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A report is made on the 2-day, 20th annual conference held by the Association for Comparative Clinical Pathology (ACCP). This included two workshops that were given by veterans of the toxicologic clinical pathology community including on haematotoxicity and on the interpretation of clinical pathology data of pre-clinical toxicology studies in support of pharmaceuticals in development. Also, included was a series of scientific and technology presentations on the latest developments in toxicologic and veterinary clinical pathology. Key developments presented on were the invention of a rapid and simple diagnostic test for lymphoma, the Atellica- automated chemistry analyser for laboratory animals, and development of an advanced flow cytometric technique for bone marrow. Distinguished invited speakers gave lectures on treatment of acute myeloid leukaemia and on comparison of surgical and medical treatments for diabetic nephropathy. Technology vendors described in 5-minute presentations their latest products. And poster presenters also gave 5-minute presentations describing their work. The report is illustrated by photographs taken during the conference, capturing the presenters of talks and featuring new student presenters. This is followed by abstracts of most of the scientific presentations that were given. A few abstracts that had been submitted the previous year are also included, as there had been no report on this ACCP meeting of 2018. There were lighter moments, including a wine reception, conversations at the conference centre pub, a great conference dinner featuring the best of English cuisine, and trips to the conference center spa and recreation facilities.

Summary Acute myeloid leukaemia (AML) is the commonest indication for allogeneic stem cell transplantation (allo‐SCT) worldwide. The accumulated experience of allografting in AML over the last four decades has provided critical insights into both the contribution of the conditioning regimen and the graft‐versus‐leukaemia effect to the curative potential of the most common form of immunotherapy utilised in standard clinical practice. Coupled with advances in donor availability and transplant technologies, this has resulted in allo‐SCT becoming an important treatment modality for the majority of adults with high‐risk AML. At the same time, advances in genomic classification, coupled with progress in the accurate quantification of measurable residual disease, have increased the precision with which allo‐mandatory patients can be identified, whilst simultaneously permitting accurate identification of those patients who can be spared the toxicity of an allograft. Despite this progress, disease recurrence still remains a major cause of transplant failure and AML has served as a paradigm for the development of strategies to reduce the risk of relapse ‒ notably the novel concept of post‐transplant maintenance, utilising pharmacological or cellular therapies.

Introduction Acute Myeloid Leukemia (AML) is a rare disease with a high incidence in the elderly. Our aim is to report the incidence of elderly patients with AML at a haematological tertiary referral centre. Method We have collected data from 2007 till 2017 from the main Malaysian haematological tertiary referral centre involving all the 1225 AML patients. Out of those, 182 elderly patients aged 65 and above with AML were examined. The patients had at least 2 years follow-up. Results The elderly represented 14.9% of the 1225 patients who presented with acute myeloid leukemia to the centre. There were 182 elderly patients with AML which were subdivided to the unspecified AML of 154 patients, 1 patient with M1, 4 patients with M2, 6 patients with M3, 5 patients with M4, 8 patients with M5, 2 patients with M6 and 2 patients with M7. There were 109 males and 73 females. The majority of the patients were Chinese (n=85) representing 46.7% of the patients, followed by the Malay (n=76), Indian (n=19) and lastly others (n=2). The average age at diagnosis was 71 years. There were 136 deaths and the mortality rate was 74.7%. The average age of the patients who had passed away (n=136) was 71.4 years. The average age of the patients who are still living (n=42) was 76.5 years. Conclusion The incidence of elderly AML is increasing. The younger patients with AML are known to have better survival rate in comparison to the elderly. More research is needed to explore the reasons for the higher mortality in the elderly and the ways to improve the outcome of this elderly population as our lifespan increases and Malaysia heads towards an ageing nation.

