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 Maja Krech ; Amos Muench ; Daniel Teichmann ; Peter Kuzman ; Abigail Kora Suwala ; Franziska M. Ippen ; Michael Müther ; Katharina J. Weber ; Katharina Wenger-Alakmeh ; Julia Onken ; Peter Vajkoczy ; Felix Behling ; Sven-Axel May ; Georgios Ntoulias ; Joachim K. Krauss ; Oday Atallah ; Majid Esmaeilzadeh ; Wolf C. Mueller ; Frank L. Heppner ; Helena Radbruch ; Carsten Dittmayer ; Werner Stenzel ; Arend Koch ; David Capper ; David Kaul ; Werner Paulus ; Karl Plate ; Joachim P. Steinbach ; Markus Czabanka ; Rudi Beschorner ; Andreas von Deimling ; Michael Bockmayr ; Julia E. Neumann ; Sebastian Brandner ; Teresa Krieger ; Christian Hartmann ; Christian Thomas ; Leonille Schweizer
Veröffentlicht: 11. Juni 2025 ; Gesehen am 29.10.2025
DNA methylation profiling; FGFR3; Neurocytoma; Progression-free survival; Radiotherapy
Central neurocytomas (CN) are intraventricular brain tumors predominantly occurring in young adults. Although prognosis is usually favorable, tumor recurrence is common, particularly following subtotal resection (STR). Currently, the risk of progression is evaluated using atypical features and an elevated Ki67 proliferation index. However, these markers lack consistent definitions, raising the need for objective criteria. Genome-wide DNA methylation profiles were examined in 136 tumors histologically classified as CN. Clinical/histopathological characteristics were assessed in 93/90 cases, and whole-exome sequencing was conducted in 12 cases. Clinical and molecular characteristics were integrated into a survival model to predict progression-free survival (PFS). A diagnosis of CN was epigenetically confirmed in 125 of 136 cases (92%). No DNA methylation subgroups were identified, but global DNA hypomethylation emerged as a hallmark feature of CN associated with higher recurrence risk. Risk stratification based on histological features of atypia and Ki67 proliferation index was not reproducible across neuropathologists. Hypomethylation at the FGFR3 locus, accompanied by increased FGFR3 protein expression, was observed in 97% of cases. Gross total resection was associated with significantly improved PFS compared to STR, while patients undergoing STR receiving radiotherapy had a better outcome (p = 0.0001). Younger patients were identified as having a higher risk of recurrence (p = 0.026). Patient age and treatment strategy were key factors associated with survival outcomes in this cohort. These findings underscore the importance of closer follow-up for younger patients and radiotherapy for STR cases. Furthermore, FGFR3 represents a hallmark feature and potential therapeutic target, warranting further investigation.
Acta neuropathologica Berlin : Springer, 1961 149(2025), Artikel-ID 61, Seite 1-16 Online-Ressource
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 Sophie Gottschalk ; Hans-Helmut König ; Tina Mallon ; Josefine Schulze ; Jan Weber ; Silke Böttcher ; Uta Sekanina ; Thomas Asendorf ; Eva Hummers ; Michael H. Freitag ; Nils Schneider ; Tim Friede ; Friedemann Nauck ; Martin Scherer ; Gabriella Marx ; Judith Dams
von Hamsa Ahmed ; Mohamed Elshabasi ; Marco A. González ; Michael Richter ; Marko Stölzel ; Alfons Weber ; Stephan John Heise ; Thomas Dalibor ; Sascha Schäfer ; Jürgen Parisi
