METHODOLOGY FOR FORMING A DATABASE OF REFERENCE IMAGES OF BONE MARROW CELLS FOR THE AUTOMATED DIAGNOSIS OF ACUTE LEUKEMIA IN ONCOHEMATOLOGY

2021 ◽  
pp. 84-89
Author(s):  
Ольга Александровна Медведева ◽  
Святослав Николаевич Простаков ◽  
Николай Николаевич Тупицын ◽  
Александра Дмитриевна Палладина
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Bone Marrow Cells ◽  
Digital Images ◽  
Automated Image Analysis ◽  
Medical Decision ◽  
Reference Images ◽  
Computer Microscopy ◽  
Marrow Cells

В статье представлено описание факторов, влияющих на качество формирования базы эталонных изображений клеток костного мозга для диагностики острых лейкозов с применением методов компьютерной микроскопии. Отмечена важность контроля качества подготовки препаратов и микроскопа для применения в автоматизированных системах анализа изображений. Рассмотрены особенности регистрации цифровых микроскопических изображений клеток костного мозга в системах компьютерной микроскопии. Исследовано влияние фокусировки оптической системы микроскопа и уровня освещения препарата на формирование цифровых изображений клеток костного мозга. Установлены требования к условиям регистрации цифровых изображений, используемых в автоматизированных системах микроскопического анализа препаратов костного мозга. Предложена концептуальная модель базы эталонных изображений костного мозга, являющаяся основой для разработки инструментов эффективного распознавания клеток костного мозга в системах компьютерной микроскопии. Следование указанным требованиям к регистрации изображений призвано обеспечить надлежащее качество эталонной базы, что имеет непосредственной влияние на повышение точности и достоверности медицинской диагностики с применением методов компьютерной микроскопии. Результаты работы могут быть использованы в системах поддержки принятия врачебных решений при диагностике острых лейкозов The article describes the factors affecting the quality of the formation of a database of reference images of bone marrow cells for the diagnosis of acute leukemia using computer microscopy methods. The importance of quality control of specimen and microscope preparation for use in automated image analysis systems is noted. The features of registration of digital microscopic images of bone marrow cells in computer microscopy systems are considered. The effect of focusing of the optical system of the microscope and the level of illumination of the specimen on the formation of digital images of bone marrow cells is investigated. The requirements for the conditions of registration of digital images used in automated systems of microscopic analysis of bone marrow preparations have been established. A conceptual model of the base of reference images of bone marrow is proposed. It is the basis for the development of tools for effective recognition of bone marrow cells in computer microscopy systems. Following the specified requirements for image registration is designed to ensure the proper quality of the reference base of images, which has a direct impact on improving the accuracy and reliability of medical diagnostics using computer microscopy. The results of the work can be used in medical decision support systems for the diagnosis of acute leukemia

METHODS OF MULTICLASSICATION OF BONE MARROW CELLS FOR THE DIAGNOSIS OF ACUTE LEUKEMIA AND MINIMAL RESIDUAL DISEASE (ON THE MATERIALS OF THE LABORATORY OF HEMATOPOIESIS OF N. N. BLOKHIN NATIONAL MEDICAL RESEARCH CENTER OF ONCOLOGY)

2020 ◽  
pp. 155-158
Author(s):  
Валентина Викторовна Дмитриева ◽  
Николай Николаевич Тупицын ◽  
Евгений Валерьевич Поляков ◽  
Софья Сергеевна Денисюк
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Medical Research ◽  
Bone Marrow Cells ◽  
Residual Disease ◽  
Binary Classification ◽  
National Medical ◽  
Cell Class ◽  
Minimal Residual ◽  
Marrow Cells