Acute myeloid leukaemia (AML) is treatable and potentially curable disease. Significant morbidity is related to the prolonged, severe neutropenia resulting from the disease as well as the intensive chemotherapy. The administration of granulocyte - colony stimulating factor (G-CSF) is recommended to reduce the neutropenic period. But the current information and guidelines are insufficient about the most appropriate time to start G-CSF and the optimum duration of treatment after chemotherapy in consolidation phase. This study explores better timing to start G-CSF after completion of chemotherapy in consolidation phase of AML patient. This prospective study was conducted in the department of Haematology, Bangabandhu Sheikh Mujib Medical University among AML patients, who received consolidation chemotherapy (high dose cytarabine). Samples were grouped into two arms. Arm-A (Absolute Neutrophil Count >1000/cmm) received prophylactic G-CSF and Arm-B (Absolute Neutrophil Count

Although infants (age

Purpose: Previous studies have shown that patients with NPM1+/FLT3-ITD+ acute myeloid leukaemia (AML) have a poor prognosis, especially those with a high FLT3-ITD allelic ratio. However, no studies have confirmed a clear prognostic impact of DNMT3A on NPM1+/FLT3-ITD+ AML patients. Methods: Our study included a total of 165 patients with newly diagnosed non-acute promyelocytic leukaemia (non-APL) AML at The First Hospital of Lanzhou University between January 2018 and June 2021. Further bioinformatics analysis was performed using the Gene Expression Omnibus (GEO) database. Results: We retrospectively studied 165 patients newly diagnosed non-APL AML and identified 11 (6.7%) patients with NPM1/FLT3-ITD/DNMT3A triple mutations. The patients with triple-mutated AML had advanced age, higher white blood cell (WBC) counts, de novo AML, normal karyotypes, and poor survival, and all were in the M4/M5 French-American-British (FAB) category. Notably, half of the patients with triple-mutated AML had mature monocyte characteristics that were difficult to distinguish from chronic myelomonocytic leukaemia (CMML). We validated the prognosis of patients with triple-mutated AML by further bioinformatics analysis and found that the GNG4 gene, one of the hub genes, was related to triple-mutated AML patients' survival. Conclusion: Our data demonstrate that DNMT3A gene mutation has adverse prognostic significance in NPM1+FLT3-ITD+comutation AML patients.

In this paper, we propose a general acute myeloid leukaemia (AML) model and introduce an immune response and time delays into this model to investigate their effects on the dynamics. Based on the existence, stability and local bifurcation of three types of equilibria, we show that the immune response is a best strategy for the control of the AML on the condition that the rates of proliferation and differentiation of the hematopoietic lineage exceed a threshold. In particular, a powerful immune response leads to bi-stability of the steady states, and a stronger response wipes out all the leukaemia cells. In addition, we further reveal that the time delays existing in the feedback regulation and immune response process induce a series of oscillations around the steady state, which shows that the leukaemia cells can hardly be eliminated. Our work in this paper aims to investigate the complex dynamics of this AML model with the immune response and time delays on the basis of mathematical models and numerical simulations, which may provide a theoretical guidance for the treatments of the AML.

Acute myeloid leukaemia (AML) is a highly heterogeneous disorder and is characterised by the proliferation of poorly differentiated myeloid cells due to underlying mutation, eventually causing bone marrow failure. Accounting for approximately 25% of cases, AML is the most frequent form of leukaemia in the world yet has the lowest survival rate among all leukaemias. Patients with haematological malignancy are more susceptible to severe acute respiratory syndrome coronavirus-2 infection and further development of severe infection, including pneumonia with poor blood oxygenation. The management of such patients is more challenging than expected. Successful management of one such case is discussed in this report. COVID-19 infection can cause great harm to a patient with underlying leukaemia and increase the mortality risk. It has a major impact on the physical and psychological health of the patient. Therefore, these patients need special care and attention. The authors emphasise the importance of supportive management (oxygen with bilevel positive airway pressure, prone positioning, and physiotherapy) to prevent complications.

Acute myeloid leukaemia (AML) is a heterogeneous disease with a difficult to predict prognosis. Ferroptosis, an iron‐induced programmed cell death, is a promising target for cancer therapy. Nevertheless, not much is known about the relationship between ferroptosis‐related genes and AML prognosis. Herein, we retrieved RNA profile and corresponding clinical data of AML patients from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Univariate Cox analysis was employed to identify ferroptosis‐related genes significantly associated with AML prognosis. Next, the least absolute shrinkage and selection operator (LASSO) regression was employed to establish a prognostic ferroptosis‐related gene profile. 12 ferroptosis‐related genes were screened to generate a prognostic model, which stratified patients into a low‐ (LR) or high‐risk (HR) group. Using Kaplan‐Meier analysis, we demonstrated that the LR patients exhibited better prognosis than HR patients. Moreover, receiver operating characteristic (ROC) curve analysis confirmed that the prognostic model showed good predictability. Functional enrichment analysis indicated that the infiltration of regulatory T cells (Treg) differed vastly between the LR and HR groups. Our prognostic model can offer guidance into the accurate prediction of AML prognosis and selection of personalized therapy in clinical practice.

