von Jule Filler ; Marios K. Georgakis ; Daniel Janowitz ; Marco Düring ; Rong Fang ; Anna Dewenter ; Felix J. Bode ; Sebastian Stösser ; Christine Kindler ; Peter Hermann ; Christian H. Nolte ; Thomas Liman ; Lucia Kerti ; Kathleen Bernkopf ; Benno Ikenberg ; Wenzel Glanz ; Michael Wagner ; Annika Spottke ; Karin Waegemann ; Michael Görtler ; Silke Wunderlich ; Matthias Endres ; Inga Zerr ; Gabor Petzold ; Martin Dichgans
Tatjana Wittenberg; Jan Friedrich Scheitz; Harald Prüß; Pia Sperber; Alexander Heinrich Nave; Anna Kufner Ibaroule; Julius Nicolai Meißner; Taraneh Ebrahimi; Julia Nordsiek; Niklas Michael Beckonert; Matthias Schmitz; Stefan Goebel; Timothy Bunck; Julia Schütte-Schmidt; Sabine Nuhn; Corinna Volpers; Peter Dechent; Matthias Bähr; Anna Maria Kopczak; Frank Arne Wollenweber; Christiane Huber; Holger Poppert; Tony Stöcker; Katja Neumann; Oliver Speck
Introduction - For rare skin cancers, few data exist on the outcome of systemic therapies, particularly immune checkpoint inhibition (ICI). The present study analysed the real-world use of different systemic therapies including ICI, and its outcome in patients with advanced rare skin cancers. - Methods - This retrospective multicenter study included patients who received systemic therapy for advanced, non-resectable cutaneous angiosarcoma (AS), Kaposi sarcoma (KS), pleomorphic dermal sarcoma (PDS), or cutaneous adnexal carcinoma (CAC). Study endpoints were best overall response (BOR), progression-free survival (PFS) and overall survival (OS). - Results - 209 patients (77 AS; 81 KS; 14 PDS; and 37 CAC) from 30 centers were included. As first-line treatment AS and KS patients predominantly received chemotherapy (77.9%; 63.0%), while PDS and CAC patients mostly received ICI (64.4%; 43.2%). BOR in first-line across all therapy types was 65.5% in KS, 50.0% in PDS, 41.6% in AS, and 10.8% in CAC. BOR for ICI was 66.6% for PDS, 58.3% for AS, 33.3% for KS, and 4.3% for CAC, irrespective of treatment line. 1-year PFS rate upon any first-line therapy was 70.7% for PDS, 45.7% for KS, 25.6% for AS, and 18.5% for CAC (p<0.001). 1-year tumor-specific OS rate was 97.3% in KS, 84.2% in AS, 67.7% in PDS, and 65.4% in CAC (p<0.001). - Conclusions - Type and outcome of systemic therapy differed between cancer entities. Efficacy of ICI was high in PDS and AS, moderate in KS, and low in CAC. Patients with advanced CAC revealed an extremely poor prognosis regardless of the type of therapy used.
European journal of cancer Amsterdam [u.a.] : Elsevier, 1992 228(2025) vom: Okt., Artikel-ID 115750, Seite 1-10
von Sophie-Kathrin Greiner ; María Dech Pons ; Ayimnisagul Ablimit ; Elisa Brauße ; Kristina Adorjan ; Monika Budde ; Maria Heilbronner ; Urs Heilbronner ; Janos L. Kalman ; Alba Navarro-Flores ; Mojtaba Oraki Kohshour ; Daniela Reich-Erkelenz ; Eva C. Schulte ; Thomas Vogl ; Till Andlauer ; Ion-George Anghelescu ; Volker Arolt ; Bernhardt T. Baune ; Udo Dannlowski ; Franziska Degenhardt ; Detlef E. Dietrich ; Andreas J. Fallgatter ; Christian Figge ; Andreas Forstner ; Markus Jäger ; Georg Juckel ; Carsten Konrad ; Markus M. Nöthen ; Fabian U. Lang ; Jens Reimer ; Eva Z. Reinighaus ; Marcella Rietschel ; Max Schmauß ; Andrea Schmitt ; Simon Senner ; Carsten Spitzer ; Jens Wiltfang ; Stephanie Witt ; Jörg Zimmermann ; Alkomiet Hasan ; Peter Falkai ; Thomas G. Schulze ; Sergi Papiol ; Fanny Senner
Online verfügbar: 13. Mai 2025, Artikelversion: 26. Mai 2025 ; Gesehen am 18.08.2025
Adverse childhood experiences; Affective disorders; Global functioning; Psychotic disorders; Quality of life
