Cholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer's disease (AD) patients, but are associated with multiple side effects and only 20-40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of administration of a single dose of galantamine on central nervous system (CNS) functioning in mild to moderate AD patients and its potential to predict long-term treatment response.

Joint replacement surgery of the lower extremities are common procedures in elderly persons who are at increased risk of postoperative falls. The use of mental state altering medications, such as opioids, antidepressants or benzodiazepines, can further contribute to impaired balance and risk of falls. The objective of the current systematic review was to evaluate the risk of the use of mental state altering medications on postoperative falls in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA).

Antibiotic exposure in intensive care patients with sepsis is frequently inadequate and is associated with poorer outcomes. Antibiotic dosing is challenging in the intensive care, as critically ill patients have altered and fluctuating antibiotic pharmacokinetics that make current one-size-fits-all regimens unsatisfactory. Real-time bedside dosing software is not available yet, and therapeutic drug monitoring is typically used for few antibiotic classes and only allows for delayed dosing adaptation. Thus, adequate and timely antibiotic dosing continues to rely largely on the level of pharmacokinetic expertise in the ICU. Therefore, we set out to assess the level of knowledge on antibiotic pharmacokinetics among these intensive care professionals.

Leukemic stem cells (LSCs) are thought to be the major cause of the recurrence of acute myeloid leukemia (AML) due to their potential for self-renewal. To identify therapeutic strategies targeting LSCs, while sparing healthy hematopoietic stem cells (HSCs), we performed gene expression profiling of LSCs, HSCs, and leukemic progenitors all residing within the same AML bone marrow and identified insulin-like growth factor-binding protein 7 (IGFBP7) as differentially expressed. Low IGFBP7 is a feature of LSCs and is associated with reduced chemotherapy sensitivity. Enhancing IGFBP7 by overexpression or addition of recombinant human IGFBP7 (rhIGFBP7) resulted in differentiation, inhibition of cell survival, and increased chemotherapy sensitivity of primary AML cells. Adding rhIGFBP7 reduced leukemic stem and/or progenitor survival and reversed a stem-like gene signature, but it had no influence on normal hematopoietic stem cell survival. Our data suggest a potential clinical utility of the addition of rhIGFBP7 to current chemotherapy regimens to decrease AML relapse rates.

This comprehensive observational study aimed to gain insight into adherence to nilotinib and the effect of (non)adherence on exposure (Cmin) and treatment outcomes.

Bayesian forecasting is crucial for model-based dose optimization based on therapeutic drug monitoring (TDM) data of vancomycin in intensive care (ICU) patients. We aimed to evaluate the performance of Bayesian forecasting using maximum a posteriori (MAP) estimation for model-based TDM.

Despite substantial progress achieved in unraveling the genetics of AML in the past decade, its treatment outcome has not substantially improved. Therefore, it is important to better understand how genetic mutations translate to phenotypic features of AML cells to further improve response predictions and to find innovative therapeutic approaches. In this respect, aberrant splicing is a crucial contributor to the pathogenesis of hematological malignancies. Thus far, altered splicing is well characterized in relation to splicing factor mutations in AML. However, splicing profiles associated with mutations in other genes remain largely unexplored. In this study, we explored differential splicing profiles associated with two of the most common aberrations in AML: FLT3-ITD and NPM1 mutations. Using RNA-sequencing data of a total of 382 primary AML samples, we found that the co-occurrence of FLT3-ITD and mutated NPM1 is associated with differential splicing of FAB-type specific gene sets. Despite the FAB-type specificity of particular gene sets, the primary functions perturbed by differential splicing in all three FAB types include cell cycle control and DNA damage response. Interestingly, we observed functional divergence between alternatively spliced and differentially expressed genes in FLT3-ITD+/NPM1+ samples in all analyzed FAB types, with differential expression affecting genes involved in hematopoietic differentiation. Altogether, these observations indicate that concomitant FLT3-ITD and mutated NPM1 are associated with the maturation state-specific differential splicing of genes with potential oncogenic relevance.

Crystalloids are the most frequently prescribed drugs in intensive care medicine and emergency medicine. Thus, even small differences in outcome may have major implications, and therefore, the choice between balanced crystalloids versus normal saline continues to be debated. We examined to what extent the currently accrued information size from completed and ongoing trials on the subject allow intensivists and emergency physicians to choose the right fluid for their patients.

The spice curcumin and its metabolites are widely used by cancer patients but have not shown proven health benefits in clinical studies, likely due to low plasma concentrations after oral intake. However, public interest in curcumin continues to grow, and companies claim enhanced absorption in their formulations. This study aims to determine if daily oral intake of curcumin leads to sufficient plasma concentrations for health effects. The study was registered in the Dutch Clinical Trial Register with ID NL5931.