The revised 4th edition of the World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues is based on clinical, morphological, immunophenotypic and genetic features. A case of acute myeloid leukaemia with myelodysplasia-related changes (AML-MRC) in which there was a mixed phenotype of blasts (B-cell/myeloid) has been previously described. We hereby also report an acute leukaemia case that had conflicting morphological and immunophenotypic findings, regarding the revised WHO classification. Patient was a 77 year-old female investigating anaemia for the past few months. Complete blood count (CBC) showed macrocytic anaemia (haemoglobin: 8.3 g/l; MCV: 102 fl) and thrombocytopenia (116 x 109/l), with a normal leukocyte count. Bone marrow assessment was performed when the patient CBC showed circulating blasts. Bone marrow flow cytometry immunophenotyping (FCI) revealed two blast cell populations: one population (about 26% of events) had an immature B-cell phenotype with expression of cytCD22, cytCD79a, CD19, CD22, CD34, CD45(dim), CD58, CD81(dim), CD200, HLA-DR, nuTdT, and an aberrant CD13 and CD123 coexpression; while the other population (about 23% of events) had an immature myeloid phenotype with expression of CD4(dim), CD13, CD25, CD33, CD34, CD58, CD81, CD117, CD123, CD200 and HLA-DR. Neither population expressed cytCD3, cytMPO, CD2, CD3, CD7, CD10, CD11b, CD11c, CD18, CD20, CD36, CD56, CD64 or CD138. If classified isolated, the myeloid population would correspond to an acute myeloid leukaemia (AML) with minimal differentiation and the B-cell population, to a B-lymphoblastic leukaemia/lymphoma (B-ALL). In addition to the FCI data, bone marrow morphological evaluation revealed hypercellularity with severe multilineage dysplasia and two types of blasts with different sizes and morphology, blast cells accounted for 58% of cellularity. Cytogenetic studies showed a karyotype with 45,Xc, t(3;21)(q26;q22). FCI diagnosis considering the EGIL scoring system would be of a biphenotypic acute leukaemia, however to fit into the WHO classification of a mixed-phenotype acute leukaemia (MPAL), the myeloid population would need to express MPO or two monocytic markers, which was not what we observed. Nevertheless, bone marrow morphological findings were suggestive of AML-MRC. There are overlapping features between MPAL and genetically defined AML-MRC. A case series of MPAL identified complex karyotype as the most common genetic abnormality and the WHO classification specifies that AML with complex karyotypes should be classified as AML-MRC. It is recommended that karyotype findings should not be the sole deciding factor to distinguish MPAL from AML-MRC and other factors such as clinical history, morphological findings, immunophenotype and presence of somatic mutations associated with other neoplasms should be considered when leukemic blasts meet criteria for MPAL and the karyotype analysis has myelodysplasia-related abnormalities. Since we did not have access to karyotype results at diagnosis, a descriptive report of FCI and morphological findings was provided. In conclusion, FCI diagnosis of MPAL in the presence of myelodysplasia-related morphological alterations remains a challenge and should take into consideration other laboratory and clinical data.

Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation. Standard therapy for paediatric AML has remained largely unchanged for over four decades and, combined with inadequate understanding of the biology of paediatric AML, has limited the progress of targeted therapies in this cohort. In recent years, the search for novel targets for the treatment of paediatric AML has accelerated in parallel with advanced genomic technologies which explore the mutational and transcriptional landscape of this disease. Exploiting the large combinatorial space of existing drugs provides an untapped resource for the identification of potential combination therapies for the treatment of paediatric AML. We have previously designed a multiplex screening strategy known as Multiplex Screening for Interacting Compounds in AML (MuSICAL), using an algorithm designed in-house, we screened all pairings of 384 FDA-approved compounds in less than 4000 wells by pooling drugs into 10 compounds per well. This approach maximised the probability of identifying new compound combinations with therapeutic potential while minimising cost, replication and redundancy. This screening strategy identified the triple combination of glimepiride, a sulfonylurea, pancuronium dibromide, a neuromuscular blocking agent, and vinblastine sulfate, a vinca alkaloid, as a potential therapy for paediatric AML. We envision that this approach can be used for a variety of disease-relevant screens allowing the efficient repurposing of drugs that can be rapidly moved into the clinic.

