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Scientific Reports Mar 2024This multicentre (22 centres in Turkey) retrospective cohort study aimed to assess the clinical outcomes of patients with neutropenic fever and SARS-CoV-2 positivity....
This multicentre (22 centres in Turkey) retrospective cohort study aimed to assess the clinical outcomes of patients with neutropenic fever and SARS-CoV-2 positivity. Study period was 15 March 2020-15 August 2021. A total of 170 cases (58 female, aged 59 ± 15.5 years) that fulfilled the inclusion criteria were included in the study. One-month mortality rate (OMM) was 44.8%. The logistic regression analysis showed the following significant variables for the mentioned dependent variables: (i) achieving PCR negativity: receiving a maximum of 5 days of favipiravir (p = 0.005, OR 5.166, 95% CI 1.639-16.280); (ii) need for ICU: receiving glycopeptide therapy at any time during the COVID-19/FEN episode (p = 0.001, OR 6.566, 95% CI 2.137-20.172), the need for mechanical ventilation (p < 0.001, OR 62.042, 95% CI 9.528-404.011); (iii) need for mechanical ventilation: failure to recover from neutropenia (p < 0.001, OR 17.869, 95% CI 3.592-88.907), receiving tocilizumab therapy (p = 0.028, OR 32.227, 95% CI 1.469-707.053), septic shock (p = 0.001, OR 15.4 96% CI 3.164-75.897), and the need for ICU (p < 0.001, OR 91.818, 95% CI 15.360-548.873), (iv) OMM: [mechanical ventilation (p = 0.001, OR 19.041, 95% CI 3.229-112.286) and septic shock (p = 0.010, OR 5.589,95% CI 1.509-20.700)]. Although it includes a relatively limited number of patients, our findings suggest that COVID-19 and FEN are associated with significant mortality and morbidity.
Topics: Humans; Female; Retrospective Studies; Shock, Septic; COVID-19; SARS-CoV-2; Prognosis; Neutropenia
PubMed: 38433274
DOI: 10.1038/s41598-024-55886-w -
The Journal of Toxicological Sciences 2024This study was conducted as part of an investigation into the cause of vesnarinone-associated agranulocytosis. When HL-60 cells were exposed to vesnarinone for 48 hr,...
This study was conducted as part of an investigation into the cause of vesnarinone-associated agranulocytosis. When HL-60 cells were exposed to vesnarinone for 48 hr, little cytotoxicity was observed, although reduced glutathione (GSH) content decreased in a concentration-dependent manner. Significant cytotoxicity and reactive oxygen species (ROS) production were observed when intracellular GSH content was reduced by treatment with L-buthionine-(S, R)-sulphoximine. The involvement of myeloperoxidase (MPO) metabolism was suggested, as when HL-60 cells were exposed to a reaction mixture of vesnarinone-MPO/HO/Cl, cytotoxicity was also observed. In contrast, the presence of GSH (1 mM) protected against these cytotoxic effects. Liquid chromatography-mass spectrometry analysis of the MPO/HO/Cl reaction mixture revealed that vesnarinone was converted into two metabolites, (4-(3,4-dimethoxybenzoyl)piperazine [Metabolite 1: M1] and 1-chloro-4-(3,4-dimethoxybenzoyl)piperazine [Metabolite 2: M2]). M2 was identified as the N-chloramine form, a reactive metabolite of M1. Interestingly, M2 was converted to M1, which was accompanied by the conversion of GSH to oxidized GSH (GSSG). Furthermore, when HL-60 cells were exposed to synthetic M1 and M2 for 24 hr, M2 caused dose-dependent cytotoxicity, whereas M1 did not. Cells were protected from M2-derived cytotoxicity by the presence of GSH. In conclusion, we present the first demonstration of the cytotoxic effects and ROS production resulting from the MPO/HO/Cl metabolic reaction of vesnarinone and newly identified the causative metabolite, M2, as the N-chloramine metabolite of M1, which induces cytotoxicity in HL-60 cells. Moreover, a protective role of GSH against the cytotoxicity was revealed. These findings suggest a possible nonimmunological cause of vesnarinone agranulocytosis.
