TY - JOUR A1 - Baur, Johannes A1 - Mathe, Katrin A1 - Gesierich, Anja A1 - Weyandt, Gerhard A1 - Wiegering, Armin A1 - Germer, Christoph-Thomas A1 - Gasser, Martin A1 - Pelz, Jörg O. W. T1 - Morbidity and oncologic outcome after saphenous vein-sparing inguinal lymphadenectomy in melanoma patients JF - World Journal of Surgical Oncology N2 - Background: Inguinal lymph node dissection (LND) is a surgical procedure with a high morbidity rate. Variations in surgical procedure, such as sparing of the saphenous vein, have been proposed to reduce surgical morbidity. While sparing of the saphenous vein has shown promising results in earlier studies, data for this procedure in melanoma patients are rare. In this retrospective study, we report 10-year findings on the effects of saphenous vein-sparing LND on surgical morbidity and oncologic outcomes in melanoma patients. Methods: A retrospective analysis of melanoma patients receiving inguinal LND in our facility between 2003 and 2013 was performed. Patients were divided into two groups: the saphenous vein resection group and the vein sparing group. Surgical morbidity, including wound infection, lymphatic fistula, severe bleeding, neurological complications, and chronic lymphedema, as well as regional recurrence-free survival were investigated. Results: A total of 106 patients were included in this study; of these, the saphenous vein was spared in 41 patients (38.7%). The rate of lymphatic fistula was 51.6 vs. 48.8%, wound infection occurred in 31.3 vs. 24.4%, and patients suffered from chronic lymphedema in 30.0 vs. 26.5% in V. saphena magna resection vs. sparing group. Differences observed, however, were not significant. No difference in regional recurrence-free survival between the two study groups was detected. Conclusions: The results of our retrospective analysis could not confirm the promising results reported in earlier studies. Thus, sparing of the saphenous vein appears to be optional. KW - malignant melanoma KW - inguinal lymph node dissection KW - regional recurrence KW - V. saphena magna Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157687 VL - 15 IS - 99 ER - TY - JOUR A1 - Wendlinger, Simone A1 - Wohlfarth, Jonas A1 - Kreft, Sophia A1 - Siedel, Claudia A1 - Kilian, Teresa A1 - Dischinger, Ulrich A1 - Heppt, Markus V. A1 - Wistuba-Hamprecht, Kilian A1 - Meier, Friedegund A1 - Goebeler, Matthias A1 - Schadendorf, Dirk A1 - Gesierich, Anja A1 - Kosnopfel, Corinna A1 - Schilling, Bastian T1 - Blood eosinophils are associated with efficacy of targeted therapy in patients with advanced melanoma JF - Cancers N2 - Background: Eosinophils appear to contribute to the efficacy of immunotherapy and their frequency was suggested as a predictive biomarker. Whether this observation could be transferred to patients treated with targeted therapy remains unknown. Methods: Blood and serum samples of healthy controls and 216 patients with advanced melanoma were prospectively and retrospectively collected. Freshly isolated eosinophils were phenotypically characterized by flow cytometry and co-cultured in vitro with melanoma cells to assess cytotoxicity. Soluble serum markers and peripheral blood counts were used for correlative studies. Results: Eosinophil-mediated cytotoxicity towards melanoma cells, as well as phenotypic characteristics, were similar when comparing healthy donors and patients. However, high relative pre-treatment eosinophil counts were significantly associated with response to MAPKi (p = 0.013). Eosinophil-mediated cytotoxicity towards melanoma cells is dose-dependent and requires proximity of eosinophils and their target in vitro. Treatment with targeted therapy in the presence of eosinophils results in an additive tumoricidal effect. Additionally, melanoma cells affected eosinophil phenotype upon co-culture. Conclusion: High pre-treatment eosinophil counts in advanced melanoma patients were associated with a significantly improved response to MAPKi. Functionally, eosinophils show potent cytotoxicity towards melanoma cells, which can be reinforced by MAPKi. Further studies are needed to unravel the molecular mechanisms of our observations. KW - melanoma KW - eosinophils KW - biomarker Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275137 SN - 2072-6694 VL - 14 IS - 9 ER - TY - JOUR A1 - Køllgaard, Tania A1 - Ugurel-Becker, Selma A1 - Idorn, Manja A1 - Andersen, Mads Hald A1 - Becker, Jürgen C. A1 - Straten, Per thor T1 - Pre-Vaccination Frequencies of Th17 Cells Correlate with Vaccine-Induced T-Cell Responses to Survivin-Derived Peptide Epitopes JF - PLoS One N2 - Various subsets of immune regulatory cells are