Search Results (65)

Background: Myeloid sarcoma (MS) is a malignant extramedullary tumor that occurs in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myeloid leukemia (CML). The standard first-line treatment for MS is intensive chemotherapy according to the AML protocol, regardless of bone marrow involvement. The role of allogeneic hematopoietic stem cell transplantation (alloHSCT) in the treatment of pediatric patients with MS requires further investigation. The aim of the study was to evaluate treatment outcomes for MS in pediatric patients with a focus on assessing the impact of allogeneic hematopoietic stem cell transplantation (alloHSCT) on treatment efficacy. Material and Methods: The study included 64 patients aged 0 to 19 years from 15 pediatric oncology centers in Poland who were diagnosed with MS between 1998 and 2024. An Excel database was created to collect data on clinical features and treatment methods and outcomes. Results: The probability of 5-year overall survival (pOS) for the entire cohort was 0.63 ± 0.07, while the 5-year event-free survival (pEFS) and 5-year relapse-free survival (pRFS) were 0.62 ± 0.07 and 0.72 ± 0.07, respectively. Treatment outcomes were compared between patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (ICR) (n1 = 17/64; 27%) and those who did not receive alloHSCT (n2 = 47/64; 73%). In the alloHSCT group (n1), the estimated survival probabilities were pOS = 0.49 ± 0.13, pEFS = 0.44 ± 0.14, and pRFS = 0.40 ± 0.14. In the non-alloHSCT group (n2), these values were pOS = 0.68 ± 0.08, pEFS = 0.68 ± 0.08, and pRFS = 0.84 ± 0.06. The difference in pRFS between groups n1 and n2 was statistically significant (p = 0.0049). Extramedullary relapses were more frequently observed in patients who had undergone allogeneic hematopoietic stem cell transplantation (alloHSCT) (p = 0.0001). Conclusions: Allogeneic hematopoietic stem cell transplantation (alloHSCT) does not improve the outcome of patients with MS. Further research is needed to identify effective strategies for sustaining remission in patients with MS after alloHSCT. Full article

Estimating how crop yield responds to site-specific nitrogen (N) fertilization is essential for maximizing yield potential under variable field conditions. However, classical Machine Learning (ML) approaches applied to observational farm data primarily focus on yield prediction and often fail to recover causal N response due to confounding arising from non-random fertilizer application. In this study, we develop and evaluate a Causal Machine Learning (CML) framework to estimate heterogeneous N treatment effects under real commercial rice-farming conditions in the Axios River Plain, Greece. The proposed approach combines Double Machine Learning (DML) with remote sensing, soil, climatic, and management data to adjust for confounding and identify causal relationships between N inputs, Leaf Nitrogen Concentration (LNC), and yield. A doubly robust (DR) learner is used to estimate yield sensitivity to N at key agronomic thresholds, while a Causal Forest model leverages LNC to assess crop physiological N status. Results demonstrate that the CML-based framework outperforms conventional XGBoost predictive models in identifying field plots that are responsive to additional N. By integrating causal effect estimation with plant-status information, the proposed decision support system identifies zones where yield gains can be achieved through targeted N increases while avoiding overfertilization in non-responsive areas. Full article

Background/Objectives: Radotinib is a second-generation tyrosine kinase inhibitor (TKI) that has been used for treatment of chronic myeloid leukemia (CML). This study was performed for the first time to characterize the pharmacokinetics of radotinib, identify the factors contributing to pharmacokinetic variabilities and explore alternative dosing regimens. Methods: A total of 640 plasma concentration–time datapoints obtained from 47 participants were evaluated using nonlinear mixed-effects modeling to estimate pharmacokinetic parameters and evaluate covariate effects. The study population comprised 23 healthy volunteers (HVs) who received a single, oral dose of 400 mg radotinib and 24 CML patients who repeatedly received 300 mg twice daily. Based on the final population pharmacokinetic model, alternative dosing regimens to the current every 12 h regimen were explored using Monte Carlo simulations. Results: A two-compartment model with first-order absorption through transit compartments and first-order elimination incorporating a circadian rhythm effect best described radotinib pharmacokinetics. Disease status significantly affected apparent clearance; it was slower by 39.2% in CML patients compared with HVs (23.0 L/h versus 37.9 L/h), resulting in a longer terminal half-life (28.8 h versus 17.5 h). Age was negatively associated with volume of distribution in the central compartment, with an estimated slope of −0.0129 L/year. A 400 mg once-daily regimen was predicted to provide comparable systemic exposures to those of other TKIs with similar physiochemical and pharmacological properties to radotinib, and a 36% lower exposure than that of the current 300 mg twice-daily regimen. Conclusions: The model developed in this study adequately describes the population pharmacokinetics of radotinib and provides a basis for optimal, individualized radotinib therapy for patients with CML. Full article