Introduction: Capecitabine is a widely prescribed oral anticancer agent. We studied medication adherence and explored its use in daily practice from a patients' perspective. Patients and Methods: Patients (n = 92) starting capecitabine were followed up to five 3-week cycles. Adherence was assessed using a pill count, pharmacy data and dosing information from the patients' medical file. Self-reported adherence was measured using the Medication Adherence Report Scale (MARS). At baseline and during week 2 of cycles 1, 3, and 5, patients filled out questionnaires about quality of life, symptoms, attitude toward medicines and disease and use in daily practice. Simultaneously, blood samples were taken to determine the area under the curve (AUC) of 5'-deoxy-5-fluorouridine (5'-DFUR), 5-fluorouracil (5-FU), and α-fluoro-β-alanine (FBAL) by a population pharmacokinetic model. Associations between AUCs and patient-reported symptoms were tested for cycles 3 and 5. Results: Most patients (84/92; 91%) had an adherence rate of ≥95 and ≤ 105%. The percentage of patients reporting any non-adherence behavior measured with MARS increased from 16% at cycle 1 to 29% at cycle 5. Symptoms were reported frequently and the dosing regimen was adjusted by the physician at least once in 62% of patients. In multivariate analysis the probability of an adjustment increased with the number of co-medication (OR 1.19, 95% CI: 1.03-1.39) and a stronger emotional response to the disease (OR 1.32, 95% CI: 1.10-1.59). The AUC of 5'-DFUR was associated with weight loss (OR 1.10, 95% CI: 1.01-1.19), AUC of FBAL with hand-foot syndrome (OR 0.90, 95% CI: 0.83-0.99), rhinorrhea (OR 1.21, 95% CI: 1.03-1.42 weight loss (OR 1.09, 95% CI: 1.00-1.20) and depression (OR 0.90, 95% CI: 0.82-0.99). Side effects were reported by one third of patients as the reason to discontinue treatment. Conclusion: Adherence to capecitabine was generally high. Nevertheless, adherence measured with MARS decreased over time Adherence management to support implementation of correct capecitabine use is specifically relevant in longer term treatment. In addition, it appears that adverse event management is important to support persistence. With the extending armamentarium of oral targeted anticancer agents and prolonged treatment duration, we expect the issue of medication adherence of increasing importance in oncology.

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (Cmax ) and trough concentration (Ctrough ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID-19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID-19.

High dose chemotherapy and radiation have been found to impair the hematopoiesis-supportive capacity of bone marrow stroma. We now provide evidence for an important role of chemotherapy-induced alterations in stromal glycosaminoglycans (GAGs) in reduction of the supportive properties of stromal fibroblasts. Exposure to cytarabine resulted in a pronounced increase in hyaluronan, both in the cell/matrix (p<0.03) and supernatant fraction (p<0.05). Gene expression analysis showed a corresponding increase in gene expression of hyaluronan synthase 1, indicating that the increase in hyaluronan is at least partly under genetic control. Functionally, hyaluronan significantly inhibited the proliferation of early megakaryocytic progenitor cells in a dose dependent way (p=0.01). The increase in hyaluronan was confirmed in vivo by showing a >2-fold increase in bone marrow hyaluronan of patients after chemo- and/or radiotherapy as conditioning for an allogeneic stem cell transplantation, indicating physiologically relevance. Furthermore, there was a trend towards a decrease in the amount and sulfation of stromal heparan sulfate proteoglycans upon exposure to cytarabine, resulting in a 40% reduced binding of SDF1-alpha to stromal cells (p<0.05). In conclusion, there is a pronounced effect of cytarabine treatment on the expression of genes involved in GAG synthesis and degradation, affecting the synthesis and function of stromal GAGs. Our results indicate that chemotherapy-induced changes in stromal GAG profile are likely to affect normal hematopoiesis.

The antitumor drug nilotinib has a large inter- and intra individual variability in pharmacokinetics. Adherence to treatment may substantially influence plasma levels and has been recognized as the most important determinant of treatment failure in chronic myeloid leukemia (CML). A better understanding of the various factors contributing to the efficacy of treatment is essential for the development of interventions to optimize the treatment of chronic phase CML (CP-CML) with a protein kinase inhibitor like nilotinib.

This study aims to retrospectively assess C-lectin-like molecule 1 (CLL-1) bimodal expression on CD34+ blasts in acute myeloid leukemia (AML) patients (total N = 306) and explore potential CLL-1 bimodal associations with leukemia and patient-specific characteristics.

No abstract available

Adherence to pharmacological therapy is a complex and multifactorial issue that can substantially alter the outcome of treatment. Especially when using long-term medication, cancer patients have adherence rates similar to those of patients with other diseases. The consequences of poor adherence are poor health outcomes and increased health care costs. Only few studies have focused on the use of oral anticancer agents in daily practice. Information about the reasons for nonadherence is essential for the development of interventions that may improve adherence. This report presents the CAPER-capecitabine protocol, which is designed to study the adherence to capecitabine and the influence of patient attitudes towards medication and self-reported side effects. Furthermore, the relationships between patient characteristics, disease characteristics, side effects, quality of life, patient beliefs and attitudes towards disease and medication, dose adjustments, reasons for discontinuation, and plasma concentration of three of the main metabolites, including the active compound 5-fluorouracil, will be explored.

