Acute Leukemia Research Articles

Establishment of human acute monocytic leukemia model with systemic infiltration in NPG mice.

A model construction of systemic acute leukemia is challenging. Herein, we established a systemic leukemia mouse model using highly immunodeficient NPG mice without any immunosuppressive treatments. NPG mice received tail intravenous injection of SHI-1 cells at the concentration of 1×107 cells (group A) or 5×107 cells (group B) and randomly sacrificed each seven days post-inoculation. Tumor development was monitored using nested-PCR, peripheral blood-smear analysis, flow cytometry, pathological examinations, and immunohistochemistry. The median survival of mice in groups A and B were 33.0 and 30.0 days, respectively. Blast cells in peripheral blood appeared on day 14 in group B, and on day 21 in group A. In addition, SHI-1 cell specific MLL-AF6 mRNA was detected in both spleen and bone marrow on day 14 post-inoculation. 21 days after inoculation, we observed human CD45+CD33+ cells with an SH-1-immunophenotype in the peripheral blood, spleen, and bone marrow, as well as solid neoplasms in multiple organs. Moreover, the histologically infiltrated leukemic cells expressed CD45. In conclusion, the current study demonstrated the normal growth of SHI-1 cells in the NPG mice without immunosuppression, which caused systemic leukemia similar to that observed in acute leukemia patients. We developed an efficient and reproducible model to study leukemia pathogenesis and progression.

Development of the esterase PestE for amide bond synthesis under aqueous conditions: Enzyme cascades for converting waste PET into tamibarotene.

A growing number of hydrolase enzymes show promiscuous acyltransferase activity, even under aqueous conditions. Here we report, for the first time, the ability of Pyrobaculum calidifontis VA1 esterase (PestE) to catalyse the formation of a wide range of amides in buffer, where the acyl donor forms a significant structural component in the amide product. The reactions occur under mild conditions and can achieve conversions up to 97% in 6 h for formation of N-benzylfuranamide as the model reaction. We demonstrate PestE's potential in enzyme cascades to make amides from waste PET plastic and the conversion of the terephthalic acid product to tamibarotene, a drug with activity against acute leukemia. Rational mutagenesis led to identification of PestE variants F33L_F289A and F33L. F33L_F289A increased conversion of N-benzylfuranamide by 1.2-fold, and F33L gave a 4-fold increase in conversion to tamibarotene.

Development of the esterase PestE for amide bond synthesis under aqueous conditions: Enzyme cascades for converting waste PET into tamibarotene.

A growing number of hydrolase enzymes show promiscuous acyltransferase activity, even under aqueous conditions. Here we report, for the first time, the ability of Pyrobaculum calidifontis VA1 esterase (PestE) to catalyse the formation of a wide range of amides in buffer, where the acyl donor forms a significant structural component in the amide product. The reactions occur under mild conditions and can achieve conversions up to 97% in 6 h for formation of N‐benzylfuranamide as the model reaction. We demonstrate PestE’s potential in enzyme cascades to make amides from waste PET plastic and the conversion of the terephthalic acid product to tamibarotene, a drug with activity against acute leukemia. Rational mutagenesis led to identification of PestE variants F33L_F289A and F33L. F33L_F289A increased conversion of N‐benzylfuranamide by 1.2‐fold, and F33L gave a 4‐fold increase in conversion to tamibarotene.

