopyrin-assoziiertes periodisches Syndrom mit familiärer NLRP3-Mutation - Wagner, Nicola; Manger, Bernhard; Kittler, Julia; Rech, Jürgen; Sticherling, Michael; Berking, Carola; Kirchberger, Michael (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
CRIS-Team Scopus Importer:2022-02-04

Driving CAR T cells towards dermatologic oncology - Uslu, Ugur (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
Whereas approximately half of metastatic melanoma patients benefit from combined immune checkpoint inhibition targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed cell death protein 1 (PD-1), for those who do not respond, further strategies and treatment options need to be developed. Thus, focus is turning to the use of chimeric antigen receptor (CAR) T cells, a novel therapy that has not yet achieved a major breakthrough in solid tumors despite the impressive response rates reported for their use in hematologic malignancies. In melanoma and other solid tumor entities, different problems still need to be addressed to improve this therapy, with mechanisms to counteract tumor escape being one of them. In this context, we could show the feasibility of combining two different transfection methods - lentiviral transduction and RNA-electroporation - for equipping the same T lymphocyte with two different tumor antigen-specific receptors. While further analysis is required to transfer this novel strategy from bench to bedside, appropriate target antigens that avoid on-target/off-tumor toxicities and additional optimization to increase CAR T cell power are also needed to maximize their potential use in dermatologic oncology.
CRIS-Team WoS Importer:2021-03-12

Drug-induced dilemma: angiokeratomas and decreased renal function - Schliep, Stefan; Kiesewetter, Franklin; Simon, Miklos; Grupp, Clemens; Heinzerling, Lucie (American Journal of Medicine, 2014)
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Dry Mouth under Immune Checkpoint Inhibitors: an Analysis of 29 Patients from 10 German Skin Cancer Centers - Hensen, J.; Thoms, K. M.; Kaehler, K.; Gutzmer, R.; Zimmer, L.; Zacher, M.; Alter, M.; Loquai, C.; Moreira, Alvaro; Hassel, J.; Utikal, J. (2018)
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Dual mtor/dna-pk inhibitor cc-115 induces cell death in melanoma cells and has radiosensitizing potential - Bürkel, Felix; Jost, Tina; Hecht, Markus; Heinzerling, Lucie; Fietkau, Rainer; Distel, Luitpold (International Journal of Molecular Sciences, 2020)
CC-115 is a dual inhibitor of the mechanistic target of rapamycin (mTOR) kinase and the DNA-dependent protein kinase (DNA-PK) that is currently being studied in phase I/II clinical trials. DNA-PK is essential for the repair of DNA-double strand breaks (DSB). Radiotherapy is frequently used in the palliative treatment of metastatic melanoma patients and induces DSBs. Melanoma cell lines and healthy-donor skin fibroblast cell lines were treated with CC-115 and ionizing irradiation (IR). Apoptosis, necrosis, and cell cycle distribution were analyzed. Colony forming assays were conducted to study radiosensitizing effects. Immunofluorescence microscopy was performed to determine the activity of homologous recombination (HR). In most of the malign cell lines, an increasing concentration of CC-115 resulted in increased cell death. Furthermore, strong cytotoxic effects were only observed in malignant cell lines. Regarding clonogenicity, all cell lines displayed decreased survival fractions during combined inhibitor and IR treatment and supra-additive effects of the combination were observable in 5 out of 9 melanoma cell lines. CC-115 showed radiosensitizing potential in 7 out of 9 melanoma cell lines, but not in healthy skin fibroblasts. Based on our data CC-115 treatment could be a promising approach for patients with metastatic melanoma, particularly in the combination with radiotherapy.
CRIS-Team Scopus Importer:2020-12-25
Keywords: DNA repair; DNA-PK; Homologous recombination (HR); Kinase inhibitor; Melanoma; MTOR; Non-homologous end-joining (NHEJ); Radiosensitivity

Dupilumab but not cyclosporine treatment shifts the microbiome toward a healthy skin flora in patients with moderate-to-severe atopic dermatitis - Hartmann, Jan; Moitinho-Silva, Lucas; Sander, Nicole; Harder, Inken; Häsler, Robert; Rodriguez, Elke; Haufe, Eva; Kleinheinz, Andreas; Abraham, Susanne; Heratizadeh, Annice; Weisshaar, Elke; Schäkel, Knut; et al. (Allergy, 2023)
Background: Atopic dermatitis (AD) patients display an altered skin microbiome which may not only be an indicator but also a driver of inflammation. We aimed to investigate associations among AD patients' skin microbiome, clinical data, and response to systemic therapy in patients of the TREATgermany registry. Methods: Skin swabs of 157 patients were profiled with 16S rRNA gene amplicon sequencing before and after 3 months of treatment with dupilumab or cyclosporine. For comparison, 16s microbiome data from 258 population-based healthy controls were used. Disease severity was assessed using established instruments such as the Eczema Area and Severity Index (EASI). Results: We confirmed the previously shown correlation of Staphylococcus aureus abundance and bacterial alpha diversity with AD severity as measured by EASI. Therapy with Dupilumab shifted the bacterial community toward the pattern seen in healthy controls. The relative abundance of Staphylococci and in particular S. aureus significantly decreased on both lesional and non-lesional skin, whereas the abundance of Staphylococcus hominis increased. These changes were largely independent from the degree of clinical improvement and were not observed for cyclosporine. Conclusions: Systemic treatment with dupilumab but not cyclosporine tends to restore a healthy skin microbiome largely independent of the clinical response indicating potential effects of IL-4RA blockade on the microbiome.
CRIS-Team Scopus Importer:2023-05-05
Keywords: atopic dermatitis; dupilumab; inflammation; microbiome

Dupilumab-induced erythema nodosum in a patient with atopic hand eczema - Ronicke, Moritz; Sticherling, Michael; Wagner, Nicola (ALLERGOLOGIE, 2022)
CRIS-Team WoS Importer:2023-03-24

Dynamic regulation and differential compartmentaliztion of C-type lectin receptors in the dendritic cell membrane - Lühr, Jennifer; Eissing, N.; Heger, Lukas; Lehmann, C.; Heidkamp, Gordon Frederik; Nimmerjahn, Falk; Balint, S.; Sezgin, E.; Eggeling, C.; Dustin, M.; Dudziak, Diana (2018)
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Dyspnoea under Immunotherapy for Patients with Melanoma: Pneumonia, Pulmonary Embolism, Pneumonitis or Myocarditis? - Koeceroglu, I.; Bosch-Voskens, C.; Erdmann, M. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Early Exanthema Upon Vemurafenib Plus Cobimetinib Is Associated With a Favorable Treatment Outcome in Metastatic Melanoma: A Retrospective Multicenter DeCOG Study - Kaehler, Katharina C.; Gutzmer, Ralf; Meier, Friedegrund; Zimmer, Lisa; Heppt, Markus; Gesierich, Anja; Thoms, Kai-Martin; Utikal, Jochen; Hassel, Jessica C.; Loquai, Carmen; Pfoehler, Claudia; Heinzerling, Lucie; et al. (Frontiers in Oncology, 2021)
Background: The combination of BRAF and MEK inhibitors has become standard of care in the treatment of metastatic BRAF V600-mutated melanoma. Clinical factors for an early prediction of tumor response are rare. The present study investigated the association between the development of an early exanthema induced by vemurafenib or vemurafenib plus cobimetinib and therapy outcome. Methods: This multicenter retrospective study included patients with BRAF V600-mutated irresectable AJCC-v8 stage IIIC/D to IV metastatic melanoma who received treatment with vemurafenib (VEM) or vemurafenib plus cobimetinib (COBIVEM). The development of an early exanthema within six weeks after therapy start and its grading according to CTCAEv4.0 criteria was correlated to therapy outcome in terms of best overall response, progression-free (PFS), and overall survival (OS). Results: A total of 422 patients from 16 centers were included (VEM, n=299; COBIVEM, n=123). 20.4% of VEM and 43.1% of COBIVEM patients developed an early exanthema. In the VEM cohort, objective responders (CR/PR) more frequently presented with an early exanthema than non-responders (SD/PD); 59.0% versus 38.7%; p=0.0027. However, median PFS and OS did not differ between VEM patients with or without an early exanthema (PFS, 6.9 versus 6.0 months, p=0.65; OS, 11.0 versus 12.4 months, p=0.69). In the COBIVEM cohort, 66.0% of objective responders had an early exanthema compared to 54.3% of non-responders (p=0.031). Median survival times were significantly longer for patients who developed an early exanthema compared to patients who did not (PFS, 9.7 versus 5.6 months, p=0.013; OS, not reached versus 11.6 months, p=0.0061). COBIVEM patients with a mild early exanthema (CTCAEv4.0 grade 1-2) had a superior survival outcome as compared to COBIVEM patients with a severe (CTCAEv4.0 grade 3-4) or non early exanthema, respectively (p=0.047). This might be caused by the fact that 23.6% of patients with severe exanthema underwent a dose reduction or discontinuation of COBIVEM compared to only 8.9% of patients with mild exanthema. Conclusions: The development of an early exanthema within 6 weeks after treatment start indicates a favorable therapy outcome upon vemurafenib plus cobimetinib. Patients presenting with an early exanthema should therefore be treated with adequate supportive measures to provide that patients can stay on treatment.
CRIS-Team Scopus Importer:2021-06-18
Keywords: BRAF/MEK inhibition; cobimetinib; melanoma; skin toxicity; therapy outcome; vemurafenib