Применение методов и средств цифровой обработки изображений при распознавании типов клеток крови и костного мозга для повышения качества диагностики острых лейкозов является актуальной научно-технической задачей, отвечающей стратегии развития технологий искусственного интеллекта в медицине. В работе предложен подход к мультиклассификации клеток костного мозга при диагностике острых лейкозов и минимальной остаточной болезни. Для проведения экспериментальных исследований сформирована выборка из 3284 изображений клеток, представленных Лабораторией гемопоэза Национального медицинского исследовательского центра онкологии им. Н.Н. Блохина. Предложенный подход к мультиклассификации клеток костного мозга основан на бинарной модели классификации для каждого из исследуемых классов относительно остальных. В рассматриваемой работе бинарная классификация выполняется методом опорных векторов. Метод мультиклассификации был программно реализован с применением интерпретатора Python 3.6.9. Входными данными программы служат файлы формата *.csv с таблицами морфологических, цветовых, текстурных признаков для каждой из клеток используемой выборки. В выборке представлено девять типов клеток костного мозга. Выходными данными программы мультиклассификации являются значения точности классификации на тестовой выборке, которые отражают совпадение прогнозируемого класса клетки с фактическим (верифицированным) классом клетки. “Эксперимент показал следующие результаты: точность мультиклассификации рассматриваемых типов клеток в среднем составила: 87% на тестовом наборе, 88% на обучающем наборе данных. Проведенное исследование является предварительным. В дальнейшем планируется увеличить число классов клеток, объем выборок различных типов клеток и с уточнением результатов мультиклассификации The use of methods and means of digital image processing in the recognition of types of blood cells and bone marrow to improve the quality of diagnosis of acute leukemia is an urgent scientific and technical task that meets the strategy for the development of artificial intelligence technologies in medicine. The paper proposes an approach to the multiclassification of bone marrow cells in the diagnosis of acute leukemia and minimal residual disease. For experimental studies, a sample of 3284 images of cells was formed, submitted by the Hematopoiesis Laboratory of the National Medical Research Center of Oncology named after V.I. N.N. Blokhin. The proposed approach to the multiclassification of bone marrow cells is based on a binary classification model for each of the studied classes relative to the others. In the work under consideration, binary classification is performed by the support vector machine. The multiclassification method was implemented programmatically using the Python 3.6.9 interpreter. The input data of the program are * .csv files with tables of morphological, color, texture features for each of the cells of the sample used. The sample contains nine types of bone marrow cells. The output data of the multiclassification program are the classification accuracy values on the test sample, which reflect the coincidence of the predicted cell class with the actual (verified) cell class. “The experiment showed the following results: the accuracy of multiclassification of the considered types of cells on average was: 87% on the test set, 88% on the training data set. This study is preliminary. In the future, it is planned to increase the number of classes of cells, the volume of samples of various types of cells and with the refinement of the results of multiclassification

Dnmt3a-Deletion Accelerates FLT3-ITD Malignancies In Mice By Hypomethylation Of Enhancer Sites and Activating Stem Cell Programs; Implications For Therapy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 595-595 ◽  
Author(s):  
Liubin Yang ◽  
Benjamin Rodriguez ◽  
Min Luo ◽  
Mira Jeong ◽  
David Ruau ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Mouse Model ◽  
Acute Leukemia ◽  
Bone Marrow Cells ◽  
Self Renewal ◽  
Expression Of Genes ◽  
Marrow Cells

