Risk Of Leukemia Research Articles

The global burden of childhood and adolescent leukaemia and attributable risk factors: An analysis of the Global Burden of Disease Study 2019.

Aim of this study is to estimate the burden of leukaemia in children and adolescents, as well as the socio-demographic index (SDI), for 21 regions around the world from 1990 to 2019. We also conducted an analysis of the Joinpoint model to estimate the time trend of childhood and adolescent leukaemia incidence, death, and disability-adjusted life years (DALYs) rate and age-standardised rates (ASR) of leukaemia. According to our analysis, the middle SDI experienced the highest decrease in incidence rate between 1990 and 2019, with an average annual percent change (AAPC) of -2.8 (95% confidence interval (CI) = -3.0, -2.6, P < 0.05). We showed that DALYs of children leukaemia is 155.98 (95% uncertainty interval (UI) = 127.18, 182.64) for global male, however, global female leukaemia DALYs is 117.65 (95% UI = 102.07, 132.70). Despite the observed decline in the incidence, mortality, and DALYs of leukaemia over the last three decades, the burden of childhood and adolescent leukaemia remains high, particularly in areas with lower SDI.

Cellular hierarchy insights reveal leukemic stem-like cells and early death risk in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) represents a paradigm for targeted differentiation therapy, with a minority of patients experiencing treatment failure and even early death. We here report a comprehensive single-cell analysis of 16 APL patients, uncovering cellular compositions and their impact on all-trans retinoic acid (ATRA) response in vivo and early death. We unveil a cellular differentiation hierarchy within APL blasts, rooted in leukemic stem-like cells. The oncogenic PML/RARα fusion protein exerts branch-specific regulation in the APL trajectory, including stem-like cells. APL cohort analysis establishes an association of leukemic stemness with elevated white blood cell counts and FLT3-ITD mutations. Furthermore, we construct an APL-specific stemness score, which proves effective in assessing early death risk. Finally, we show that ATRA induces differentiation of primitive blasts and patients with early death exhibit distinct stemness-associated transcriptional programs. Our work provides a thorough survey of APL cellular hierarchies, offering insights into cellular dynamics during targeted therapy.

Finite-Sample Bias of the Linear Excess Relative Risk in Cohort Studies of Computed Tomography-Related Radiation Exposure and Cancer.

The linear excess relative risk (ERR) is the most commonly reported measure of association in radiation epidemiological studies, when individual dose estimates are available. While the asymptotic properties of the ERR estimator are well understood, there is evidence of small sample bias in case-control studies of treatment-related radiation exposure and second cancer risk. Cohort studies of cancer risk after exposure to low doses of radiation from diagnostic procedures, e.g., computed tomography (CT) examinations, typically have small numbers of cases and risks are small. Therefore, understanding the properties of the estimated ERR is essential for interpretation and analysis of such studies. We present results of a simulation study that evaluates the finite-sample bias of the ERR estimated by time-to-event analyses and its confidence interval using simulated data, resembling a retrospective cohort study of radiation-related leukemia risk after CT examinations in childhood and adolescence. Furthermore, we evaluate how the Firth-corrected estimator reduces the finite-sample bias of the classical estimator. We show that the ERR is overestimated by about 30% for a cohort of about 150,000 individuals, with 42 leukemia cases observed on average. The bias is reduced for higher baseline incidence rates and for higher values of the true ERR. As the number of cases increases, the ERR is approximately unbiased. The Firth correction reduces the bias for all cohort sizes to generally around or under 5%. Epidemiological studies showing an association between radiation exposure from pediatric CT and cancer risk, unless very large, may overestimate the magnitude of the relationship, while there is no evidence of an increased chance for false-positive results. Conducting large studies, perhaps by pooling individual studies to increase the number of cases, should be a priority. If this is not possible, Firth correction should be applied to reduce small-sample bias.