Adverse childhood experiences (ACE) contribute significantly to mental disorders. While existing research has primarily focused on specific diagnostic categories, a comprehensive understanding of how childhood trauma interacts with biological factors, symptom severity and functioning requires a broader perspective. Therefore, this study adopted a cross-diagnostic approach to examine the impact of ACE on quality of life (QoL), psychosocial functioning, and symptom burden by analyzing data from the PsyCourse Study, a longitudinal, multicenter research project conducted in Germany and Austria. We used multivariate linear regression models and cluster analysis to evaluate data from 725 participants with affective and psychotic disorders and healthy controls who completed the self-assessed Childhood Trauma Screener (CTS) during the course of the study. The results showed that across diagnoses, QoL was significantly impacted by ACE, particularly emotional neglect. An ablation study revealed that 2.3 % to 6.2 % of the variability in QoL domains could be attributed to ACE. Across diagnoses, symptoms of depression were significantly associated with ACE, especially emotional abuse, but psychotic and manic symptoms were not. Polygenic risk scores (PRS) did not emerge as significant predictors for any examined outcomes. Cluster analysis revealed distinct symptom profiles: Averaged over time, patients with less trauma exposure were rather in the subclinical than in the clinically ill clusters. We conclude that the pervasive influence of ACE on disease severity should be considered when evaluating and treating patients with affective and psychotic disorders.
Psychiatry research Amsterdam [u.a.] : Elsevier Science, 1979 350(2025) vom: Aug., Artikel-ID 116536, Seite 1-10 Online-Ressource
von Anette Friedrichs ; Roman Wenz ; Daniel Pape ; Katharina Appel ; Thomas Bahmer ; Karsten Becker ; Sven Bercker ; Sabine Blaschke ; Josephine Braunsteiner ; Jana Butzmann ; Edgar Dahl ; Johanna Erber ; Lisa Fricke ; Ramsia Geisler ; Siri Göpel ; Andreas Güldner ; Marina Hagen ; Axel Hamprecht ; Stefan Hansch ; Peter Heuschmann ; Sina Hopff ; Björn-Erik Ole Jensen ; Nadja Käding ; Julia Koepsell ; Carolin E.M. Koll ; Marcin Krawczyk ; Thomas Lücke ; Patrick Meybohm ; Milena Milovanovic ; Lazar Mitrov ; Carolin Nürnberger ; Christoph Römmele ; Margarete Scherer ; Lena Schmidbauer ; Melanie Stecher ; Phil-Robin Tepasse ; Andreas Teufel ; Jörg Janne Vehreschild ; Christof Alexander Winter ; Oliver Witzke ; Christoph Wyen ; Frank Hanses ; Amke Caliebe
Purpose The benefit of antibiotic treatment (ABT) for patients with moderate COVID-19 is unclear and overtreatment poses the risk of adverse effects such as Clostridioides difficile infection and antibiotic resistance. This multi-center study compares health status improvement between patients with and without ABT at hospital admission. Methods Between March 2020 and May 2023, hospitalized adults with confirmed SARS-CoV-2 infection were recruited from the German National Pandemic Cohort Network (NAPKON), which includes patients from various hospitals across Germany. The study population included patients with moderate or severe COVID-19 at baseline. The primary objective was to compare health improvement or decline after two weeks between patients who received ABT at baseline and those who did not in the moderate COVID-19 population. The statistical analysis adjusted for confounders such as gender, age, vaccination status, clinical condition, and comorbidities. The severe COVID-19 population was investigated as a secondary objective. Results A total of 1,317 patients (median age 59 years; 38% women) were eligible for analysis, of whom 1,149 had moderate and 168 severe COVID-19 disease. ABT for pneumonia was administered to 467 patients with moderate and 117 with severe COVID-19. ABT at baseline was significantly associated with a higher deterioration rate after two weeks in patients with moderate COVID-19 (ABT: 292 improvement, 61 deterioration; no ABT: 429 improvement, 14 deterioration). A similar result was obtained in the multiple regression analysis where an odds ratio of 5.00 (95% confidence interval: 2.50 - 10.93) for ABT was observed. Conclusion We found no benefit of antibiotic therapy in patients with moderate COVID-19. Use of ABT was associated with a higher likelihood of clinical deterioration. Graphical abstract
Infection München : Urban & Vogel, 1973 53(2025), 6, Seite 2543-2555 Online-Ressource
