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1.
Resuscitation ; 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34995686

RESUMO

AIM: To introduce and evaluate a new, open-source algorithm to detect chest compression periods automatically by the rhythmic, high amplitude signals from an accelerometer, without processing single chest compression events, and to consecutively calculate the chest compression fraction (CCF). METHODS: A consecutive sample of defibrillator records from the German Resuscitation Registry was obtained and manually annotated in consensus as ground truth. Chest compression periods were determined by different automatic approaches, including the new algorithm. The diagnostic performance of these approaches was assessed. Further, using the different approaches in conjunction with different granularities of manual annotation, several CCF versions were calculated and compared by intraclass correlation coefficient (ICC). RESULTS: 131 defibrillator recordings with a total duration of 5755 minutes were analysed. The new algorithm had a sensitivity of 99.39 (95% CI 99.38, 99.41)% and specificity of 99.17 (95% CI 99.15; 99.18)% to detect chest compressions at any given timepoint. The ICC compared to ground truth was 0.998 for the new algorithm and 0.999 for manual annotation, while the ICC of the proposed algorithm compared to the proprietary software was 0.978. The time required for manual annotation to calculate CCF was reduced by 70.48 (22.55, [94.35, 14.45])%. CONCLUSION: The proposed algorithm reliably detects chest compressions in defibrillator recordings. It can markedly reduce the workload for manual annotation, which may facilitate uniform reporting of measured quality of cardiopulmonary resuscitation. The algorithm is made freely available and may be used in big data analysis and machine learning approaches.

2.
Hemasphere ; 6(1): e676, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34964040

RESUMO

Measurable residual disease (MRD) quantified by multiparameter flow cytometry (MFC) is a strong and independent prognostic factor in acute myeloid leukemia (AML). However, several technical factors may affect the final read-out of the assay. Experts from the MRD Working Party of the European LeukemiaNet evaluated which aspects are crucial for accurate MFC-MRD measurement. Here, we report on the agreement, obtained via a combination of a cross-sectional questionnaire, live discussions, and a Delphi poll. The recommendations consist of several key issues from bone marrow sampling to final laboratory reporting to ensure quality and reproducibility of results. Furthermore, the experiences were tested by comparing two 8-color MRD panels in multiple laboratories. The results presented here underscore the feasibility and the utility of a harmonized theoretical and practical MFC-MRD assessment and are a next step toward further harmonization.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34894176

RESUMO

BACKGROUND: Flow cytometry (FCM) aids the diagnosis and prognostic stratification of patients with suspected or confirmed myelodysplastic syndrome (MDS). Over the past few years, significant progress has been made in the FCM field concerning technical issues (including software and hardware) and pre-analytical procedures. METHODS: Recommendations are made based on the data and expert discussions generated from 13 yearly meetings of the European LeukemiaNet international MDS Flow working group. RESULTS: We report here on the experiences and recommendations concerning (1) the optimal methods of sample processing and handling, (2) antibody panels and fluorochromes, and (3) current hardware technologies. CONCLUSIONS: These recommendations will support and facilitate the appropriate application of FCM assays in the diagnostic workup of MDS patients. Further standardization and harmonization will be required to integrate FCM in MDS diagnostic evaluations in daily practice.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34897979

RESUMO

This article discusses the rationale for inclusion of flow cytometry (FCM) in the diagnostic investigation and evaluation of cytopenias of uncertain origin and suspected myelodysplastic syndromes (MDS) by the European LeukemiaNet international MDS Flow Working Group (ELN iMDS Flow WG). The WHO 2016 classification recognizes that FCM contributes to the diagnosis of MDS and may be useful for prognostication, prediction, and evaluation of response to therapy and follow-up of MDS patients.

5.
Artigo em Inglês | MEDLINE | ID: mdl-34967500

RESUMO

BACKGROUND: It was proposed that peripheral blood (PB) monocyte profiles evaluated by flow cytometry, called "monocyte assay," could rapidly and efficiently distinguish chronic myelomonocytic leukemia (CMML) from other causes of monocytosis by highlighting an increase in the classical monocyte (cMo) fraction above 94%. However, the robustness of this assay requires a large multicenter validation and the assessment of its feasibility on bone marrow (BM) samples, as some centers may not have access to PB. METHODS: PB and/or BM samples from patients displaying monocytosis were assessed with the "monocyte assay" by 10 ELN iMDS Flow working group centers with harmonized protocols. The corresponding files were reanalyzed in a blind fashion and the cMo percentages obtained by both analyses were compared. Confirmed diagnoses were collected when available. RESULTS: The comparison between cMo percentages from 267 PB files showed a good global significant correlation (r = 0.88) with no bias. Confirmed diagnoses, available for 212 patients, achieved a 94% sensitivity and an 84% specificity. Hence, 95/101 CMML patients displayed cMo ≥94% while cMo <94% was observed in 83/99 patients with reactive monocytosis and in 10/12 patients with myeloproliferative neoplasms (MPN) with monocytosis. The established Receiver Operator Curve again provided a 94% cut-off value of cMo. The 117 BM files reanalysis led to an 87% sensitivity and an 80% specificity, with excellent correlation between the 43 paired samples to PB. CONCLUSIONS: This ELN multicenter study demonstrates the robustness of the monocyte assay with only limited variability of cMo percentages, validates the 94% cutoff value, confirms its high sensitivity and specificity in PB and finally, also confirms the possibility of its use in BM samples.