Oral decitabine plus cedazuridine and venetoclax in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: a single-centre, phase 1/2 study

Hypomethylating agents are approved in higher-riskmyelodysplastic syndromes. The combination of a hypomethylating agent with venetoclax is standard of care in acute myeloid leukaemia. We investigated the safety and activity of the first totally oral combination of decitabine plus cedazuridine and venetoclax in patients with higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia. We did a single-centre, dose-escalation and dose-expansion, phase 1/2, clinical trial. Patients with treatment-naive higher-risk-myelodysplastic syndromes or chronic myelomonocytic leukaemia (risk level categorised as intermediate-2 or higher by the International Prognostic Scoring System) with excess blasts (>5%). Treatment consisted of oral decitabine 35 mg plus cedazuridine 100 mg on days 1-5 and venetoclax (variable doses of 100-400 mg, day 1 to 14, 28-day cycle). The primary outcomes were safety for the phase 1 part and the overall response for the phase 2 part of the study. The trial is ongoing and this analysis was not prespecified. This study is registered with ClinicalTrials.gov, NCT04655755, and is currently enrolling participants. Between Jan 21, 2021, and Jan 20, 2023, we enrolled 39 patients (nine in phase 1 and 30 in phase 2). The median age was 71 years (range 27-94), 28 (72%) patients were male, and 11 (28%) were female. The maximum tolerated dose was not reached, and the recommended phase 2 dose was established as oral decitabine 35 mg plus cedazuridine 100 mg for 5 days and venetoclax (400 mg) for 14 days. The most common grade 3-4 adverse events were thrombocytopenia (33 [85%] of 39), neutropenia (29 [74%]), and febrile neutropenia (eight [21%]). Four non-treatment-related deaths occurred on the study drugs due to sepsis (n=2), lung infection (n=1), and undetermined cause (n=1). The median follow-up time was 10·8 months (IQR 5·6-16·4). The overall response rate was 95% (95% CI 83-99; 37/39). 19 (49%) patients proceeded to hematopoietic stem-cell transplantation. This early analysis suggests that the combination of oral decitabine plus cedazuridine with venetoclax for higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia is safe in most patients, with encouraging activity. Longer follow-up will be needed to confirm these data. MD Anderson Cancer Center, MDS/AML Moon Shot, Genentech/AbbVie, and Astex Pharmaceuticals.

Abstract PR008: Cell state transitions drive the evolution of disease progression in B-cell acute lymphoblastic leukemia

Abstract A mathematical framework is constructed to predict the risk of B-lymphoblastic leukemia (B-ALL) relapse post-induction chemotherapy. The framework is a Markov chain model that quantifies spontaneous cell state transitions between distinct immunophenotypic subpopulations defined by CD34 and CD38 expression relative to neutrophils. Cell states are analyzed via flow cytometry pre- and post-treatment, providing insight into the evolution of cell state transition rates during disease progression. Cancer stem cells (CSCs) are hypothesized to promote tumor progression through innate chemoresistance and self-renewal. Ostensible CSCs were first identified in acute myeloid leukemia and were found to have a CD34+/CD38- immunophenotype similar to hematopoietic stem cells. However, the isolation of CSCs from B-ALL has proved more difficult. B-ALL cells with stem cell-like properties have been reported with variable immunophenotype, perhaps due to temporal variation of CD34 and CD38 expression in this setting. We hypothesized that transitions between stem cell-like, hematogone-like, and naive B-cell-like leukemia subpopulations play a significant role in B-ALL disease progression. To test this hypothesis, we trained a Markov chain mathematical model using flow cytometry characterization of four B-ALL cell states with their normal counterpart appearing in parentheses: CD34+/CD38- (hematopoietic stem cells), CD34+/CD38+ (stage 1 hematogones), CD34-/CD38+ (stage 2 and 3 hematogones), and CD34-/CD38- (naïve B-cells). An iterative numerical search procedure was used to derive patient-specific Markov matrices, describing the stochastic cell state transitions. This flow cytometry evaluation was performed on a cohort of patient samples of peripheral blood (N=46) and bone marrow (N=63) with matched clinical features such as BCR::ABL1 status, comprehensive genomic profiling, minimal residual disease (MRD) post-induction chemotherapy, and 3-year relapse. Critical to our goal of quantifying the evolution of state transition rates, we also obtained bone marrow measurements for a cohort of normal/healthy individuals. Patients were divided into post-induction flow MRD positive (N=16), MRD negative (N=30), healthy (N=6) cohorts, as well as relapsed and non-relapsed cohorts to compare features of the transition matrices. Importantly, pre-treatment flow cytometry derived cell state distribution alone is not predictive of relapse or MRD. In contrast, pre-treatment Markov chain transition parameters are found to be clinically predictive of relapse and MRD. MRD correlates to high reciprocity (the product of incoming and outgoing transitions) of the stem cell state. This approach provides supporting evidence that cell state transitions drive B-ALL disease progression. There is an additional strong correlation between Markov transition parameters and both BCR::ABL1 and BCR::ABL1-like B-ALL classification. Finally, comparison of Markov parameters pre- and post-treatment quantifies the evolutionary selection pressures acting on transition rates induced by chemotherapy treatment. Citation Format: Curtis Gravenmier, Ling Zhang, Lynn Moscinski, Jeffrey West. Cell state transitions drive the evolution of disease progression in B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR008.

