von Petros Christopoulos ; Martina Kirchner ; Farastuk Bozorgmehr ; Nikolaus Magios ; Daniel Kazdal ; Anna-Lena Volckmar ; Lena Marie Brückner ; Tilmann Bochtler ; Mark Kriegsmann ; Volker Endris ; Roland Penzel ; Katharina Kriegsmann ; Martin E. Eichhorn ; Felix Herth ; Claus Peter Heußel ; Rami El-Shafie ; Marc Schneider ; Thomas Muley ; Michael Meister ; Peter Schirmacher ; Helge Bischoff ; Frank Griesinger ; Albrecht Stenzinger ; Michael Thomas
Objective - Panel-based next-generation sequencing (NGS) is increasingly used for the diagnosis of EGFR-mutated non-small-cell lung cancer (NSCLC) and could improve risk assessment in combination with clinical parameters. - Materials and methods - To this end, we retrospectively analyzed the outcome of 400 tyrosine kinase inhibitor (TKI)-treated EGFR+ NSCLC patients with validation of results in an independent cohort (n = 130). - Results - EGFR alterations other than exon 19 deletions (non-del19), TP53 co-mutations, and brain metastases at baseline showed independent associations of similar strengths with progression-free (PFS hazard ratios [HR] 2.1-2.3) and overall survival (OS HR 1.7-2.2), in combination defining patient subgroups with distinct outcome (EGFR+ NSCLC risk Score, "ENS", p < 0.001). Co-mutations beyond TP53 were rarely detected by our multigene panel (<5%) and not associated with clinical endpoints. Smoking did not affect outcome independently, but was associated with non-del19 EGFR mutations (p < 0.05) and comorbidities (p < 0.001). Laboratory parameters, like the blood lymphocyte-to-neutrophil ratio and serum LDH, correlated with the metastatic pattern (p < 0.01), but had no independent prognostic value. Reduced ECOG performance status (PS) was associated with comorbidities (p < 0.05) and shorter OS (p < 0.05), but preserved TKI efficacy. Non-adenocarcinoma histology was also associated with shorter OS (p < 0.05), but rare (2-3 %). The ECOG PS and non-adenocarcinoma histology could not be validated in our independent cohort, and did not increase the range of prognostication alongside the ENS. - Conclusions - EGFR variant, TP53 status and brain metastases predict TKI efficacy and survival in EGFR+ NSCLC irrespective of other currently available parameters ("ENS"). Together, they constitute a practical and reproducible approach for risk stratification of newly diagnosed metastatic EGFR+ NSCLC.
Lung cancer Amsterdam [u.a.] : Elsevier, 1985 148(2020), Seite 105-112 Online-Ressource
von Mehmet N. Cizmeci ; Floris Groenendaal ; Kian D. Liem ; Ingrid C. van Haastert ; Isabel Benavente-Fernandez ; Henrica L.M. van Straaten ; Sylke Steggerda ; Bert J. Smit ; Andrew Whitelaw ; Peter Woerdeman ; Axel Heep ; Linda S. de Vries
von Hanna Koch ; Nora Germscheid ; Heike M. Freese ; Beatriz Elizabeth Noriega Ortega ; Dominik Lücking ; Martine Berger ; Galaxy Qiu ; Ezequiel M. Marzinelli ; Alexandra H. Campbell ; Peter D. Steinberg ; Jörg Overmann ; Thorsten Dittmar ; Meinhard Simon ; Matthias Wietz
von Sabine Illsinger ; Christoph Korenke ; Sylvia Boesch ; Michael Nocker ; Daniela Karall ; Jean M. Nuoffer ; Lucia Laugwitz ; Johannes A. Mayr ; Sabine Scholl-Bürgi ; Peter Freisinger ; Tobias Kowald ; Stefan Kölker ; Holger Prokisch ; Tobias B. Haack
Background - ECHS1 encodes the mitochondrial short chain enoyl CoA hydratase 1 (SCEH). Biallelic ECHS1 variants have been associated with Leigh-like presentations and milder phenotypes with paroxysmal exercise-induced dystonia. - Patients/methods - We used exome sequencing to investigate molecular bases of paroxysmal and non-paroxysmal dystonia in three patients and performed functional studies in fibroblasts. Disease presentation and response upon dietary interventions were documented. - Results - We identified compound heterozygous ECHS1 missense variants in all individuals; all of them harbouring an c.518C > T (p.Ala173Val) variant. SCEH activity was impaired in patients’ fibroblasts, respiratory chain-, and pyruvate-dehydrogenase-complex activities were normal in one individual. Patient 1 presented from the age of 2.5 years on with paroxysmal opisthotonic posturing. Patient 2 had a first metabolic crisis at the age 20 months developing recurrent exercise-induced dystonic episodes. Disease history of patient 3 was unremarkable for neurological findings until he first presented at the age of 20 years with persistent dystonia. Ketogenic diet had beneficial effects in patient 1. Neither ketogenic nor low protein diets led to milder symptoms in patient 2. Patient 3 benefits from low protein diet with improvement of his torticollis. - Conclusions - In line with literature, our findings corroborate that the pathogenic ECHS1 variant c.518C > T (p.Ala173Val) is associated with milder phenotypes characterized by paroxysmal and non-paroxysmal dystonia. Because of the potentially treatable defect, especially in milder affected patients, it is important to consider SCEH deficiency not only in patients with Leigh-like syndrome but also in patients with paroxysmal dystonia and normal neurological findings between episodes.
European journal of medical genetics New York, NY [u.a.] : Elsevier, 2005 63(2020,11) Artikel-Nummer 104046, 8 Seiten Online-Ressource
von Pauline E. Schneeberger ; Leonie von Elsner ; Emma L. Barker ; Peter Meinecke ; Iris Marquardt ; Malik Alawi ; Katharina Steindl ; Pascal Joset ; Anita Rauch ; Petra J.G. Zwijnenburg ; Marjan M. Weiss ; Catherine L.R. Merry ; Kerstin Kutsche
von Steffen D. Kriechbaum ; Niklas F. Boeder ; Luise Gaede ; Martin Bernhard Arnold ; Ursula Vigelius-Rauch ; Peter Roth ; Michael Sander ; Andreas Böning ; Matthias Bayer ; Albrecht Elsässer ; Helge Möllmann ; Christian Hamm ; Holger M. Nef
von Tim Van Damme ; Thatjana Gardeitchik ; Miski Mohamed ; Sergio Guerrero-Castillo ; Peter Freisinger ; Brecht Guillemyn ; Ariana Kariminejad ; Daisy Dalloyaux ; Sannevan Kraaij ; Dirk J. Lefeber ; Delfien Syx ; Wouter Steyaert ; Riet De Rycke ; Alexander Hoischen ; Erik-Jan Kamsteeg ; Sunnie Y. Wong ; Monique van Scherpenzeel ; Payman Jamili ; Ulrich Brandt ; Leo Nijtmans ; Christoph Korenke ; Brian H.Y. Chung ; Christopher C.Y. Mak ; Ingrid Hausser ; Uwe Kornak ; Björn Fischer-Zirnsak ; Tim M. Strom ; Thomas Meitinger ; Yasemin Alanay ; Gulem E. Utine ; Peter K.C. Leung ; Siavash Ghaderi-Sohi ; Paul Coucke ; Sofie Symoens ; Anne De Paepe ; Christian Thiel ; Tobias B. Haack ; Fransiska Malfait ; Eva Morava ; Bert Callewaert ; Ron A. Wevers