7.
Blood ; 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34724563

RESUMO

Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European LeukemiaNet (ELN) MRD working party evaluates standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations based on significant developments in the field. New and revised recommendations were established during in-person and online meetings, and a two-stage Delphi poll was conducted to optimize consensus. All recommendations are graded by levels of evidence and agreement. Major changes include technical specifications for next generation sequencing (NGS)-based MRD testing and integrative assessments of MRD irrespective of technology. Other topics include use of MRD as a prognostic and surrogate endpoint for drug testing; selection of the technique, material, and appropriate time points for MRD assessment; and clinical implications of MRD assessment. In addition to technical recommendations for flow- and molecular- MRD analysis, we provide MRD thresholds and define MRD response, and detail how MRD results should be reported and combined if several techniques are used. MRD assessment in AML is complex and clinically relevant, and standardized approaches to application, interpretation, technical conduct, and reporting are of critical importance.

9.
Patterns (N Y) ; 2(10): 100351, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34693376

RESUMO

Multi-parameter flow cytometry (MFC) is a cornerstone in clinical decision making for leukemia and lymphoma. MFC data analysis requires manual gating of cell populations, which is time-consuming, subjective, and often limited to a two-dimensional space. In recent years, deep learning models have been successfully used to analyze data in high-dimensional space and are highly accurate. However, AI models used for disease classification with MFC data are limited to the panel they were trained on. Thus, a key challenge in deploying AI into routine diagnostics is the robustness and adaptability of such models. This study demonstrates how transfer learning can be applied to boost the performance of models with smaller datasets acquired with different MFC panels. We trained models for four additional datasets by transferring the features learned from our base model. Our workflow increased the model's overall performance and, more prominently, improved the learning rate for small training sizes.

10.
Blood Adv ; 5(21): 4426-4434, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34570179

RESUMO

Acquired somatic mutations are crucial for the development of most cancers. We performed a comprehensive comparative analysis of the mutational landscapes and their correlation with CHIP-related (clonal hematopoiesis of indeterminate potential) mutations and patient age of 122 genes in 3096 cases of 28 different hematological malignancies. Differences were observed regarding (1) the median number of mutations (highest, median n = 4; lowest, n = 0); (2) specificity of certain mutations (high frequencies in atypical chronic myeloid leukemia [aCML; ASXL1, 86%], follicular lymphoma [FL; KMT2D, 87%; CREBBP, 73%], hairy cell lymphoma [BRAF, 100%], lymphoplasmacytic lymphoma [MYD88, 98%; CXCR4, 51%], myeloproliferative neoplasm [MPN; AK2, 68%]); (3) distribution of mutations (broad distribution within/across the myeloid/lymphoid lineage for TET2, ASXL1, DNMT3A, TP53, BCOR, and ETV6); (4) correlation of mutations with patient's age (correlated with older age across entities: TET2, DNMT3A, ASXL1, TP53, EZH2, BCOR, GATA2, and IDH2; younger age: KIT, POT1, RAD21, U2AF2, and WT1); (5) correlation of mutation number per patient with age. Moreover, we observed high frequencies of mutations in RUNX1, SRSF2, IDH2, NRAS, and EZH2 in cases comprising at least 1 DTA (DNMT3A, TET2, ASXL1) mutation, whereas in cases without DTA mutations, TP53, KRAS, WT1, and SF3B1 were more frequent across entities, suggesting differences in pathophysiology. These results give further insight into the complex genetic landscape and the role of DTA mutations in hematological neoplasms and define mutation-driven entities (myelodysplastic syndrome/MPN overlap; secondary acute myeloid) in comparison with entities defined by chromosomal fusions (chronic myeloid leukemia; myeloid/lymphoid neoplasm with eosinophilia).