Topics: Humans; Chloramines; Glutathione; HL-60 Cells; Hydrogen Peroxide; Reactive Oxygen Species; Agranulocytosis; Antineoplastic Agents; Chlorides; Piperazines; Pyrazines; Quinolines
PubMed: 38432956
DOI: 10.2131/jts.49.95 -
Scientific Reports Mar 2024The clinical application of conventional doxorubicin (CDOX) was constrained by its side effects. Liposomal doxorubicin was developed to mitigate these limitations,...
The clinical application of conventional doxorubicin (CDOX) was constrained by its side effects. Liposomal doxorubicin was developed to mitigate these limitations, showing improved toxicity profiles. However, the adverse events associated with liposomal doxorubicin and CDOX have not yet been comprehensively evaluated in clinical settings. The FAERS data from January 2004 to December 2022 were collected to analyze the adverse events of liposomal doxorubicin and CDOX. Disproportionate analysis and Bayesian analysis were employed to quantify this association. Our analysis incorporated 68,803 adverse event reports related to Doxil/Caelyx, Myocet and CDOX. The relative odds ratios (RORs, 95%CI) for febrile neutropenia associated with CDOX, Doxil/Caelyx, and Myocet were 42.45 (41.44; 43.48), 17.53 (16.02; 19.20), and 34.68 (26.63; 45.15) respectively. For cardiotoxicity, they were 38.87(36.41;41.49), 17.96 (14.10; 22.86), and 37.36 (19.34; 72.17). For Palmar-Plantar Erythrodysesthesia (PPE), the RORs were 6.16 (5.69; 6.68), 36.13 (32.60; 40.06), and 19.69 (11.59; 33.44). Regarding onset time, significant differences adverse events including neutropenia, PPE, pneumonia and malignant neoplasm progression. This study indicates that clinical monitoring for symptoms of cardiotoxicity of CDOX and Myocet, and PPE and interstitial lung disease of Doxil should be performed. Additionally, the onset time of febrile neutropenia, malignant neoplasm progression, and pneumonia associated with Doxil and Myocet merits particular attention. Continuous surveillance, risk evaluations, and additional comparative studies between liposomal doxorubicin and CDOX were recommended.
Topics: Humans; Cardiotoxicity; Bayes Theorem; Doxorubicin; Liposomes; Neoplasms; Neutropenia; Pneumonia; Polyethylene Glycols
PubMed: 38429374
DOI: 10.1038/s41598-024-55185-4 -
In Vivo (Athens, Greece) 2024Acute lung injury (ALI) is associated with a high mortality rate and cancer patients who receive chemotherapy are at high risk of ALI during neutropenia recovery....
BACKGROUND/AIM
Acute lung injury (ALI) is associated with a high mortality rate and cancer patients who receive chemotherapy are at high risk of ALI during neutropenia recovery. Galantamine is a cholinesterase inhibitor used for Alzheimer's disease treatment. Previous studies have shown that galantamine reduced inflammatory response in lipopolysaccharide (LPS)-induced ALI in rats. Mer protein was negatively associated with inflammatory response. The aim of the study was to investigate whether galantamine is effective in LPS-induced ALI during neutropenia recovery and its effect on Mer tyrosine kinase (MerTK) expression in mice.
MATERIALS AND METHODS
Intraperitoneal cyclophosphamide was given to mice to induce neutropenia. After 7 days, LPS was administered by intratracheal instillation. Intraperitoneal galantamine was given once before LPS administration and in another group, galantamine was given twice before LPS administration.
RESULTS
Galantamine attenuated LPS-induced ALI in histopathological analysis. The neutrophil percentage was lower in the group where galantamine was injected once, compared to the LPS group (p=0.007). MerTK expression was also higher in the group where galantamine was injected once but did not reach statistical significance (p=0.101).