Easy performance of 6-color confocal immunofluorescence with 4-laser line microscopes - Eissing, Nathalie; Heger, Lukas; Baranska, Anna; Cesnjevar, Robert; Büttner, Maike; Söder, Stephan; Hartmann, Arndt; Heidkamp, Gordon Frederik; Dudziak, Diana (Immunology Letters, 2014)
Confocal laser scanning microscopy is an advanced technique for imaging tissue samples in vitro and in vivo at high optical resolution. The development of new fluorochrome variants do not only make it possible to perform multicolor flow cytometry of single cells, but in combination with high resolution laser scanning systems also to investigate the distribution of cells in lymphoid tissues by confocal immunofluorescence analyses, thus allowing the distinction of various cell populations directly in the tissue. Here, we provide a protocol for the visualization of at least six differently fluorochrome-labeled antibodies at the same time using a conventional confocal laser scanning microscope with four laser lines (405 nm, 488 nm, 555 nm, and 639 nm laser wavelength) in both murine and human tissue samples. We further demonstrate that compensation correction algorithms are not necessary to reduce spillover of fluorochromes into other channels when the used fluorochromes are combined according to their specific emission bands and the varying Stokes shift for co-excited fluorochromes with the same laser line.
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Eccrine porocarcinoma mimicking a venous leg ulcer - Erdmann, Michael; Brauner, Kathrin; Bauerschmitz, Jürgen; Erfurt-Berge, Cornelia (International Wound Journal, 2016)
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ECP as prognostic Marker for Melanoma - Moreira, Alvaro; Krueckel, A.; Schuler, Gerold; Utikal, J.; Heinzerling, Lucie (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-09-13

Editorial: Foundations of Theoretical Approaches in Systems Biology - Marin-Sanguino, Alberto; Vera, Julio; Alves, Rui (Frontiers in Genetics, 2018)
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Editorial: Local Immune Modulation of Macrophages and Dendritic Cells - Local Matters - Bock, Felix; Saban, Daniel; Steinkasserer, Alexander (Frontiers in Immunology, 2022)
CRIS-Team Scopus Importer:2022-07-22
Keywords: cornea; dendritic cells; immune modulation; macrophages; microenviroment; transplantation

Editorial: Loss of Epithelial Barrier Integrity in Inflammatory Diseases: Cellular Mediators and Therapeutic Targets - Weidinger, Carl; Krug, Susanne M.; Voskens, Caroline; Moschen, Alexander R.; Atreya, Imke (Frontiers in Medicine, 2021)
CRIS-Team WoS Importer:2022-01-14

Editorial: Multiomics and multiparametric analyses to characterize myeloid cell subsets - Vu Manh, Thien Phong; Dalod, Marc; Dudziak, Diana (Frontiers in Immunology, 2023)
CRIS-Team Scopus Importer:2023-10-20
Keywords: cell state characterization; cell type identification; multiomics; multiparametric analysis; myeloid cells

Editorial: Sentinel CLECs at Immunological Decision Nodes - Hoober, J. Kenneth; van Vliet, Sandra J.; Dudziak, Diana; Eggink, Laura L. (Frontiers in Immunology, 2020)
CRIS-Team Scopus Importer:2020-10-02
Keywords: CLEC receptors; dendritic cells; immunomodulation; ligand diversity; sentinel receptors

Effective anti-programmed death-1 therapy in a SUFU-mutated patient with Gorlin-Goltz syndrome - Moreira, Alvaro; Kirchberger, M. C.; Toussaint, Frédéric; Erdmann, M.; Schuler, Gerold; Heinzerling, Lucie (British Journal of Dermatology, 2018)
We present the case of a 77-year-old male patient with more than 50 basal cell carcinomas on the head and upper trunk. The patient did not respond to several lines of treatment, including surgery, imiquimod, retinoids, itraconazole and therapy with the hedgehog inhibitor vismodegib. The patient responded well to off-label therapy with the anti-programmed death-1 antibody pembrolizumab after four infusions.
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Effectiveness and Safety of Dabrafenib and Trametinib in Patients with BRAFV600 Mutated Metastatic Melanoma in the Real-World Setting - Final Results of the Non-Interventional COMBI-r Study - Berking, Carola; Livingstone, E.; Weichenthal, M.; Leiter-Stoeppke, U.; Remy, J.; Eigentler, T.; Mohr, P.; Kiecker, F.; Loquai, C.; Debus, D.; Gutzmer, R. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2022)
CRIS-Team WoS Importer:2022-09-23

Effectiveness and tolerability of ipilimumab: experiences from 198 patients included in a named-patient program in various daily-practice settings and multiple institutions - Eigentler, Thomas K.; Schlaak, Max; Hassel, Jessica C.; Loquai, Carmen; Stoffels, Ingo; Gutzmer, Ralf'; Paetzold, Sylvie; Mohr, Peter; Keller, Ulrich; Starz, Hans; Ulrich, Jens; Tsianakas, Athanasios; et al. (Journal of Immunotherapy, 2014)
Ipilimumab is an approved anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody introducing immune responses in melanoma patients. Treatment experiences from named-patient programs support the evaluation of the efficacy and tolerability of new medicines under usual circumstances of health care practice. Here, the largest ever reported cohort treated with ipilimumab 3 mg/kg alone is described.This report retrospectively analyzes data of 198 patients who were followed up in 15 hospital centers in Germany between April 2010 and March 2013. Patients had received prior therapy for unresectable stage III or IV melanoma before receiving ipilimumab (4 doses of 3 mg/kg every 21 d). Routine staging and tumor response evaluation procedures were applied.Of the patients, 119 received the planned 4-course therapy schedule; in further 79 patients, the number of doses was reduced mainly because of toxicity or fast progression. In all, 196 patients were eligible for evaluation of the efficacy of ipilimumab under routine care conditions. Median overall survival (OS) was 6.8 months [95% confidence interval, 5.6-10.3] from the start of therapy. OS differed significantly among patients who received 4 doses (n=119) and those receiving <4 doses (n=79) (14.2 vs. 2.0 mo; P<0.0001). The overall response rate (ORR) of 11% was in the same range as reported from previous clinical trials; and stable disease (SD) was observed in 11% resulting in a disease control rate (ORR+SD) of 22%. In 23 of the 79 patients with reduced dosing, dose omission was most probably caused by toxicity, whereas 56 patients had progressive disease before receiving all 4 treatment cycles. Immune-related adverse events (irAE) were reported in 30% of all treated patients, the occurrence of irAE correlated significantly with the probability of response to therapy and prolonged OS.In this named-patient program including heavily pretreated patients, the efficacy and tolerability of ipilimumab 3 mg/kg corresponds with findings from the confirmatory clinical trial.
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Effectiveness of an employee skin cancer screening program for secondary prevention - Uslu, Ugur; Hees, Felix; Winnik, Eva; Uter, Wolfgang; Sticherling, Michael (Cutis, 2016)
Incidences of UV-induced skin cancer are continuously increasing. For this reason, early diagnosis is becoming more important. In this study, 783 employees of a technical company participated in an employee skin cancer screening program, which consisted of a physical examination for benign and malignant skin lesions and premalignant conditions. To ensure the quality of the examinations, screening was only performed by 5 trained dermatologists. Participants also were asked to complete a standardized questionnaire prior to examination. A total of 661 skin lesions were diagnosed among 48% of participants; 12.8% of participants exhibited 50 or more melanocytic nevi and the risk for developing skin cancer was categorized as at least moderate for 64.9%. Additionally, 84.4% of participants with at least 1 skin lesion were advised to have a checkup within 1 year. The high rate of suspicious nevi detected in this study suggested that employee skin cancer screening programs are effective and also should be recommended at companies where employees are not at increased risk for developing skin cancer due to the nature of their work (eg, those who work outdoors). Despite the comparatively selective and young study population, these examinations provide evidence of the importance of skin cancer screening for the wider population.
EVALuna2:5563

Effectiveness of Dabrafenib plus Trametinib during the Treatment of Melanoma Patients with BRAFV600 mutated Brain Metastases - Berking, Carola; Schadendorf, D.; Weichenthal, M.; Eigentler, T.; Schober, K.; Mohr, P.; Kiecker, F.; Loquai, C.; Debus, D.; Gutzmer, R.; Leiter-Stoeppke, U. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2020)
CRIS-Team WoS Importer:2020-09-11

Effectiveness, safety and drug survival of dupilumab in patients with moderate to severe atopic dermatitis: an interim analysis of the TREATgermany registry - Stoelzl, D.; Boraczynski, N.; Heratizadeh, A.; Haufe, Eva; Harder, I.; Abraham, S.; Heinrich, Luise; Kleinheinz, A.; Wollenberg, A.; Weisshaar, E.; Schaekel, K.; Ertner, K.; et al. (EXPERIMENTAL DERMATOLOGY, 2022)
CRIS-Team WoS Importer:2022-03-04

Effectiveness, safety and utilization of vismodegib in locally advanced basal cell carcinoma under real-world conditions in Germany - The non-interventional study NIELS - Gutzmer, R.; Schulze, H. -J.; Hauschild, A.; Leiter, U.; Meier, F.; Haferkamp, S.; Ulrich, C.; Wahl, R. U.; Berking, Carola; Herbst, R.; Haeckl, M.; Schadendorf, D. (Journal of the European Academy of Dermatology and Venereology, 2021)
Background Basal cell carcinoma (BCC) can arise by the uncontrolled proliferation of cells from multiple epidermal compartments due to aberrant activation of the Hedgehog (Hh) signalling pathway. Vismodegib, a small-molecule inhibitor of this pathway, is approved for treatment of patients with locally advanced (la) BCC inappropriate for surgery or radiotherapy or patients with symptomatic metastatic (m) BCC.
CRIS-Team WoS Importer:2021-06-04

Effect of abrocitinib in a patient with extensive necrobiosis lipoidica - Arnet, Lisa; Erfurt-Berge, Cornelia (Journal of the European Academy of Dermatology and Venereology, 2023)
CRIS-Team WoS Importer:2023-06-02

Effect of sCD83 on direct allosensitization after corneal transplantation - Schoenberg, Alfrun Patricia; Peckert-Maier, Katrin; Hadrian, Karina; Hamdorf, Matthias; Cursiefen, Claus; Zinser, Elisabeth; Bock, Felix (INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2022)
CRIS-Team WoS Importer:2022-09-30