Simple Summary The Tribbles Research and Innovation Network (TRAIN) was developed in the context of the medical need to understand the contribution that Tribbles (TRIB) proteins make in regulating processes governing the physiological functioning of macrophages and other immune cells, adipocytes and prostate epithelial cells in immuno-metabolic disease (such as obesity) and several cancers. To summarize, TRAIN provided a cohort of PhD students with a unique opportunity to undertake multidisciplinary research aimed at uncovering the cell-specific mechanisms by which TRIBs exert control over immuno-metabolism and impact on prostate cancer progression. The associated training programme was enhanced by contributions from the TRIB community. This review highlights the science that motivated the establishment of TRAIN, including the discovery of how the TRIB1 protein enables the marking of the transcription factor C/EBPα for degradation, and regulatory mechanisms underlying cell-specific TRIB expression. It briefly reflects on the type of TRAIN-associated tools developed for future TRIB research. Abstract This commentary integrates historical and modern findings that underpin our understanding of the cell-specific functions of the Tribbles (TRIB) proteins that bear on tumorigenesis. We touch on the initial discovery of roles played by mammalian TRIB proteins in a diverse range of cell-types and pathologies, for example, TRIB1 in regulatory T-cells, TRIB2 in acute myeloid leukaemia and TRIB3 in gliomas; the origins and diversity of TRIB1 transcripts; microRNA-mediated (miRNA) regulation of TRIB1 transcript decay and translation; the substantial conformational changes that ensue on binding of TRIB1 to the transcription factor C/EBPα; and the unique pocket formed by TRIB1 to sequester its C-terminal motif bearing a binding site for the E3 ubiquitin ligase COP1. Unashamedly, the narrative is relayed through the perspective of the Tribbles Research and Innovation Network, and its establishment, progress and future ambitions: the growth of TRIB and COP1 research to hasten discovery of their cell-specific contributions to health and obesity-related cancers.

SERIES EDITORS- NOTE 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.

This study proposes to evaluate the performance of Acute Myeloid Leukaemia (AML) blast cell detection models in microscopic examination images for faster diagnosis and disease monitoring. One of the popular deep learning algorithms such as You Only Look Once (YOLO) developed for object detection is the successful state-of-the-art algorithms in real-time object detection systems. We employ four versions of the YOLO algorithm: YOLOv3, YOLOv3-Tiny, YOLOv2 and YOLOv2-Tiny for detection of 15-class of AML blood cells in examination images. We also acquired the publicly available dataset from The Cancer Imaging Archive (TCIA), which consists of 18,365 expert-labelled single-cell images. Data augmentation techniques are additionally applied to enhance and balance the training images in the dataset. The overall results indicated that four types of YOLO approach have outstanding performances of more than 92% in precision and sensitivity. In comparison, YOLOv3 has more reliable performance than the other three approaches. Consistently, the AUC values for the four YOLO models are 0.969 (YOLOv3), 0.967 (YOLOv3-Tiny), 0.963 (YOLOv2), and 0.948 (YOLOv2-Tiny). Furthermore, we compare the best model’s performance between approaches that use the entire training dataset without using data augmentation techniques and image division with data augmentation techniques. Remarkably, by using 33.51 percent of the training data in model training, the prediction outcomes from the model that used image partitioning with data augmentation were similar to those obtained using the complete training dataset. This work potentially provides a beneficial digital rapid tool in the screening and evaluation of numerous haematological disorders.