CONCLUSION
Galantamine attenuated inflammation in LPS-induced ALI during neutropenia recovery.
Topics: Humans; Mice; Rats; Animals; Galantamine; Lipopolysaccharides; c-Mer Tyrosine Kinase; Acute Lung Injury; Neutropenia; Protein-Tyrosine Kinases; Lung
PubMed: 38418160
DOI: 10.21873/invivo.13479 -
Journal of Medicine and Life Nov 2023Clozapine is an atypical antipsychotic indicated for treating patients resistant to antipsychotic therapy when other medications in this class have no therapeutic...
Clozapine is an atypical antipsychotic indicated for treating patients resistant to antipsychotic therapy when other medications in this class have no therapeutic effect. Clozapine has greater efficacy but more side effects than other atypical antipsychotics (e.g., agranulocytosis, seizures, sedation, and weight gain). Side effects can cause discomfort to patients and can affect patient compliance, interfering with therapeutical outcomes. This study aims to identify the side effects of clozapine use in patients at the Psychiatric Hospital Grhasia, in Yogyakarta, Indonesia. Using a cross-sectional design, this research provides a retrospective descriptive analysis using medical records of patients at the Psychiatric Hospital Ghrasia Yogyakarta. Inpatient and outpatient medical records of patients who had received a clozapine prescription from January to December 2019 were analyzed. In the 336 patients that met the inclusion criteria, the incidence of side effects from clozapine use was 16.07% (95%, CI:2.2-4.1), with the most frequent being dizziness, vomiting, diarrhea, and hypersalivation. There was no effect of age, gender, profession, or patient's disease on their incidence. The management of side effects is classified into three aspects: the drug is stopped, the patient is given additional therapy, and the patient is not given therapy. The results showed that the use of clozapine at the Psychiatric Hospital Ghrasia Yogyakarta was relatively safe. Identification of side effects is necessary to determine the follow-up treatment.
Topics: Humans; Clozapine; Antipsychotic Agents; Retrospective Studies; Indonesia; Cross-Sectional Studies; Hospitals, Psychiatric; Schizophrenia
PubMed: 38406784
DOI: 10.25122/jml-2023-0145 -
Critical Reviews in Oncology/hematology Apr 2024Filgrastim is approved for several indications, including reduction of the incidence and duration of chemotherapy-induced neutropenia and for stem cell mobilization. The... (Review)
Review
Filgrastim is approved for several indications, including reduction of the incidence and duration of chemotherapy-induced neutropenia and for stem cell mobilization. The filgrastim biosimilar, EP2006, has been available in Europe since 2009, and in the United States since 2015. In this time, preclinical and clinical data used to support the approval of EP2006 have been published. These data established the biosimilarity of EP2006 to reference filgrastim in terms of structure, pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity. Additional real-world evidence studies have also demonstrated equivalent efficacy and safety of EP2006 compared with reference filgrastim, both in the reduction of neutropenia and in stem cell mobilization in clinical practice. This review summarizes these preclinical, clinical, and real-world data, as well as the available cost-effectiveness data, for EP2006 since its approval 15 years ago.
Topics: Humans; United States; Filgrastim; Biosimilar Pharmaceuticals; Double-Blind Method; Neutropenia; Antineoplastic Combined Chemotherapy Protocols; Granulocyte Colony-Stimulating Factor
PubMed: 38401695
DOI: 10.1016/j.critrevonc.2024.104306 -
International Journal of Molecular... Feb 2024Serine/arginine-rich splicing factors (SRSFs) are a family of proteins involved in RNA metabolism, including pre-mRNA constitutive and alternative splicing. The role of...