Hemato-oncology services and COVID-19 Pandemic: The experience of Kazakhstan

Abstract Objectives The COVID-19 pandemic in Kazakhstan disrupted numerous healthcare services, including those critical for hemato-oncology patients, due to the strained healthcare system. This study examines how the COVID-19 pandemic has affected access to hemato-oncology healthcare services in Almaty, Kazakhstan. Methods We retrospectively analyzed patient data from two tertiary centers, City Clinical Hospital 7 (H7) and Kazakh Institute of Oncology and Radiology (KazIOR), from March 1, 2019, to February 28, 2022. Variables included age, gender, residence, hospitalization rate, treatment outcomes (discharged/deceased/transferred), diagnoses (acute leukemia, lymphoproliferative diseases, myeloproliferative diseases), and referral sources. The Statistical Yearbook of Kazakhstan provided comparative data. Results From 2019-2022, 6,763 hemato-oncology hospitalizations were registered: 3,583 in H7 and 3,180 in KazIOR. The mean age was 55.04 (SD = 16.07) for females and 51.2 (SD = 16.7) for males. Urban and rural patient proportions were 6,191 (92%) and 571 (8.4%), respectively (Chi-square 13.8, P = 0.001). Fewer patients were discharged in 2020-2021 (n = 2,047) compared to 2019-2020 (n = 2,387) and 2021-2022 (n = 2,081) (Chi-square 20.09, P = 0.003). The death rate was higher in 2020-2021 (3.5%) than in 2019-2020 (3.2%) and 2021-2022 (2.6%) (Chi-square 20.09, P = 0.003). Emergency admissions were 403 (19%) in 2020-2021, 368 (14.8%) in 2019-2020, and 394 (18.3%) in 2021-2022 (Chi-square 2,231, P < 0.001). Transfers from other hospitals increased by 12.4% in 2020-2021. Conclusions The COVID-19 pandemic negatively impacted access to hemato-oncology services, increasing mortality. Further studies are needed to understand the factors affecting hospitalization and mortality trends during healthcare crises. Funding: Grant No. AP09260497. Key messages • Access to healthcare services during COVID-19 pandemic for hemato-oncology patients. • Impact of the pandemic on access to healthcare.

Recording diagnostic conversations for communication research purposes in pediatric leukemia.

Recordings of patient-doctor interactions is a recommended method in communication research. However, concerns are expressed regarding audio-recording of conversations with vulnerable patients. Our study examined experiences of children, parents, and oncologists with recording diagnostic conversations in the pediatric acute leukemia setting. Results show that recording conversations is generally well received by virtually all children and parents. Pediatric oncologists seem to overestimate the expected emotional burden for children and parents, which may lead to gatekeeping by professionals. This in turn may lead to a decrease in patient autonomy and research quality when addressing relevant questions in communication science.

Clostridium spiroforme-induced diarrhea in a patient with acute myeloid leukemia: A case report

Clostridium spiroforme is a Gram-positive, obligate anaerobic bacillus. Previous studies have suggested that C. spiroforme mainly causes typhlocolitis and enterotoxemia in rabbits, with few documented cases of human infections. We present a rare case of acute diarrhea caused by C. spiroforme in a 78-year-old female patient with acute leukemia. In the early stages of infection, the patient experienced up to 10 episodes of diarrhea per day. She was subsequently treated with live Clostridium butyricum capsules to modulate the intestinal microflora, and her symptoms resolved after 7 days of treatment. This case report highlights an uncommon intestinal infection with C. spiroforme in a patient with a hematologic malignancy, contributing valuable clinical insights into this rare infection.

Efficacy of haploidentical allogeneic hematopoietic cell transplantation following two courses of venetoclax and azacytidine therapy in patients over 55 years old with acute myelogenous leukemia.

The combination of venetoclax (VEN) and azacytidine (AZA) has demonstrated potential in achieving rapid and effective remissions in elderly patients with acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation is a promising potential cure for high-risk AML, as VEN-based therapies have a worse prognosis in elderly patients. This study aimed to assess the efficacy of sequential haploidentical HSCT following two courses of VEN and AZA therapy in patients with AML aged 55 years and older. We conducted a retrospective study on AML patients aged 55 to 70 years who received intensive chemotherapy or two courses of VEN/AZA therapy, followed by haplo-HSCT based on disease risk degree, measurable residual disease status and patient's preference. Between January 2019 and December 2023, 141 newly diagnosed AML patients received initial treatment with intensive chemotherapy or VEN/AZA therapy. Among them, 64 patients received haplo-HSCT, while 77 did not. The 1-year over survival (OS) and relapse-free survival (RFS) of patients who received haplo-HSCT were significantly higher than those who did not receive haplo-HSCT (P<0.05). Among patients who received transplantation, there was no significant difference in 1-year OS and RFS between the VEN/AZA and intensive chemotherapy groups: 76.3% vs 69.3% (P = 0.367) for OS, and 74.5% vs 69.7% (P = 0.473) for RFS. High-risk ELN stratification and the presence of ≥4 gene mutations were associated with lower OS and RFS in both univariate and multivariate analysis. AML patients over 55 years of age who received haplo-HSCT after two courses of VEN/AZA therapy had outcomes similar to those who received haplo-HSCT after intensive chemotherapy, suggesting that two courses of VEN/AZA therapy as a bridge to halpo-HSCT are feasible for patients over 55 years old.