Epstein –Barr virus related post-transplant lymphoproliferative disorder is a fatal and life-threatening complication because of immunocompromised state.1 Haemophagocytic lymphohistiocytosis is a sign of poor outcome in EBV associated PTLD after allogeneic stem cell transplantation. It is particularly common when in vivo T cell depletion strategies have been applied.2 In both situations, post-transplant lymphoproliferative disorder and Haemophagocytic lymphohistiocytosis, infection with EBV is the key mechanism. Here I present a case of 29 years old female with acute myeloid leukaemia after second allogeneic stem cell transplant, who developed PTLD complicated with Haemophagocytic lymphohistiocytosis secondary to Epstein – Barr virus (EBV) infection. Patient was treated with chemo immunotherapy and responded but ultimately died after 100 days of transplant. The association of HLH and EBV related PTLD is rare and data on outcome of these patients are limited with very high mortality.

Background Recognition of molecular abnormalities in acute myeloid leukaemia (AML) has improved our understanding of its biology. NPM1 and FLT3-ITD mutations are recurrent in AML and clinically significant. NPM1 mutations are associated with a favourable prognosis, while FLT3-ITD mutations are an independent poor prognostic factor in AML. Objective This study described the prevalence and molecular characteristics of the NPM1 and FLT3-ITD mutations in a newly diagnosed AML patient cohort in central South Africa. Methods The study included 40 de novo AML patients. An NPM1 and FLT3-ITD multiplex polymerase chain reaction assay was optimised to screen patients for the respective mutations and were confirmed using Sanger sequencing. The prevalence of the NPM1 and FLT3-ITD mutations were determined, and mutation-specific characteristics were described in relation to patients' demographic information and AML classifications. Results The patients' median age was 38.5 years, with 77.5% (n = 31) of patients being self-proclaimed Black Africans. AML with recurrent genetic abnormalities was most prevalent (57.5%; n = 23), of which acute promyelocytic leukaemia (APL) was most common (40.0%; n = 16). None of the patients had the NPM1 mutation. FLT3-ITD was present in 37.5% (6/16) of APL patients and in one (20.0%) of five AML patients with a t(8;21) translocation. Most patients had an FLT3-ITD allele ratio of ≥ 50% and ITD lengths of > 39 bp. Conclusion FLT3-ITD mutations were mainly found in APL cases at a similar prevalence as reported in the literature. High FLT3-ITD allele ratios and long ITD lengths predominated. No NPM1 mutations were detected.

Azacitidine (AZA) is important in the management of patients with acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. Romidepsin (ROM) is a histone deacetylase inhibitor which synergises with AZA in vitro. The ROMAZA trial established the maximum tolerated dose (MTD) of combined ROM/AZA therapy in patients with AML, as ROM 12 mg/m2 on Days 8 and 15, with AZA 75 mg/m2 administered for 7/28 day cycle. Nine of the 38 (23·7%) patients treated at the MTD were classified as responders by Cycle 6 (best response: complete remission [CR]/incomplete CR n = 7, partial response n = 2). Correlative next-generation sequencing studies demonstrated important insights into therapy resistance.

BackgroundAcute myeloid leukaemia (AML) is a heterogeneous disease where outcome is substantially influenced by age. Over the last 30-40 years, significant improvements have been made in survival for younger patients (those under 60). However, with the median age of the disease at diagnosis at 65 years, outcome in older patients has improved much less. Additionally, many elderly patients are not considered suitable for intensive chemotherapy and the current standard treatment is considered unsatisfactory. MethodsLI1 will evaluate several relevant therapeutic questions in AML patients over 60 years of age for whom intensive chemotherapy is not considered suitable. Patients are invited to enter a randomized comparison of standard therapy (LD Ara-C) versus a novel treatment. A number of different treatment options are available at any one time, but there is no comparison between novel agents. If, at initial review, a novel agent is deemed unlikely to demonstrate the required improvement, it may be removed from the protocol and replaced with another novel agent, via protocol amendment. Agents are initially entered into a phase II comparison against standard of care - where an agent is considered promising at interim review (based on remission rates), the randomisation may be extended to a fully powered phase III comparison based on survival. Agents which may prolong survival or improve remission rates will also be required to demonstrate equivalence or better of quality of life in patients – therefore, quality of life assessments are undertaken throughout, in each arm. DiscussionEven when less intensive treatment options are delivered, the outcomes are not satisfactory. The NCRI AML working group has a strong network, required for delivery of this trial program. The UK network is augmented by international collaborative groups, most notably from New Zealand and Denmark. The use of the Pick-a-Winner design improves efficiency and speed of review of the available novel agents with the aim of benefitting the increasing number of patients in this age group.Trial registration: ISCRTN40571019, EUDRACT2011-000479-19 (12th May 2011)