Abstract The de novo DNA methyltransferase (DNMT) 3A is mutated in 50% of patients with mixed phenotype acute leukemia, 20% with acute myeloid leukemia (AML) and 18% with T-cell acute lymphoblastic leukemia (T-ALL). The mechanisms through which mutant DNMT3A contributes to hematologic malignancy are poorly understood. In mice, deletion of Dnmt3a in hematopoietic stem cells (HSCs) leads to abnormal DNA methylation and inhibition of differentiation, but is insufficient for leukemic transformation. To study the role of Dnmt3a in leukemia, we combined Dnmt3a-deletion with the activated FLT3 proto-oncogene (FLT3-ITD), a frequent co-mutation with DNMT3A in AML patients, to establish a murine model of Dnmt3a-associated malignancy. In mice transplanted with Dnmt3a-knockout (KO) or wild-type (WT) bone marrow cells transduced with a FLT3-ITD retrovirus, Dnmt3a-loss dramatically impacted the disease phenotype. Dnmt3aKO/ITD transplanted mice had significantly shortened survival (79 days vs. 116 days) and increased rate of acute leukemia compared to mice with ITD alone. The mice developed CD4+CD8+ Notch activation-associated T-ALL or myeloproliferative disease (MPD), or concurrently both, consistent with previous studies of FLT3-ITD in mice. To determine the leukemia-initiating population, we transplanted sorted HSC, myeloid, and lymphoid progenitors transduced with FLT3-ITD. All mice transplanted with HSC and myeloid progenitors succumbed to both malignancies. To uncover the mechanisms by which Dnmt3a-deletion accelerated acute leukemia, we analyzed changes in DNA methylation in T-ALL blasts by whole genome bisulfite sequencing. Compared to Dnmt3aWT/ITD, Dnmt3aKO/ITD blasts exhibited global hypomethylation, particularly at distal enhancer sites. These hypomethylated enhancer sites were associated with genes in signaling pathways, transcription regulators, and metabolic pathways in cancer (KEGG and GO Analysis). Transcriptome analysis showed that relative to Dnmt3aWT/ITD, the Dnmt3aKO/ITD blasts had 1577 significantly differentially expressed genes positively related to cancer, cellular growth, and proliferation, and negatively to apoptosis by Ingenuity Pathway Analysis (IPA). Surprisingly, we observed increased expression of genes related to HSCs and myeloid function and decreased expression of genes related to lymphocyte function. Human AML signature genes (Oncomine) were also upregulated in our mouse model. Predicted activated pathways include Myc, Nfe2l2, Eif4e, E2f1, Csf2, Cebpb, Vegf, Rxra, Ezh2, and Brd4 and inhibited pathways include tumor suppressors Rb, let7, Cdkn2a, and Tob1 (IPA). We did not observe changes in genomic copy number variation by chromosomal comparative hybridization (cCGH). To test whether Dnmt3a-deletion could functionally bestow stem cell properties on pre-leukemic cells, we examined self-renewal capabilities of malignant cells of Flt3+/ITD knock-in mouse (an ITD mutation knocked in to the endogenous murine Flt3 allele causing MPD). Remarkably, when Dnmt3aKO; Flt3+/ITD bone marrow cells were serially transplanted, MPD was seen in all recipients, compared to none in Dnmt3aWT; Flt3+/ITD transplanted mice (n=7). Further, we transplanted sorted CLP, CMP, GMP, MPP, ST-HSC, LT-HSC populations and observed myeloproliferation in transplanted non-stem (CMP, GMP, ST-HSC) and stem cell (LT-HSC) populations. This strongly suggests that Dnmt3aKO synergized with Flt3-ITD to confer stem cell self-renewal abilities to transformed progenitor and stem cells. Increasingly, decitabine is being used to treat patients with AML and MDS, but whether patients with DNMT3A mutations could benefit is unclear, so we examined the impact of decitabine treatment on the retroviral transduced Dnmt3aKO/ITD mice. Monthly treatment led to significantly increased survival of Dnmt3aKO/ITD mice from T-ALL and MPD and reduced presence of ITD-transduced KO cells. Together, we demonstrate that Dnmt3aKO accelerated malignancies induced by FLT3-ITD in mouse and may shed light on how DNMT3A mutations contribute to lymphoid and myeloid disease in patients. Dnmt3a deletion ignited multilineage and stem cell programs at the expense of lymphoid programs to accelerate disease, but was extinguishable by decitabine therapy. The findings from our mouse model can be used for the development and testing of targeted epigenetic therapy for DNMT3A-associated malignancies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals In VivoChemoprotective Activity of Bovine Dialyzable Leukocyte Extract in Mouse Bone Marrow Cells against Damage Induced by 5-Fluorouracil

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Erika Evangelina Coronado-Cerda ◽  
Moisés Armides Franco-Molina ◽  
Edgar Mendoza-Gamboa ◽  
Heriberto Prado-García ◽  
Lydia Guadalupe Rivera-Morales ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Count ◽  
Cancer Patients ◽  
Bone Marrow Cells ◽  
Mouse Bone Marrow ◽  
Colony Forming Units ◽  
Nrf2 Activation ◽  
Total Bone Marrow ◽  
Marrow Cells