Cervical Granulocytic Sarcoma Without Acute Leukemia: A Case Report and Review of 42 Additional Cases

Cervical Granulocytic Sarcoma Without Acute Leukemia: A Case Report and Review of 42 Additional Cases

Acute promyelocytic leukemia can be fully treated on an outpatient basis: a single institution experience.

The objective of this study is to explore the possibility of treating APL patients fully as outpatients. A total of 21 consecutive APL patients were identified over 30 years in the Centro de Hematología y Medicina Interna de Puebla, at Clínica Ruiz, but only 17 were studied, treated as outpatients, and followed for at least 1 month; they were observed for median of 95 months, their median age was 27 years and all were treated with ATRA, prednisone, and adriamycin as outpatients. Treatment was completed on an outpatient basis in 15/17 cases. Molecular remission was achieved in 16/17 patients. The median follow-up was 95 months (IQR 19 - 360). The median OS and LFS were not reached, and the 12-month LFS was 94%. We have confirmed that APL can be treated entirely on an outpatient basis: this observation is of utmost relevance in a resource-limited setting, such as those prevailing in low- and middle-income countries.

Health-related quality of life benefits of arsenic trioxide in patients with non-high-risk acute promyelocytic leukemia are sustained over time: long-term results of the GIMEMA APL0406 trial.

Very limited evidence is available on the long-term health-related quality of life (HRQoL) of patients with acute promyelocytic leukemia (APL) treated with arsenic trioxide (ATO). We performed an extended follow-up of the APL0406 randomized controlled trial to investigate HRQoL of patients treated with either ATO or chemotherapy. A secondary objective was to describe the prevalence of clinically important problems and symptoms of these patients by type of treatment. Overall, 117 patients were included in this analysis after a median follow-up of 10 years (IQR 8-11) since diagnosis. Of these, 60 (51.3%) were treated with ATO, and 57 (48.7%) with chemotherapy. A statistically significant and clinically relevant difference, favoring patients treated with ATO, was found in 2 of the 3 main prespecified EORTC QLQ-C30 scales, that is, cognitive functioning (∆ = 7.7; 95% CI 0.5 to 14.9; p = 0.036) and fatigue (∆ = -9.4; 95% CI -17.9 to -0.8; p = 0.031). The prevalence of clinically important problems and symptoms tended to be slightly higher in patients treated with chemotherapy. These findings suggest that previously observed HRQoL advantages of ATO therapy of patients included in the APL0406 trial are sustained over the long-term period. This study was registered at ClinicalTrials.gov (NCT03096496).

Automating cancer diagnosis using advanced deep learning techniques for multi-cancer image classification

Cancer detection poses a significant challenge for researchers and clinical experts due to its status as the leading cause of global mortality. Early detection is crucial, but traditional cancer detection methods often rely on invasive procedures and time-consuming analyses, creating a demand for more efficient and accurate solutions. This paper addresses these challenges by utilizing automated cancer detection through AI-based techniques, specifically focusing on deep learning models. Convolutional Neural Networks (CNNs), including DenseNet121, DenseNet201, Xception, InceptionV3, MobileNetV2, NASNetLarge, NASNetMobile, InceptionResNetV2, VGG19, and ResNet152V2, are evaluated on image datasets for seven types of cancer: brain, oral, breast, kidney, Acute Lymphocytic Leukemia, lung and colon, and cervical cancer. Initially, images undergo segmentation techniques, proceeded by contour feature extraction where parameters such as perimeter, area, and epsilon are computed. The models are rigorously evaluated, with DenseNet121 achieving the highest validation accuracy as 99.94%, 0.0017 as loss, and the lowest Root Mean Square Error (RMSE) values as 0.036056 for training and 0.045826 for validation. These results revealed the capability of AI-based techniques in improving cancer detection accuracy, with DenseNet121 emerging as the most effective model in this study.