Interaction between birth characteristics and CRHR1, MC2R, NR3C1, GLCCI1 variants in the childhood lymphoblastic leukemia risk.

The incidence rate of childhood acute lymphoblastic leukemia (ALL) differs worldwide, and the interplay between hemostasis actors and the maladaptive responses to environmental exposures has been explored. It has been proposed that endogenous cortisol, induced by different triggers, would eliminate pre-leukemic clones originated in utero. Herein, we tested if the interaction between CRHR1rs242941 C>A, MC2Rrs1893219 A>G, NR3C1rs41423247 G>C, and GLCCI1rs37972 C>T (players in glucocorticoid secretion) and birth characteristics would be associated with ALL risk. Children aged <10 years were enrolled within the EMiLI project (period: 2012 to 2020). The study had three steps: (1) observational analysis of birth characteristics (n = 533 cases and 1,603 controls); (2) genotyping to identify single-nucleotide variants (n = 756 cases and 431 controls); and (3) case-only to test gene-environment interactions (n = 402 cases). Genetic syndromes were exclusion criteria. The controls were healthy children. The distribution of the variables was assessed through Pearson's chi-square test. Logistic regression (LR) tests were run fitted and adjusted for selected covariate models to estimate the association risk. Formal interaction analysis was also performed. Genotyping was tested by qPCR with TaqMan probes (NR3C1) or by high-resolution melting (MC2R and GLCCI1). Hardy-Weinberg equilibrium (HWE) was accessed by the chi-square test. The genotype-risk association was tested in co-dominant, dominant, and recessive models. The gene-environment interaction odds ratio (iOR) was assessed in case-only. Low birthweight, C-section, and low maternal schooling were associated with increased risk for ALL, adjOR 2.11, 95% CI, 1.02-4.33; adjOR 1.59, 95% CI, 1.16-2.17; and adjOR 3.78, 95% CI, 2.47-5.83, respectively, in a multiple logistic regression model. MC2R rs1893219 A>G was negatively associated with ALL (AG: OR = 0.68; 95% CI = 0.50-0.94 and GG: OR = 0.60; 95% CI = 0.42-0.85), while for GLCCI1 rs37972 C>T, TT was positively associated with ALL (OR = 1.91; 95% CI = 1.21-3.00). The combination of genotypes for MC2R (AA) and GLCCI1 (TT) increased ALL risk (OR = 2.61; 95% CI = 1.16-5.87). In a multiplicative interaction, MC2R rs1893219 A>G was associated with children whose mothers had less than 9 years of schooling (iOR = 1.99; 95% CI = 1.11-1.55). Our study has demonstrated a significant association between MC2R rs1893219 A>G (reduced risk) and GLCCI1 rs37972 C>T variants (increased risk) and childhood ALL susceptibility. Based on this evidence, genes controlling the HPA axis activity may play a role in leukemogenesis, and further investigation is needed to substantiate our findings.

Wood Dust and Risk of Leukemia: A Protocol of Systematic Review and Meta-Analysis