suggested to influence the outcome of therapeutic antigen-specific anti-tumor vaccinations. We performed an exploratory analysis of a possible correlation of pre-vaccination Th17 cells, MDSCs, and Tregs with both vaccination-induced T-cell responses as well as clinical outcome in metastatic melanoma patients vaccinated with survivin-derived peptides. Notably, we observed dysfunctional Th1 and cytotoxic T cells, i.e. down-regulation of the CD3\(\zeta\)chain (p=0.001) and an impaired IFN\(\gamma\)-production (p=0.001) in patients compared to healthy donors, suggesting an altered activity of immune regulatory cells. Moreover, the frequencies of Th17 cells (p=0.03) and Tregs (p=0.02) were elevated as compared to healthy donors. IL-17-secreting CD4\(^{+}\) T cells displayed an impact on the immunological and clinical effects of vaccination: Patients characterized by high frequencies of Th17 cells at pre-vaccination were more likely to develop survivin-specific T-cell reactivity post-vaccination (p=0.03). Furthermore, the frequency of Th17 (p=0.09) and Th17/IFN\(\gamma\)\(^{+}\) (p=0.19) cells associated with patient survival after vaccination. In summary, our explorative, hypothesis-generating study demonstrated that immune regulatory cells, in particular Th17 cells, play a relevant role for generation of the vaccine-induced anti-tumor immunity in cancer patients, hence warranting further investigation to test for validity as predictive biomarkers. KW - suppressor cells KW - melanoma patients KW - patient survival KW - cancer patients KW - Th17 KW - tumor immunity KW - blood Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151509 VL - 10 IS - 7 ER - TY - JOUR A1 - Buhl, Timo A1 - Beissert, Stefan A1 - Gaffal, Evelyn A1 - Goebeler, Matthias A1 - Hertl, Michael A1 - Mauch, Cornelia A1 - Reich, Kristian A1 - Schmidt, Enno A1 - Schön, Michael P. A1 - Sticherling, Michael A1 - Sunderkötter, Cord A1 - Traidl‐Hoffmann, Claudia A1 - Werfel, Thomas A1 - Wilsman‐Theis, Dagmar A1 - Worm, Margitta T1 - COVID‐19 and implications for dermatological and allergological diseases JF - JDDG: Journal der Deutschen Dermatologischen Gesellschaft N2 - 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. KW - COVID-19 KW - dermatology KW - allergies Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-217860 VL - 18 IS - 8 SP - 815 EP - 824 ER - TY - JOUR A1 - Glutsch, Valerie A1 - Amaral, Teresa A1 - Garbe, Claus A1 - Thoms, Kai-Martin A1 - Mohr, Peter A1 - Hauschild, Axel A1 - Schilling, Bastian T1 - Indirect Comparison of Combined BRAF and MEK Inhibition in Melanoma Patients with Elevated Baseline Lactate Dehydrogenase JF - Acta Dermato-Venereologica N2 - The approval of BRAF and MEK inhibitors has signifi-cantly improved treatment outcomes for patients with BRAF-mutated metastatic melanoma. The 3 first-line targeted therapy trials have provided similar results, and thus the identification of predictive biomarkers may generate a more precise basis for clinical deci-sion-making. Elevated baseline lactate dehydrogenase (LDH) has already been determined as a strong prog-nostic factor. Therefore, this indirect analysis compa-red subgroups with elevated baseline LDH across the pivotal targeted therapy trials co-BRIM, COMBI-v and COLUMBUS part 1. The Bucher method was used to compare progression-free survival, objective response rate and overall survival indirectly. The results show a non-significant risk reduction for progression in the subgroup with elevated baseline LDH receiving vemu-rafenib plus cobimetinib compared with dabrafenib plus trametinib and encorafenib plus binimetinib. Al-though an indirect comparison, these data might pro-vide some guidance for treatment recommendations in melanoma patients with elevated LDH. KW - melanoma KW - BRAF KW - lactate dehydrogenase Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230190 VL - 100 ER - TY - JOUR A1 - Benoit, Sandrine A1 - Scheurlen, Michael A1 - Goebeler, Matthias A1 - Stoevesandt, Johanna T1 - Structured diagnostic approach and risk assessment in mucous membrane pemphigoid with oesophageal involvement JF - Acta Dermato-Venereologica N2 - Oesophageal involvement in mucous membrane pemphigoid is considered rare, but it may be underdiagnosed. To assess the incidence of oesophageal involvement in a group of patients with newly diagnosed mucous membrane pemphigoid we retrospectively analysed the medical records of 30 consecutive patients with mucous membrane pemphigoid diagnosed between 2006 and 2016 at the Department of Dermatology, University Hospital Würzburg. Twenty-one patients (70%) reported symptoms indicative of oesophageal mucous membrane