Effect of sCD83 on macrophages in corneal high-risk transplantation - Schoenberg, Alfrun; Peckert-Maier, Katrin; Wild, Andreas; Royzman, Dmytro; Braun, Gabriele; Stich, Lena; Cursiefen, Claus; Steinkasserer, Alexander; Bock, Felix; Zinser, Elisabeth (INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2021)
CRIS-Team WoS Importer:2021-10-15

Effects of Label Noise on Deep Learning-Based Skin Cancer Classification - Hekler, Achim; Kather, Jakob N.; Krieghoff-Henning, Eva; Utikal, Jochen S.; Meier, Friedegund; Gellrich, Frank F.; Upmeier zu Belzen, Julius; French, Lars; Schlager, Justin G.; Ghoreschi, Kamran; Wilhelm, Tabea; Kutzner, Heinz; et al. (Frontiers in Medicine, 2020)
Recent studies have shown that deep learning is capable of classifying dermatoscopic images at least as well as dermatologists. However, many studies in skin cancer classification utilize non-biopsy-verified training images. This imperfect ground truth introduces a systematic error, but the effects on classifier performance are currently unknown. Here, we systematically examine the effects of label noise by training and evaluating convolutional neural networks (CNN) with 804 images of melanoma and nevi labeled either by dermatologists or by biopsy. The CNNs are evaluated on a test set of 384 images by means of 4-fold cross validation comparing the outputs with either the corresponding dermatological or the biopsy-verified diagnosis. With identical ground truths of training and test labels, high accuracies with 75.03% (95% CI: 74.39–75.66%) for dermatological and 73.80% (95% CI: 73.10–74.51%) for biopsy-verified labels can be achieved. However, if the CNN is trained and tested with different ground truths, accuracy drops significantly to 64.53% (95% CI: 63.12–65.94%, p < 0.01) on a non-biopsy-verified and to 64.24% (95% CI: 62.66–65.83%, p < 0.01) on a biopsy-verified test set. In conclusion, deep learning methods for skin cancer classification are highly sensitive to label noise and future work should use biopsy-verified training images to mitigate this problem.
CRIS-Team Scopus Importer:2020-06-02
Keywords: artificial intelligence; dermatology; label noise; melanoma; nevi; skin cancer

Effects of structured patient education in adults with atopic dermatitis: Multicenter randomized controlled trial - Heratizadeh, Annice; Werfel, Thomas; Wollenberg, Andreas; Abraham, Susanne; Plank-Habibi, Sibylle; Schnopp, Christina; Sticherling, Michael; Apfelbacher, Christian; Biedermann, Tilo; Breuer, Kristine; Fell, Isabel; Foelster-Holst, Regina; et al. (Journal of Allergy and Clinical Immunology, 2017)
BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing skin disease prevalent in 1% to 3% of adults in Western industrialized countries. OBJECTIVE: We sought to investigate the effectiveness of educational training in an outpatient setting on coping with the disease, quality of life, symptoms, and severity in adults with AD. METHODS: In this German prospective, randomized controlled multicenter study, adult patients with moderate-to-severe AD were educated by referring to a comprehensive 12-hour training manual consented by a multiprofessional study group from different centers (Arbeitsgemeinschaft Neurodermitisschulung für Erwachsene [ARNE]). Patients were randomly allocated to the intervention or waiting control groups. Study visits were performed at baseline and after 1 year (1 year of follow-up). Primary outcomes were defined as a decrease in (1) "catastrophizing cognitions" with respect to itching (Juckreiz-Kognitions-Fragebogen questionnaire), (2) "social anxiety" (Marburger Hautfragebogen questionnaire), (3) subjective burden by symptoms of the disease (Skindex-29 questionnaire), and (4) improvement of disease signs and symptoms assessed by using the SCORAD index at 1 year of follow-up. Data were analyzed on an intention-to-treat basis. RESULTS: At 1 year of follow-up, patients from the intervention group (n = 168) showed a significantly better improvement compared with the waiting group (n = 147) in the following defined primary study outcomes: coping behavior with respect to itching (P < .001), quality of life assessed by using the Skindex-29 questionnaire (P < .001), and the SCORAD index (P < .001). CONCLUSIONS: This is the first randomized, controlled multicenter study on patient education in adult AD. The ARNE training program shows significant beneficial effects on a variety of psychosocial parameters, as well as AD severity.
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Effects of the German organ transplant scandal 2012 on the tissue donation project of the Institute of Legal Medicine Munich A retrospective evaluation of informed consent for tissue donation given by the next of kin - Bender-Säbelkampf, Sophia; Troschuetz, Stephan; Graw, Matthias; Braun, Christian (Rechtsmedizin, 2022)
Background The German organ donation scandal in 2012 led to a dramatic drop in consent rates. With 51 musculoskeletal, 145 corneal and 38 heart valve donations in 2013-2015, the Institute of Legal Medicine Munich procured a sizeable quantity of donated tissues performed in southern Germany. Objective The main goal of this study was to identify any traceable decrease in donations and the role the interview with the next of kin of tissue donors played in this context. Material and methods We retrospectively analyzed our donor database from July 2012 to December 2015 concerning discussions about and/or a stated effect of the scandal on the decision to consent to donation. We also contacted the next of kin within 1 year after the donation for a retrospective evaluation using a questionnaire consisting of 9 items. Results For a total of 388 potential donors consent was given in 54.9%. In 40 cases, the scandal was a topic of discussion and in 15 cases resulted in refusal. Among these, 6 persons destroyed their donor card in light of the scandal. After a thorough discussion, a tissue donation was finally allowed in 4 of these 6 cases. A total of 142 consenting next of kin retrospectively evaluated the primary contact as positive and meaningful. The decisions were stable in 100% of the cases. Conclusion With overall positive results in the retrospective interview evaluating the donation contact, we conclude that the relatively minor impact of the scandal on tissue donation relies on comprehensive information given by an empathetic, trained tissue coordinator. Active information and transparency about donation processes are key factors to gain the necessary trust of the public.
CRIS-Team WoS Importer:2022-05-27
Keywords: Next of kin; Telephone interview; Donor’s will; Medical ethics; Informed consent

Effekte des Organspendeskandals 2012 auf die Gewebespende am Institut für Rechtsmedizin München - Bender-Säbelkampf, Sophia; Troschuetz, Stephan; Graw, Matthias; Braun, Christian (Rechtsmedizin, 2022)
Hintergrund Der Organspendeskandal (OSS) 2012 führte zu einem dramatischen Einbruch der Spendebereitschaft. Im Zeitraum nach dem OSS verantwortete die Rechtsmedizin München 2013–2015 mit 51 muskuloskeletalen, 145 Cornea- und 38 Herzklappenentnahmen zahlreiche Gewebespenden im süddeutschen Raum. Fragestellung Die Ziele dieser Studie waren die Bestimmung des Einflusses des OSS auf die Gewebespende sowie die Auswirkung des ärztlichen Aufklärungsgespräches auf das Entscheidungsverhalten der Angehörigen. Material und Methoden Die Protokolle der Aufklärungsgespräche mit den Angehörigen im Zeitraum von Juli 2012 bis Dezember 2015 wurden auf Diskussionen, Erwähnungen sowie Entscheidungsverhalten im Zusammenhang mit dem OSS evaluiert. Zudem erfolgte im Jahresabstand nach der Spende eine retrospektive Evaluation des Aufklärungsgespräches durch die Angehörigen anhand eines Fragenkatalogs mit 9 Items. Ergebnisse Bei 388 potenziellen Spendern lag die Zustimmung bei 54,9 %. In 40 Fällen war der OSS Diskussionspunkt und resultierte in 15 Fällen in Ablehnung. Davon wurde in 6 Fällen ein Spendeausweis zuvor vom Verstorbenen aufgrund des OSS vernichtet, wobei in 4 Fällen nach Diskussion mit den Angehörigen eine Zustimmung erreicht wurde. Insgesamt bewerteten 142 Angehörige das Aufklärungsgespräch als positiv und die Spende als sinnstiftend. Die Entscheidungen waren zu 100 % stabil. Diskussion Die guten Resultate der Evaluation sowie der dieses Spendeprojekt nur gering beeinflussende OSS beruhen vor allem auf der mit Empathie und Erfahrung durchgeführten Aufklärung. Zum Vertrauensaufbau der Bevölkerung benötigt es ärztlicherseits ein aktives Informationsangebot und lückenlose Transparenz.
Keywords: Angehörigenkontakt; Telefoninterview; Spenderwille; Medizinethik; Informierte Entscheidungsfindung

Efficacy of different Interventions for the Treatment of cutaneous Squamous Cell Carcinoma in situ (Bowen's Disease) - a systematic Literature Review and Meta-Analysis - Petzold, Anne; Steeb, Theresa; Wessely, Anja; Berking, Carola; Heppt, Markus (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Efficient generation of a monoclonal antibody against the human C-type lectin receptor DCIR by targeting murine dendritic cells. - Heidkamp, Gordon Frederik; Neubert, Kirsten; Härtel, Eric; Nimmerjahn, Falk; Nussenzweig, Michel C.; Dudziak, Diana (Immunology letters, 2010)
Dendritic cells (DCs) are very important for the generation of long lasting immune responses against pathogens or the induction of anti-tumor responses. Targeting antigen to dendritic cells via monoclonal antibodies specific for DC cell surface receptors such as DEC205 was shown to elicit potent cellular and humoral immune responses in vivo. Therefore, we investigated whether this novel strategy might also be useful for the generation of new monoclonal antibodies against molecules of choice. We show, that by targeting the extracellular domain of the human C-type lectin receptor ClecSF6/DCIR/LLIR (hDCIR) to DEC205 on DCs in vivo, we were able to generate highly specific monoclonal antibodies against hDCIR.

eImmunonkologie: Development and Launch of a Virtual Education Platform for the Immunotherapy of Cutaneous Neoplasms - Kaufmann, Matthias; Steeb, Theresa; Wessely, Anja; Meyerolbersleben, Marion; French, Lars E. E.; Berking, Carola; Heppt, Markus (Medical Science Educator, 2022)
The use of immunotherapies in clinical practice has significantly expanded treatment options and improved the prognosis of patients with advanced cancers over the past decade. We have developed a virtual teaching module entitled "eImmunonkologie" which is the first interdisciplinary virtual course on immuno-oncology for medical students in German-speaking countries.
CRIS-Team WoS Importer:2023-01-20