Assuntos
Neoplasias Hematológicas , Leucemia Mieloide , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Idoso , Neoplasias Hematológicas/genética , Humanos , Mutação , Fator de Processamento U2AF
11.
BMC Cancer ; 21(1): 886, 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34340673

RESUMO

BACKGROUND: Considering the clinical and genetic characteristics, acute lymphoblastic leukemia (ALL) is a rather heterogeneous hematological neoplasm for which current standard diagnostics require various analyses encompassing morphology, immunophenotyping, cytogenetics, and molecular analysis of gene fusions and mutations. Hence, it would be desirable to rely on a technique and an analytical workflow that allows the simultaneous analysis and identification of all the genetic alterations in a single approach. Moreover, based on the results with standard methods, a significant amount of patients have no established abnormalities and hence, cannot further be stratified. METHODS: We performed WTS and WGS in 279 acute lymphoblastic leukemia (ALL) patients (B-cell: n = 211; T-cell: n = 68) to assess the accuracy of WTS, to detect relevant genetic markers, and to classify ALL patients. RESULTS: DNA and RNA-based genotyping was used to ensure correct WTS-WGS pairing. Gene expression analysis reliably assigned samples to the B Cell Precursor (BCP)-ALL or the T-ALL group. Subclassification of BCP-ALL samples was done progressively, assessing first the presence of chromosomal rearrangements by the means of fusion detection. Compared to the standard methods, 97% of the recurrent risk-stratifying fusions could be identified by WTS, assigning 76 samples to their respective entities. Additionally, read-through fusions (indicative of CDKN2A and RB1 gene deletions) were recurrently detected in the cohort along with 57 putative novel fusions, with yet untouched diagnostic potentials. Next, copy number variations were inferred from WTS data to identify relevant ploidy groups, classifying an additional of 31 samples. Lastly, gene expression profiling detected a BCR-ABL1-like signature in 27% of the remaining samples. CONCLUSION: As a single assay, WTS allowed a precise genetic classification for the majority of BCP-ALL patients, and is superior to conventional methods in the cases which lack entity defining genetic abnormalities.


Assuntos
Perfilação da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transcriptoma , Sequenciamento Completo do Exoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Biologia Computacional , Análise Citogenética , Variações do Número de Cópias de DNA , Feminino , Rearranjo Gênico , Histocitoquímica/métodos , Humanos , Imunofenotipagem/métodos , Hibridização in Situ Fluorescente , Lactente , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adulto Jovem
12.
Leukemia ; 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376804

RESUMO

In AML patients, recurrent mutations were shown to persist in remission, however, only some have a prognostic value and persistent mutations might therefore reflect a re-established premalignant state or truly active disease causing relapse. We aimed to dissect the nature of co-mutations in NPM1 mutated AML where the detection of NPM1 transcripts allows highly specific and sensitive detection of complete molecular remission (CMR). We analysed 150 consecutive patients who achieved CMR following intensive treatment by next generation sequencing on paired samples at diagnosis, CMR and relapse (38/150 patients). Patients with persistence or the acquisition of non-DTA (DNMT3A, TET2, ASXL1) mutations at CMR (23/150 patients, 15%) have a significantly worse prognosis (EFS HR = 2.7, p = 0.003; OS HR = 3.6, p = 0.012). Based on clonal evolution analysis of diagnostic, CMR and relapse samples, we redefine pre-malignant mutations and include IDH1, IDH2 and SRSF2 with the DTA genes in this newly defined group. Only the persistence or acquisition of CHOP-like (clonal hematopoiesis of oncogenic potential) mutations was significantly associated with an inferior outcome (EFS HR = 4.5, p = 0.0002; OS HR = 5.5, p = 0.002). Moreover, the detection of CHOP-like mutations at relapse was detrimental (HR = 4.5, p = 0.01). We confirmed these findings in a second independent whole genome sequencing cohort.

13.
Leuk Lymphoma ; : 1-10, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34380369

RESUMO

MYC rearrangements (MYCr) occur in several B-cell neoplasms and impact disease progression and overall survival. We used whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) to analyze and compare MYCr in different B-cell neoplasms. The MYCr features of cases with plasma cell myeloma (PCM) (n = 88) showed distinct characteristics compared to cases with mature B-cell lymphomas (n = 62, including Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and high grade lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL)): they were more complex and showed a wider variety of translocation partners and breakpoints. Additionally, unlike B-cell lymphomas, they showed no evidence of activation-induced deaminase (AID) involvement in the formation of MYCr with immunoglobolin heavy chain (IGH), indicating a different mechanism of origin. The different MYCr characteristics resulted in poor MYCr detection rates by fluorescence in situ hybridization of only 50% in PCM, compared to 94% in lymphoma.