pemphigoid. Twelve patients (40%) underwent oesophagogastroduodenoscopy, and oesophageal pathology compatible with mucous membrane pemphigoid was endoscopically found in 9 cases (30%). In all patients indirect and direct immunofluorescence were performed. Patients with and without oesophageal involvement did not differ with regard to the results of indirect immunofluorescence on salt-split human skin and monkey oesophagus. Study results demonstrate the necessity of a standardized diagnostic work-up, including adequate tissue samples for direct immunofluorescence, to prevent underdiagnosis of oesophageal mucous membrane pemphigoid. KW - cicatricial pemphigoid KW - mucous membrane pemphigoid KW - oesophagogastroduodenoscopy KW - laminin 332 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176191 VL - 98 ER - TY - JOUR A1 - Halfmann, Marie A1 - Castioni, Noah A1 - Wetzel, Lea A1 - Koopmann, Anne A1 - König, Sarah A1 - Schmieder, Astrid T1 - Effects of the COVID-19 pandemic on the mental health of medical students and young physicians in Germany: Gender-specific results of an online survey JF - Heliyon N2 - Background Healthcare workers and medical students faced new challenges during the COVID-19 pandemic. Processes within many hospitals were completely disrupted. In addition, the face to face teaching of medical students was drastically reduced. Those at risk of developing mental health problems appear to be younger health care workers and women. Objective To investigate potential COVID-19 pandemic-related gender differences in psychological distress among medical students and physicians in their first years of practice. Design and setting An anonymous survey was carried out online between December 1, 2021, and March 31, 2022, at the Mannheim Medical Faculty and the Würzburg Medical Faculty, Germany, after obtaining informed consent. Primary outcome measures were changes in anxiety and depression symptoms using the Hospital Anxiety and Depression Scale (HADS), and changes in participants' current quality of life using the WHO Quality of Life BREF. Results The results show wave-like courses for perceived anxiety and burden overlapping with the course of the COVID-19 incidence. In comparison to men, women showed a significant higher increase in HADS (p = 0.005) and a reduced life quality (p = 0.007) after COVID-19. Both sexes showed different frequencies of the factors influencing quality of life, with the presence of a previous mental illness and mean anxiety having a significant higher negative impact in women. Conclusion Future and young female physicians reported a disproportionate higher burden during COVID-19 compared to their male colleges. These observations suggest an increased need for support and prevention efforts especially in this vulnerable population. KW - mental health KW - Covid-19 KW - medical students KW - sex differences Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350502 SN - 2405-8440 VL - 10 IS - 1 ER - TY - JOUR A1 - Houben, Roland T1 - Reduced frequency of migraine attacks following coronavirus disease 2019: a case report JF - Journal of Medical Case Reports N2 - Background Severe acute respiratory syndrome coronavirus 2 is a virus affecting different organs and causing a wide variety and severity of symptoms. Headache as well as loss of smell and taste are the most frequently reported neurological manifestations of coronavirus disease 2019 induced by severe acute respiratory syndrome coronavirus 2. Here we report on a patient with chronic migraine and medication overuse headache, who experienced remarkable mitigation of migraine following coronavirus disease 2019. Case presentation For many years prior to the severe acute respiratory syndrome coronavirus 2 infection, a 57-year-old Caucasian male suffered from very frequent migraine attacks and for control of headaches he had been taking triptans almost daily. In the 16-month period before the outbreak of coronavirus disease 2019, triptan was taken 98% of the days with only a 21-day prednisolone-supported triptan holiday, which, however, had no longer-lasting consequences on migraine frequency. Upon severe acute respiratory syndrome coronavirus 2 infection, the patient developed only mild symptoms including fever, fatigue, and headache. Directly following recovery from coronavirus disease 2019, the patient surprisingly experienced a period with largely reduced frequency and severity of migraine attacks. Indeed, during 80 days following coronavirus disease 2019, migraine as well as triptan usage were restricted to only 25% of the days, no longer fulfilling criteria of a chronic migraine and medication