Eine übermäßige Phagozytose von Myelomzellen induziert Pyroptose in Myelom-assoziierten Makrophagen und beeinträchtigt die Wirksamkeit therapeutischer Antikörper - Flamann, Cindy; Biedermann, Alexander; Mougiakakos, D.; Bitterer, Katrin; Karg, K.; Bittenbring, J.; Büttner-Herold, Maike; Liebisch, G.; Leffler, M.; Lischer, Christopher; Eberhardt, Martin; Vera-Gonzales, J.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

Ein Lues-ähnliches Bild verursacht durch PVL-positive Staphylokokken - Busch, Dorothee; Schliep, Stefan; Berking, Carola; Bosch-Voskens, Caroline (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
CRIS-Team Scopus Importer:2023-05-05

Ein Lues-ähnliches Bild verursacht durch PVL-positive Staphylokokken - Busch, Dorothee; Schliep, Stefan; Berking, Carola; Bosch-Voskens, Caroline (Journal der Deutschen Dermatologischen Gesellschaft, 2023)
EVALuna2:537510

Elective Discontinuation of Checkpoint Inhibitor Therapy in Patients with advanced Melanoma - Persa, O. D.; Schatton, K.; Ruebben, A.; Berking, Carola; Erdmann, M.; Schlaak, M.; Mauch, C.; Steeb, T. (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2021)
CRIS-Team WoS Importer:2021-09-24

Electrocardiographic features of immune checkpoint inhibitor associated myocarditis - Zlotoff, Daniel A.; Hassan, Malek Z.O.; Zafar, Amna; Alvi, Raza M.; Awadalla, Magid; Mahmood, Syed S.; Zhang, Lili; Chen, Carol L.; Ederhy, Stephane; Barac, Ana; Banerji, Dahlia; Jones-O'connor, Maeve; et al. (Journal for ImmunoTherapy of Cancer, 2021)
Background Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis. Methods From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested. Results Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39). Conclusions The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.
CRIS-Team Scopus Importer:2021-03-19
Keywords: autoimmunity; immune tolerance; immunotherapy; inflammation; self tolerance

Electroporated Antigen-Encoding mRNA Is Not a Danger Signal to Human Mature Monocyte-Derived Dendritic Cells - Hoyer, Stefanie; Gerer, Kerstin F.; Pfeiffer, Isabell A.; Prommersberger, Sabrina; Hoefflin, Sandra; Jaitly, Tanushree; Beltrame, Luca; Cavalieri, Duccio; Schuler, Gerold; Vera, Julio; Schaft, Niels; Dörrie, Jan (Journal of immunology research, 2015)
For therapeutic cancer vaccination, the adoptive transfer of mRNA-electroporated dendritic cells (DCs) is frequently performed, usually with monocyte-derived, cytokine-matured DCs (moDCs). However, DCs are rich in danger-sensing receptors which could recognize the exogenously delivered mRNA and induce DC activation, hence influencing the DCs' immunogenicity. Therefore, we examined whether electroporation of mRNA with a proper cap and a poly-A tail of at least 64 adenosines had any influence on cocktail-matured moDCs. We used 16 different RNAs, encoding tumor antigens (MelanA, NRAS, BRAF, GNAQ, GNA11, and WT1), and variants thereof. None of those RNAs induced changes in the expression of CD25, CD40, CD83, CD86, and CD70 or the secretion of the cytokines IL-8, IL-6, and TNFα of more than 1.5-fold compared to the control condition, while an mRNA encoding an NF-B-activation protein as positive control induced massive secretion of the cytokines. To determine whether mRNA electroporation had any effect on the whole transcriptome of the DCs, we performed microarray analyses of DCs of 6 different donors. None of 60,000 probes was significantly different between mock-electroporated DCs and MelanA-transfected DCs. Hence, we conclude that no transcriptional programs were induced within cocktail-matured DCs by electroporation of single tumor-antigen-encoding mRNAs.
CRIS-Team Scopus Importer:2021-10-01

Electroporation of mRNA as universal technology platform to transfect a variety of primary cells with antigens and functional proteins - Gerer, Kerstin F.; Hoyer, Stefanie; Dörrie, Jan; Schaft, Niels (RNA Vaccines - Methods and Protocols, 2017)
Electroporation (EP) of mRNA into human cells is a broadly applicable method to transiently express proteins of choice in a variety of different cell types. We have spent more than a decade to optimize and adapt this method, first for antigen-loading of dendritic cells (DCs), and subsequently for T cells, B cells, bulk PBMCs, and several cell lines. In this regard, antigens were introduced, processed, and presented in context of MHC class I and II. Next to that, functional proteins like adhesion receptors, T-cell receptors (TCRs), chimeric antigen receptors (CARs), constitutively active signal transducers, and others were successfully expressed. We have also established this protocol under full GMP compliance as part of a manufacturing license to produce mRNA-electroporated DCs for therapeutic vaccination in clinical trials. Therefore, we here want to share our universal mRNA electroporation protocol and the experience we have gathered with this method. The advantages of the transfection method presented here are: (1) easy adaptation to different cell types, (2) scalability from 106to approximately 108cells per shot, (3) high transfection efficiency (80-99 %), (4) homogenous protein expression, (5) GMP compliance if the EP is performed in a class A clean room, and (6) no transgene integration into the genome. The provided protocol involves: Opti-MEM® as EP medium, a square-wave pulse with 500 V, and 4 mm cuvettes. To adapt the protocol to differently sized cells, simply the pulse time is altered. Next to the basic protocol, we also provide an extensive list of hints and tricks, which in our opinion are of great value for everyone who intends to use this transfection technique.
CRIS-Team Scopus Importer:2021-10-01
Keywords: Antigen expression; B cell; CAR; GMP; Immunotherapy; Monocyte-derived DC (moDC); mRNA electroporation; Protein expression; T cell; TCR

Electroporation of siRNA into Mouse Bone Marrow-Derived Macrophages and Dendritic Cells - Siegert, Isabel; Schatz, Valentin; Prechtel, Alexander T.; Steinkasserer, Alexander; Bogdan, Christian; Jantsch, Jonathan (Methods in Molecular Biology, 2014)
Dendritic cells (DC) and macrophages (M?) play a pivotal role in antimicrobial defense, in the regulation of immune responses, and in maintaining tissue homeostasis. The analysis of DC and M? function relies on primary cells albeit these cells are known to be difficult to transfect. This makes the use of small interfering RNA (siRNA) for targeted manipulation of gene expression by RNA interference difficult. In the following chapter, we provide a detailed protocol for the successful transfer of siRNA via electroporation into a defined population of mouse bone marrow-derived M? or DC that does not cause toxicity to the myeloid cells or nonspecific alterations of their biological functions. Factors that influence the transfection and knockdown rate will be highlighted.
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Elevated aluminum excretion in patients by long-term subcutaneous immunotherapy – A cross-sectional case-control study - Hiller, Julia; Göen, Thomas; Drexler, Hans; Berking, Carola; Wagner, Nicola (International Journal of Hygiene and Environmental Health, 2024)
Background: Aluminum (Al) adjuvants have been used in vaccines and subcutaneous immunotherapy (SCIT) for decades. Despite indisputable neurotoxic properties of Al, there is no clear evidence of a causal relationship between their use and any neurotoxic side effects. However, recent rat studies have shown an accumulation of Al from adjuvants in tissues, especially in bones. Objectives: Since the human toxicokinetics of Al-adjuvants are poorly understood, this study aimed to evaluate whether up-dosed or long-term SCIT with Al-coupled extracts leads to increased Al load in humans. Methods: This observational cross-sectional case-control study explored Al excretion in hymenoptera venom allergy patients recruited in 2020 before initiation (n = 10) and during ongoing (n = 12) SCIT with Al-based preparations. Urine samples were collected before and 24 h after the SCIT injections and analyzed for aluminum content by using atomic absorption spectrometry. The cumulative administered Al dose was extracted from patient records. Patients receiving long-term immunotherapy were treated between 2.8 and 13.6 years (mean 7.1). Other potential sources of Al exposure were surveyed. Results: Patients who had received Al-coupled immunotherapy for several years showed significantly (p < 0.001) higher Al excretion than the controls at initiation of immunotherapy (mean 18.2 μg/gC vs. 7.9 μg/gC) and predominantly (73%) were above the 95th percentile of the general populations' exposure (>15 μg/gC), however, without reaching levels of toxicological concern (>50 μg/gC). Taking both groups together excreted Al levels correlated with the cumulative administered Al dose from SCIT (linear regression: Alurine = 8.258 + 0.133*Alcum; p = 0.001). Discussion: These results suggest a relevant iatrogenic contribution of long-term SCIT to human internal Al burden and potential accumulation. Considering the medical benefits of Al-adjuvants and SCIT a differentiated risk-benefit analysis is needed. For certain scenarios of potential toxicological concern in clinical practice biomonitoring might be advisable.
CRIS-Team Scopus Importer:2024-03-15
Keywords: Adjuvant; Aluminum; Biomonitoring; Immunologic desensitization; Risk assessment; Venom hypersensitivity