Chemotherapy treatments induce a number of side effects, such as leukopenia neutropenia, peripheral erythropenia, and thrombocytopenia, affecting the quality of life for cancer patients. 5-Fluorouracil (5-FU) is wieldy used as myeloablative model in mice. The bovine dialyzable leukocyte extract (bDLE) or IMMUNEPOTENT CRP® (ICRP) is an immunomodulatory compound that has antioxidants and anti-inflammatory effects. In order to investigate the chemoprotection effect of ICRP on bone marrow cells in 5-FU treated mice, total bone marrow (BM) cell count, bone marrow colony forming units-granulocyte/macrophage (CFU-GM), cell cycle, immunophenotypification, ROS/superoxide and Nrf2 by flow cytometry, and histological and hematological analyses were performed. Our results demonstrated that ICRP increased BM cell count and CFU-GM number, arrested BM cells in G0/G1 phase, increased the percentage of leukocyte, granulocytic, and erythroid populations, reduced ROS/superoxide formation and Nrf2 activation, and also improved hematological levels and weight gain in 5-FU treated mice. These results suggest that ICRP has a chemoprotective effect against 5-FU in BM cells that can be used in cancer patients.

scholarly journals Bone marrow cell count per cubic millimeter bone marrow: a new parameter for quantitating therapy-induced cytoreduction in acute leukemia

Blood ◽  
1982 ◽  
Vol 59 (2) ◽  
pp. 216-225 ◽  
Author(s):  
W Hiddemann ◽  
BD Clarkson ◽  
T Buchner ◽  
MR Melamed ◽  
M Andreeff
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Bone Marrow Cell ◽  
Bone Marrow Cells ◽  
Marrow Cell ◽  
High Dose ◽  
Acute Leukemias ◽  
Cell Counts ◽  
Hodgkin's Lymphomas ◽  
Marrow Cells

Abstract A new technique is introduced for determining the number of bone marrow cells per cubic millimeter marrow, providing an accurate and objective means for quantitating therapy-induced cytoreduction. The method requires a correction for admixed peripheral blood in bone marrow aspirates to measure the fraction of remaining pure marrow. While cell kinetic differences between blood, aspirates, and biopsies identify the proportion of contaminating blood cells, the ratio of red cell hematocrits in blood and aspirate gives the volume of trapped blood. By combining both procedures, bone marrow cell counts per unit volume pure marrow result (BMC/cu mm BM), which were found highly reproducible. Blast cell counts (BMBC/cu mm BM) were obtained by additional morphological differentiation. BMC and BMBC/cu mm BM were monitored in 16 patients with acute nonlymphoblastic leukemia treated with daunorubicin, cytosine arabinoside, and 6-thioguanine in combination and in 4 patients with end-stage acute leukemias and non-Hodgkin's lymphomas during high-dose thymidine therapy. Total and daily therapy- induced cytoreduction rates were significantly greater (P less than 0.01) in responders than nonresponders to either regimen. Changes in BMC/cu mm BM were also found representative for changes in BMBC/cu mm BM, since the majority of bone marrow cells were blasts. In acute leukemia. BMC/cu mm BM thus provides accurate and objective measurements of treatment efficacy in vivo and after short periods of drug exposure. Differences in cytoreduction rates within the group of responders also suggest possible prognostic implications.

scholarly journals Bone marrow cell count per cubic millimeter bone marrow: a new parameter for quantitating therapy-induced cytoreduction in acute leukemia

Blood ◽  
1982 ◽  
Vol 59 (2) ◽  
pp. 216-225 ◽  
Author(s):  
W Hiddemann ◽  
BD Clarkson ◽  
T Buchner ◽  
MR Melamed ◽  
M Andreeff
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Bone Marrow Cell ◽  
Bone Marrow Cells ◽  
Marrow Cell ◽  
High Dose ◽  
Acute Leukemias ◽  
Cell Counts ◽  
Hodgkin's Lymphomas ◽  
Marrow Cells

A new technique is introduced for determining the number of bone marrow cells per cubic millimeter marrow, providing an accurate and objective means for quantitating therapy-induced cytoreduction. The method requires a correction for admixed peripheral blood in bone marrow aspirates to measure the fraction of remaining pure marrow. While cell kinetic differences between blood, aspirates, and biopsies identify the proportion of contaminating blood cells, the ratio of red cell hematocrits in blood and aspirate gives the volume of trapped blood. By combining both procedures, bone marrow cell counts per unit volume pure marrow result (BMC/cu mm BM), which were found highly reproducible. Blast cell counts (BMBC/cu mm BM) were obtained by additional morphological differentiation. BMC and BMBC/cu mm BM were monitored in 16 patients with acute nonlymphoblastic leukemia treated with daunorubicin, cytosine arabinoside, and 6-thioguanine in combination and in 4 patients with end-stage acute leukemias and non-Hodgkin's lymphomas during high-dose thymidine therapy. Total and daily therapy- induced cytoreduction rates were significantly greater (P less than 0.01) in responders than nonresponders to either regimen. Changes in BMC/cu mm BM were also found representative for changes in BMBC/cu mm BM, since the majority of bone marrow cells were blasts. In acute leukemia. BMC/cu mm BM thus provides accurate and objective measurements of treatment efficacy in vivo and after short periods of drug exposure. Differences in cytoreduction rates within the group of responders also suggest possible prognostic implications.

