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Haematologica Apr 2023
Topics: Humans; Leukemia, Myeloid, Acute
PubMed: 36005564
DOI: 10.3324/haematol.2022.281742 -
Best Practice & Research. Clinical... Sep 2020Artificial intelligence, and more narrowly machine-learning, is beginning to expand humanity's capacity to analyze increasingly large and complex datasets. Advances in... (Review)
Review
Artificial intelligence, and more narrowly machine-learning, is beginning to expand humanity's capacity to analyze increasingly large and complex datasets. Advances in computer hardware and software have led to breakthroughs in multiple sectors of our society, including a burgeoning role in medical research and clinical practice. As the volume of medical data grows at an apparently exponential rate, particularly since the human genome project laid the foundation for modern genetic inquiry, informatics tools like machine learning are becoming crucial in analyzing these data to provide meaningful tools for diagnostic, prognostic, and therapeutic purposes. Within medicine, hematologic diseases can be particularly challenging to understand and treat given the increasingly complex and intercalated genetic, epigenetic, immunologic, and regulatory pathways that must be understood to optimize patient outcomes. In acute myeloid leukemia (AML), new developments in machine learning algorithms have enabled a deeper understanding of disease biology and the development of better prognostic and predictive tools. Ongoing work in the field brings these developments incrementally closer to clinical implementation.
Topics: Genome, Human; Human Genome Project; Humans; Leukemia, Myeloid, Acute; Machine Learning
PubMed: 33038981
DOI: 10.1016/j.beha.2020.101192 -
British Journal of Haematology Jan 2020Comprehensive cataloguing of the acute myeloid leukaemia (AML) genome has revealed a high frequency of mutations and deletions in epigenetic factors that are frequently... (Review)
Review
Comprehensive cataloguing of the acute myeloid leukaemia (AML) genome has revealed a high frequency of mutations and deletions in epigenetic factors that are frequently linked to treatment resistance and poor patient outcome. In this review, we discuss how the epigenetic mechanisms that underpin normal haematopoiesis are subverted in AML, and in particular how these processes are altered in childhood and adolescent leukaemias. We also provide a brief summary of the burgeoning field of epigenetic-based therapies, and how AML treatment might be improved through provision of better conceptual frameworks for understanding the pleiotropic molecular effects of epigenetic disruption.
Topics: Adolescent; Child; Drug Resistance, Neoplasm; Epigenesis, Genetic; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Mutation
PubMed: 31804725
DOI: 10.1111/bjh.16361 -
Bone Marrow Transplantation Jan 2022Imagine you and your colleagues have done 1000 transplants in persons with acute myeloid leukaemia (AML) in 1st remission. 5 percent of the 20 percent of recipients...
Imagine you and your colleagues have done 1000 transplants in persons with acute myeloid leukaemia (AML) in 1st remission. 5 percent of the 20 percent of recipients relapsing posttransplant have an isolated central nervous system relapse. You are curious and want to know whether there is anything special about this 5 percent, specifically whether this risk corelates with any pretransplant clinical and laboratory co-variates. You have extensive clinical data and some typical laboratory data on all 1000 but you suspect the culprit is mutation topography. What to do? Fortunately you have bio-banked DNA from the 1000. If resources and monies are not limiting you can do targeted or next generation sequencing on all 1000 DNA samples and off you go. However, most of us lack unlimited resources and monies. How can you sensibly and efficiently tackle this research problem? The answer is a case-cohort design study. In the typescript which follows Profs. Cai and Kim explain how to accomplish this. If you follow their advice you may need only to analyze samples from < 300 recipients rather than 1000 to test your hypothesis. They explain how to design such a study and provide references to estimate sample size.Sadly, their typescript will not tell you how to get funding for the study, whish poor devil who will have to write the protocol, worse, who will shepherd it though endless committees for approval and the like. Help on these issues is outside the scope of our statistics series. In this context we suggest advice from Woody Allen's article in the New Yorker: The Kugelmass Episode (April 24, 1977). When Prof. Kugelmass (English, City College) tells his analyst Dr. Mandel he has fallen in love with Emma Bovary who died of arsenic poisoning near Rouen, France 120 years earlier the analyst says: After all, I'm an analyst, not a magician. Kugelmass' reply: Then perhaps what I need is a magician and is off to Coney Island to find one. Good luck, the magician may still be there! (Note: This typescript is R-rated. It contains an equation.)Robert Peter Gale, Imperial College London, and Mei-Jie Zhang, Medical College of Wisconsin and CIBMTR.
Topics: Cohort Studies; France; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Neoplasm Recurrence, Local
PubMed: 34400795
DOI: 10.1038/s41409-021-01433-4 -
British Journal of Haematology Jan 2020Acute myeloid leukaemia (AML) is a heterogeneous disease in which prognosis is determined by cytogenetic and molecular aberrations as well as patient-related factors,... (Review)
Review
Acute myeloid leukaemia (AML) is a heterogeneous disease in which prognosis is determined by cytogenetic and molecular aberrations as well as patient-related factors, including age, prior haematologic disorders, and comorbidities. Despite the diverse disease biology, the standard of care for remission induction therapy has changed very little since its inception in 1973. Next generation sequencing has helped to increase our knowledge of the disease pathogenesis, allowing us to develop targeted and possibly more effective treatment options. Seven new agents have been approved for the treatment of AML since 2017, all of which are directed toward a specific molecular subtype or patient population. With the advent of these therapies, a more optimal, patient-specific approach rather than the historical 'one-size fits all' model can be utilised. This review will discuss the role of these novel therapies in the remission induction setting.