Emerging functional markers for cancer stem cell-based therapies: Understanding signaling networks for targeting metastasis - Marquardt, Stephan; Solanki, Manish; Spitschak, Alf; Vera, Julio; Puetzer, Brigitte M. (Seminars in Cancer Biology, 2018)
Metastasis is one of the most challenging issues in cancer patient management, and effective therapies to specifically target disease progression are missing, emphasizing the urgent need for developing novel anti-metastatic therapeutics. Cancer stem cells (CSCs) gained fast attention as a minor population of highly malignant cells within liquid and solid tumors that are responsible for tumor onset, self-renewal, resistance to radio- and chemotherapies, and evasion of immune surveillance accelerating recurrence and metastasis. Recent progress in the identification of their phenotypic and molecular characteristics and interactions with the tumor microenvironment provides great potential for the development of CSC-based targeted therapies and radical improvement in metastasis prevention and cancer patient prognosis. Here, we report on newly uncovered signaling mechanisms controlling CSC's aggressiveness and treatment resistance, and CSC-specific agents and molecular therapeutics, some of which are currently under investigation in clinical trials, gearing towards decisive functional CSC intrinsic or surface markers. One special research focus rests upon subverted regulatory pathways such as insulin-like growth factor 1 receptor signaling and its interactors in metastasis-initiating cell populations directly related to the gain of stem cell- and EMT-associated properties, as well as key components of the E2F transcription factor network regulating metastatic progression, microenvironmental changes, and chemoresistance. In addition, the study provides insight into systems biology tools to establish complex molecular relationships behind the emergence of aggressive phenotypes from high-throughput data that rely on network-based analysis and their use to investigate immune escape mechanisms or predict clinical outcome-relevant CSC receptor signaling signatures. We further propose that customized vector technologies could drastically enhance systemic drug delivery to target sites, and summarize recent progress and remaining challenges. This review integrates available knowledge on CSC biology, computational modeling approaches, molecular targeting strategies, and delivery techniques to envision future clinical therapies designed to conquer metastasis-initiating cells.
EVALuna2:203615

Employing Graph Representations for Cell-Level Characterization of Melanoma MELC Samples - Rivera Monroy, Luis; Rist, Leonhard; Eberhardt, Martin; Ostalecki, Christian; Baur, Andreas; Vera, Julio; Breininger, Katharina; Maier, Andreas (2023 IEEE 20th International Symposium on Biomedical Imaging (ISBI), 2023)
Histopathology imaging is crucial for the diagnosis and treatment of skin diseases. For this reason, computer-assisted approaches have gained popularity and shown promising results in tasks such as segmentation and classification of skin disorders. However, collecting essential data and sufficiently high-quality annotations is a challenge. This work describes a pipeline that uses suspected melanoma samples that have been characterized using Multi-Epitope-Ligand Cartography (MELC). This cellular level characterization of the tissue is then represented as a graph and finally used to train a graph neural network. This imaging technology, combined with the methodology proposed in this work, achieves a classification accuracy of 87 %, outperforming existing approaches by 10 %.<br

EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells - Lindner, Pablo; Paul, Sushmita; Eckstein, Markus; Hampel, Chuanpit; Muenzner, Julienne K.; Erlenbach-Wuensch, Katharina; Ahmed, Husayn P.; Mahadevan, Vijayalakshmi; Brabletz, Thomas; Hartmann, Arndt; Vera, Julio; Schneider-Stock, Regine (Cell Death & Disease, 2020)
Epigenetic deregulation remarkably triggers mechanisms associated with tumor aggressiveness like epithelial–mesenchymal transition (EMT). Since EMT is a highly complex, but also reversible event, epigenetic processes such as DNA methylation or chromatin alterations must be involved in its regulation. It was recently described that loss of the cell cycle regulator p21 was associated with a gain in EMT characteristics and an upregulation of the master EMT transcription factor ZEB1. In this study, in silico analysis was performed in combination with different in vitro and in vivo techniques to identify and verify novel epigenetic targets of ZEB1, and to proof the direct transcriptional regulation of SETD1B by ZEB1. The chorioallantoic-membrane assay served as an in vivo model to analyze the ZEB1/SETD1B interaction. Bioinformatical analysis of CRC patient data was used to examine the ZEB1/SETD1B network under clinical conditions and the ZEB1/SETD1B network was modeled under physiological and pathological conditions. Thus, we identified a self-reinforcing loop for ZEB1 expression and found that the SETD1B associated active chromatin mark H3K4me3 was enriched at the ZEB1 promoter in EMT cells. Moreover, clinical evaluation of CRC patient data showed that the simultaneous high expression of ZEB1 and SETD1B was correlated with the worst prognosis. Here we report that the expression of chromatin modifiers is remarkably dysregulated in EMT cells. SETD1B was identified as a new ZEB1 target in vitro and in vivo. Our study demonstrates a novel example of an activator role of ZEB1 for the epigenetic landscape in colorectal tumor cells.
CRIS-Team Scopus Importer:2020-03-20

Endogenous Expression of the Human CD83 Attenuates EAE Symptoms in Humanized Transgenic Mice and Increases the Activity of Regulatory T Cells - Zinser, Elisabeth; Naumann, Ronald; Wild, Andreas; Michalski, Julia; Deinzer, Anja; Stich, Lena; Kuhnt, Christine; Steinkasserer, Alexander; Knippertz, Ilka (Frontiers in Immunology, 2019)
The CD83 is a type I membrane protein and part of the immunoglobulin superfamily of receptors. CD83 is involved in the regulation of antigen presentation and dendritic cell dependent allogeneic T cell proliferation. A soluble form of CD83 inhibits dendritic cell maturation and function. Furthermore, CD83 is expressed on activated B cells, T cells, and in particular on regulatory T cells. Previous studies on murine CD83 demonstrated this molecule to be involved in several immune-regulatory processes, comprising that CD83 plays a key role in the development and function of different immune cells. In order to get further insights into the function of the human CD83 and to provide preclinical tools to guide the function of CD83/sCD83 for therapeutic purposes we generated Bacterial Artificial Chromosomes (BAC) transgenic mice. BACs are excellent tools for manipulating large DNA fragments and are utilized to engineer transgenic mice by pronuclear injection. Two different founders of BAC transgenic mice expressing human CD83 (BAC-hCD83(tg) mice) were generated and were examined for the hCD83 expression on different immune cells as well as both the in vitro and in vivo role of human CD83 (hCD83) in health and disease. Here, we found the hCD83 molecule to be present on activated DCs, B cells and subtypes of CD4(+) T cells. CD8(+) T cells, on the other hand, showed almost no hCD83 expression. To address the function of hCD83, we performed in vitro mixed lymphocyte reactions (MLR) as well as suppression assays and we used the in vivo model of experimental autoimmune encephalomyelitis (EAE) comparing wild-type and hCD83-BAC mice. Results herein showed a clearly diminished capacity of hCD83-BAC-derived T cells to proliferate accompanied by an enhanced activation and suppressive activity of hCD83-BAC-derived Tregs. Furthermore, hCD83-BAC mice were found to recover faster from EAE-associated symptoms than wild-type mice, encouraging the relevance also of the hCD83 as a key molecule for the regulatory phenotype of Tregs in vitro and in vivo.
CRIS-Team WoS Importer:2019-07-12

Engulfment of mast cell secretory granules on skin inflammation boosts dendritic cell migration and priming efficiency - Dudeck, Jan; Froebel, Julia; Kotrba, Johanna; Lehmann, Christian; Dudziak, Diana; Speier, Stephan; Nedospasov, Sergei A.; Schraven, Burkhart; Dudeck, Anne (Journal of Allergy and Clinical Immunology, 2019)
Background: Mast cells (MCs)are best known as key effector cells of allergic reactions, but they also play an important role in host defense against pathogens. Despite increasing evidence for a critical effect of MCs on adaptive immunity, the underlying mechanisms are poorly understood. Objective: Here we monitored MC intercellular communication with dendritic cells (DCs), MC activation, and degranulation and tracked the fate of exocytosed mast cell granules (MCGs)during skin inflammation. Methods: Using a strategy to stain intracellular MCGs in vivo, we tracked the MCG fate after skin inflammation–induced MC degranulation. Furthermore, exogenous MCGs were applied to MC-deficient mice by means of intradermal injection. MCG effects on DC functionality and adaptive immune responses in vivo were assessed by combining intravital multiphoton microscopy with flow cytometry and functional assays. Results: We demonstrate that dermal DCs engulf the intact granules exocytosed by MCs on skin inflammation. Subsequently, the engulfed MCGs are actively shuttled to skin-draining lymph nodes and finally degraded inside DCs within the lymphoid tissue. Most importantly, MCG uptake promotes DC maturation and migration to skin-draining lymph nodes, partially through MC-derived TNF, and boosts their T-cell priming efficiency. Surprisingly, exogenous MCGs alone are sufficient to induce a prominent DC activation and T-cell response. Conclusion: Our study highlights a unique feature of peripheral MCs to affect lymphoid tissue–borne adaptive immunity over distance by modifying DC functionality through delivery of granule-stored mediators.
CRIS-Team Scopus Importer:2019-05-03
Keywords: adaptive immune response; dendritic cells; Mast cells; skin inflammation; T-cell response

Enhancing lentiviral transduction to generate melanoma-specific human T cells for cancer immunotherapy - Simon, Bianca; Harrer, Dennis C.; Thirion, Christian; Schuler-Thurner, Beatrice; Schuler, Gerold; Uslu, Ugur (Journal of Immunological Methods, 2019)
Introduction of a tumor antigen-specific T cell receptor (TCR) into patient-derived lymphocytes has already exhibited promising results for the treatment of melanoma and other malignancies in clinical trials. However, insufficient or unsuccessful ex vivo manufacturing of engineered T cells due to low expansion and/or transduction rate can still be observed in some patients. Thus, we isolated human CD8+ T cells from healthy donors and equipped them with a gp100-specific TCR using a lentiviral construct in combination with a novel chemical lentiviral transduction enhancer (Lentiboost) to increase the rate of transduced cells. Following experiments to determine the ideal multiplicity of infection (MOI) and to analyze the efficacy of the transduction enhancer using a GFP-encoding lentivirus, we analyzed in the next step the transduction rate, cell count, and functionality of gp100 TCR-transduced T cells, i.e. antigen-specific cytokine secretion and lytic capacity. In order to increase the number of transduced cells, antigen-specific stimulation was performed, either once for 1 week (1st activation) or twice for another week (2nd activation). In general, each cycle of antigen-specific stimulation resulted in expansion of TCR-positive cells, while no further significant increase of transduced cells was observed after 2nd activation. Cytokine production pattern of transduced cells after antigen encounter, however, revealed significant antigen-specific secretion of TNF and IFNγ after the 1st as well as the 2nd activation. Furthermore, TCR T cells, either activated once or twice, showed significant cytotoxicity towards antigen-positive tumor cells. Taken together, these results show that it is feasible to transduce human T cells using a lentiviral construct in combination with this novel lentiviral transduction enhancer, which shows potential in the growing field of cancer immunotherapy.
CRIS-Team Scopus Importer:2019-06-25
Keywords: Adoptive T cell therapy; gp100; Lentiboost; Lentivirus; T cell receptor; Tumor antigen