Serine/arginine-rich splicing factors (SRSFs) are a family of proteins involved in RNA metabolism, including pre-mRNA constitutive and alternative splicing. The role of SRSF proteins in regulating mitochondrial activity has already been shown for SRSF6, but SRSF4 altered expression has never been reported as a cause of bone marrow failure. An 8-year-old patient admitted to the hematology unit because of leukopenia, lymphopenia, and neutropenia showed a missense variant of unknown significance of the gene (p.R235W) found via whole genome sequencing analysis and inherited from the mother who suffered from mild leuko-neutropenia. Both patients showed lower SRSF4 protein expression and altered mitochondrial function and energetic metabolism in primary lymphocytes and Epstein-Barr-virus (EBV)-immortalized lymphoblasts compared to healthy donor (HD) cells, which appeared associated with low mTOR phosphorylation and an imbalance in the proteins regulating mitochondrial biogenesis (i.e., CLUH) and dynamics (i.e., DRP1 and OPA1). Transfection with the wt gene restored mitochondrial function. In conclusion, this study shows that the described variant of the gene is pathogenetic and causes reduced SRSF4 protein expression, which leads to mitochondrial dysfunction. Since mitochondrial function is crucial for hematopoietic stem cell maintenance and some genetic bone marrow failure syndromes display mitochondrial defects, the mutation could have substantially contributed to the clinical phenotype of our patient.
Topics: Child; Humans; Alternative Splicing; Bone Marrow; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Neutropenia; Phosphoproteins; RNA Precursors; Serine-Arginine Splicing Factors
PubMed: 38396760
DOI: 10.3390/ijms25042083 -
BMC Infectious Diseases Feb 2024Hematopoietic stem cell transplantation (HSCT) was associated with potentially life-threatening complications. Among patients supported by extracorporeal membrane...
Extracorporeal membrane oxygenation in long-term COVID-19 with severe neutropenia and thrombocytopenia after allogeneic hematopoietic stem cell transplantation: a case report.
BACKGROUND
Hematopoietic stem cell transplantation (HSCT) was associated with potentially life-threatening complications. Among patients supported by extracorporeal membrane oxygenation (ECMO), those who underwent HSCT had a worse prognosis than those who did not. Advances in HSCT and critical care management have improved the prognosis of ECMO-supported HSCT patients.
CASE
The patient in the remission stage of lymphoma after 22 months of allogeneic hematopoietic stem cell transplantation, suffered from ARDS, severe neutropenia, thrombocytopenia, and long-term COVID-19. We evaluated the benefits and risks of ECMO for the patient, including the possibility of being free from ECMO, the status of malignancy, the interval from HSCT to ARDS, the function of the graft, the amount of organ failure, and the comorbidities. ECMO was ultimately used to save his life.
CONCLUSIONS
We did not advocate for the general use of ECMO in HSCT patients and we believed that highly selected patients, with well-controlled tumors, few comorbidities, and fewer risk factors for death, tended to benefit from ECMO with well ICU management.
Topics: Humans; Extracorporeal Membrane Oxygenation; COVID-19; Respiratory Distress Syndrome; Thrombocytopenia; Neutropenia; Neoplasms; Hematopoietic Stem Cell Transplantation
PubMed: 38378534
DOI: 10.1186/s12879-024-09121-6 -
Antimicrobial Agents and Chemotherapy Apr 2024The objective of this study was to support posaconazole dose regimens in pediatric patients aged ≥2 years, using a population pharmacokinetic (PK) approach with data...