overuse headache. Conclusion Severe acute respiratory syndrome coronavirus 2 infection might be capable of triggering mitigation of migraine. KW - migraine KW - triptan KW - severe acute respiratory syndrome coronavirus 2 KW - coronavirus disease 2019 KW - case report Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357327 VL - 17 ER - TY - JOUR A1 - Huttelmaier, Johanna A1 - Benoit, Sandra A1 - Goebeler, Matthias T1 - Comorbidity in bullous pemphigoid: up-date and clinical implications JF - Frontiers in Immunology N2 - Bullous pemphigoid is the most common autoimmune blistering disease in industrialized countries and particularly affects the elderly. In this patient population, comorbid diseases are frequent and may complicate management and treatment of bullous pemphigoid. A better understanding why distinct diseases are more frequent in bullous pemphigoid patients may lead to new pathophysiological insights and - as a consequence - result in better patient care. The association of bullous pemphigoid with neurological and psychiatric diseases is well known and confirmed by several case-control studies. Association with further diseases such as malignancy and metabolic diseases are still discussed controversially. In recent years new relationships between bullous pemphigoid and autoimmune as well as inflammatory skin diseases have been reported. This review provides a systematic overview on studies addressing comorbidity in bullous pemphigoid patients. Increasing the awareness of both, common and rare comorbid diseases, may enable clinicians to optimize patient support and individualized treatment of bullous pemphigoid. KW - bullous pemphigoid KW - autoimmune skin blistering disease KW - comorbidity KW - neurologic disease KW - metabolic disease KW - malignancy KW - inflammatory disease Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321671 VL - 14 ER - TY - JOUR A1 - Goebeler, M. A1 - Bata-Csörgő, Z. A1 - Simone, C. de A1 - Didona, B. A1 - Remenyik, E. A1 - Reznichenko, N. A1 - Stoevesandt, J. A1 - Ward, E. S. A1 - Parys, W. A1 - Haard, H. de A1 - Dupuy, P. A1 - Verheesen, P. A1 - Schmidt, E. A1 - Joly, P. T1 - Treatment of pemphigus vulgaris and foliaceus with efgartigimod, a neonatal Fc receptor inhibitor: a phase II multicentre, open-label feasibility trial JF - British Journal of Dermatology N2 - Background Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. There is an unmet need for fast-acting drugs that enable patients to achieve early sustained remission with reduced corticosteroid reliance. Objectives To investigate efgartigimod, an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor, thereby reducing serum IgG levels, for treating pemphigus. Methods Thirty-four patients with mild-to-moderate pemphigus vulgaris or foliaceus were enrolled in an open-label phase II adaptive trial. In sequential cohorts, efgartigimod was dosed at 10 or 25 mg kg\(^{-1}\) intravenously with various dosing frequencies, as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome. The study is registered at ClinicalTrials.gov (identifier NCT03334058). Results Adverse events were mostly mild and were reported by 16 of 19 (84%) patients receiving efgartigimod 10 mg kg\(^{-1}\) and 13 of 15 (87%) patients receiving 25 mg kg−1, with similar adverse event profiles between dose groups. A major decrease in serum total IgG and anti-desmoglein autoantibodies was observed and correlated with improved Pemphigus Disease Area Index scores. Efgartigimod, as monotherapy or combined with prednisone, demonstrated early disease control in 28 of 31 (90%) patients after a median of 17 days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of prednisone 0·26 mg \(^{-1}\) per day (range 0·06–0·48) led to complete clinical remission in 14 of 22 (64%) patients within 2–41 weeks. Conclusions Efgartigimod was well tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus. KW - pemphigus vulgaris KW - efgartigimod KW - pemphigus foliaceus Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258328 VL - 186 IS - 3 ER - TY - JOUR A1 - Paudel, Rupesh A1 - Fusi, Lorenza A1 - Schmidt, Marc T1 - The MEK5/ERK5 pathway in health and disease JF - International Journal of Molecular Sciences N2 - The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway. KW - atherosclerosis KW - bone KW - cartilage KW - endothelium KW - extracellular-regulated kinase 5 KW - Krüppel-like factor KW - mechanotransduction KW - mitogen-activated protein kinase KW - stress signaling KW - tumor Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261638 SN - 1422-0067 VL - 22 IS - 14 ER - TY - JOUR A1 - Frings, Verena Gerlinde A1 - Schöffski, Oliver A1 - Goebeler, Matthias A1 - Presser, Dagmar T1 - Economic analysis of the costs associated with Hidradenitis suppurativa at a German University Hospital JF - PLoS One N2 - Background and objectives Hidradenitis suppurativa (HS) significantly affects the patient`s quality of life and leads to multiple medical consultations. Aim of this study was to assess the utilization of medical care of HS patients. Patients and methods All patients presenting in 2017 for an outpatient, day patient and / or inpatient treatment with leading claim type HS at the Department of Dermatology, University Hospital Würzburg, were included. Primary outcome was the economic burden of HS patients, measured by resource utilization in €. Results The largest share of the direct medical costs for HS were the inpatient costs with a leading surgical diagnosis-related group (DRG). Antiseptics were the predominant topical prescription. While doxycycline was the most frequently prescribed systemic therapy, adalimumab was the main cost driver. The difference between in-patient (€ 110.25) and outpatient (€ 26.34) direct non-medical costs was statistically significant (p < 0.001). With regards to indirect medical costs, a statistically significantly higher loss of gross value added (inpatient mean € 1,827.00; outpatient mean € 203.00) and loss of production (inpatient mean € 1,026.00; outpatient mean € 228.00) could be noted (p < 0.001), respectively. Conclusions The present study on disease-specific costs of HS confirms that the hospital care of patients with this disease is cost-intensive. However, the primary goal of physicians is not and should not be to save costs regarding their patients`treatment, but rather the premise to utilize the existing resources as efficient as possible. Reducing the use of costly therapeutics and inpatient stays therefore requires more effective therapy options with an improved cost-benefit profile. KW - inpatients KW - outpatients KW - health insurance KW - dermatology KW - surgical and invasive medical procedures KW - health economics KW - psoriasis KW - indirect costs Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261668 VL - 16 IS - 8 ER - TY - JOUR A1 - Glutsch, Valerie A1 - Wobser, Marion A1 - Schilling, Bastian A1 - Gesierich, Anja A1 - Goebeler, Matthias A1 - Kneitz, Hermann T1 - PRAME expression as helpful immunohistochemical marker in rhabdoid melanoma JF - Dermatopathology N2 - Background: Rhabdoid melanoma is a rare variant of malignant melanoma with characteristic cytomorphologic features. Due to the potential loss of conventional melanocytic markers, histopathologic diagnosis is often challenging. We hypothesize that immunostaining for PReferentially expressed Antigen in MElanoma (PRAME) might have the potential to uncover the melanocytic origin of these dedifferentiated tumors. Methods: Four cases of rhabdoid primary melanomas were assessed by immunohistochemistry for expression of PRAME and conventional melanocytic markers. Immunohistochemical expression patterns were analyzed in the rhabdoid primaries and, if available, associated metastases. Results: All four cases of rhabdoid primary melanomas showed a strong nuclear positivity for PRAME, while the expression of conventional melanocytic markers S100, MART-1, SOX-10 and HMB-45 was variable between the analyzed cases. Conclusions: In summary, we report four cases of rhabdoid primary melanoma with high to intermediate expression of PRAME despite the partial and variable loss of other melanocytic markers. Hence, PRAME might facilitate the recognition of this highly aggressive entity to avoid misdiagnosis due to histopathologic pitfalls. KW - PRAME KW - rhabdoid differentiation KW - rhabdoid melanoma KW - immunohistochemistry KW - melanocytic markers Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284115 SN - 2296-3529 VL - 9 IS - 2 SP - 148 EP - 157 ER - TY - JOUR A1 - Isberner, Nora A1 - Gesierich, Anja A1 - Balakirouchenane, David A1 - Schilling, Bastian A1 - Aghai-Trommeschlaeger, Fatemeh A1 - Zimmermann, Sebastian A1 - Kurlbaum, Max A1 - Puszkiel, Alicja A1 - Blanchet, Benoit A1 - Klinker, Hartwig A1 - Scherf-Clavel, Oliver T1 - Monitoring of dabrafenib and trametinib in serum and self-sampled capillary blood in patients with BRAFV600-mutant melanoma JF - Cancers N2 - Simple Summary In melanoma patients treated with dabrafenib and trametinib, dose reductions and treatment discontinuations related to adverse events (AE) occur frequently. However, the associations between patient characteristics, AE, and exposure are unclear. Our prospective study analyzed serum (hydroxy-)dabrafenib and trametinib