Background: Leukemia is a type of cancer caused by the growth of blood cells, especially in the bones and blood. Although extensive research has investigated various environmental factors that increase the risk of leukemia, the relationship between dust exposure and leukemia remains a topic of interest. Wood dusting is a common activity in industries such as carpentry and woodworking, and its potential link to leukemia warrants a comprehensive review to evaluate the available evidence. Understanding this organization is important for occupational health and safety advice and will assist in prevention strategies for those at risk. Methods: We conducted a systematic review and analysis of the existing literature on the relationship between wood dust and leukemia. A comprehensive search of electronic databases, including PubMed, Scopus, and Web of Science, was conducted to identify relevant studies up to the date of review. Methods included peer-reviewed literature, cohort studies, case-control studies, and meta-analyses of peer-reviewed studies such as chip injury and leukemia. Priority will be given to studies with clear evaluation criteria and strong analytical ability. Results: The review identified a total of [X] studies that met the inclusion criteria. These studies reveal different groups of people and workplaces with different levels of wood dust. The extracted data showed various associations between wood dust and leukemia, including positive, negative or neutral effects. Meta-analyses were conducted to provide a synthesis of the available evidence. Subgroup analysis was based on characteristics such as study design, population characteristics, and dust levels. A sensitivity analysis was performed to evaluate the effectiveness of all outcomes. Potential sources of heterogeneity between studies were explored and the quality of evidence was assessed by design.

The Role of Chloroform Exposure and Risk of Leukemia: A Protocol of Systematic Review and Meta-Analysis

Background: Leukemia is a serious health problem and the possibility of its association with chloroform raises the question of environmental risk. This systematic review aims to provide a comprehensive review of the available evidence on the association between chloroform and leukemia. Methods: Qualitative research using qualitative methods in primary literature. Studies were selected and data extracted, followed by qualitative analysis. Meta-analysis, subgroup analysis, sensitivity analysis, dose-response analysis, heterogeneity study, integration of GRADE assessment, forest plots, published results, assessment of the prevalence of injustice, and fairness judgments are systematically addressed.Results: The study selection process outlined inclusion and exclusion criteria. Descriptive analysis describes the key characteristics of the included studies, while quantitative analysis presents the results of the meta-analysis. A sensitivity analysis assessed the quality of the results and examined publication bias due to poor reporting. Conclusion: This systematic review summarizes the current evidence on chloroform exposure and leukemia risk and provides public information for future research and health interventions.

A phase II study of maintenance rucaparib in patients with platinum sensitive, advanced pancreatic cancer and a pathogenic germline or somatic variant in BRCA1, BRCA2 or PALB2: A four year survival update.

661 Background: We previously reported the results of a single arm, phase II study of maintenance rucaparib in patients with advanced, platinum-sensitive pancreatic cancer and pathogenic germline or somatic BRCA1, BRCA2 or PALB2 variants (Reiss et al, JCO, 2021). We now report the five year follow-up of this trial. Methods: Patients with advanced PC and a pathogenic germline or somatic variant in BRCA1, BRCA2 or PALB2 were enrolled in this single arm phase II study performed at the Abramson Cancer Center. Patients were required to have received ≥16 weeks of platinum-based treatment without evidence of platinum resistance, which was defined as growing lesions, new lesions or steadily rising tumor markers. Chemotherapy was discontinued and patients received rucaparib 600mg PO BID until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: Of 42 evaluable patients, seven (16.7%) remain progression-free for over four years (5 gBRCA2, 1 sBRCA2, 1 gPALB2) of whom four (9.5%) have been progression-free for five years. Two of these four patients discontinued rucaparib due to adverse events after three and four years of therapy, respectively, without signs or symptoms of progression to date. At the cutoff date, we observe an mPFS 12.9 months, mOS 24.3 months, ORR 41.6% (9 PRs, 6 CRs), noting that three patients converted from partial to complete response since our prior publication. Two patients with ongoing responses succumbed to treatment-related MDS/AML following 2.1 and 4.8 years on study, respectively. Prior to receiving rucaparib, these individuals had received 13 and 10 months of cytotoxic chemotherapy for pancreatic cancer, respectively. Conclusions: Here we report the four year progression-free survival rate of maintenance rucaparib in patients with BRCA or PALB2 related pancreatic cancer. Our data suggest that a select portion of this patient population achieves highly durable clinical remissions. This finding is further highlighted by two patients who have discontinued rucaparib for adverse events one and two years ago, respectively, and have not had biochemical or imaging evidence of progression to date. Given the cost and risk of treatment-related leukemia associated with PARP inhibition, this data highlights the need to better understand the highly variable biology of patients with PC and BRCA or PALB2 variants, and raises the possibility of whether a very small, select group may be cured by PARP inhibitors. Clinical trial information: NCT03140670 .

Effects of Prenatal Breastfeeding Education on Breastfeeding Duration Beyond 12 Weeks: A Systematic Review.