Background/Objectives: The advent of tyrosine kinase inhibitors (TKIs) revolutionized the management of chronic myeloid leukemia (CML), achieving survival rates near those of the general population. Despite this success, prolonged therapy presents challenges, including physical, emotional, and financial burdens. Treatment-free remission (TFR), defined as sustained deep molecular response (DMR) after discontinuing TKIs, has emerged as a viable clinical goal. This study evaluates real-world data from the Canary Islands Registry of CML (RCLMC) to explore outcomes, predictors, and the feasibility of TFR. Methods: This retrospective observational study included 393 patients diagnosed with CML-CP between 2007 and 2023. Molecular response was monitored according to international guidelines. Survival probabilities were estimated using the Kaplan–Meier method. Logistic regression analysis was performed to identify predictors of molecular relapses after TKI discontinuation. Results: Of the 383 patients who received TKI treatment, 58.3% achieved molecular response grade 2 (MR2) (BCR-ABL1 ≤ 1%), 95.05% achieved MR2, and 50.5% reached MR4 within the first year. Of the 107 patients attempting TFR, 73.2% maintained remission at 36 months. Relapses occurred in 24 patients, all regaining molecular response upon reintroduction of TKIs. No cases of disease progression were observed. Conclusions: Our findings support the feasibility and safety of TFR in a real-world clinical setting for well-selected patients, with outcomes consistent with international studies. The study underscores the importance of molecular monitoring and patient-specific strategies to optimize outcomes. Full article

When breastfeeding is not possible, infant formulas may be used instead of human milk. However, harmful advanced glycation end-products (AGEs) may be formed during thermal processing of infant formulas. The exposure to AGEs at such an early age can lead to chronic diseases in the future. Therefore, the aim of this study was to develop a sensitive method to determine the content of AGEs in infant formulas. Twenty commercial infant formulas (initial and follow-on) in liquid and powder form were investigated using liquid chromatography with tandem mass spectrometry (LC-MS/MS) with a multistep sample pretreatment procedure. Five selected glycation products were analyzed: N^ε-carboxyethyllysine (CEL), N^ε-carboxymethyllysine (CML), furosine, glyoxal lysine dimer (GOLD), and methylglyoxal lysine dimer (MOLD). The mean contents of the tested glycation products did not differ significantly between the initial and follow-on formulas. No significant differences were found in the concentrations of the analyzed compounds from different manufacturers. However, the liquid formulas contained significantly more CML. The estimated dietary exposure to the tested compounds was in the range of 42.5–92.6 μg/day, except for furosine (almost 2 mg/day). The developed method enabled the determination of selected AGEs in complex matrices such as infant formulas. Consumption of liquid infant formulas can result in higher exposure to some AGEs. Full article

Background/Objectives: Patients with chronic myeloid leukemia (CML) have a long life expectancy due to modern treatment. However, treatment may have adverse effects that hamper work ability. Methods: Patients aged 25–60 years diagnosed in 2002–2020 were included in this nationwide matched cohort study examining work ability from diagnosis (index date), including the need for permanent disability compensation (flexible job or disability pension). Each patient was matched 1:5 on sex, birth year, and level of comorbidity with citizens from the general Danish population without CML. The risks of requiring flexible job and disability pension were calculated by cause-specific hazard ratios (HRs) using Cox proportional hazards regression, and the Aalen–Johansen estimator was used to determine cumulative risks. Results: A total of 489 patients with CML and 2445 matched comparators were included. The median age was 46 years, and males comprised 59.5% of the cohort. Matched comparators were more likely to work at index date and 1, 3, 5, and 10 years after the index date (p < 0.001). The HRs of requiring both flexible job (HR 8.7 (95% confidence interval (CI): 6.1;12.2, p < 0.001)) and disability pension (HR 3.7 (95% CI: 2.8;4.9, p < 0.001)) were higher among patients diagnosed with CML compared to matched comparators. The cumulative risk of requiring flexible job and disability pension also increased in patients with CML compared to matched comparators (p < 0.001). Conclusions: Patients with CML have a reduced work ability compared to the general population. More research is needed to determine the cause of their loss of ability to work. Full article

Missense mutations in the BCR::ABL1 kinase domain are found in approximately 12–80% of patients with chronic myeloid leukemia (CML). Clinically significant mutations include T315I, M244V, Y253H/F, E255K/V, V299L, and F359V. The aim of this study was to create a diagnostic system for rapid and inexpensive detection of the above mutations. We used genomic DNA and RNA from peripheral blood and bone marrow cells of 57 patients with a Ph-positive CML diagnosis established in the chronic phase. We have developed a method to detect mutations in the BCR::ABL1 gene based on allele-specific real-time polymerase chain reaction (AS-PCR). In parallel, we analyzed the RNA sequence of the protein kinase domain of the same samples by next-generation sequencing (NGS) covering the points of putative mutations. In this work, we compared the results obtained by both methods for mutation detection and variant allele frequency (VAF) estimation of mutated vs. normal alleles. The sensitivity and specificity of our diagnostic system were also evaluated. It was found that AS-PCR gives reliable results at VAF up to 0.01%. AS-PCR has high sensitivity and may serve as an alternative for the more time-consuming NGS in some cases, as well as for monitoring CML treatment and for analyzing archival material. Full article