Changes in acute myeloid leukaemia (AML) treatment may affect requirement for admission to and treatments in intensive care units (ICUs). We evaluated trends in ICU admission, use of organ support, and 1-year mortality in Danish AML patients. Of 1417 AML patients diagnosed 2005-2016, 28.0% (n=397) were ICU-admitted within 3 years, with no major change in admission rate during the 12-year period. Use of mechanical ventilation and dialysis decreased (66.7% to 40.6%), while use of non-invasive ventilation increased (20.0% to 50.0%). Concurrently, 1-year mortality declined among all patients (36.0% in 2005 to 28.8% in 2016) and ICU-admitted patients (80.0% to 65.6%).

Acute Myeloid Leukaemia (AML) continues to have a poor prognosis, especially in the elderly. One reason for this is that many treatment regimens are not well tolerated by elderly patients. Much current focus is on the development of therapies that can target specific vulnerabilities of AML while having fewer toxic side effects. However, despite much recent progress in developing better drugs, many patients with AML still die within a year of diagnosis, partly due to the fact that it is difficult to identify therapeutic targets that are effective across multiple AML subtypes. One common factor across AML subtypes is the presence of a block in differentiation. Thus screening for compounds that can overcome this block in genetically diverse AML models should allow for the identification of agents that are not dependent on a specific mutation for their efficacy. Here, we used a phenotypic screen to identify novel compounds that stimulate differentiation in several AML cell lines. Lead compounds were shown to decrease tumour burden and to increase survival in vivo. Using multiple complementary target deconvolution approaches, these compounds were revealed to be anti-mitotic tubulin disruptors that cause differentiation by inducing a G2-M mitotic arrest. Together, these results reveal a novel function for tubulin disruptors in causing differentiation of AML cells.

Acute myeloid leukaemia (AML) is a haematopoietic malignancy with a dismal outcome. Consequently, risk stratification based on more effective prognostic biomarkers is crucial to make accurate therapy decisions. T cell receptor gamma alternative reading frame protein (TARP) has been reported in prostate and breast cancers, but its correlation with AML remains unclear.Differential expression of TARP mRNA in different AML subtypes was analysed using the UALCAN online platform. Its relationship with baseline clinical attributes, survival and efficacy were analysed based on three GSE1159, GSE425 and GSE6891 microarray datasets downloaded from Gene Expression Omnibus (GEO) and Oncomine databases. Quantitative real-time PCR was performed to determine mRNA levels of TARP in bone marrow mononuclear cells (BMMCs) isolated from AML patients.TARP was significantly overexpressed in AML patients. In AML, relatively low TARP expression was associated with theOur findings suggest that TARP might be a potential prognostic marker of AML and serve as a promising immunotherapeutic target.

In the present study, we quantify the progress in overall survival (OS) during the period 2000-2016 among Danish patients with acute myeloid leukaemia (AML). This population-based study, including 3820 adult patients with AML, demonstrates a significantly improved OS over time with the 2-year age-standardised OS increasing from 22% in 2002 to 31% in 2016. The improvement in OS was exclusively seen in patients with AML aged ≥50 years, with absolute improvements in 2-year OS from 2002 to 2016 of ≥10% among patients aged 50-75 years and a small absolute increase in those aged >75 years.

While the understanding of the genomic aberrations that underpin chronic and acute myeloid leukaemia (CML and AML) has allowed the development of therapies for these diseases, limitations remain. These become apparent when looking at the frequency of treatment resistance leading to disease relapse in leukaemia patients. Key questions regarding the fundamental biology of the leukaemic cells, such as their metabolic dependencies, are still unresolved. Even though a majority of leukaemic cells are killed during initial treatment, persistent leukaemic stem cells (LSCs) and therapy-resistant cells are still not eradicated with current treatments, due to various mechanisms that may contribute to therapy resistance, including cellular metabolic adaptations. In fact, recent studies have shown that LSCs and treatment-resistant cells are dependent on mitochondrial metabolism, hence rendering them sensitive to inhibition of mitochondrial oxidative phosphorylation (OXPHOS). As a result, rewired energy metabolism in leukaemic cells is now considered an attractive therapeutic target and the significance of this process is increasingly being recognised in various haematological malignancies. Therefore, identifying and targeting aberrant metabolism in drug-resistant leukaemic cells is an imperative and a relevant strategy for the development of new therapeutic options in leukaemia. In this review, we present a detailed overview of the most recent studies that present experimental evidence on how leukaemic cells can metabolically rewire, more specifically the importance of OXPHOS in LSCs and treatment-resistant cells, and the current drugs available to target this process. We highlight that uncovering specific energy metabolism dependencies will guide the identification of new and more targeted therapeutic strategies for myeloid leukaemia.