The proportion of infants in the United States who are breastfed at 1 year remains well below the Healthy People 2030 target. The health implications of suboptimal breastfeeding durations are significant, including increased risk of childhood leukemia and maternal Type 2 diabetes. Prenatal breastfeeding education provides an opportunity to improve breastfeeding self-efficacy among pregnant individuals and to establish their coping skills in case future breastfeeding problems arise. Although prenatal breastfeeding education is known to improve breastfeeding self-efficacy, characteristics of prenatal breastfeeding education interventions that are successful at increasing breastfeeding duration have not been well defined. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and the Health Action Process Approach, we conducted a systematic review of the literature examining the impact of prenatal breastfeeding education interventions on breastfeeding duration measured at least 12 weeks postpartum. Twenty-one studies were identified. Prenatal breastfeeding education was most likely to increase breastfeeding duration when education interventions integrated psychological components (Health Action Process Approach coping planning) or were paired with in-person postpartum breastfeeding support. Additional research is needed to examine the role of psychological components in breastfeeding education interventions in diverse populations and to determine the specific psychological intervention components with the greatest impact on breastfeeding duration.

The genetic risk of acute lymphoblastic leukemia and its implications for children of Latin American origin.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and disproportionately affects children of Hispanic/Latino ethnicity in the United States, who have the highest incidence of disease compared with other racial/ethnic groups. Incidence of childhood ALL is similarly high in several Latin American countries, notably in Mexico, and of concern is the rising incidence of childhood ALL in some Hispanic/Latino populations that may further widen this disparity. Prior studies have implicated common germline genetic variants in the increased risk of ALL among Hispanic/Latino children. In this review, we describe the known disparities in ALL incidence as well as patient outcomes that disproportionately affect Hispanic/Latino children across the Americas, and we focus on the role of genetic variation as well as Indigenous American ancestry in the etiology of these disparities. Finally, we discuss future avenues of research to further our understanding of the causes of the disparities in ALL incidence and outcomes in children of Latin American origin, which will be required for future precision prevention efforts.

Epidemiology of childhood acute leukemias

Abstract Acute leukemias are the largest group of childhood cancers. According to the latest WHO data 80,491 leukemias were diagnosed in 2020 alone. In the coming years the incidence worldwide will continue at a similar level. The morbidity correlates with biological determinants such age, gender and race. The etiology of leukemia formation is complex and depends on genetic, physiological, environmental and even prior treatment-related factors. Both the incidence and curability are also influenced by age, gender, and race. The peak of incidence of leukemia occurs between the ages of 1–4 years and 9–19. The etiology of leukemia formation is complex and depends on genetic, physiological, environmental and even prior treatment-related factors. Boys suffer from leukemia more often than girls. In 2020 58.2% of diagnoses were for boys. Numerous factors contribute to the development of acute leukemia. In the case of young children, a notable association exists between acute leukemia and infections caused by viruses such as EBV or HHV-6. Furthermore, the risk of leukemia can be elevated by allergies, which involve Th1/Th2 lymphocyte-dependent mechanisms. A familial predisposition to tumorigenesis in children is observed in Li-Fraumeni Syndrome. Also, genetic diseases such as Down syndrome and Fanconi anemia are associated with an increased risk of acute leukemia. Previous exposure to radiation therapy or the use of anti-cancer drugs can also lead to the development of secondary cancers, including leukemia. The analysis of risk factors can be used to support efforts aimed to reduce potentially harmful exposure and to decrease the risk of disease.

Leukemia risk assessment of exposure to low-levels of benzene based on the linearized multistage model.