scholarly journals Integrated information and measurement system for the diagnosis of acute leukemia and minimal residual disease based on computer microscopy, flow laser cytofluorimetry and artificial intelligence

2021 ◽  
Vol 2058 (1) ◽  
pp. 012033
Author(s):  
V G Nikitayev ◽  
A N Pronichev ◽  
N N Tupitsin ◽  
V Yu Selchuk ◽  
V V Dmitrieva ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
Bone Marrow ◽  
Acute Leukemia ◽  
Minimal Residual Disease ◽  
Measurement System ◽  
Bone Marrow Cells ◽  
Residual Disease ◽  
Computer Microscopy ◽  
Minimal Residual ◽  
Integrated Information

Abstract The article considers a new integrated information and measurement system for the diagnosis of acute leukemia and minimal residual disease based on computer microscopy and flow laser cytometry. The system is based on combining the results of computer microscopy in the analysis of bone marrow preparations and the results of flow laser cytofluorimetry. A special feature of the system is the use of artificial intelligence technologies in the recognition of images of bone marrow cells in the computer microscopy subsystem. The work was the result of joint work of the Department of Computer Medical Systems of the National Research Nuclear University "MEPhI" and the Laboratory of Hematopoietic Immunology of the National Medical Research Center of Oncology named after N. N. Blokhin.

Oncogenic interaction between BCR-ABL andNUP98-HOXA9 demonstrated by the use of an in vitro purging culture system

Blood ◽  
2002 ◽  
Vol 100 (12) ◽  
pp. 4177-4184 ◽  
Author(s):  
Nadine Mayotte ◽  
Denis-Claude Roy ◽  
Jing Yao ◽  
Evert Kroon ◽  
Guy Sauvageau
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Disease Progression ◽  
Bone Marrow Cells ◽  
Myelogenous Leukemia ◽  
Mouse Bone Marrow ◽  
Genetic Level ◽  
Marrow Cells

Chronic myelogenous leukemia (CML) is a clonal stem cell disease caused by the BCR-ABL oncoprotein and is characterized, in its early phase, by excessive accumulation of mature myeloid cells, which eventually leads to acute leukemia. The genetic events involved in CML's progression to acute leukemia remain largely unknown. Recent studies have detected the presence of theNUP98-HOXA9 fusion oncogene in acute leukemia derived from CML patients, which suggests that these 2 oncoproteins may interact and influence CML disease progression. Using in vitro purging of BCR-ABL–transduced mouse bone marrow cells, we can now report that recipients of bone marrow cells engineered to coexpressBCR-ABL with NUP98-HOXA9 develop acute leukemia within 7 to 10 days after transplantation. However, no disease is detected for more than 2 months in mice receiving bone marrow cells expressing either BCR-ABL orNUP98-HOXA9. We also provide evidence of high levels ofHOXA9 expressed in leukemic blasts from acute-phase CML patients and that it interacts significantly on a genetic level withBCR-ABL in our in vivo CML model. Together, these studies support a causative, as opposed to a consequential, role forNUP98-HOXA9 (and possibly HOXA9) in CML disease progression.

Studies of myelopoiesis in vitro on blood and bone marrow cells of patients with acute leukemia in long-term remission

1983 ◽  
Vol 7 (3) ◽  
pp. 397-406 ◽  
Author(s):  
Christian Peschel ◽  
Günther Konwalinka ◽  
Dietmar Geissler ◽  
Brigitte Tomaschek ◽  
Kurt Grünewald ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Bone Marrow Cells ◽  
Marrow Cells
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