Entwicklung und Evaluation eines interprofessionellen Lehrkonzepts zum modernen Wundmanagement - Bergendahl, Lukas; Werner, Felix; Schmidt, Anita; Ronicke, Moritz; Renner, Regina; Erfurt-Berge, Cornelia (Journal der Deutschen Dermatologischen Gesellschaft, 2020)
CRIS-Team Scopus Importer:2020-10-09

Environment affects dendritic cells' response via Aryl Hydrocarbon Receptor ligands: a comparison between endogenous and exogenous ligands - Sadeghi Shermeh, Atefeh; Wild, Andreas; Michalski, Julia; Steinkasserer, Alexander (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Environmental signals rather than layered ontogeny imprint the function of type 2 conventional dendritic cells in young and adult mice - Papaioannou, Nikos E.; Salei, Natallia; Rambichler, Stephan; Ravi, Kaushikk; Popovic, Jelena; Küntzel, Vanessa; Lehmann, Christian; Fiancette, Remi; Salvermoser, Johanna; Gajdasik, Dominika W.; Mettler, Ramona; Messerer, Denise; et al. (Nature Communications, 2021)
Conventional dendritic cells (cDC) are key activators of naive T cells, and can be targeted in adults to induce adaptive immunity, but in early life are considered under-developed or functionally immature. Here we show that, in early life, when the immune system develops, cDC2 exhibit a dual hematopoietic origin and, like other myeloid and lymphoid cells, develop in waves. Developmentally distinct cDC2 in early life, despite being distinguishable by fate mapping, are transcriptionally and functionally similar. cDC2 in early and adult life, however, are exposed to distinct cytokine environments that shape their transcriptional profile and alter their ability to sense pathogens, secrete cytokines and polarize T cells. We further show that cDC2 in early life, despite being distinct from cDC2 in adult life, are functionally competent and can induce T cell responses. Our results thus highlight the potential of harnessing cDC2 for boosting immunity in early life.
CRIS-Team Scopus Importer:2021-01-29

Envisioning the application of systems biology in cancer immunology - Jaitly, Tanushree; Gupta, Shailendra K.; Wolkenhauer, Olaf; Schuler, Gerold; Vera, Julio (Cancer Immunology: A Translational Medicine Context, 2020)
Biomedical research is nowadays concerned with the investigation of complex biological networks, in which dozens to thousands of proteins, genes, and miRNAs interact to control cellular or tissue-level phenotypes. Investigation of these complex biological networks requires the use of various experimental methodologies that generate massive amounts of quantitative data. In this scenario, Systems Biology emerged a decade ago as a methodological approach that combines quantitative experimental data, mathematical modeling, and other tools from computational biology, aiming to understand the regulation of these complex biochemical systems. The interaction between tumors and the immune system is not an exception to this scenario. The immune system is by definition a multiscale system not only because it involves biochemical networks that regulate the fate of immune cells, but also because immune cells communicate with each other by direct contact or through secretion of local or global signals. Furthermore, tumor and immune cells communicate, and this interaction is affected by the features of the microenvironment in which the tumor is hosted. Altogether, we are envisioning a complex multiscale biological system, whose analysis requires a systemic view to succeed integrating massive amounts of quantitative experimental data coming from different temporal and spatial scales. In this book chapter, we introduce the elements of the systems biology approach. Furthermore, we discuss some published results that suggest how systems biology can be used in the context of oncology and tumor immunology, with a focus on the development and assessment of anticancer therapies. To facilitate the reading, the chapter contains a glossary of systems biology terms.
CRIS-Team Scopus Importer:2020-06-19
Keywords: Biochemical Networks; Computational Approaches; Immunolgy; Omics; Tumor

Eosinophil-cationic protein - a novel liquid prognostic biomarker in melanoma - Krueckel, Annika; Moreira, Alvaro; Froehlich, Waltraud; Schuler, Gerold; Heinzerling, Lucie (BMC Cancer, 2019)
BackgroundThe role of eosinophils in cancer is not yet completely understood, but patients with eosinophilia show a trend towards longer survival in several types of cancer, including melanoma. However, eosinophil count at initial diagnosis of metastatic melanoma does not predict survival. Since eosinophil cationic protein (ECP) mediates anticancer effects, such as tissue remodelling and cytotoxic activity, we investigated this marker as an early prognostic marker in metastatic melanoma.MethodsSerum of 56 melanoma patients was collected at the time of diagnosis of metastatic disease. ECP levels as measured by ELISA were correlated with overall survival (OS) in patients before systemic therapy with immunotherapy or chemotherapy. Statistical analyses were performed using the Log-Rank (Mantel-Cox) test.ResultsThe median OS for patients with high serum ECP above 12.2ng/ml was 12months (n=39), compared to 28months for patients with ECP below this threshold (n=17; p=0.0642). In patients with cutaneous melanoma, excluding patients with uveal and mucosal melanoma, the survival difference was even more striking (p=0.0393). ECP's effect size on OS was observed independently of the consecutive therapy. ECP levels were not correlated with LDH levels.ConclusionECP seems to be a novel prognostic serum marker for the outcome of melanoma patients, which is independent of LDH and easy to perform in clinical practice. The striking negative prognostic value of high ECP level is unanticipated and can guide patient management.
CRIS-Team WoS Importer:2019-03-22

Eosinophil-cationic protein: A novel liquid prognostic biomarker in melanoma - Moreira, Alvaro; Krueckel, Annika; Schuler, Gerold; Heinzerling, Lucie (2018)
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Eosinophilic count as a biomarker for prognosis of melanoma patients and its importance in the response to immunotherapy - Moreira, Alvaro; Leisgang, Waltraud; Schuler, Gerold; Heinzerling, Lucie (Immunotherapy, 2017)
AIM: The prognostic role of eosinophils in cancer has been controversial. Some entities such as gastrointestinal cancers show a better survival, while others such as Hodgkin's lymphoma a worse survival in patients with eosinophilia. Patients who exhibited an increase in eosinophils upon therapy with ipilimumab or pembrolizumab were shown to survive longer. We wanted to investigate whether eosinophilia is a prognostic marker in metastatic melanoma. METHODS: In total, 173 patients with metastatic melanoma from our data base (median age 60 years; n = 86 with immunotherapy, n = 87 without immunotherapy) were analyzed for eosinophil counts and survival over the course of 12 years. Eosinophilic count was detected by peripheral blood smear. The ethical committee had approved this retrospective study. RESULTS: Melanoma patients with eosinophilia at any point in their course of disease show a trend toward longer survival independently of their therapy. There is a statistically significant difference for the patients who survive at least 12 months (p < 0.005). In patients with checkpoint inhibitor therapy, survival was significantly prolonged in every patient with eosinophilia (p < 0.05). Furthermore, 69% of the patients treated with immunotherapy experienced at least once an eosinophilia of 5% or greater compared with 46% in the immunotherapy naive-group; for an eosinophilia of 10% values were 30 and 9%, respectively. Interestingly, in patients with more than 20% eosinophils (n = 7) survival was prolonged with a median of 35 months (range 19-60 months) as compared with 16 months (range 1-117 months). CONCLUSION: Eosinophilia is a prognostic marker in patients with metastatic melanoma.
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Eosinophilic count as a biomarker for prognosis of melanoma patients - Moreira, Alvaro; Heinzerling, Lucie (2017)
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Eosinophilic Fasciitis by Treatment with Checkpoint Inhibitors in metastatic Melanoma - Toussaint, Frédéric; Erdmann, M.; Moreira, Alvaro; Kirchberger, M. C.; Schuler, Gerold; Heinzerling, Lucie (2018)
EVALuna2:34779

Eosinophilic polymorphic and pruritic eruption associated with radiotherapy: case report and overview of disease characteristics - Löbelenz, L.; Schliep, S.; Wörl, Petra; Uslu, Ugur (Clinical and Experimental Dermatology, 2019)
CRIS-Team Scopus Importer:2019-06-25

Epidemiology, comorbidities, and healthcare utilization of patients with chronic urticaria in Germany - Weller, K.; Maurer, M.; Bauer, A.; Wedi, B.; Wagner, Nicola; Schliemann, S.; Kramps, T.; Baeumer, D.; Multmeier, J.; Hillmann, E.; Staubach, P. (Journal of the European Academy of Dermatology and Venereology, 2021)
Background: Comprehensive data on the epidemiology and comorbidities of chronic urticaria (CU) in Germany are either limited, or not contemporary. Objectives: To investigate the epidemiology of CU, overall comorbidities and healthcare resource utilized by patients with CU in Germany, using an anonymized statutory health insurance (SHI) database. Methods: Anonymized SHI claims research database of the Institute for Applied Health Research, Berlin [InGef] (01 January 2015–30 September 2018) was used to analyse insured individuals with a confirmed diagnosis of CU (ICD-10-GM codes). Twelve-month diagnosed prevalence and incidence, comorbidities (vs. atopic dermatitis and psoriasis), and healthcare utilization by patients with CU were investigated. Results: Of 4 693 772 individuals of all ages listed in the database, 3 538 540 were observable during 2017. Overall, 17 524 patients (˜0.5%) were diagnosed with CU; chronic spontaneous urticaria (CSU: 71.2%), chronic inducible urticaria (CIndU: 19.7%), CSU+CIndU (9.1%). Females, vs. males, had higher diagnosed prevalence (0.62% vs. 0.37%) and diagnosed incidence (0.18% vs. 0.11%) of CU among all patients. Patients most frequently visited general practitioners (41.3% of total visits). Hypertensive diseases (43.5%), lipoprotein metabolism disorders (32.1%) and affective disorders (26.0%) were the most frequently reported comorbidities of special interest. Rates of most comorbidities of special interests were similar to atopic dermatitis and psoriasis patients, and all higher vs. overall population. More than half (54.1%) of all CU patients were not prescribed any treatment. Second-generation H1-antihistamines were the most commonly prescribed medication for adult (17.9%) and paediatric (27.9%) patients. Patients with CIndU (paediatric, 15.5%; adult, 7.8%) were more often hospitalized versus patients with CSU (paediatric, 9.9%; adult, 4.6%). Conclusions: In Germany, prevalence of CU along with multiple comorbidities may pose increased burden on the healthcare system. Awareness of adhering to treatment guidelines, and aiming for complete control of urticaria, needs to be driven and may improve outcomes.
CRIS-Team Scopus Importer:2021-11-19