To assess leukemia risk in occupational populations exposed to low levels of benzene. Leukemia incidence data from the Chinese Benzene Cohort Study were fitted using the Linearized multistage (LMS) model. Individual benzene exposure levels, urinary S-phenylmercapturic acid (S-PMA) and trans, trans-muconic acid (t, t-MA) were measured among 98 benzene-exposed workers from factories in China. Subjects were categorized into four groups by rounding the quartiles of cumulative benzene concentrations (< 3, 3-5, 5-12, ≥12 mg/m3·year, respectively). The risk of benzene-induced leukemia was assessed using the LMS model, and the results were validated using the EPA model and the Singapore semi-quantitative risk assessment model. The leukemia risks showed a positive correlation with increasing cumulative concentration in the four exposure groups (excess leukemia risks were 4.34, 4.37, 4.44 and 5.52 × 10-4, respectively; Ptrend < 0.0001) indicated by the LMS model. We also found that the estimated leukemia risk using urinary t, t-MA in the LMS model was more similar to those estimated by airborne benzene compared to S-PMA. The leukemia risk estimated by the LMS model was consistent with both the Singapore semi-quantitative risk assessment model at all concentrations and the EPA model at high concentrations (5-12, ≥12 mg/m3·year), while exceeding the EPA model at low concentrations (< 3 and 3-5 mg/m3·year). However, in all four benzene-exposed groups, the leukemia risks estimated by these three models exceeded the lowest acceptable limit for carcinogenic risk set by the EPA at 1 × 10-6. This study demonstrates the utility of the LMS model derived from the Chinese benzene cohort in assessing leukemia risk associated with low-level benzene exposure, and suggests that leukemia risk may occur at cumulative concentrations below 3 mg/m3·year.

Refining the relationship between gut microbiota and common hematologic malignancies: insights from a bidirectional Mendelian randomization study.

The relationship between gut microbiota and hematologic malignancies has attracted considerable attention. As research progresses, it has become increasingly clear that the composition of gut microbiota may influence the onset and progression of hematologic malignancies. However, our understanding of this association remains limited. In our study, we classified gut microbiota into five groups based on information at the phylum, class, order, family, and genus levels. Subsequently, we obtained data related to common hematologic malignancies from the IEU Open GWAS project. We then employed a bidirectional Mendelian Randomization (MR) approach to determine whether there is a causal relationship between gut microbiota and hematologic malignancies. Additionally, we conducted bidirectional MR analyses to ascertain the directionality of this causal relationship. Through forward and reverse MR analyses, we found the risk of lymphoid leukemia was significantly associated with the abundance of phylum Cyanobacteria, order Methanobacteriales, class Methanobacteria, family Peptococcaceae, family Methanobacteriaceae, and genera Lachnospiraceae UCG010, Methanobrevibacter, Eubacterium brachy group, and Butyrivibrio. The risk of myeloid leukemia was significantly associated with the abundance of phylum Actinobacteria, phylum Firmicutes, order Bifidobacteriales, order Clostridiales, class Actinobacteria, class Gammaproteobacteria, class Clostridia, family Bifidobacteriaceae, and genera Fusicatenibacter, Eubacterium hallii group, Blautia, Collinsella, Ruminococcus gauvreauii group, and Bifidobacterium. The risk of Hodgkin lymphoma was significantly associated with the abundance of family Clostridiales vadinBB60 group, genus Peptococcus, and genus Ruminococcaceae UCG010. The risk of malignant plasma cell tumor was significantly associated with the abundance of genera Romboutsia and Eubacterium rectale group. The risk of diffuse large B-cell lymphoma was significantly associated with the abundance of genera Erysipelatoclostridium and Eubacterium coprostanoligenes group. The risk of mature T/NK cell lymphomas was significantly associated with the abundance of phylum Verrucomicrobia, genus Ruminococcaceae UCG013, genus Lachnoclostridium, and genus Eubacterium rectale group. Lastly, the risk of myeloproliferative neoplasms was significantly associated with the abundance of genus Coprococcus 3 and Eubacterium hallii group. Our study provided new evidence for the causal relationship between gut microbiota and hematologic malignancies, offering novel insights and approaches for the prevention and treatment of these tumors.

Diagnostic and Prognostic Value of DNA Repair Gene XRCC1 ARG399GLN Polymorphism in Childhood Acute Lymphoblastic Leukemia: A Single-Center Egyptian Study

Background Repair pathways for DNA damage are essential for repairing various forms of DNA damage. Leukemia risk may be increased by poor DNA repair. This study was conducted to better understand the significance of XRCC1Arg399 Gln polymorphisms in acute lymphoblastic leukemia (ALL) susceptibility and prognosis. Patients and methods Twenty children with ALL participated in the pediatric trial at Tanta University. Thirty healthy controls were of the same age and sex. Complete blood counts, bone marrow aspirates, immunophenotyping, flow cytometry, and XRCC1 genotyping by PCR were performed. Results The allele Gln/Gln was found in one (3.3%) of the controls and two (10%) cases had an odds ratio of 0.13 (0.27–38.1), P=0.34. Eight (40%) patients and six controls [odds ratio of 2.66 (0.75–9.4), P=0.11], had the Arg/Gln allele. Finally, 23 (76.7%) members of the control group and 10 (50%) patients carried this allele (Arg/Arg). The genotype’s prognostic value for alleles: two (20%) of patients with the allele (Arg/Arg) were refractory. Two (25%) patients died during the induction for the allele (Arg/Gln), while four (50%) patients were refractory. Last but not least, no one experienced total remission under the allele (Gln/Gln). Conclusion The XRCC1 polymorphism is not linked to the development of ALL; nevertheless, having mutant alleles was linked to a poorer prognosis.

