The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 ...recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients <60 years, and particularly in those with intermediate-risk cytogenetics. NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations were identified as important molecular prognosticators of OS irrespective of patient age. In summary, our study provides a comprehensive overview of the spectrum, clinical associations, and prognostic relevance of recurrent driver gene mutations in a large cohort representing a broad spectrum and age range of intensively treated AML patients.
•We present comprehensive information on genetic driver events in a uniformly treated cohort of 664 adult AML patients aged 18 to 86 years.•Mutations in NPM1, FLT3, CEBPA, TP53, and, in patients <60 years, DNMT3A and RUNX1, are the most important molecular risk factors in AML.
Recreating complex structures and functions of natural organisms in a synthetic form is a long-standing goal for humanity
. The aim is to create actuated systems with high spatial resolutions and ...complex material arrangements that range from elastic to rigid. Traditional manufacturing processes struggle to fabricate such complex systems
. It remains an open challenge to fabricate functional systems automatically and quickly with a wide range of elastic properties, resolutions, and integrated actuation and sensing channels
. We propose an inkjet deposition process called vision-controlled jetting that can create complex systems and robots. Hereby, a scanning system captures the three-dimensional print geometry and enables a digital feedback loop, which eliminates the need for mechanical planarizers. This contactless process allows us to use continuously curing chemistries and, therefore, print a broader range of material families and elastic moduli. The advances in material properties are characterized by standardized tests comparing our printed materials to the state-of-the-art. We directly fabricated a wide range of complex high-resolution composite systems and robots: tendon-driven hands, pneumatically actuated walking manipulators, pumps that mimic a heart and metamaterial structures. Our approach provides an automated, scalable, high-throughput process to manufacture high-resolution, functional multimaterial systems.
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•Unique multiscale representation to model the microstructure of different clay bricks.•Model-predicted elastic stiffness and thermal conductivity match experimental results.•Neither ...stiffness nor conductivity are generally correlated to the brick density.•The developed model paves the way for efficient optimization of modern brick products.
Quantification of elastic stiffness and thermal conductivity of fired clay bricks is still often limited to empirical rules and laboratory testing, which becomes progressively more challenging given the large variety of raw materials used to optimize the properties of modern brick products. Applying a continuum micromechanics multiscale approach, we herein aim at upscaling of microstructural features to quantify the bricks’ macroscopic properties. Microstructural features such as assemblage and morphometry of mineral phases (quartz, feldspar, and micas), of pores, and of the binding matrix phase, respectively, as well as thermoelastic phase properties are provided by recently published results from extensive microscopic testing including electron microscopy imaging, mercury intrusion porosimetry, nanoindentation, and scanning thermal microscopy. These results are incorporated into the micromechanics model by introducing spheroidal phases with characteristic orientation distribution at two observation scales. The homogenized macroscopic stiffness and conductivity agree very well with independent results from novel macroscopic tests for all seven studied brick compositions. This corroborates the microstructure-informed multiscale model approach and its assumptions: the linear increase of the binding matrix properties with the material’s carbonate content, and the inability of large quartz with interface cracks to take over any mechanical loads.
Summary Background About 50% of patients (age ≥60 years) who have acute myeloid leukaemia and are otherwise medically healthy (ie, able to undergo intensive chemotherapy) achieve a complete remission ...(CR) after intensive chemotherapy, but with a substantially increased risk of early death (ED) compared with younger patients. We verified the association of standard clinical and laboratory variables with CR and ED and developed a web-based application for risk assessment of intensive chemotherapy in these patients. Methods Multivariate regression analysis was used to develop risk scores with or without knowledge of the cytogenetic and molecular risk profiles for a cohort of 1406 patients (aged ≥60 years) with acute myeloid leukaemia, but otherwise medically healthy, who were treated with two courses of intensive induction chemotherapy (tioguanine, standard-dose cytarabine, and daunorubicin followed by high-dose cytarabine and mitoxantrone; or with high-dose cytarabine and mitoxantrone in the first and second induction courses) in the German Acute Myeloid Leukaemia Cooperative Group 1999 study. Risk prediction was validated in an independent cohort of 801 patients (aged >60 years) with acute myeloid leukaemia who were given two courses of cytarabine and daunorubicin in the Acute Myeloid Leukaemia 1996 study. Findings Body temperature, age, de-novo leukaemia versus leukaemia secondary to cytotoxic treatment or an antecedent haematological disease, haemoglobin, platelet count, fibrinogen, and serum concentration of lactate dehydrogenase were significantly associated with CR or ED. The probability of CR with knowledge of cytogenetic and molecular risk (score 1) was from 12% to 91%, and without knowledge (score 2) from 21% to 80%. The predicted risk of ED was from 6% to 69% for score 1 and from 7% to 63% for score 2. The predictive power of the risk scores was confirmed in the independent patient cohort (CR score 1, from 10% to 91%; CR score 2, from 16% to 80%; ED score 1, from 6% to 69%; and ED score 2, from 7% to 61%). Interpretation The scores for acute myeloid leukaemia can be used to predict the probability of CR and the risk of ED in older patients with acute myeloid leukaemia, but otherwise medically healthy, for whom intensive induction chemotherapy is planned. This information can help physicians with difficult decisions for treatment of these patients. Funding Deutsche Krebshilfe and Deutsche Forschungsgemeinschaft.