14.
Blood Adv ; 5(17): 3254-3265, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34448812

RESUMO

Splicing factor (SF) mutations are important contributors to the pathogenesis of hematological malignancies; however, their relevance in risk classification of acute myeloid leukemia (AML) warrants further investigation. To gain more insight into the characteristics of patients with AML carrying SF mutations, we studied their association with clinical features, cytogenetic and molecular abnormalities, and clinical outcome in a large cohort of 1447 patients with AML and high-risk myelodysplastic syndrome. SF mutations were identified in 22% of patients and were associated with multiple unfavorable clinical features, such as older age, antecedent myeloid disorders, and adverse risk factors (mutations in RUNX1 and ASXL1). Furthermore, they had significantly shorter event-free and overall survival. Notably, in European LeukemiaNet (ELN) 2017 favorable- and intermediate-risk groups, SF3B1 mutations were indicative of relatively poor prognosis. In addition, patients carrying concomitant SF mutations and RUNX1 mutations had a particularly adverse prognosis. In patients without any of the 4 most common SF mutations, RUNX1 mutations were associated with relatively good outcome, which was comparable to that of intermediate-risk patients. In this study, we propose that SF mutations be considered for incorporation into prognostic classification systems. First, SF3B1 mutations could be considered an intermediate prognostic factor when co-occurring with favorable risk features and as an adverse prognostic factor for patients currently categorized as having intermediate risk, according to the ELN 2017 classification. Second, the prognostic value of the current adverse factor RUNX1 mutations seems to be limited to its co-occurrence with SF mutations.


Assuntos
Leucemia Mieloide Aguda , Idoso , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Fatores de Processamento de RNA/genética , Fatores de Risco
15.
Cancers (Basel) ; 13(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34439083

RESUMO

Despite substantial progress achieved in unraveling the genetics of AML in the past decade, its treatment outcome has not substantially improved. Therefore, it is important to better understand how genetic mutations translate to phenotypic features of AML cells to further improve response predictions and to find innovative therapeutic approaches. In this respect, aberrant splicing is a crucial contributor to the pathogenesis of hematological malignancies. Thus far, altered splicing is well characterized in relation to splicing factor mutations in AML. However, splicing profiles associated with mutations in other genes remain largely unexplored. In this study, we explored differential splicing profiles associated with two of the most common aberrations in AML: FLT3-ITD and NPM1 mutations. Using RNA-sequencing data of a total of 382 primary AML samples, we found that the co-occurrence of FLT3-ITD and mutated NPM1 is associated with differential splicing of FAB-type specific gene sets. Despite the FAB-type specificity of particular gene sets, the primary functions perturbed by differential splicing in all three FAB types include cell cycle control and DNA damage response. Interestingly, we observed functional divergence between alternatively spliced and differentially expressed genes in FLT3-ITD+/NPM1+ samples in all analyzed FAB types, with differential expression affecting genes involved in hematopoietic differentiation. Altogether, these observations indicate that concomitant FLT3-ITD and mutated NPM1 are associated with the maturation state-specific differential splicing of genes with potential oncogenic relevance.

18.
Cancer Discov ; 11(11): 2846-2867, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34103329

RESUMO

Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of BCL11B, a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose BCL11B to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to BCL11B. Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed BCL11B allele and association of BCL11B with activated hematopoietic progenitor cell cis-regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic BCL11B expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. SIGNIFICANCE: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of BCL11B driven by diverse structural alterations, including de novo superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries.This article is highlighted in the In This Issue feature, p. 2659.

19.
Oncogene ; 40(25): 4271-4280, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34103684

RESUMO

Artificial intelligence (AI) is about to make itself indispensable in the health care sector. Examples of successful applications or promising approaches range from the application of pattern recognition software to pre-process and analyze digital medical images, to deep learning algorithms for subtype or disease classification, and digital twin technology and in silico clinical trials. Moreover, machine-learning techniques are used to identify patterns and anomalies in electronic health records and to perform ad-hoc evaluations of gathered data from wearable health tracking devices for deep longitudinal phenotyping. In the last years, substantial progress has been made in automated image classification, reaching even superhuman level in some instances. Despite the increasing awareness of the importance of the genetic context, the diagnosis in hematology is still mainly based on the evaluation of the phenotype. Either by the analysis of microscopic images of cells in cytomorphology or by the analysis of cell populations in bidimensional plots obtained by flow cytometry. Here, AI algorithms not only spot details that might escape the human eye, but might also identify entirely new ways of interpreting these images. With the introduction of high-throughput next-generation sequencing in molecular genetics, the amount of available information is increasing exponentially, priming the field for the application of machine learning approaches. The goal of all the approaches is to allow personalized and informed interventions, to enhance treatment success, to improve the timeliness and accuracy of diagnoses, and to minimize technically induced misclassifications. The potential of AI-based applications is virtually endless but where do we stand in hematology and how far can we go?

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