Background: Renal adverse drug reactions (ADRs) associated with tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML) are relatively rare, and there is currently no standardized protocol for their management. Therefore, this study aimed to summarize renal ADRs related to TKIs use in CML and propose an evidence-based approach to monitor and manage these ADRs. Methods: A systematic literature review was performed to identify renal ADRs associated with TKIs in CML. Two authors screened the search results and extracted data from 37 eligible studies. These findings were then used to develop a scheme for clinicians to monitor and manage these ADRs. Results: Overall, imatinib seemed to be significantly linked to renal adverse events compared to other TKIs, and switching to dasatinib or nilotinib significantly improved renal function. Similar events were reported with bosutinib, although they were not statistically significant. However, most of the renal events reported on dasatinib were described as nephrotic syndrome that resolved with switching to imatinib. Few cases were reported with nilotinib that described tumor lysis syndrome (TLS)-related kidney injury. Conclusions: Recommendations include monitoring for progressive decline in the estimated glomerular filtration rate with imatinib, nephrotic syndrome with dasatinib, and TLS with nilotinib. Additionally, holding the offending TKI and managing renal ADRs according to local guidelines were adopted more frequently than reducing the TKI dose. Full article

The brown wheat mite, Petrobia tritici, poses a significant threat to wheat fields. While fertilizers can increase crop productivity, imbalanced application may exacerbate plant susceptibility to pests. This study aimed to evaluate the impact of various NPK fertilization programs on P. tritici infestations over two consecutive cropping seasons. The results revealed significant differences in mite infestation among the treatment groups (p < 0.001). The lowest populations (1.1 and 3.0 mites/leaf) were observed in the treatments sprayed with phosphoric acid (at 0.75 and 1.00 cm/L), where the infestation appeared approximately 120 days after sowing; in contrast, it appeared early at 75 days in the other treatments. Conversely, treatments lacking potassium fertilizer presented the greatest degree of mite injury levels (49.5–57.7 mites/leaf). Although these treatments provided moderate leaf nutrition and crop yield, the highest nutritional content and total yield (10.49 and 9.71 1 t/ha for the two years) were observed in the treatment that received 224:70:100 kg fad⁻¹ commercial fertilizers (=178:25:114 kg ha⁻¹ NPK units) as soil fertilization, which was followed by the treatment with a foliar application of phosphoric acid (1.00 cm/L) with a total yield of 9.34 and 8.53 1 t/ha for the two years. In this treatment, the P. tritici density was moderately high at 9.40 and 6.32 mites/leaf over the two years, respectively. The consistency of P. tritici density and total yield ranking across both years indicated reliable estimates of the impact of fertilization. This study suggests that potassium sulfate application is crucial for reducing P. tritici density and that foliar phosphoric acid application instead of soil application reduces the number of P. tritici and delays its occurrence. Full article

Current therapy in chronic myeloid leukemia (CML) has improved patient life expectancy close to that of healthy individuals. However, molecular alterations other than BCR::ABL1 fusion gene in CML are barely known. MicroRNAs are important regulators of gene expression, and variants in some of the components of microRNA biosynthesis pathways have been associated with genetic susceptibility to different types of cancer. Thus, the aim of this study was to evaluate the association of variants located in genes involved in the biogenesis of microRNAs with susceptibility to CML. Fifteen variants in eight genes involved in the biogenesis of miRNAs were genotyped in 296 individuals with CML and 485 healthy participants using TaqMan probes. The association of gene variants with CML and clinical variables was evaluated by a Chi-square test, and odds ratios and 95% confidence intervals were estimated by logistic regression. The variant rs13078 in DICER1 was significantly higher among CML individuals than in healthy participants. In addition, the variants rs7813 and rs2740349 were significantly associated with worse prognosis, according to their Hasford scores, whereas the rs2740349 variant was also associated with a later age at diagnosis. These findings suggest that variants in components of the microRNA biogenesis pathway could be involved in CML genetic risk. Full article