Deciphering the Causal Relationship between Sodium-glucose Cotransporter 2 Inhibition and Cancer Risks: A Comprehensive Mendelian Randomization Study.

Background: Controversy persists regarding the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cancer. The underlying causal relationship remains unclear. Method: A two-sample Mendelian randomization (MR) strategy was employed to investigate the causal associations between SGLT2 inhibitors and 26 site-specific malignancies. Instrumental variants strongly associated with SLC5A2 gene expression and glycated hemoglobin A1c levels were identified as the genetic proxy for SGLT2 inhibition. Cancer-related outcome datasets sourced from the OpenGWAS project were separated into discovery and replication datasets. The meta-analysis was conducted to determine the final causality. Results: Genetically proxied SGLT2 inhibition showed a significant association with bronchial and lung cancer (beta: -0.028 [-0.041, -0.015], P < 0.001), bladder cancer (beta: 0.018 [0.008, 0.027], P < 0.001), prostate cancer (beta: 1.168 [0.594, 1.742], P < 0.001), cervical cancer (beta: -0.019 [-0.031, -0.008], P = 0.001), corpus uterine cancer (beta: 0.015 [0.006, 0.025], P = 0.001) and non-melanoma skin cancer (beta: -0.080 [-0.116, -0.044], P < 0.001) in the discovery cohort. The suggestive causal effect of SGLT2 inhibition on the increased risk of cervical cancer (beta: 3.241 [0.855, 5.627], P = 0.008) and lymphoid leukemia (beta: 4.126 [0.383, 7.868], P = 0.031) was found in the replication cohort. The combined causality of the following types of cancer was observed to remain significant after meta-analysis: bronchial and lung cancer, bladder cancer, prostate cancer, corpus uterine cancer, and non-melanoma skin cancer (all P ≤ 0.001). Conclusion: For the first time we discovered that the SGLT2 inhibition may exert protection on bronchial and lung cancer and non-melanoma skin cancer from a genetic perspective. However, suggestive higher cancer risks of bladder, prostate, and corpus uteri were also noted, which warrants real-world data validation in the future.

Response to "Comment on 'Association between Residential Proximity to Viticultural Areas and Childhood Acute Leukemia Risk in Mainland France: GEOCAP Case-Control Study, 2006-2013'".

Response to "Comment on 'Association between Residential Proximity to Viticultural Areas and Childhood Acute Leukemia Risk in Mainland France: GEOCAP Case-Control Study, 2006-2013'".

Residential exposure to magnetic fields from transformer stations and risk of childhood leukemia

BackgroundSeveral studies have documented an increased risk of leukemia among children exposed to magnetic fields from high-voltage power lines, with some evidence of dose-response relation. However, findings in some studies have been inconsistent, and data on the effects of different sources of exposure are lacking. In this study, we evaluated the relation of childhood leukemia risk to exposure to magnetic fields from transformer stations. MethodsWe conducted a population-based case-control study in a pediatric population of two Northern Italian provinces of Modena and Reggio Emilia. We included 182 registry-identified childhood leukemia cases diagnosed during 1998–2019 and 726 population controls matched on sex, year of birth, and province of residence. We assessed exposure by calculating distance from childhood residence to the nearest transformer station within a geographical information system, computing disease odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, adjusting for potential confounders. We evaluated exposure using two buffers (15 m and 25 m radius) and assessed two case groups: leukemia (all subtypes) and acute lymphoblastic leukemia (ALL). ResultsResiding within 15 m of a transformer station (vs. ≥15 m) was not appreciably associated with risk of leukemia (all subtypes) or ALL. We found similar results using a less stringent exposure buffer (25 m). Among children aged ≥5 years, the adjusted ORs were 1.3 (95% CI 0.1–12.8) for leukemia and 1.3 (95% CI 0.1–12.4) for ALL using the 15 m buffer, while they were 1.7 (95% CI 0.4–7.0) for leukemia and 0.6 (95% CI 0.1–4.8) for ALL using the 25 m buffer. ConclusionsWhile we found no overall association between residential proximity to transformer stations and childhood leukemia, there was some evidence for elevated risk of childhood leukemia among children aged ≥5 years. Precision was limited by the low numbers of exposed children.

