Introduction: The incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non-neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of anAspergilluslateral-flow device (LFD) test for BAL IPA detection in critically ill patients.Methods: A total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria.Results: Two patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%.Conclusion: LFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available.Trial registration: ClinicalTrials.govNCT02058316. Registered 20 January 2014.

To the editor: Acute myeloid leukemia (AML) is the most common acute leukemia in adults with an annual, age-adjusted incidence of 3.5/100 000 men and women rising to 15 to 20 above the age of 60 years.[1][1] Extensive work has now led to the elucidation of its genomic backbone, a refined

Acute myeloid leukemia (AML) is caused by malignant transformation of hematopoietic stem or progenitor cells and displays the most frequent acute leukemia in adults. Although some patients can be cured with high dose chemotherapy and allogeneic hematopoietic stem cell transplantation, the majority still succumbs to chemoresistant disease. Micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNA fragments and act as key players in the regulation of both physiologic and pathologic gene expression profiles. Aberrant expression of various non-coding RNAs proved to be of seminal importance in the pathogenesis of AML, as well in the development of resistance to chemotherapy. In this review, we discuss the role of miRNAs and lncRNAs with respect to sensitivity and resistance to treatment regimens currently used in AML and provide an outlook on potential therapeutic targets emerging thereof.

The recent identification of DNMT3A mutations in de novo acute myeloid leukemia prompted us to determine their frequency, patterns and clinical impact in a cohort of 98 patients with either therapy-related or secondary acute myeloid leukemia developing from an antecedent hematologic disorder. We identified 24 somatic mutations in 23 patients with a significantly higher frequency in secondary acute myeloid leukemia (35.1%) as compared to therapy-related acute myeloid leukemia (16.4%, P=0.0486). DNMT3A mutations were associated with a normal karyotype and IDH1/2 mutations, but did not affect survival. In contrast to de novo acute myeloid leukemia, most mutations did not affect arginine on position 882, but were predominantly found in the methyltransferase domain. All DNMT3A mutations identified in secondary acute myeloid leukemia were already present in the antecedent disorders indicating an early event. Reduction to homozygosity by uniparental disomy was observed in 2 patients with secondary acute myeloid leukemia during disease progression.

The granulocyte colony-stimulating factor receptor (G-CSF-R) transmits signals for proliferation and differentiation of myeloid progenitor cells. Here we report on the identification of a rare single nucleotide polymorphism within its intracellular domain (G-CSF-R_Glu785Lys). Screening a cohort of 116 patients with primary myelodysplastic syndromes (MDS), de novo acute myeloid leukemia (AML) (84 patients), as well as 232 age- and sex-matched controls revealed a highly significant association of the G-CSF-R_785Lys allele with the development of high-risk MDS as defined by more than 5% bone marrow blasts (9.7% versus 0.9% in controls; P = .001; odds ratio [OR], 12.5; 95% confidence interval [CI], 2.4-58.9) or an International Prognostic Scoring System score of intermediate-2 or high (13.0% versus 0.9%; P < .001; OR, 14.0; 95% CI, 3.4-85.0). Functional analysis by retroviral transfer of G-CSF-R_785Lys into myeloid progenitor cells of G-CSF-R-deficient mice showed a significantly diminished colony-formation capacity after G-CSF stimulation as compared with cells transduced with the wild-type receptor. These results suggest that lifelong altered G-CSF response by the G-CSF-R_785Lys may render individuals susceptible to development of high-risk MDS.

Acute myeloid leukemia (AML) is driven by a minor fraction of leukemic stem cells (LSCs) whose persistence is considered being the primary cause of disease relapse. A detailed characterization of the surface immunophenotype of LSCs to discriminate them from bulk leukemic blasts may enable successful targeting of this population thereby improving patient outcomes in AML. To identify surface markers, which may reflect LSC activity at diagnosis, we performed a detailed analysis of 16 putative LSC markers in CD34/38 leukemic subcompartments of 150 diagnostic AML samples using multicolor flow cytometry. The most promising markers were then selected to determine a possible correlation of their expression with a recently published LSC gene signature. We found GPR56 and CLL‐1 to be the most prominently differently expressed surface markers in AML subcompartments. While GPR56 was highest expressed within the LSC‐enriched CD34⁺38⁻ subcompartment as compared to CD34⁺38⁺ and CD34⁻ leukemic bulk cells, CLL‐1 expression was lowest in CD34⁺38⁻ leukemic cells and increased in CD34⁺38⁺ and CD34⁻ blasts. Furthermore, high GPR56 surface expression in CD34⁺38⁻ leukemic cells correlated with a recently published LSC gene expression signature and was associated with decreased overall survival in patients receiving intensive chemotherapy. In contrast, CLL‐1 expression correlated inversely with the LSC gene signature and was not informative on outcome. Our data strongly support GPR56 as a promising clinically relevant marker for identifying leukemic cells with LSC activity at diagnosis in CD34‐positive AML.