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Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among the most frequent alterations in acute myeloid leukemia (AML) and can be found in ∼20% of patients at diagnosis. Among 4930 patients (median age, 56 years; interquartile range, 45-66) with newly diagnosed, intensively treated AML, we identified IDH1 mutations in 423 (8.6%) and IDH2 mutations in 575 (11.7%). Overall, there were no differences in response rates or survival for patients with mutations in IDH1 or IDH2 compared with patients without mutated IDH1/2. However, distinct clinical and comutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with increased age, lower white blood cell (WBC) count, less frequent comutation of NPM1 and FLT3 internal tandem mutation (ITD) as well as with lower rate of complete remission and a trend toward reduced overall survival (OS) compared with other IDH1 mutation variants and wild-type (WT) IDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC count, more karyotype abnormalities, and less frequent comutations of NPM1 and/or FLT3-ITD. Among patients within the European LeukemiaNet 2017 intermediate- and adverse-risk groups, relapse-free survival and OS were significantly better for those with IDH2-R172K compared with WT IDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific comutation pattern and favorable outcome. In summary, the presented data from a large cohort of patients with IDH1/2 mutated AML indicate novel and clinically relevant findings for the most common IDH mutation subtypes.
Simple Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation.
Abstract: Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
Die Horizontausrichtung von 48 jungsteinzeitlichen Ganggräbern bei Carnac in der Bretagne wurde ausgemessen. Der größte Teil (40, entsprechend 83 %) ist nach Südosten orientiert. Es wird diskutiert, inwieweit diese Ausrichtung nach den Gestirnen erfolgt sein könnte, etwa nach dem Aufgangspunkt der Sonne zum Winteranfang.
Der Komet Hyakutake 1996
(1996)
Die Wetterstation und die Photovoltaikanlage (Leihgabe der Stadtwerke Osnabrück) auf dem Dach des Museums am Schölerberg wurde von Hänel (1998a) beschrieben. In einem weiteren Artikel sind die Daten der Wetterstation und der Photovoltaikanlage für das Jahr 1997 zusammengefasst (Hänel, 1998b), dort ist auch die Herkunft der Vergleichsdaten beschrieben. In Tabelle 1 sind die Monatswerte für 1998 zusammengestellt.
Die Horizontausrichtung von 44 jungsteinzeitlichen Steinkammern des Osnabrücker Raumes wurde vermessen. Wie in Mecklenburg sind die Zugänge zu den Gräbern nach Süden orientiert, während die Gräber (Dolmen) um Carnac/Bretagne nach Südosten ausgerichtet sind. Es wird diskutiert, inwieweit die Ausrichtungen nach astronomischen Gesichtspunkten erfolgt sein könnten.
Die Beobachtung der totalen Sonnenfinsternis in der Champagne mit verschiedenen Geräten wird beschrieben. Mit langbrennweitigen Optiken wurde die Korona und die Chromosphäre aufgenommen, die Dias digitalisiert und dann digital weiterverarbeitet. Mit einem Objektivgitter-Filter wurde das Flash-Spektrum fotografiert. Der Temperaturverlauf wurde in der Totalitätszone und in Osnabrück erfasst, ebenso wie die Sonneneinstrahlung und die Erträge der Photovoltaikanlage.