exposure and investigated its association with toxicity and patient characteristics. Additionally, the feasibility of at-home sampling of capillary blood was assessed, and a model to convert capillary blood concentrations to serum concentrations was developed. (Hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or AE. Co-medication with P-glycoprotein inducers was associated with lower trough concentrations of trametinib but not (hydroxy-)dabrafenib. The applicability of the self-sampling of capillary blood was demonstrated. Our conversion model was adequate for estimating serum exposure from micro-samples. The monitoring of dabrafenib and trametinib may be useful for dose modification and can be optimized by at-home sampling and our new conversion model. Abstract Patients treated with dabrafenib and trametinib for BRAF\(^{V600}\)-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). Dabrafenib and trametinib exposure was prospectively analyzed, and the relevant patient characteristics and AE were reported. Their association with the observed concentrations and Bayesian estimates of the pharmacokinetic (PK) parameters of (hydroxy-)dabrafenib and trametinib were investigated. Further, the feasibility of at-home sampling of capillary blood was assessed. A population pharmacokinetic (popPK) model-informed conversion model was developed to derive serum PK parameters from self-sampled capillary blood. Results showed that (hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or toxicity. Co-medication with P-glycoprotein inducers was associated with significantly lower trough concentrations of trametinib (p = 0.027) but not (hydroxy-)dabrafenib. Self-sampling of capillary blood was feasible for use in routine care. Our conversion model was adequate for estimating serum PK parameters from micro-samples. Findings do not support a general recommendation for monitoring dabrafenib and trametinib but suggest that monitoring can facilitate making decisions about dosage adjustments. To this end, micro-sampling and the newly developed conversion model may be useful for estimating precise PK parameters. KW - dabrafenib KW - trametinib KW - hydroxy-dabrafenib KW - melanoma KW - BRAF mutation KW - volumetric absorptive micro-sampling (VAMS) KW - at-home sampling KW - drug monitoring KW - population pharmacokinetics Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288109 SN - 2072-6694 VL - 14 IS - 19 ER - TY - JOUR A1 - Wobser, Marion A1 - Goebeler, Matthias T1 - Special Issue “Cutaneous Lymphomas” JF - Cancers N2 - No abstract available KW - cutaneous lymphomas Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304180 SN - 2072-6694 VL - 15 IS - 5 ER - TY - JOUR A1 - Houben, Roland A1 - Celikdemir, Büke A1 - Kervarrec, Thibault A1 - Schrama, David T1 - Merkel cell polyomavirus: infection, genome, transcripts and its role in development of Merkel cell carcinoma JF - Cancers N2 - The best characterized polyomavirus family member, i.e., simian virus 40 (SV40), can cause different tumors in hamsters and can transform murine and human cells in vitro. Hence, the SV40 contamination of millions of polio vaccine doses administered from 1955–1963 raised fears that this may cause increased tumor incidence in the vaccinated population. This is, however, not the case. Indeed, up to now, the only polyomavirus family member known to be the most important cause of a specific human tumor entity is Merkel cell polyomavirus (MCPyV) in Merkel cell carcinoma (MCC). MCC is a highly deadly form of skin cancer for which the cellular origin is still uncertain, and which appears as two clinically very similar but molecularly highly different variants. While approximately 80% of cases are found to be associated with MCPyV the remaining MCCs carry a high mutational load. Here, we present an overview of the multitude of molecular functions described for the MCPyV encoded oncoproteins and non-coding RNAs, present the available MCC mouse models and discuss the increasing evidence that both, virus-negative and -positive MCC constitute epithelial tumors. KW - Merkel cell carcinoma KW - polyomavirus KW - T antigen Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305021 SN - 2072-6694 VL - 15 IS - 2 ER - TY - JOUR A1 - Marquardt, André A1 - Hartrampf, Philipp A1 - Kollmannsberger, Philip A1 - Solimando, Antonio G. A1 - Meierjohann, Svenja A1 - Kübler, Hubert A1 - Bargou, Ralf A1 - Schilling, Bastian A1 - Serfling, Sebastian E. A1 - Buck, Andreas A1 - Werner, Rudolf A. A1 - Lapa, Constantin A1 - Krebs, Markus T1 - Predicting microenvironment in CXCR4- and FAP-positive solid tumors — a pan-cancer machine learning workflow