Investigation of Apoptosis-mediated Cytotoxic Effects of Royal Jelly on HL-60 Cells

In recent years, the use of nontoxic natural products that can be effective on cancer cells as new agents has attracted the attention of scientists in order to reduce the negative side effects of existing cancer drugs and their toxicity to normal cells. Some in vivo and in vitro studies have shown that royal jelly (RJ) inhibits cell proliferation and induces apoptosis. In this research, we aimed to investigate the effects of RJ on proliferative and apoptotic processes in the human acute promyelocytic leukemia cell line (HL-60). The HL60 cell line was treated with different concentrations of RJ for 24, 48, and 72 hours. The half maximum inhibitory concentration (IC50) of RJ was determined using 3-(4.5 dimethylthiazol-2-yl)-2.5-diphenyltetrazolium bromide test (MTT) and the proliferation activity of HL-60 cells was evaluated. Flow cytometry analysis was performed to measure apoptosis in HL-60 cells. IC50 values for RJ were calculated as 13.98, 6.45, and 2.06 mg/mL for 24, 48, and 72 hours, respectively. Flow cytometry results also showed that RJ had apoptotic effects at the concentrations found. The results showed that RJ treatment significantly induced apoptosis and reduced the proliferation of HL-60 cells. This study shows that RJ can be a complementary treatment against HL-60 acute myeloid leukemia cells due to its anticancer and antiproliferative effects.

Plasma protein binding of arsenic species in acute promyelocytic leukemia patients and their relationships with hepatic and renal function

ABSTRACT Objectives Percentage protein binding (%PB) of arsenic species in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide remains unclear. It can be different depending on the status of hepatic or renal function. Methods This study obtained steady-state blood samples from normal APL patients and those with hepatic or renal impairment. %PB of inorganic arsenic (iAs), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) was determined by analyzing free and total plasma concentrations using ultrafiltration method by HPLC-HG-AFS. Results There is a linear relationship between free and total plasma concentrations for iAs (r2 = 0.952), MMAV (r2 = 0.603), and DMAV (r2 = 0.945). For patients with normal hepatic and renal function, mean %PB was as follows: iAs at 26.7 ± 14.3%, MMAV at 53.3 ± 11.9%, and DMAV at 24.7 ± 7.8%. %PB decreased in patients with renal impairment, with MMAV and DMAV showing statistically significant differences (p < 0.05 for MMAV, p < 0.01 for DMAV). No significant differences in %PB between normal and hepatic impairment group were observed. Conclusion Free arsenic species fraction can be estimated by total concentration. DMAV and iAs present low %PB, while MMAV exhibits a relatively high %PB in plasma. Level of %PB is more likely to be affected by renal function and age.

A deep transfer learning based approaches for the detection and classification of acute lymphocytic leukemia using microscopic images

A deep transfer learning based approaches for the detection and classification of acute lymphocytic leukemia using microscopic images

Analysis of early and treatment related deaths among children and adolescents with acute myeloid leukemia in Poland: 2005–2023