Evaluations of the 'real-world' efficacy and safety of tyrosine kinase inhibitors in patients with chronic myeloid leukemia are scarce. A nationwide, population-based, chronic myeloid leukemia registry was analyzed to evaluate (deep) response rates to first and subsequent treatment lines and eligibility for a treatment cessation attempt in adults diagnosed between January 2008 and April 2013 in the Netherlands. The registry covered 457 patients; 434 in chronic phase (95%) and 15 (3%) in advanced disease phase. Seventy-five percent of the patients in chronic phase were treated with imatinib and 25% with a second-generation tyrosine kinase inhibitor. At 3 years 44% of patients had discontinued their first-line treatment, mainly due to intolerance (21%) or treatment failure (19%). At 18 months 73% of patients had achieved a complete cytogenetic response and 63% a major molecular response. Deep molecular responses (MR4.0 and MR4.5) were achieved in 69% and 56% of patients, respectively, at 48 months. All response milestones were achieved faster in patients treated upfront with a second-generation tyrosine kinase inhibitor, but ultimately patients initially treated with imatinib also reached similar levels of responses. The 6-year cumulative incidence of eligibility for a tyrosine kinase cessation attempt, according to EURO-SKI criteria, was 31%. Our findings show that in a 'real-world' setting the long-term outcome of patients treated with tyrosine kinase inhibitors is excellent and the conditions for an attempt to stop tyrosine kinase inhibitor therapy are met by a third of the patients.

Mass-spectrometry (MS) based phosphoproteomics is increasingly used to explore aberrant cellular signaling and kinase driver activity, aiming to improve kinase inhibitor (KI) treatment selection in malignancies. Phosphorylation is a dynamic, highly regulated post-translational modification that may be affected by variation in pre-analytical sample handling, hampering the translational value of phosphoproteomics-based analyses. Here, we investigate the effect of delay in mononuclear cell isolation on acute myeloid leukemia (AML) phosphorylation profiles. We performed MS on immuno-precipitated phosphotyrosine (pY)-containing peptides isolated from AML samples after seven pre-defined delays before sample processing (direct processing, thirty minutes, one hour, two hours, three hours, four hours and 24 h delay). Up to four hours, pY phosphoproteomics profiles show limited variation. However, in samples processed with a delay of 24 h, we observed significant change in these phosphorylation profiles, with differential phosphorylation of 22 pY phosphopeptides (p < 0.01). This includes increased phosphorylation of pY phosphopeptides of JNK and p38 kinases indicative of stress response activation. Based on these results, we conclude that processing of AML samples should be standardized at all times and should occur within four hours after sample collection. SIGNIFICANCE: Our study provides a practical time-frame in which fresh peripheral blood samples from acute myeloid patients should be processed for phosphoproteomics, in order to warrant correct interpretation of in vivo biology. We show that up to four hours of delayed processing after sample collection, pY phosphoproteomic profiles remain stable. Extended delays are associated with perturbation of phosphorylation profiles. After a delay of 24 h, JNK activation loop phosphorylation is markedly increased and may serve as a biomarker for delayed processing. These findings are relevant for biomedical acute myeloid leukemia research, as phosphoproteomic techniques are of particular interest to investigate aberrant kinase signaling in relation to disease emergence and kinase inhibitor response. With these data, we aim to contribute to reproducible research with meaningful outcomes.

Develop and validate models that predict mortality of patients diagnosed with COVID-19 admitted to the hospital.

Although chemotherapy induces complete remission in the majority of acute myeloid leukemia (AML) patients, many face a relapse. This relapse is caused by survival of chemotherapy-resistant leukemia (stem) cells (measurable residual disease; MRD). Here, we demonstrate that the anthracycline doxorubicin epigenetically reprograms leukemia cells by inducing histone 3 lysine 27 (H3K27) and H3K4 tri-methylation. Within a doxorubicin-sensitive leukemia cell population, we identified a subpopulation of reversible anthracycline-tolerant cells (ATCs) with leukemic stem cell (LSC) features lacking doxorubicin-induced H3K27me3 or H3K4me3 upregulation. These ATCs have a distinct transcriptional landscape than the leukemia bulk and could be eradicated by KDM6 inhibition. In primary AML, reprogramming the transcriptional state by targeting KDM6 reduced MRD load and survival of LSCs residing within MRD, and enhanced chemotherapy response in vivo. Our results reveal plasticity of anthracycline resistance in AML cells and highlight the potential of transcriptional reprogramming by epigenetic-based therapeutics to target chemotherapy-resistant AML cells.