This study aims to evaluate in detail the environmental impacts of the turbines used for electricity generation by wind energy, from a life cycle perspective. For this purpose, a comprehensive literature review is conducted and the life cycle environmental impacts of two sizes of wind turbines, namely 3.6 and 4.8 MW, in Turkey are analyzed. Sustainability studies, especially life cycle assessment (LCA) findings, yield healthy results only if the data used are site-specific. The system has been modeled using GaBi software and the Ecoinvent database. The functional unit is defined as 1 kWh of generated electricity. The impacts have been estimated using the CML 2 Baseline 2001 method. The 4.8 MW turbine has lower environmental impacts than the other turbine. The construction of wind turbines has the greatest share of the environmental impacts of all the options considered. Recycling materials at the end of plant life can reduce unwanted environmental impacts by up to 49%. Similar studies based on site-specific data will help to inform electricity producers and policymakers about wind energy’s current impacts and environmental hotspots. Conducting analogous studies is critical to reducing the environmental impacts of wind energy, which will play an important part in the future of the energy sector. Full article

Background: ABL1 tyrosine kinase inhibitor discontinuation securely became among the therapeutic goal for chronic myeloid leukemia chronic phase patients (CML-CP). To establish successful prognostic factors for treatment-free remission (TFR), it is necessary to diagnose the patients with high-risk molecular relapse, however, a biomarker for the achievement of TFR has not been completely elucidated. Recent investigations have determined that neutrophils function crucially in cancer immunology. Patients and Methods: The research was a multicenter retrospective observational study to examine the correlation between TFR and neutrophil counts before TKI discontinuation. The investigation included patients having Philadelphia chromosome-positive CML-CP who attempted the discontinuation of TKIs after a durable deep molecular response between January 2012 and July 2021 at four institutions in Japan. Results: 118 CML-CP patients in total discontinued TKIs and an estimated 36-month TFR rate was 65.1%. 52 patients received second-generation TKIs as frontline. Higher neutrophil count (>3210/μL) at TKIs discontinuation was determined as an independent prognostic variable for TFR in patients who received second-generation TKIs as frontline [(HR, 0.235 (95%, confidence interval (CI) 0.078–0.711); p = 0.010]. Conclusions: The neutrophil-mediated immunomodulation can be a significant component for the effective achievement of TFR in CML supported by our clinical observation. Full article

Tyrosine kinase inhibitor (TKI) drugs have significantly improved chronic myeloid leukemia (CML) outcomes. Neopeptides from CML cells may induce specific immune responses, which are crucial for deep molecular (DMR) and treatment-free remission (TFR). In this study of Ethiopian patients with CML (n = 162), the HLA alleles and single-nucleotide polymorphisms of five cytokines revealed significant associations with clinical outcomes. Clinically unfavorable outcomes correlated with HLA alleles A*03:01/02, A*23:17:01, B*57:01/02/03, and HLA-DRB4*01:01 (p-value = 0.0347, p-value = 0.0285, p-value = 0.037, and p-value = 0.0127, respectively), while HLA-DRB4*01:03:01 was associated with favorable outcomes (p-value = 0.0058). After assigning values for the ‘low’, ‘intermediate’, and ‘high’ gene expression of the SNPs’ respective cytokine genes, Kaplan–Meier estimates for relapse-free survival, adjusted for age, treatment duration, and relapse risk among patients after the administration of TKIs, indicated that a gene expression ratio above the overall median of TNF-α, IL-6, and the combination of TGF-β1/IL-10, IFNγ, and IL-6/IL-10 TGF-β1 was correlated with a higher likelihood of treatment failure ((RR: 3.01; 95% CI: 1.1–8.3; p-value = 0.0261) and (RR: 2.4; 95% CI: 1.1–5.2; p-value = 0.022), respectively). Multi-SNPs, surpassing single-SNPs, and HLA allele polymorphisms showed promise in predicting outcomes of patients with CML during TKI treatment, prompting further exploration into their potential utility. Full article

While overdispersion is a common phenomenon in univariate count time series data, its exploration within bivariate contexts remains limited. To fill this gap, we propose a bivariate integer-valued autoregressive model. The model leverages a modified binomial thinning operator with a dispersion parameter $\rho$ and integrates random coefficients. This approach combines characteristics from both binomial and negative binomial thinning operators, thereby offering a flexible framework capable of generating counting series exhibiting equidispersion, overdispersion, or underdispersion. Notably, our model includes two distinct classes of first-order bivariate geometric integer-valued autoregressive models: one class employs binomial thinning (BVGINAR(1)), and the other adopts negative binomial thinning (BVNGINAR(1)). We establish the stationarity and ergodicity of the model and estimate its parameters using a combination of the Yule–Walker (YW) and conditional maximum likelihood (CML) methods. Furthermore, Monte Carlo simulation experiments are conducted to evaluate the finite sample performances of the proposed estimators across various parameter configurations, and the Anderson-Darling (AD) test is employed to assess the asymptotic normality of the estimators under large sample sizes. Ultimately, we highlight the practical applicability of the examined model by analyzing two real-world datasets on crime counts in New South Wales (NSW) and comparing its performance with other popular overdispersed BINAR(1) models. Full article