von Christoph Jüschke ; Kira Linsel ; Marta Owczarek-Lipska ; Nicola Brandt ; Sarah Zunken ; Janine Altmüller ; Markus N. Preising ; Dennis Kastrati ; Holger Thiele ; Mervyn G. Thomas ; Peter Nürnberg ; Birgit Lorenz ; Ulrich Kellner ; Anja U. Bräuer ; Christoph Korenke ; Irene Gottlob ; John Neidhardt
von Ujwal Mukund Mahajan ; Bettina Oehrle ; Elisabetta Goni ; Oliver Strobel ; Jörg Kaiser ; Robert Grützmann ; Jens Werner ; Helmut Friess ; Thomas M Gress ; Thomas W Seufferlein ; Waldemar Uhl ; Uwe Will ; John P. Neoptolemos ; Uwe A Wittel ; Marlies Vornhülz ; Simon Sirtl ; Georg Beyer ; Ivonne Regel ; Stefan Boeck ; Volker Heinemann ; Fabian Frost ; Antje Steveling ; Henry Völzke ; Astrid Petersmann ; Matthias Nauck ; Eckhard Weber ; Beate Kamlage ; Markus M Lerch ; Julia Mayerle
Online verfügbar: 16. Mai 2025, Artikelversion: 4. Juni 2025 ; Gesehen am 21.01.2026
Background - Earlier diagnosis of pancreatic ductal adenocarcinoma is key to improving overall survival in patients with this hard-to-treat cancer. We independently validated two previously identified plasma-based metabolic signatures for exclusion of pancreatic ductal adenocarcinoma in cohorts with an increased annual risk. - Methods - The METAPAC study was a prospective, multicentre, investigator-masked, enrichment design, phase 4 trial done in 23 centres in Germany. Patients with pancreatic lesions identified by diagnostic imaging that required further diagnostic assessment were recruited and followed up for 24 months. Targeted quantitative plasma metabolite analysis was done on a liquid chromatography-tandem mass spectrometry platform. The improved metabolic (i-Metabolic) signature consisted of 12 analytes plus carbohydrate antigen (CA) 19-9, and the minimalistic metabolic (m-Metabolic) signature consisted of four analytes plus CA 19-9. The primary endpoint of the study was the exclusion of pancreatic ductal adenocarcinoma with an 85% specificity and the highest possible diagnostic accuracy. All statistical analyses were done per protocol. This study is registered with the German Clinical Trials Register (DRKS00010866). - Findings - Between Sept 9, 2016, and April 8, 2022, 1370 patients with CT-identified pancreatic lesions necessitating further diagnostic assessment were screened, of whom 1129 patients (489 with pancreatic ductal adenocarcinoma, 640 controls) were included in the primary analysis (median age 67 years [IQR 58-75]; 556 [49%] female, 572 [51%] male). The control group consisted of high-risk individuals with acute pancreatitis (11 [1%] of 1129 participants), chronic pancreatitis (113 [10%]), intraductal papillary mucinous neoplasms (232 [21%]), cystic lesions other than intraductal papillary mucinous neoplasms (271 [24%]), and metastases of extrapancreatic origin (13 [1%]). The i-Metabolic signature detected pancreatic ductal adenocarcinoma with an area under the curve (AUC) of 0·846 (95% CI 0·842-0·849), specificity of 90·4% (89·8-91·1), sensitivity of 67·5% (66·9-68·0), and balanced accuracy of 80·5% (80·2-80·8), compared with CA 19-9 alone (AUC 0·799 [0·797-0·802], p<0·0001; specificity 79·1% [78·7-79·4]; sensitivity 81·8% [81·5-82·0]; balanced accuracy 80·6% [80·4-80·9]). The m-Metabolic signature detected pancreatic ductal adenocarcinoma with an AUC of 0·846 (95% CI 0·842-0·849; p<0·0001 vs CA 19-9 alone), specificity of 93·6% (93·1-94·0), sensitivity of 59·9% (59·3-60·4), and accuracy of 79·0% (78·8-79·2). In a population of 242 individuals with new-onset diabetes (three cases of incident pancreatic ductal adenocarcinoma), the m-Metabolic signature (without CA 19-9) significantly discriminated patients with pancreatic ductal adenocarcinoma from those without (p=0·038). AUC, specificity, and sensitivity remained constant after random bootstrapping for a prevalence of pancreatic ductal adenocarcinoma between 1% and 20%. - Interpretation - Two plasma-based metabolic signatures showed significant improvement in performance compared with CA 19-9 alone in excluding pancreatic ductal adenocarcinoma in a prospective real-world cohort. These findings could offer a surveillance tool in patients with an annual risk of pancreatic ductal adenocarcinoma of 1% to reduce unnecessary invasive procedures and facilitate earlier detection of resectable disease. - Funding - Federal Ministry of Education and Research (BMBF, Germany).