Higher cyclosporine-A concentration increases the risk of relapse in AML following allogeneic stem cell transplantation from unrelated donors using anti-thymocyte globulin

Cyclosporine-A (CsA) is used to prevent acute graft-versus-host disease (aGvHD). European Society for Blood and Marrow transplantation (EBMT) recommends a CsA target serum concentration of 200–300 µg/L during the first month after allogeneic hematopoietic stem cell transplantation (HSCT). With this study, we investigated whether a median CsA concentration > 200 µg/L (CsAhigh) the first month after HSCT, compared to ≤ 200 µg/L (CsAlow), increased the relapse risk of acute myloid leukemia (AML), using unrelated donors (URD) and antithymocyte globulin (ATG). Data was collected from 157 patients with AML, transplanted 2010–2016. The cumulative incidence of relapse (CIR) at 60 months was 50% in the CsAhigh versus 32% in the CsAlow group (p = 0.016). In univariate analysis, CsAhigh versus CsAlow (p = 0.028), 10-unit increase of CsA as a continuous variable (p = 0.017) and high risk disease (p = 0.003) were associated with higher CIR. The results remained after adjusting for disease risk. Death following relapse occurred more frequently in the CsAhigh group (p = 0.0076). There were no significant differences in rates of aGvHD, chronic GvHD (cGvHD), EBV/CMV-infections or overall survival (OS) between the two groups. In conclusion, we found that a median CsA concentration > 200 µg/L, the first month after HSCT, results in higher CIR of AML when combined with ATG.

Global burden of leukemia attributable to occupational exposure to formaldehyde from 1990 to 2019.

The objective of this study was to evaluate the worldwide burden of leukemia owing to occupational exposure to formaldehyde (OEF) from 1990 to 2019. Data on leukemia due to OEF were obtained from the Global Burden of Disease Study (GBD) 2019. By region, age, sex, and disease subtype, the numbers and age-standardized rates (ASRs) associated with deaths, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs) were analyzed. Annual average percentage change (AAPC) was used to estimate disease burden trends from 1990 to 2019. To measure the risk of leukemia due to OEF, the population attributable fraction (PAF) was introduced. From 1990 to 2019, the number of deaths, DALYs, YLLs, and YLDs for leukemia caused by OEF increased by 44%, 34%, 33%, and 124%, respectively. Regarding the change in ASRs, the age-standardized YLDs (ASYLDs) rate of leukemia due to OEF, which was 38.03% (AAPC = 1.17 [95% confidence interval [CI] 1.11, 1.23]), indicated an increased trend. But the age-standardized mortality rate (ASMR), age-standardized DALY (ASDALY) rate, and age-standardized YLL (ASYLL) rate showed decline trends, with - 11.90% (AAPC = - 0.41 [95% CI - 0.45, - 0.37]), - 14.19% (AAPC = - 0.5 [95% CI - 0.55, - 0.45]), and - 14.97% (AAPC = - 0.53 [95% CI - 0.58, - 0.48]), respectively. In terms of PAFs, there were increasing trends in PAFs of age-standardized deaths, ASDALYs, ASYLLs, and ASYLDs for leukemia caused by OEF, with 20.15% (95% uncertainty interval [UI] 11.76%, 30.25%), 36.28% (95% UI 21.46%, 53.42%), 51.91% (95% UI 35.05%, 72.07%), and 36.34% (95% UI 21.58%, 53.63%), respectively. Across the socio-demographic index (SDI) regions, the leukemia burden caused by OEF was concentrated in middle and high-middle SDI regions. Besides, OEF poses a more serious risk for acute leukemia among the leukemia subtype. Globally, leukemia caused by OEF remains a public health burden. Policies must be developed to avoid the burden of leukemia caused by OEF.