Acute Myeloblastic Leukaemia (AML) is a malignant haemopathy characterized by infiltration and accumulation in the bone marrow by myeloblastic-type blast cells causing medullary insufficiency. At the global level, the search for improved AML treatment is a long-standing concern.PurposeTo evaluate a new protocol AML MA 2003 its therapeutic results and tolerance in de novo AML patients.MethodsIt was a prospective and descriptive unicentre study carried out from January 2003 to December 2010. It included adults of 20 to 60 years with a diagnosis of de novo AML except a promyelocytic leukemia and without treatment by hydroxyurea.ResultsA total of 962 AMLs were diagnosed, 438 met the inclusion criteria, 48.4% women and 51.6% men with a median age of 39.8 years. 36.1% received hydroxyurea in pre-induction. 96.3% patients were induced, 76 (18%) died. A total of 178 (40.6%) of the 438 evaluable patients reached the maintenance phase. The overall survival of all patients was 32.4% at 5 years. Survival without event was 17.6% for all patients.ConclusionThe results of this single-center study illustrate the difficulty of treating AML patients despite the use of drugs recognised for their effectiveness in appropriate doses.

Internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3-ITD) constitutes an independent indicator of poor prognosis in acute myeloid leukaemia (AML). AML with FLT3-ITD usually presents with poor treatment outcomes, high recurrence rate and short overall survival. Currently, polymerase chain reaction and capillary electrophoresis are widely adopted for the clinical detection of FLT3-ITD, whereas the length and mutation frequency of ITD are evaluated using fragment analysis. With the development of sequencing technology and the high incidence of FLT3-ITD mutations, a multitude of bioinformatics tools and pipelines have been developed to detect FLT3-ITD using next-generation sequencing data. However, systematic comparison and evaluation of the methods or software have not been performed. In this study, we provided a comprehensive review of the principles, functionality and limitations of the existing methods for detecting FLT3-ITD. We further compared the qualitative and quantitative detection capabilities of six representative tools using simulated and biological data. Our results will provide practical guidance for researchers and clinicians to select the appropriate FLT3-ITD detection tools and highlight the direction of future developments in this field. Availability: A Docker image with several programs pre-installed is available at https://github.com/niu-lab/docker-flt3-itd to facilitate the application of FLT3-ITD detection tools.

Acute Myeloid Leukaemia (AML) is a phenotypically and genetically heterogenous blood cancer characterised by very poor prognosis, with disease relapse being the primary cause of treatment failure. AML heterogeneity arise from different genetic and non-genetic sources, including its proposed hierarchical structure, with leukemic stem cells (LSCs) and progenitors giving origin to a variety of more mature leukemic subsets. Recent advances in single-cell molecular and phenotypic profiling have highlighted the intra and inter-patient heterogeneous nature of AML, which has so far limited the success of cell-based immunotherapy approaches against single targets. Machine Learning (ML) can be uniquely used to find non-trivial patterns from high-dimensional datasets and identify rare sub-populations. Here we review some recent ML tools that applied to single-cell data could help disentangle cell heterogeneity in AML by identifying distinct core molecular signatures of leukemic cell subsets. We discuss the advantages and limitations of unsupervised and supervised ML approaches to cluster and classify cell populations in AML, for the identification of biomarkers and the design of personalised therapies.