Epidermotropie von Immunzellen unterscheidet Pyoderma gangraenosum vom Ulcus cruris venosum - Ronicke, Moritz; Baur, Andreas; Kirr, Michael; Erdmann, Michael; Erfurt-Berge, Cornelia; Ostalecki, Christian (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
HINTERGRUND UND ZIELE: Pyoderma gangraenosum ist eine ulzerierende, autoinflammatorische Erkrankung. Es gibt keine eindeutigen histopathologischen Merkmale zur Differenzierung von anderen Ursachen chronischer Wunden wie dem Ulcus cruris venosum. Ziel dieser Studie war es, histopathologische Merkmale von Pyoderma gangraenosum und Unterschiede zu venösen Ulzerationen zu detektieren. PATIENTEN UND METHODIK: Acht Gewebeproben von Pyoderma gangraenosum, zwölf Proben von Ulcus cruris venosum und sechs Proben von gesunder Haut wurden einer immunhistologischen Multi-Antigen-Analyse unterzogen. Das Immuninfiltrat und seine räumliche Verteilung wurden anhand von Fluoreszenzbildern mit einer Gewebezytometriesoftware analysiert. ERGEBNISSE: Die dichte epidermale Präsenz von CD45RO+ -T-Gedächtnis-Zellen und die Rarefizierung von CD1a+ -Langerhans-Zellen in der Epidermis waren Marker für Pyoderma gangraenosum, welche auch auf eine epidermale Immunreaktion schließen lassen. Darüber hinaus konnte dermal eine hohe Anzahl CD11c+ CD68+ pro-inflammatorischer M1-Makrophagen nachgewiesen werden. Diese überstieg die Anzahl der in venösen Ulzerationen beobachteten Makrophagen deutlich. SCHLUSSFOLGERUNGEN: Die histopathologischen Unterschiede zwischen Pyoderma gangraenosum und Ulcus cruris venosum können zur Unterscheidung der beiden Erkrankungen herangezogen werden und somit eine wichtige Hilfe zur schnellen Einleitung einer adäquaten Therapie sein. Darüber hinaus deuten unsere Daten auf einen antigengesteuerten Prozess in der Epidermis hin, möglicherweise unter Beteiligung von CD1a+ Langerhans-Zellen.
CRIS-Team Scopus Importer:2022-06-03

Epidermotropism of inflammatory cells differentiates pyoderma gangrenosum from venous leg ulcers - Ronicke, Moritz; Baur, Andreas; Kirr, Michael; Erdmann, Michael; Erfurt-Berge, Cornelia; Ostalecki, Christian (Journal der Deutschen Dermatologischen Gesellschaft, 2022)
Background and objectives Pyoderma gangrenosum is an ulcerative autoinflammatory disease, lacking distinct histopathological characteristics to differentiate from other ulcerating conditions, like venous leg ulcers. The objective of this study was therefore to find histopathological characteristics of pyoderma gangrenosum in a head-to-head comparison to venous leg ulcers. Patients and methods Eight tissue samples of pyoderma gangrenosum, twelve samples of venous leg ulcers and six samples of healthy skin were stained using an immunohistological multi antigen staining technology. The immune infiltrate and its spatial distribution were analyzed with contextual tissue cytometry software using fluorescence images. Results The dense epidermal presence of CD45RO(+) memory T cells and the rarefication of CD1a(+) Langerhans cells in the epidermis were defining markers for pyoderma gangrenosum, implicating an epidermal immune reaction. In addition, high numbers of CD11c(+)CD68(+) pro-inflammatory M1 macrophages were detected in the dermis, significantly extending the numbers seen in venous leg ulcers. Conclusions The histopathological differences found between pyoderma gangrenosum and venous leg ulcer can be used to distinguish between the two diseases and thus provide an important aid for the rapid initiation of adequate therapy. In addition, our data hint at an antigen-driven process in the epidermis, possibly involving CD1a(+) Langerhans cells.
CRIS-Team WoS Importer:2022-05-13

Erkennen und Management relevanter Komorbiditäten bei chronischer spontaner Urtikaria - Wagner, Nicola; Berking, Carola (Die Dermatologie, 2024)
Various mechanisms contributing to the activity of chronic spontaneous urticaria (CU) have been postulated. Associated comorbidities are increasingly leading to the discovery of further signaling pathways which may support the activity of chronic urticaria or contribute to low-grade systemic inflammation. Moreover psychoimmunological factors may also be involved. The aim of this work is to improve the clinical care of patients with CU by increasing knowledge regarding optional influencing factors due to comorbidities and to possibly influence disease activity. Chronic urticaria due to autoimmune mechanisms may dispose to other autoimmune diseases, especially autoimmune thyroiditis, which can trigger chronic disease. Association of CU with metabolic syndrome has received little attention to date. Obesity may contribute to low-grade systemic inflammation by cytokine-secreting adipose tissue and hence to mediator-release of mast cells. Furthermore, neuroimmunological pathways, especially increased release of substance P, an activating ligand of Mas-related G protein-coupled receptor X2 (MRGPX2) on mast cells, should be addressed when optimizing therapy.
CRIS-Team Scopus Importer:2024-03-08
Keywords: Chronic disease; Co-factors; Disease progression; Risk factors; Treatment optimization

European Dermatology Forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 1: localized scleroderma, systemic sclerosis and overlap syndromes - Knobler, R.; Moinzadeh, P.; Hunzelmann, N.; Kreuter, A.; Cozzio, A.; Mouthon, L.; Cutolo, M.; Rongioletti, F.; Denton, C. P.; Rudnicka, L.; Frasin, L. A.; Smith, V.; et al. (Journal of the European Academy of Dermatology and Venereology, 2017)
The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 1 of this guideline provides clinicians with an overview of the diagnosis and treatment of localized scleroderma (morphea), and systemic sclerosis including overlap syndromes of systemic sclerosis with diseases of the rheumatological spectrum.
EVALuna2:34344

European dermatology forum S1-guideline on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxedema, scleredema and nephrogenic systemic fibrosis - Knobler, R.; Moinzadeh, P.; Hunzelmann, N.; Kreuter, A.; Cozzio, A.; Mouthon, L.; Cutolo, M.; Rongioletti, F.; Denton, C. P.; Rudnicka, L.; Frasin, L. A.; Smith, V.; et al. (Journal of the European Academy of Dermatology and Venereology, 2017)
The term 'sclerosing diseases of the skin' comprises specific dermatological entities which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present guideline focuses on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, current strategies in the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this guideline provides clinicians with an overview of the diagnosis and treatment of scleromyxedema, scleredema (of Buschke) and nephrogenic systemic sclerosis (nephrogenic fibrosing dermopathy).
EVALuna2:34341

European patch test results with audit allergens as candidates for inclusion in the European Baseline Series, 2019/20: Joint results of the ESSCAA and the EBSB working groups of the ESCD, and the GEIDACC - Uter, Wolfgang; Wilkinson, S. Mark; Aerts, Olivier; Bauer, Andrea; Borrego, Leopoldo; Buhl, Timo; Cooper, Susan M.; Dickel, Heinrich; Gallo, Rosella; Gimenez-Arnau, Ana M.; John, Swen M.; Navarini, Alexander A.; et al. (Contact Dermatitis, 2022)
Background: In 2019, a number of allergens (haptens), henceforth, “the audit allergens,” were considered as potential additions to the European Baseline Series (EBS), namely, sodium metabisulfite, 2-bromo-2-nitropropane-1,3-diol, diazolidinyl urea, imidazolidinyl urea, Compositae mix II (2.5% or 5% pet), linalool hydroperoxides (lin-OOH), limonene hydroperoxides (lim-OOH), benzisothiazolinone (BIT), octylisothiazolinone (OIT), decyl glucoside, and lauryl glucoside; Evernia furfuracea (tree moss), was additionally tested by some departments as well. Objectives: To collect further data on patch test reactivity and clinical relevance of the audit allergens in consecutive patients across Europe. Methods: Patch test data covering the audit allergens in 2019 and 2020 were collected by those departments of the European Surveillance System on Contact Allergies testing these, as well as further collaborators from the EBS working group of the European Society of Contact Dermatitis (ESCD), and the Spanish Grupo Español de Investigación en Dermatitis de Contacto y Alergia Cutánea. As patch test outcome, reactions between day (D) 3 and D5 were considered. Results: Altogether n = 12 403 patients were tested with any of the audit allergen. Positive reactions were most common to lin-OOH 1% pet. (8.74% [95%CI: 8.14–9.37%]), followed by lin-OOH 0.5% pet., and lim-OOH 0.3% pet (5.41% [95% CI: 4.95–5.89%]). Beyond these terpene hydroperoxides, BIT 0.1% pet. was the second most common allergen with 4.72% (95% CI: 4.2–5.28%), followed by sodium metabisulfite 1% pet. (3.75% [95%CI: 3.32–4.23%]) and Compositae mix 5% pet. (2.31% [95% CI: 1.84–2.87%]). For some allergens, clinical relevance was frequently difficult to ascertain. Conclusions: Despite many positive patch test reactions, it remains controversial whether lin- and lim-OOH should be tested routinely, while at least the two preservatives BIT and sodium metabisulfite appear suitable. The present results are a basis for further discussion and ultimately decision on their implementation into routine testing among the ESCD members.
CRIS-Team Scopus Importer:2022-03-04
Keywords: baseline series; benzisothiazolinone; clinical epidemiology; contact allergy; decyl glucoside; patch testing; RRID:SCR_001905; sodium metabisulfite; surveillance