The lancet. Gastroenterology & Hepatology London : Elsevier, 2016 10(2025), 7 vom: Juli, Seite 634-647 Online-Ressource
von Jacqueline E. Taudien ; Diana Bracht ; Heike Olbrich ; Sebastian Swirski ; Fulvio D’Abrusco ; Bert Van der Zwaag ; Maike Möller ; Thomas Lücke ; Norbert Teig ; Ulrika Lindberg ; Kai Wohlgemuth ; Julia Wallmeier ; Anja Blanque ; Christos Gatsogiannis ; Sebastian George ; Christoph Jüschke ; Marta Owczarek-Lipska ; Dorothee Veer ; Hester Y. Kroes ; Enza Maria Valente ; Christoph Korenke ; Heymut Omran ; John Neidhardt
von Frank Martin Brunkhorst ; Michael Adamzik ; Hubertus Axer ; Michael Bauer ; Christian Bode ; Hans-Georg Bone ; Thorsten Brenner ; Michael Bucher ; Sascha Igor David ; Maximilian Dietrich ; Christian Eckmann ; Gunnar Elke ; Torben Esser ; Thomas Felbinger ; Christine Geffers ; Herwig Gerlach ; Beatrice Grabein ; Matthias Gründling ; Ulf Günther ; Stefan Hagel ; Andreas Hecker ; Stefan Henkel ; Babila Janusan ; Stefan John ; Achim Jörres ; Achim Kaasch ; Stefan Kluge ; Matthias Kochanek ; Agnieszka Lajca ; Gernot Marx ; Konstantin Mayer ; Patrick Meybohm ; Onnen Mörer ; Michael Oppert ; Vladimir Patchev ; Mathias Pletz ; Christian Putensen ; Tim Rahmel ; Jenny Rosendahl ; Rolf Rossaint ; Bernd Salzberger ; Michael Sander ; Stefan Schaller ; Christina Scharf-Janssen ; Felix Schmitt ; Matthias Unterberg ; Markus A. Weigand ; Arved Weimann ; Sebastian Weis ; Björn Weiß ; Alexander Wolf ; Alexander Zarbock
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
von Dana Pisică ; Victor Volovici ; John K. Yue ; Thomas van Essen ; Hugo F. den Boogert ; Thijs Vande Vyvere ; Iain Haitsma ; Daan Nieboer ; Amy J. Markowitz ; Esther L. Yuh ; Ewout W. Steyerberg ; Wilco C. Peul ; Clemens M. F. Dirven ; David K. Menon ; Geoffrey T. Manley ; Andrew I. Maas ; Hester F. Lingsma ; Renán Sánchez-Porras
von Florian Giesl ; Alexander K. Hartmann ; Patrick Eraerds ; Christian Schubbert ; Hossam Elanzeery ; Stephan John Heise ; Thomas Dalibor ; Jürgen Parisi
von Julie George ; Lukas Maas ; Nima Abedpour ; Maria Cartolano ; Laura Kaiser ; Rieke Nila Fischer ; Andreas H. Scheel ; Jan-Philipp Weber ; Martin Hellmich ; Graziella Bosco ; Caroline Volz ; Christian Müller ; Ilona Dahmen ; Felix John ; Cleidson Padua Alves ; Lisa Werr ; Jens Peter Panse ; Martin Kirschner ; Walburga Engel-Riedel ; Jessica Jürgens ; Erich Stoelben ; Michael Brockmann ; Stefan Grau ; Martin Sebastian ; Jan Alexander Stratmann ; Jens Kern ; Horst-Dieter Hummel ; Balazs Hegedus ; Martin Schuler ; Till Plönes ; Clemens Aigner ; Thomas Elter ; Karin Toepelt ; Yon-Dschun Ko ; Sylke Kurz ; Christian Grohé ; Monika Serke ; Katja Anne Höpker ; Lars Gerd Hagmeyer ; Fabian Doerr ; Khosro Hekmath ; Judith Strapatsas ; Karl-Otto Kambartel ; Geothy Chakupurakal ; Annette Hülsmeyer ; Franz-Georg Bauernfeind ; Frank Griesinger ; Anne Lüers ; Wiebke Dirks ; Rainer Gerhard Wiewrodt ; Andrea Luecke ; Ernst Michael Rodermann ; Andreas Diel ; Volker Hagen ; Kai Severin ; Roland Ullrich ; Christian Reinhardt ; Alexander Quaas ; Magdalena Bogus ; Cornelius Courts ; Peter Nürnberg ; Kerstin Becker ; Viktor Achter ; Reinhard Büttner ; Jürgen Wolf ; Martin Peifer ; Roman Thomas
von Rick J. G. Vreeburg ; Ranjit D. Singh ; Inge A. M. van Erp ; Tommi K. Korhonen ; John K. Yue ; Harry Mee ; Ivan Timofeev ; Angelos Kolias ; Adel Helmy ; Bart Depreitere ; Wouter A. Moojen ; Alexander Younsi ; Peter J. Hutchinson ; Geoffrey T. Manley ; Ewout W. Steyerberg ; Godard C. W. de Ruiter ; Andrew I. Maas ; Wilco C. Peul ; Jeroen T. J. M. van Dijck ; Hugo F. den Boogert ; Jussi P. Posti ; Thomas van Essen ; Renán Sánchez-Porras
CENTER-TBI participants and investigators: Cecilia Åkerlund, Julia Mattern, Oliver Sakowitz, Andreas Unterberg, Alexander Younsi und zahlreiche weitere ; Gesehen am 20.08.2025
Journal of neurosurgery Charlottesville, Va. : American Assoc. of Neurological Surgeons, 1944 141(2024), 4 vom: Okt., Seite 895-907 Online-Ressource