for theranostic target structures JF - Cancers N2 - (1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database — representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets. KW - machine learning KW - tumor microenvironment KW - immune infiltration KW - angiogenesis KW - mRNA KW - miRNA KW - transcriptome Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305036 SN - 2072-6694 VL - 15 IS - 2 ER - TY - THES A1 - Demeter, Eran T1 - Retrospektive Untersuchung zur Häufigkeit von unerwünschten immunvermittelten Ereignissen unter Immuntherapie mit Nivolumab oder Pembrolizumab bei älteren und jüngeren Patient*innen T1 - Incidence of Immune-Related Adverse Events in Older and Younger Patients Receiving Immunotherapy with Nivolumab or Pembrolizumab: A Retrospective Analysis N2 - ICIs sind inzwischen integrales Therapiemittel vieler Tumoren, selbst in nicht metastasierten Stadien. Das Management von dabei eventuell entstehenden Nebenwirkungen bleibt wichtiger Bestandteil der Therapie vor allem im fortgeschrittenen Alter. Retrospektive Untersuchungen wie unsere tragen dazu bei, das in vielen klinischen Studien unterrepräsentierte Patientenkollektiv älterer Patienten in den klinischen Alltag sowie in Therapieentscheidungen und -planungen zu integrieren. Der primäre Studienendpunkt unserer Arbeit unterstützt wichtige Erkenntnisse anderer Studien, dass irAEs insgesamt unter älteren Patienten nicht häufiger auftreten. Zwischen allen drei Altersklassen von ~55, ~70 und ~80 Jahren zeigten sich keine signifikanten Unterschiede im Auftreten von irAEs aller Grade, wobei irAEs Grad III/IV etwas häufiger bei ~80-Jährigen auftraten. In unserem Fall stellten wir fest, dass auftretende irAEs im Alter häufiger behandelt wurden, und dass die Immuntherapie häufiger pausiert oder abgebrochen wurde. Zudem war der Anteil an Therapieabbrüchen unter den älteren Patienten wegen bestimmter Ereignisse wie TRAEs und dem Einsatz von Glukokortikoiden höher als bei jüngeren Patienten. Die Ergebnisse unserer Studie deuten außerdem darauf hin, dass selbst unter Polypharmazie und Multimorbidität irAEs nicht häufiger bei Älteren auftraten. Ebenso können wir die interessante Beobachtung verzeichnen, dass Patienten mit >5 Medikamenten und gleichzeitig >5 Erkrankungen signifikant mehr irAEs Grad III/IV aufwiesen oder mehr Patienten Glukokortikoide verabreicht bekommen haben. Auch der Anteil an Interventionsbedarf oder Therapieabbruch war hier in allen Altersklassen höher. Es stellt sich die Frage, inwiefern hohes Alter, Komorbidität und Polypharmazie Risikofaktoren für Interventionsbedarf oder Therapieabbruch in der Immuntherapie sind, und ob ihnen eher besondere Gewichtung als Risikofaktor zukommt als dem Alter selbst. N2 - ICIs are now an important part of the treatment of many tumors, even in the non-metastatic stage. Managing potential side effects is a significant aspect of treatment, particularly for elderly patients. Retrospective studies, such as the one presented here, help to integrate the underrepresented elderly patient population in many clinical trials into clinical practice, as well as into treatment decisions and planning. The primary outcome of this study supports the important findings of previous studies showing there is no overall increased incidence of irAEs in elderly patients. There were no significant differences in the occurrence of irAEs among the three age groups (~55, ~70, and ~80 years), although irAEs grade III/IV occurred slightly more frequently in patients aged ~80 years. In our study, we found that older patients who experienced irAEs required more medical intervention and that immunotherapy was interrupted or discontinued more frequently. Additionally, older patients experienced a higher incidence of treatment discontinuation due to events such as treatment-related adverse events (TRAEs) and the use of glucocorticoids when compared to younger patients. The study findings indicate that elderly patients do not have a higher incidence of irAEs, even in cases of polypharmacy and multimorbidity. However, patients of all age groups who were taking more than five medications and had more than five comorbidities experienced a higher incidence of irAEs grade III/IV. Additionally, more patients were administered glucocorticoids and had higher treatment discontinuation rates. The question arises as to whether advanced age, comorbidity and polypharmacy are more significant risk factors for discontinuing immunotherapy or medical intervention than age alone. KW - Immuntherapie KW - Ältere Patienten KW - Unerwünschte immunvermittelte Ereignisse KW - IrAEs Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-352586 