BACKGROUND: Outcomes for children with relapsed or refractory acute myeloid leukemia (AML) remain poor. The BCL-2 inhibitor venetoclax has shown promising activity in combination with hypomethylating agents and low-dose cytarabine in older, unfit adults with newly diagnosed AML. The aims of the present study were to determine the safety and explore the activity of venetoclax with standard and high-dose chemotherapy in pediatric patients with relapsed AML. METHODS: Patients with relapsed or refractory AML or acute leukemia of ambiguous lineage who were 2–22 years old and who had adequate organ function and performance status were eligible. We tested the safety and activity of venetoclax (240 or 360mg/m(2)/day orally for 28 days) in combination with cytarabine (100mg/m(2)/dose IV every 12 hours for 20 doses or 1000mg/m(2)/dose IV every 12 hours for 8 doses) with or without idarubicin (12mg/m(2) IV). The primary endpoint was the recommended phase 2 dose (RP2D) of venetoclax plus chemotherapy and the secondary endpoint was the proportion of patients treated at the RP2D who achieved complete remission (CR) or complete remission with incomplete count recovery (CRi). Analyses were done per protocol. The study was at ClinicalTrials.gov (NCT03194932). The primary objective has been reached and the study is enrolling to address exploratory objectives. FINDINGS: Thirty-eight patients were enrolled from July 1, 2017 to July 2, 2019, with a median follow-up of 7.1 months (IQR 5.1–11.2). The RP2D of venetoclax was 360mg/m(2) (600mg max) combined with cytarabine (1000mg/m(2)/dose for 8 doses) with or without idarubicin (12mg/m(2) as a single dose). Overall responses were observed in 24 (69%) of 35 evaluable patients, including 16 CR (11 MRD negative), 4 CRi (2 MRD negative), and 4 PR. Among the 20 patients treated at the RP2D 14 (70%) achieved CR or CRi and 16 (80%) CR/CRi/PR. The most common grade 3–4 adverse events were febrile neutropenia (25 patients), bloodstream infections (6 patients), and invasive fungal infections (6 patients). Treatment-related death occurred in only one patient. INTERPRETATION: The safety and activity of venetoclax plus chemotherapy in patients with heavily pre-treated, relapsed and refractory AML suggests that this combination should be tested in newly diagnosed patients with high-risk AML. FUNDING: ALSAC, AbbVie, Gateway for Cancer Research, National Institutes of Health CA21765

The association of small lymphocytic lymphoma/chronic lymphocytic leukaemia (CLL) with different malignancies has been reported in the literature. Also the occurrence of a second haematological disease has been described, more frequently as a secondary event in patients receiving chemotherapeutic agents. We report a case of CLL with concurrent acute myeloid leukaemia in an untreated patient, with emphasis on the need of a detailed immunomorphological study to identify the coexistence of the two diseases in the same pathological tissue.

Objectives: Currently, there is no standard treatment for patients with acute myeloid leukaemia (AML) ineligible for standard induction chemotherapy (IC). This study aimed to report real-world evidence data on the efficacy and safety of decitabine in this patient group.Methods: This study was a Belgian, retrospective, non-interventional, multicentre registry of patients ≥ 65 years, with newly-diagnosed de novo or secondary AML ineligible for IC. Patients were treated according to routine clinical practice. Overall survival (OS), progression-free survival (PFS) and transfusion independence for ≥8 consecutive weeks were evaluated.Results: Forty-five patients were enrolled, including 67% (n = 30) with secondary AML. Median OS and PFS were 7.3 months (95% CI: 2.2-11.1) and 4.1 months (95% CI: 2.1-7.6) respectively. A subpopulation analysis showed that patients treated with ≥4 cycles (n = 21) had significantly better outcomes compared to patients receiving

Centaurea africana L. (Compositae: Cardueae: Centaureinae) is illustrated and described. The species has a long history of cultivation that probably exceeds 350 years, although it is apparently rarely available from commercial sources as seed or plant material. Other than the tribal name to use when placing this species, its more recent recognition as a species of Rhaponticoides Vaill. is not accepted; the issue of Vaillant names is once again raised. The capitula of C. africana are considered heterogamous and disciform, not radiant, with the few marginal florets possessing equal length, certainly non‐showy, corolla lobes, and usually containing staminodes. A number of synonyms, appearing in a couple of well‐known databases, are excluded; one belongs to a purple‐flowered species endemic to northern Morocco, the other to a yellow‐flowered, pinnatisect‐leaved plant of northern Spain. A potentially exciting use of one flavonoid extracted from flowering parts of the plant, algerianin, in combatting human myeloid leukaemia, is highlighted.