The objective of this study was to support posaconazole dose regimens in pediatric patients aged ≥2 years, using a population pharmacokinetic (PK) approach with data from a phase 1b study (NCT02452034). A one-compartment model with first-order absorption was fit to pharmacokinetic data from 144 participants aged 2 to 17 years, who were administered posaconazole as intravenous (IV) and powder for oral suspension (PFS) formulations, or IV only, at dosing regimens of 3.5, 4.5, and 6 mg/kg. The influence of demographic and clinical factors on pharmacokinetic parameters was evaluated using a stepwise forward inclusion/backward exclusion procedure. The final model simulated posaconazole exposure in patients aged 2 to <7 and 7 to 17 years at dosing regimens of 4.5, 6, and 7.5 mg/kg. Plasma concentration data following IV and PFS administration were well-described by a one-compartment model with first-order absorption and estimated bioavailability, where clearance and volume were subject to allometric scaling by body weight. The 6-mg/kg dosing regimen achieved the pharmacokinetic target (90% of the pediatric population having an average steady-state plasma concentration of ≥500 and <2,000 ng/mL) for both age groups, regardless of whether patients received IV and PFS or IV only. In a virtual adolescent population (body weight >40 kg), the 300 mg/day posaconazole tablet was also predicted to achieve the pharmacokinetic target and remain within a safe range of exposure. These data informed a weight-based nomogram for PFS dosing to maximize the number of pediatric patients achieving the pharmacokinetic target across weight bands, while also maintaining a favorable benefit/risk profile.
Topics: Adolescent; Child; Humans; Administration, Oral; Antifungal Agents; Body Weight; Neutropenia; Powders; Triazoles; Child, Preschool
PubMed: 38376229
DOI: 10.1128/aac.01197-23 -
Frontiers in Cellular and Infection... 2024Metagenomic next-generation sequencing (mNGS) is a novel technique for detecting pathogens. This retrospective study evaluated the diagnostic value of mNGS using plasma...
Application of plasma metagenomic next-generation sequencing improves prognosis in hematology patients with neutropenia or hematopoietic stem cell transplantation for infection.
INTRODUCTION
Metagenomic next-generation sequencing (mNGS) is a novel technique for detecting pathogens. This retrospective study evaluated the diagnostic value of mNGS using plasma for infections in hematology patients and its impact on clinical treatment and prognosis in different subgroups of hematology patients.
METHODS
A total of 153 hematology patients with suspected infection who underwent mNGS using plasma were enrolled in the study. Their clinical histories, conventional microbiological test (CMT) results, mNGS results, treatment and prognosis were retrospectively analyzed.
RESULTS
In 153 plasma samples, mNGS yielded a higher positivity rate than CMT (total: 88.24% vs. 40.52%, P<0.001; bacteria: 35.95% vs. 21.57%, P < 0.01; virus: 69.93% vs. 21.57%, P<0.001; fungi: 20.26% vs. 7.84%, P<0.01). mNGS had a higher positivity rate for bacteria and fungi in the neutropenia group than in the non-neutropenia group (bacteria: 48.61% vs. 24.69%, P<0.01; fungi: 27.78% vs. 13.58%, P<0.05). mNGS demonstrated a greater advantage in the group of patients with hematopoietic stem cell transplantation (HSCT). Both the 3-day and 7-day efficacy rates in the HSCT group were higher than those in the non-HSCT group (3-day: 82.22% vs. 58.65%, P < 0.01; 7-day: 88.89% vs. 67.31%, P < 0.01), and the 28-day mortality rate was lower in the HSCT group than in the non-HSCT group (6.67% vs. 38.89%, P < 0.000). The neutropenia group achieved similar efficacy and mortality rates to the non-neutropenia group (7-day efficiency rate: 76.39% vs. 71.43%, P > 0.05; mortality rate: 29.17% vs. 29.63%, P > 0.05) with more aggressive antibiotic adjustments (45.83% vs. 22.22%, P < 0.01).
CONCLUSION
mNGS can detect more microorganisms with higher positive rates, especially in patients with neutropenia. mNGS had better clinical value in patients with hematopoietic stem cell transplantation (HSCT) or neutropenia, which had a positive effect on treatment and prognosis.
Topics: Humans; Retrospective Studies; Neutropenia; High-Throughput Nucleotide Sequencing; Hematopoietic Stem Cell Transplantation; Metagenomics; Hematology; Sensitivity and Specificity
PubMed: 38371300
DOI: 10.3389/fcimb.2024.1338307