ER - TY - JOUR A1 - Haake, Markus A1 - Haack, Beatrice A1 - Schäfer, Tina A1 - Harter, Patrick N. A1 - Mattavelli, Greta A1 - Eiring, Patrick A1 - Vashist, Neha A1 - Wedekink, Florian A1 - Genssler, Sabrina A1 - Fischer, Birgitt A1 - Dahlhoff, Julia A1 - Mokhtari, Fatemeh A1 - Kuzkina, Anastasia A1 - Welters, Marij J. P. A1 - Benz, Tamara M. A1 - Sorger, Lena A1 - Thiemann, Vincent A1 - Almanzar, Giovanni A1 - Selle, Martina A1 - Thein, Klara A1 - Späth, Jacob A1 - Gonzalez, Maria Cecilia A1 - Reitinger, Carmen A1 - Ipsen-Escobedo, Andrea A1 - Wistuba-Hamprecht, Kilian A1 - Eichler, Kristin A1 - Filipski, Katharina A1 - Zeiner, Pia S. A1 - Beschorner, Rudi A1 - Goedemans, Renske A1 - Gogolla, Falk Hagen A1 - Hackl, Hubert A1 - Rooswinkel, Rogier W. A1 - Thiem, Alexander A1 - Romer Roche, Paula A1 - Joshi, Hemant A1 - Pühringer, Dirk A1 - Wöckel, Achim A1 - Diessner, Joachim E. A1 - Rüdiger, Manfred A1 - Leo, Eugen A1 - Cheng, Phil F. A1 - Levesque, Mitchell P. A1 - Goebeler, Matthias A1 - Sauer, Markus A1 - Nimmerjahn, Falk A1 - Schuberth-Wagner, Christine A1 - Felten, Stefanie von A1 - Mittelbronn, Michel A1 - Mehling, Matthias A1 - Beilhack, Andreas A1 - van der Burg, Sjoerd H. A1 - Riedel, Angela A1 - Weide, Benjamin A1 - Dummer, Reinhard A1 - Wischhusen, Jörg T1 - Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment JF - Nature Communications N2 - Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development. KW - cancer microenvironment KW - immunotherapy KW - T cells KW - tumour immunology Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357333 VL - 14 ER - TY - JOUR A1 - Wobser, Marion A1 - Weber, Alexandra A1 - Glunz, Amelie A1 - Tauch, Saskia A1 - Seitz, Kristina A1 - Butelmann, Tobias A1 - Hesbacher, Sonja A1 - Goebeler, Matthias A1 - Bartz, René A1 - Kohlhof, Hella A1 - Schrama, David A1 - Houben, Roland T1 - Elucidating the mechanism of action of domatinostat (4SC-202) in cutaneous T cell lymphoma cells JF - Journal of Hematology & Oncology N2 - Background Targeting epigenetic modifiers is effective in cutaneous T cell lymphoma (CTCL). However, there is a need for further improvement of this therapeutic approach. Here, we compared the mode of action of romidepsin (FK228), an established class I histone deacetylase inhibitor, and domatinostat (4SC-202), a novel inhibitor of class I HDACs, which has been reported to also target the lysine-specific histone demethylase 1A (LSD1). Methods We performed MTS assays and flow cytometric analyses of propidium iodide or annexin V-stained cells to assess drug impact on cellular proliferation, cell cycle distribution, and survival. Histone acetylation and methylation as well as caspase activation was analyzed by immunoblot. Gene expression analysis was performed using NanosString technology. Knockdown and knockout of LSD1 was achieved with shRNA and CRISPR/Cas9, respectively, while the CRISPR/Cas9 synergistic activation mediator system was used to induce expression of endogenous HDACs and LSD1. Furthermore, time-lapse fluorescence microscopy and an in vitro tubulin polymerization assay were applied. Results While FK228 as well as 4SC-202 potently induced cell death in six different CTCL cell lines, only in the case of 4SC-202 death was preceded by an accumulation of cells in the G2/M phase of the cell cycle. Surprisingly, apoptosis and accumulation of cells with double DNA content occurred already at 4SC-202 concentrations hardly affecting histone acetylation and methylation, and provoking significantly less changes in gene expression compared to biologically equivalent doses of FK228. Indeed, we provide evidence that the 4SC-202-induced G2/M arrest in CTCL cells is independent of de novo transcription. Furthermore, neither enforced expression of HDAC1 nor knockdown or knockout of LSD1 affected the 4SC-202-induced effects. Since time-lapse microscopy revealed that 4SC-202 could affect mitotic spindle formation, we performed an in vitro tubulin polymerization assay revealing that 4SC-202 can directly inhibit microtubule formation. Conclusions We demonstrate that 4SC-202, a drug currently tested in clinical trials, effectively inhibits growth of CTCL cells. The anti-cancer cell activity of 4SC-202 is however not limited to LSD1-inhibition, modulation of histone modifications, and consecutive alteration of gene expression. Indeed, the compound is also a potent microtubule-destabilizing agent. KW - Cutaneous lymphoma KW - Epigenetic regulation KW - Histone deacetylase KW - HDAC KW - Lysine-specific methylase KW - LSD1 KW - Tubulin Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200703 VL - 12 ER -