BackgroundA personalised approach to the treatment of acute myeloid leukemia (AML) in children and adolescents, as well as the development of supportive therapies, has significantly improved survival. Despite this, some patients still die before starting treatment or in an early phase of therapy before achieving remission. The study analysed the frequency, clinical features and risk factors for early deaths (ED) and treatment related deaths (TRD) of children and adolescents with AML.MethodsFrom January 2005 to November 2023, 646 children with AML treated in the centers of the Polish Pediatric Leukemia and Lymphoma Study Group according to three subsequent therapeutic protocols were evaluated: AML-BFM 2004 Interim (385 children), AML-BFM 2012 Registry (131 children) and AML-BFM 2019 (130 children).ResultsOut of 646 children, early death occurred in 30 children, including 15 girls. The median age was 10.7 years (1 day to 18 years). More than half of the patients (53%) were diagnosed with acute myelomonocytic leukemia (M5) and 13% with acute promyelocytic leukemia (M3). The ED rate for the three consecutive AML-BFM protocols was 4.9% vs. 5.3% vs. 3.1%, respectively. In 19 patients, death occurred before the 15th day of treatment, in 11 between the 15th and 42nd day. The most common cause of death before the 15th day (ED15) was leukostasis and bleeding, whereas between the 15th and 42nd day (ED15-42), infections, mainly bacterial sepsis. A significant association was found between ED15 and high leukocyte count (&amp;gt;10 × 109/L), M3 leukemia (p &amp;lt; 0.001), and ED15-42 and age &amp;lt;1 year (p = 0.029). In the univariate analysis only initial high leukocyte count &amp;gt;100 × 109/L, was a significant predictor of early death. The overall TRD for the entire study period was 3.4%. The main cause of death were infections, mainly bacterial sepsis (10 children out of 22, 45.4%).ConclusionsHyperleukocytosis remains significant factor of early mortality in patients with AML, despite the introduction of various cytoreductive methods. Infections are still the main cause of treatment related deaths. A more individualized approach by using new targeted drugs may be the therapeutic option of choice in the future.

Single-cell sequencing technology to characterize stem T-cell subpopulations in acute T-lymphoblastic leukemia and the role of stem T-cells in the disease process.

Precursor T-cell acute lymphoblastic leukemia (Pre-T ALL) is a malignant neoplastic disease in which T-cells proliferate in the bone marrow. Single-cell sequencing technology could identify characteristic cell types, facilitating the study of the therapeutic mechanisms in Pre-T ALL. The single-cell sequencing data (scRNA-seq) of Pre-T ALL were obtained from public databases. Key immune cell subpopulations involved in the progression of Pre-T ALL were identified by clustering and annotating the cellular data using AUCell. Next, pseudo-temporal analysis was performed to identify the differentiation trajectories of immune cell subpopulations using Monocle. Copy number mutation landscape of cell subpopulations was characterized by inferCNV. Finally, cellphoneDB was used to analyze intercellular communication relationships. A total of 10 cellular subpopulations were classified, with Pre-T ALL showing a higher proportion of NK/T cells. NK/T cells were further clustered into two subpopulations. Stem T cells showed a high expression of marker genes related to hematopoietic stem cells, Naive T cells had a high expression of CCR7, CCR7, RCAN3, and NK cells high-expressed KLRD1, TRDC. The cell proliferation was reduced and the activation of T cell was increased during the differentiation of stem T cells to Naive T cells. We observed interaction between stem T cells with dendritic cells such as CD74-COPA, CD74-MIF as well as co-inhibition-related interactions such as LGALS9-HAVCR2, TGFB1-TGFBR3. Stem T cells were involved in the development of Pre-T-ALL through the regulatory effects of transcription factors (TFs) KLF2 and FOS and multiple ligand-receptor pairs.

High glucose condition aggravates inflammatory response induced by Porphyromonas gingivalis in THP-1 macrophages via autophagy inhibition

BackgroundPorphyromonase gingivalis (P. gingivalis) is a type of bacteria that causes periodontitis, which is strongly correlated with systemic diseases such as diabetes. However, the effect of hyperglycemia on periodontitis are unclear. The present study examined the effects of high glucose levels on the response to P. gingivalis infection.ResultsThe expression of P. gingivalis-induced interleukin-1β (IL-1β) and inflammasomes increased as the glucose concentration increased. High glucose conditions suppressed P. gingivalis–induced autophagy in human acute monocytic leukemia cell line (THP-1) macrophages. Zingerone increased autophagy and alleviated P. gingivalis-induced inflammatory response in THP-1 macrophages under high glucose conditions. In addition, P. gingivalis- induced inflammation in bone marrow-derived macrophages of diabetic mice was higher than in wild-type mice, but a zingerone treatment decreased the levels. Alveolar bone loss due to a P. gingivalis infection was significantly higher in diabetic mice than in wild-type mice.ConclusionsHigh-glucose conditions aggravated the inflammatory response to P. gingivalis infection by suppressing of autophagy, suggesting that autophagy induction could potentially to treat periodontitis in diabetes. Zingerone has potential use as a treatment for periodontal inflammation induced by P. gingivalis in diabetes patients.