Monitoring minimal residual disease is an important way to identify patients with acute myeloid leukemia at high risk of relapse. In this study we investigated the prognostic potential of minimal ...residual disease monitoring by quantitative real-time polymerase chain reaction analysis of NPM1 mutations in patients treated in the AMLCG 1999, 2004 and 2008 trials. Minimal residual disease was monitored - in aplasia, after induction therapy, after consolidation therapy, and during follow-up - in 588 samples from 158 patients positive for NPM1 mutations A, B and D (with a sensitivity of 10(-6)). One hundred and twenty-seven patients (80.4%) achieved complete remission after induction therapy and, of these, 56 patients (44.1%) relapsed. At each checkpoint, minimal residual disease cut-offs were calculated. After induction therapy a cut-off NPM1 mutation ratio of 0.01 was associated with a high hazard ratio of 4.26 and the highest sensitivity of 76% for the prediction of relapse. This was reflected in a cumulative incidence of relapse after 2 years of 77.8% for patients with ratios above the cut-off versus 26.4% for those with ratios below the cut-off. In the favorable subgroup according to European LeukemiaNet, the cut-off after induction therapy also separated the cohort into two prognostic groups with a cumulative incidence of relapse of 76% versus 6% after 2 years. Our data demonstrate that in addition to pre-therapeutic factors, the course of minimal residual disease in an individual is an important prognostic factor and could be included in clinical trials for the guidance of post-remission therapy. The trials from which data were obtained were registered at www.clinicaltrials.gov (#NCT01382147, #NCT00266136) and at the European Leukemia Trial Registry (#LN_AMLINT2004_230).
Today's use of large-scale industrial robots is enabling extraordinary achievement on the assembly line, but these robots remain isolated from the humans on the factory floor because they are very ...powerful, and thus dangerous to be around. In contrast, the soft robotics research community has proposed soft robots that are safe for human environments. The current state of the art enables the creation of small-scale soft robotic devices. In this article we address the gap between small-scale soft robots and the need for human-sized safe robots by introducing a new soft robotic module and multiple human-scale robot configurations based on this module. We tackle large-scale soft robots by presenting a modular and reconfigurable soft robotic platform that can be used to build fully functional and untethered meter-scale soft robots. These findings indicate that a new wave of human-scale soft robots can be an alternative to classic rigid-bodied robots in tasks and environments where humans and machines can work side by side with capabilities that include, but are not limited to, autonomous legged locomotion and grasping.
This retrospective, multicenter study aimed to reveal risk predictors for mortality in the intensive care unit (ICU) as well as survival after ICU discharge in patients with acute myeloid leukemia ...(AML) requiring treatment in the ICU.
Multivariate analysis of data for 187 adults with AML treated in the ICU in one institution revealed the following as independent prognostic factors for death in the ICU: arterial oxygen partial pressure below 72 mmHg, active AML and systemic inflammatory response syndrome upon ICU admission, and need for hemodialysis and mechanical ventilation in the ICU. Based on these variables, we developed an ICU mortality score and validated the score in an independent cohort of 264 patients treated in the ICU in three additional tertiary hospitals. Compared with the Simplified Acute Physiology Score (SAPS) II, the Logistic Organ Dysfunction (LOD) score, and the Sequential Organ Failure Assessment (SOFA) score, our score yielded a better prediction of ICU mortality in the receiver operator characteristics (ROC) analysis (AUC = 0.913 vs. AUC = 0.710 SAPS II, AUC = 0.708 LOD, and 0.770 SOFA in the training cohort; AUC = 0.841 for the developed score vs. AUC = 0.730 SAPSII, AUC = 0.773 LOD, and 0.783 SOFA in the validation cohort). Factors predicting decreased survival after ICU discharge were as follows: relapse or refractory disease, previous allogeneic stem cell transplantation, time between hospital admission and ICU admission, time spent in ICU, impaired diuresis, Glasgow Coma Scale <8 and hematocrit of ≥25% at ICU admission. Based on these factors, an ICU survival score was created and used for risk stratification into three risk groups. This stratification discriminated distinct survival rates after ICU discharge.
Our data emphasize that although individual risks differ widely depending on the patient and disease status, a substantial portion of critically ill patients with AML benefit from intensive care.
Searching for a job has been an everyday affair in both modern and past societies, and employment a concern for both individuals and institutions. The case studies in this volume investigate job ...search and placement practices in European countries, Australia, and India in the nineteenth and twentieth centuries. The contributors explore how looking for work becomes a means by which participants (individuals, placement agents, trade unions, municipalities, administrations, state authorities, and schools) articulated specific interests, perspectives, and agendas. Taking an exploratory approach, the chapters illustrate different approaches to the history of employment and job searching, ranging from organizational and regulatory histories to the analysis of practices and autobiographical accounts. In the process, they uncover the interrelations of search practices and attempts to arrange placement services.
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.
Prospective, randomised, open, phase II trial with parallel group design and fixed sample size.
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.
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.
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.
This trial is registered at clinical trials.gov (identifier: NCT00915252).
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