European Surveillance System on Contact Allergies (ESSCA): Characteristics of patients patch tested and diagnosed with irritant contact dermatitis - Loman, Laura; Uter, Wolfgang; Armario-Hita, Jose C.; Ayala, Fabio; Balato, Anna; Ballmer-Weber, Barbara K.; Bauer, Andrea; Bircher, Andreas J.; Buhl, Timo; Czarnecka-Operacz, Magdalena; Dickel, Heinrich; Fuchs, Thomas; et al. (Contact Dermatitis, 2021)
Background Irritant contact dermatitis (ICD) is caused by the acute locally toxic effect of a strong irritant, or the cumulative exposure to various weaker physical and/or chemical irritants.
CRIS-Team WoS Importer:2021-05-28

European Surveillance System on Contact Allergies (ESSCA): Contact allergies in relation to body sites in patients with allergic contact dermatitis - Oosterhaven, Jart A. F.; Uter, Wolfgang; Aberer, Werner; Armario-Hita, Jose C.; Ballmer-Weber, Barbara K.; Bauer, Andrea; Czarnecka-Operacz, Magdalena; Elsner, Peter; Garcia-Gavin, Juan; Gimenez-Arnau, Ana M.; John, Swen M.; Krecisz, Beata; et al. (Contact Dermatitis, 2019)
Background: Analyses of the European Surveillance System on Contact Allergies (ESSCA) database have focused primarily on the prevalence of contact allergies to the European baseline series, both overall and in subgroups of patients. However, affected body sites have hitherto not been addressed.
CRIS-Team WoS Importer:2019-04-16

Evaluating deep learning-based melanoma classification using immunohistochemistry and routine histology: A three center study - Wies, Christoph; Schneider, Lucas; Haggenmüller, Sarah; Bucher, Tabea Clara; Hobelsberger, Sarah; Heppt, Markus; Ferrara, Gerardo; Krieghoff-Henning, Eva I.; Brinker, Titus J. (PLoS ONE, 2024)
Pathologists routinely use immunohistochemical (IHC)-stained tissue slides against MelanA in addition to hematoxylin and eosin (H&E)-stained slides to improve their accuracy in diagnosing melanomas. The use of diagnostic Deep Learning (DL)-based support systems for automated examination of tissue morphology and cellular composition has been well studied in standard H&E-stained tissue slides. In contrast, there are few studies that analyze IHC slides using DL. Therefore, we investigated the separate and joint performance of ResNets trained on MelanA and corresponding H&E-stained slides. The MelanA classifier achieved an area under receiver operating characteristics curve (AUROC) of 0.82 and 0.74 on out of distribution (OOD)-datasets, similar to the H&E-based benchmark classification of 0.81 and 0.75, respectively. A combined classifier using MelanA and H&E achieved AUROCs of 0.85 and 0.81 on the OOD datasets. DL MelanA-based assistance systems show the same performance as the benchmark H&E classification and may be improved by multi stain classification to assist pathologists in their clinical routine.
CRIS-Team Scopus Importer:2024-02-02

Evaluating HIV Prevention Programs: Herpes Simplex Virus Type 2 Antibodies as Biomarker for Sexual Risk Behavior in Young Adults in Resource-Poor Countries - Behling, Juliane; Chan, Adrienne K.; Zeh, Clement; Nekesa, Carolyne; Heinzerling, Lucie (PLoS ONE, 2015)
Measuring effectiveness of HIV prevention interventions is challenged by bias when using self-reported knowledge, attitude or behavior change. HIV incidence is an objective marker to measure effectiveness of HIV prevention interventions, however, because new infection rates are relatively low, prevention studies require large sample sizes. Herpes simplex virus type 2 (HSV-2) is similarly transmitted and more prevalent and could thus serve as a proxy marker for sexual risk behavior and therefore HIV infection.HSV-2 antibodies were assessed in a sub-study of 70,000 students participating in an education intervention in Western Province, Kenya. Feasibility of testing for HSV-2 antibodies was assessed comparing two methods using Fisher's exact test. Three hundred and ninety four students (aged 18 to 22 years) were randomly chosen from the cohort and tested for HIV, Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis. Out of these, 139 students were tested for HSV-2 with ELISA and surveyed for sexual risk behavior and 89 students were additionally tested for HSV-2 with a point-of-contact (POC) test.Prevalence rates were 0.5%, 1.8%, 0.3% and 2.3% for HIV, Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis, respectively. Prevalence of HSV-2 antibodies was 3.4 % as measured by POC test (n=89) and 14.4 % by ELISA (n=139). Specificity of the POC test compared with ELISA was 100%, and the sensitivity only 23.1%. Associations between self-reported sexual behavior and HSV-2 serostatus could not be shown.Associations between self-reported sexual risk behavior and HSV-2 serostatus could not be shown, probably due to social bias in interviews since its transmission is clearly linked. HSV-2 antibody testing is feasible in resource-poor settings and shows higher prevalence rates than other sexually transmitted diseases thus representing a potential biomarker for evaluation of HIV prevention interventions.
EVALuna2:19581

Evaluating the Efficacy and Safety of 4% 5-Fluorouracil Cream in Patients with Actinic Keratosis: An Expert Opinion - Stockfleth, Eggert; Heppt, Markus; Bégeault, Nathalie; Delarue, Alain (Acta Dermato-Venereologica, 2023)
Actinic keratosis is a lesion that develops in sun-exposed areas of the skin and is considered to be a precancerous condition or an early in situ squamous cell carcinoma. Treatment of actinic keratosis is important for reducing skin cancer risk, with treatment choice based on patient-, lesion- and treatment-related considerations. Of the topical treatments used for field-directed therapy, those containing 5-fluorouracil are among the most effective and widely prescribed. The most recently developed topical 5-fluorouracil preparation (Tolak®; Pierre Fabre, France) contains 4% 5-fluorouracil in an aqueous cream. This narrative review discusses data on 4% 5-fluorouracil cream to treat actinic keratosis, and provides the authors' expert opinion on issues associated with it use. The effect of the cream has been evaluated in phase 2 and 3 trials of adult patients with actinic keratosis on the face, ears or scalp. These trials included patients with severe baseline disease, defined by high lesion counts and large-size treatment fields, which possibly affected the proportion of patients who were able to achieve complete clearance. Other efficacy parameters (e.g. percentage change in lesion count, ≥ 75% clearance of lesions or clinically significant changes in validated severity scales) should also be assessed to fully evaluate 4% 5-fluorouracil treatment efficacy in these patients. Nevertheless, 4% 5-fluorouracil is associated with high efficacy, a low level of recurrence and a satisfactory safety profile.
CRIS-Team Scopus Importer:2023-12-01

Evaluation of Long-term Clearance Rates of Interventions for Actinic Keratosis. A Systematic Review - Steeb, Theresa; Wessely, Anja; Petzold, Anne; Brinker, Titus Josef; Schmitz, Lutz; Leiter, Ulrike; Garbe, Claus; Schöffski, Oliver; Berking, Carola; Heppt, M. V. (JAMA Dermatology, 2021)
Importance Multiple interventions are available for the treatment of actinic keratosis (AK). However, most randomized clinical trials and meta-analyses focus on short-term efficacy outcomes. Objective To investigate and synthesize the long-term efficacy (≥12 months) of interventions for AK from parallel-arm randomized clinical trials. Data Sources Searches in MEDLINE, Embase, and Central were conducted from inception until April 6, 2020. The reference lists of the included studies and pertinent trial registers were hand searched. The study was completed February 27, 2021. Study Selection Two reviewers screened the titles and abstracts of 2741 records. Finally, 17 published reports (original studies and follow-up reports) referring to 15 independent randomized clinical trials with an overall sample size of 4252 patients were included. Data Extraction and Synthesis Two reviewers independently extracted data on study, patient, and intervention characteristics. Network meta-analysis (NMA) of each outcome was conducted with a frequentist approach. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidance for NMA was used to assess the certainty of evidence. The revised Cochrane risk-of-bias tool for randomized clinical trials was used to evaluate the methodologic quality. Main Outcomes and Measures Participant complete clearance, participant partial clearance, and lesion-specific clearance were the outcomes, with each assessed at least 12 months after the end of treatment. Results Data from 15 independent randomized clinical trials including 4252 patients were extracted and synthesized. Ten studies were included in an NMA for the outcome of participant complete clearance, with photodynamic therapy with aminolevulinate (ALA-PDT) showing the most favorable risk ratio (RR) compared with placebo (RR, 8.06; 95% CI, 2.07-31.37; GRADE, moderate), followed by imiquimod, 5% (RR, 5.98; 95% CI, 2.26-15.84; GRADE, very low), photodynamic therapy with methyl aminolevulinate (MAL-PDT) (RR, 5.95; 95% CI, 1.21-29.41; GRADE, low), and cryosurgery (RR, 4.67; 95% CI, 1.36-16.66; GRADE, very low). Similarly, ALA-PDT had the highest RR in the NMA for lesion-specific clearance (RR, 5.08; 95% CI, 2.49-10.33; GRADE, moderate). No NMA was possible for participant partial clearance owing to poor reporting of this outcome. Conclusions and Relevance This systematic review and network meta-analysis found that therapy including ALA-PDT, imiquimod, 5%, MAL-PDT, and cryosurgery was associated with significant long-term efficacy in the NMA. This study provides data for a possible use in an evidence-based framework for selecting interventions with sustained lesion clearanc
CRIS-Team WoS Importer:2021-08-13