An mHealth App to Support Caregivers in the Medical Management of Their Child With Cancer: Beta Stage Usability Study.

Previous research demonstrated that caregivers of children with cancer desired a mobile health (mHealth) tool to aid them in the medical management of their child. Prototyping and alpha testing of the Cope 360 app (Commissioning Agents, Inc) resulted in improvements in the ability to track symptoms, manage medications, and prepare for urgent medical needs. This study aims to engage caregivers of children with cancer in beta testing of a smartphone app for the medical management of children with cancer, assess acceptance, identify caregivers' perceptions and areas for improvement, and validate the app's design concepts and use cases. In this pilot, study caregivers of children with cancer used the Cope 360 mHealth app for 1 week, with the goal of daily logging. Demographics and a technology acceptance survey were obtained from each participant. Recorded semistructured interviews were transcribed and analyzed iteratively using NVivo (version 12, QSR International) and analyzed for information on usage, perceptions, and suggestions for improvement. A total of 10 caregivers participated in beta testing, primarily women (n=8, 80%), married, with some college education, and non-Hispanic White (n=10, 100%). The majority of participants (n=7, 70%) had children with acute lymphocytic leukemia who were being treated with chemotherapy only (n=8, 80%). Overall, participants had a favorable opinion of Cope 360. Almost all participants (n=9, 90%) believed that using the app would improve their ability to manage their child's medical needs at home. All participants reported that Cope 360 was easy to use, and most would use the app if given the opportunity (n=8, 80%). These values indicate that the app had a high perceived ease of use with well-perceived usefulness and behavioral intention to use. Key topics for improvement were identified including items that were within the scope of change and others that were added to a future wish list. Changes that were made based on caregiver feedback included tracking or editing all oral and subcutaneous medications and the ability to change the time of a symptom tracked or medication administered if unable to do so immediately. Wish list items included adding a notes section, monitoring skin changes, weight and nutrition tracking, and mental health tracking. The Cope 360 app was well received by caregivers of children with cancer. Our validation testing suggests that the Cope 360 app is ready for testing in a randomized controlled trial to assess outcome improvements.

Then and Now Treatment for Acute Leukemia in Older Adults: Two Decades of Remarkable Progress

<i>Then and Now</i> Treatment for Acute Leukemia in Older Adults: Two Decades of Remarkable Progress

Auer rod-positive acute leukemia with predominantly lymphoid immunophenotype: Report on 11 cases and review of literature.

Auer rods (AuRs) are prominent intracellular structures found almost exclusively in myeloid cell malignancies, such as acute myeloid leukemia (AML), chronic and juvenile myelomonocytic leukemia and myelodysplastic syndrome. Extremely rare AuRs have been reported in patients with acute lymphoblastic leukemia (ALL) or among ambiguous lineage leukemia patients with a dominantly lymphoblastic immunophenotype. We report diagnostic and follow-up data of an international cohort of 11 children suffering from leukemias with AuRs and with significant presence of T and myeloid markers, majority of whom categorized as early T-cell precursor (ETP, n=7); or T-ALL (ETP status unknown, n=2), ALAL (acute leukemia of ambiguous lineage, n=1), and AML reclassified from ALAL (n=1). We described other diagnostic details and treatment types and responses. Moreover, we summarize previously published data. Among the four patients who started and remained on ALL-type therapy, all were in the first complete remission, whereas both patients who started and remained on AML-type therapy relapsed and died. Of the patients who followed either a combined ALL/AML protocol (Interfant 06) or who switched from one of the two types of therapy to the other, one patient died, and the remaining four were in first complete remission at the most recent follow-up. We also searched for similar cases in the literature and found only three additional children with nonmyeloid leukemia and AuRs and 10 adults with this type of leukemia. Briefly, ALL- or combined ALL/AML-type therapy may be effective for treating AuR-positive leukemia patients with a lymphoid immunophenotype.