Background - Cancer immunotherapy has revolutionized melanoma treatment, but the high number of non-responders still emphasizes the need for improvement of therapy. One potential avenue for enhancing anti-tumor treatment is through the modulation of coagulation and platelet activity. Both have been found to play an important role in the tumor microenvironment, tumor growth and metastasis. Preclinical studies indicate a beneficial effect, clinical data has been inconsistent. - Methods - We examined a cohort of advanced, non-resectable melanoma patients (n = 2419) derived from the German prospective multicenter skin cancer registry ADOReg, who were treated with immune checkpoint inhibitors (ICI). The patients were classified based on whether it was documented that they received platelet aggregation inhibition (PAI) (n = 137) (acetylsalicylic acid (ASA) or clopidogrel), anticoagulation (AC) (n = 185) (direct oral anticoagulation (DOAC), phenprocoumon, heparins) at the start of ICI or no antithrombotic medication (n = 2097) at any point during ICI treatment. The study endpoints were best overall response (BOR), progression-free survival (PFS) and overall survival (OS). - Results - A significantly improved PFS was observed in patients documented to receive ASA (15.1 vs 6.4 months, HR 0.67, 95 % CI: 0.5 to 0.88, p = 0.0047) as well as in patients to receive AC (15.1 vs. 6.4 months, HR 0.7, 95 % CI: 0.53 to 0.91, p = 0.01) compared to patients for whom no antithrombotic medication was documented. Multivariate analysis of OS showed significant risk reduction in patients who received DOAC (HR 0.68, 95 % CI: 0.49 to 0.92, p = 0.0170) or phenprocoumon (HR: 0.44, 95 % CI: 0.19 to 0.85, p = 0.0301). - Conclusion - Our study indicates a positive prognostic effect of anticoagulant and antiplatelet concomitant medication in melanoma patients receiving ICI. Further studies are needed to confrim the cancer-related benefit of adding anticoagulation or platelet inhibition to ICI treatment.
European journal of cancer Amsterdam [u.a.] : Elsevier, 1992 214(2025) vom: Jan., Artikel-ID 115159, Seite 1-11
von Iris Verbinnen ; Sofia Douzgou Houge ; Tzung-Chien Hsieh ; Hellen Lesmann ; Aron Kirchhoff ; David Geneviève ; Elise Brimble ; Lisa Lenaerts ; Dorien Haesen ; Rebecca J. Levy ; Julien Thevenon ; Laurence Faivre ; Elysa Marco ; Jessica X. Chong ; Mike Bamshad ; Karynne Patterson ; Ghayda M. Mirzaa ; Kimberly Foss ; William Dobyns ; Susan M. White ; Lynn Pais ; Emily O’Heir ; Raphaela Itzikowitz ; Kirsten A. Donald ; Celia Van der Merwe ; Alessandro Mussa ; Raffaela Cervini ; Elisa Giorgio ; Tony Roscioli ; Kerith-Rae Dias ; Carey-Anne Evans ; Natasha J. Brown ; Anna Ruiz ; Juan Pablo Trujillo Quintero ; Rachel Rabin ; John Pappas ; Hai Yuan ; Katherine Lachlan ; Simon Thomas ; Anita Devlin ; Michael Wright ; Richard Martin ; Joanna Karwowska ; Renata Posmyk ; Nicolas Chatron ; Zornitza Stark ; Oliver Heath ; Martin Delatycki ; Rebecca Buchert ; Christoph Korenke ; Keri Ramsey ; Vinodh Narayanan ; Dorothy K. Grange ; Judith L. Weisenberg ; Tobias B. Haack ; Stephanie Karch ; Patricia Kipkemoi ; Moses Mangi ; Karen G. C. B. Bindels de Heus ; Marie-Claire Y. de Wit ; Tahsin Stefan Barakat ; Derek Lim ; Géraldine Van Winckel ; Rebecca C. Spillmann ; Vandana Shashi ; Maureen Jacob ; Antonia M. Stehr ; Peter Krawitz ; Gunnar Douzgos Houge ; Veerle Janssens
Pathogenic variants resulting in protein phosphatase 2A (PP2A) dysfunction result in mild to severe neurodevelopmental delay. PP2A is a trimer of a catalytic (C) subunit, scaffolding (A) subunit, and substrate binding/regulatory (B) subunit, encoded by 19 different genes. De novo missense variants in PPP2R5D (B56δ) or PPP2R1A (Aα) and de novo missense and loss-of-function variants in PPP2CA (Cα) lead to syndromes with overlapping phenotypic features, known as Houge-Janssens syndrome (HJS) types 1, 2, and 3, respectively. Here, we describe an additional condition in the HJS spectrum in 26 individuals with variants in PPP2R5C, encoding the regulatory B56γ subunit. Most changes were de novo and of the missense type. The clinical features were well within the HJS spectrum with strongest resemblance to HJS type 1, caused by B56δ variants. Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features. Head circumferences were above average or macrocephalic. The degree of intellectual disability was, on average, milder than in other HJS types. All variants affected either substrate binding (2/19), C-subunit binding (2/19), or both (15/19). Five variants were recurrent. Catalytic activity of the phosphatase was variably affected by the variants. Of note, PPP2R5C total loss-of-function variants could be inherited from a non-symptomatic parent. This implies that a dominant-negative mechanism on substrate dephosphorylation or general PP2A function is the most likely pathogenic mechanism.
The American journal of human genetics New York, NY [u.a.] : Cell Press, 1949 112(2025), 3 vom: März, Seite 554-571
Online verfügbar: 13. Februar 2025 ; Gesehen am 10.09.2025
Background - In the ESCAPE-NA1 trial, treatment with nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, was associated with improved functional outcome among patients with acute ischaemic stroke due to large vessel occlusion undergoing endovascular thrombectomy without co-treatment with an intravenous thrombolytic agent. There was no benefit when intravenous thrombolytic agent co-treatment was used. We sought to confirm the clinical benefit of nerinetide in the absence of previous intravenous thrombolytic drug treatment. - Methods - In this multicentre, randomised, double-blind, placebo-controlled study, done in 77 centres in Canada (16), the USA (16), Germany (21), Italy (four), the Netherlands (three), Norway (four), Switzerland (three), Australia (eight), and Singapore (two), we enrolled patients with acute ischaemic stroke due to anterior circulation large vessel occlusion within 12 h from onset. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation (baseline National Institutes of Health Stroke Scale [NIHSS] score >5), who had been functioning independently in the community (Barthel Index score >90) before the stroke, had Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and who were not treated with a plasminogen activator. Patients were randomly allocated (1:1) to receive intravenous infusion of nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, based upon estimated or actual weight (if known) or saline placebo using a real-time, dynamic, internet-based, stratified randomised minimisation procedure. All patients underwent endovascular thrombectomy. The primary outcome was a favourable functional outcome 90 days from randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. The analysis was by intention to treat and adjusted for time from stroke onset to randomisation (≤4·5 h [yes or no]), age, sex, baseline NIHSS score, occlusion location, time from qualifying imaging to randomisation, baseline ASPECTS, and region. Secondary outcomes were measures of mortality, worsening of stroke, improved functional independence, and measures of neurological disability. This trial is registered with ClinicalTrials.gov, NCT04462536. - Findings - From Dec 6, 2020, to Jan 31, 2023, 850 patients were assigned to receive nerinetide (n=454) or placebo (n=396). 206 (45%) participants in the nerinetide group and 181 (46%) participants in the placebo group achieved an mRS score of 0-2 at 90 days (odds ratio 0·97, 95% CI 0·72-1·30; p=0·82). Serious adverse events occurred equally between groups. - Interpretation - While nerinetide did not improve outcomes in patients with acute ischaemic stroke, it was not associated with excess adverse events. Further study is needed to identify the ideal timing of treatment and the sub-population of stroke patients who might benefit from treatment combined with current reperfusion therapies. - Funding - Canadian Institutes for Health Research and NoNO.
The lancet London [u.a.] : Elsevier, 1823 405(2025), 10478 vom: Feb., Seite 560-570 Online-Ressource
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