Topics: Disease-Free Survival; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myeloid, Acute; Precision Medicine; Remission Induction
PubMed: 31828798
DOI: 10.1111/bjh.16353 -
The Oncologist Jul 2018This unique narrative offers a moving story about the power of pathology and the joys of the pathologist.
This unique narrative offers a moving story about the power of pathology and the joys of the pathologist.
Topics: Humans; Leukemia, Myeloid, Acute; Male
PubMed: 29487222
DOI: 10.1634/theoncologist.2017-0652 -
British Journal of Haematology Nov 2017Acute myeloid leukaemia (AML) is a biologically complex, molecularly and clinically heterogeneous disease. Despite major advances in understanding the genetic landscape... (Review)
Review
Acute myeloid leukaemia (AML) is a biologically complex, molecularly and clinically heterogeneous disease. Despite major advances in understanding the genetic landscape of AML and its impact on the pathophysiology and biology of the disease, standard treatment options have not significantly changed during the past three decades. AML is characterized by multiple somatically acquired mutations that affect genes of different functional categories. Mutations in genes encoding epigenetic modifiers, such as DNMT3A, ASXL1, TET2, IDH1, and IDH2, are commonly acquired early and are present in the founding clone. By contrast, mutations involving NPM1 or signalling molecules (e.g., FLT3, RAS gene family) are typically secondary events that occur later during leukaemogenesis. This review aims to provide an overview of advances in new prognostic markers, including targetable mutations that will probably guide the development and use of novel molecularly targeted therapies.
Topics: Carcinogenesis; Epigenesis, Genetic; Genes, ras; Genomics; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Mutation; Mutation Accumulation; Nuclear Proteins; Nucleophosmin; Prognosis; fms-Like Tyrosine Kinase 3
PubMed: 28653397
DOI: 10.1111/bjh.14823 -
Blood Aug 2022
Topics: Humans; Leukemia, Myeloid, Acute; Neoplasm Recurrence, Local; Neoplasm, Residual; Prospective Studies
PubMed: 35925646
DOI: 10.1182/blood.2022017138 -
Leukemia Dec 2021Children with Down syndrome are at an elevated risk of leukemia, especially myeloid leukemia (ML-DS). This malignancy is frequently preceded by transient abnormal... (Review)
Review
Children with Down syndrome are at an elevated risk of leukemia, especially myeloid leukemia (ML-DS). This malignancy is frequently preceded by transient abnormal myelopoiesis (TAM), which is self-limited expansion of fetal liver-derived megakaryocyte progenitors. An array of international studies has led to consensus in treating ML-DS with reduced-intensity chemotherapy, leading to excellent outcomes. In addition, studies performed in the past 20 years have revealed many of the genetic and epigenetic features of the tumors, including GATA1 mutations that are arguably associated with all cases of both TAM and ML-DS. Despite these advances in understanding the clinical and biological aspects of ML-DS, little is known about the mechanisms of relapse. Upon relapse, patients face a poor outcome, and there is no consensus on treatment. Future studies need to be focused on this challenging aspect of leukemia in children with DS.
Topics: Down Syndrome; GATA1 Transcription Factor; Humans; Leukemia, Myeloid; Mutation
PubMed: 34518645
DOI: 10.1038/s41375-021-01414-y -
Cells Nov 2019Acute myeloid leukaemia (AML) is a group of malignant diseases of the haematopoietic system. AML occurs as the result of mutations in haematopoietic stem/progenitor... (Review)
Review
Acute myeloid leukaemia (AML) is a group of malignant diseases of the haematopoietic system. AML occurs as the result of mutations in haematopoietic stem/progenitor cells, which upregulate Wnt signalling through a variety of mechanisms. Other mechanisms of Wnt activation in AML have been described such as Wnt antagonist inactivation through promoter methylation. Wnt signalling is necessary for the maintenance of leukaemic stem cells. Several molecules involved in or modulating Wnt signalling have a prognostic value in AML. These include: β-catenin, LEF-1, phosphorylated-GSK3β, PSMD2, PPARD, XPNPEP, sFRP2, RUNX1, AXIN2, PCDH17, CXXC5, LLGL1 and PTK7. Targeting Wnt signalling for tumour eradication is an approach that is being explored in haematological and solid tumours. A number of preclinical studies confirms its feasibility, albeit, so far no reliable clinical trial data are available to prove its utility and efficacy.
Topics: Animals; Biomarkers; Disease Management; Disease Susceptibility; Humans; Leukemia, Myeloid, Acute; Molecular Targeted Therapy; Prognosis; Wnt Signaling Pathway
PubMed: 31703382
DOI: 10.3390/cells8111403