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Der Einfluss von turbulenten Strömungen auf die Photodissoziation von CO in interstellaren Wolken
(2001)
Seit 1988 ist bekannt, dass die Photodissoziation von COMolekülen durch Linienabsorption von UVPhotonen stattfindet. Wie jede Linienabsorption ist damit auch die Photodissoziation von CO abhängig von Geschwindigkeitsfeldern innerhalb des absorbierenden Mediums. DopplerVerschiebung kann die Absorption in einen Frequenzbereich verschieben, in dem sich die lokale Intensität von der Intensität in der Linienmitte wesentlich unterscheidet. Jede Untersuchung, die sich mit der Bildung und Vernichtung von COMolekülen am Rand interstellarer Wolken beschäftigt, muss diese turbulenten Geschwindigkeitsfelder berücksichtigen. Da die Existenz von turbulenten Strömungen in interstellaren Molekülwolken unbestritten ist, wird in Untersuchungen üblicherweise der Dopplerparameter der Gaußschen Profilfunktion um eine Turbulenzgeschwindigkeit erweitert. Diese mikroturbulente Näherung ist die simpelste Möglichkeit zur Berücksichtigung von Turbulenz. In vorangegangenen Arbeiten (Albrecht, M.A., Kegel, W.H. (1987)), (Kegel, W.H., Piehler, G., Albrecht, M.A. (1993)), (Piehler, G., Kegel, W.H. (1995)) ist gezeigt worden, dass die Berücksichtigung eines turbulenten Geschwindigkeitsfeldes mit endlicher Korrelationslänge (Mesoturbulenz) jedoch wesentlich dazu beitragen kann, realistischere Linienprofile zu erhalten. Während in den letzten Jahren einiger Aufwand betrieben wurde, die Berechnung der chemischen und thermischen Struktur einer Molekülwolke zu verfeinern, ist der Modellierung des zugrundegelegten Strahlungstransports weniger Aufmerksamkeit gewidmet worden. Die Ergebnisse unserer Rechnungen zeigen, dass die Berück sichtigung eines mesoturbulenten Strahlungstransports den Verlauf der COHäufigkeit entlang des Sehstrahls wesentlich beeinflussen kann. Zusammengefasst haben wir folgende Ergebnisse erhalten: - Rechnungen mit einem EinzellinienModell zeigen den großen Einfluss von Korrelationslänge und Turbulenzgeschwindigkeit auf den Verlauf der Photodissoziationsrate und damit auch auf die resultierende COHäufigkeit. - Bei Mesoturbulenz werden die absorptionsrelevanten Linien schneller optisch dick als bei reiner Mikroturbulenz. Dadurch kann sich eine stabile Zone großer CODichte in Tiefen bilden, von denen bisher angenommen wurde, sie würden eine zu große UVIntensität aufweisen. - Rechnungen, die das volle UVSpektrum berücksichtigen, zeigen eine geringere Sensitivität der COHäufigkeit gegenüber Variationen der Turbulenzparameter als solche mit nur einer Linie. Trotzdem haben Korrelationslänge und Turbulenzgeschwindigkeit starken Einfluss auf die Tiefe, ab der eine stabile COHäufigkeit erreicht wird. - Im Vergleich zu Rechnungen mit einer parametrisierten Photodissoziationswahrscheinlichkeit fällt im mesoturbulenten Fall z CO wesentlich schneller ab. Das bedeutet, dass in größeren Tiefen der Wolke die Werte für z CO um einige Größenordnungen voneinander abweichen können. Für Größe und Isotopenverhältnis des Wolkenmodells kann das zu einer signifikanten Überschätzung der wahren Werte führen. - Das zugrundegelegte Modell der chemischen Reaktionen weist eine hohe Stabilität gegenüber Veränderungen der Turbulenzparameter auf. Auch wenn die COHäufigkeit davon relativ stark betroffen ist, wirken sich diese Veränderungen nur sehr langsam auf die chemische Gesamtstruktur der Wolke aus. - Die Anwendung unserer Ergebnisse auf Beobachtungen von NGC 2024 zeigen, dass sich die Werte, die man für Dichte und Größe der Region aus den Modellen ermittelt, stark von dem zugrundegelegten Strahlungstransportmodell abhängen. Folgerungen, die aufgrund einer zu einfachen Modellierung gemacht werden, sind somit mit einiger Vorsicht zu betrachten. Es zeigt sich, dass der numerische Aufwand, stochastische Strahlungstransportmodelle zu rechnen, durchaus gerechtfertigt ist. Möchte man die Bildung von CO Molekülen am Rand einer interstellaren Molekülwolke genauer verstehen, muss eine endliche Korrelationslänge berücksichtigt werden. Es macht wenig Sinn, immer detailliertere chemische Modelle zu entwickeln und die wichtigen Effekte mesoturbulenten Strahlungstransports zu vernachlässigen.
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.
A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21~22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with greater than or equal to4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21~22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype.
Background: The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) can induce high complete remission rates with acceptable toxicity in elderly patients with acute myeloid leukemia (AML). We present the final results of a randomized-controlled trial comparing IMA with the standard 7 + 3 induction regimen consisting of continuous infusion cytarabine plus daunorubicin (DA).
Patients and methods: Patients with newly diagnosed AML >60 years were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 twice daily on days 1, 3, 5, 7) plus mitoxantrone (10 mg/m2 days 1–3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1–7) plus daunorubicin (45 mg/m2 days 3–5) (DA). Patients in complete remission after DA received intermediate-dose cytarabine plus amsacrine as consolidation treatment, whereas patients after IMA were consolidated with standard-dose cytarabine plus mitoxantrone.
Results: Between February 2005 and October 2009, 485 patients were randomized; 241 for treatment arm DA and 244 for IMA; 76% of patients were >65 years. The complete response rate after DA was 39% [95% confidence interval (95% CI): 33–45] versus 55% (95% CI: 49–61) after IMA (odds ratio 1.89, P = 0.001). The 6-week early-death rate was 14% in both arms. Relapse-free survival curves were superimposable in the first year, but separated afterwards, resulting in 3-year relapse-free survival rates of 29% versus 14% in the DA versus IMA arms, respectively (P = 0.042). The median overall survival was 10 months in both arms (P = 0.513).
Conclusion: The dose escalation of cytarabine in induction therapy lead to improved remission rates in the elderly AML patients. This did not translate into a survival advantage, most likely due to differences in consolidation treatment. Thus, effective consolidation strategies need to be further explored. In combination with an effective consolidation strategy, the use of intermediate-dose cytarabine in induction may improve curative treatment for elderly AML patients.
INTRODUCTION: Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML.
TRIAL DESIGN: Prospective, randomised, open, phase II trial with parallel group design and fixed sample size.
PATIENTS AND METHODS: Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of <20,000/µl at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint.
RESULTS: Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days.
CONCLUSIONS: The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm.
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.