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Scientific Reports Jul 2023Cyclophosphamide, an oxazaphosphorine prodrug is frequently used in treatment of neuroblastoma, which is one of the most prevalent solid organ malignancies in infants...
Cyclophosphamide, an oxazaphosphorine prodrug is frequently used in treatment of neuroblastoma, which is one of the most prevalent solid organ malignancies in infants and young children. Cytochrome P450 2B6 (CYP2B6) is the major catalyst and CYP2C19 is the minor enzyme in bioactivation and inactivation pathways of cyclophosphamide. CYP-mediated metabolism may contribute to the variable pharmacokinetics of cyclophosphamide and its toxic byproducts leading to insufficient response to the therapy and development of clinically significant side effects. The aim of the study was to reveal the contribution of pharmacogenetic variability in CYP2B6 and CYP2C19 to the treatment efficacy and cyclophosphamide-induced side effects in pediatric neuroblastoma patients under cyclophosphamide therapy (N = 50). Cyclophosphamide-induced hematologic toxicities were pivotal in all patients, whereas only moderate hepatorenal toxicity was developed. The patients' CYP2B6 metabolizer phenotypes were associated with the occurrence of lymphopenia, thrombocytopenia, and monocytopenia as well as of liver injury, but not with kidney or urinary bladder (hemorrhagic cystitis) toxicities. Furthermore, the patients' age (< 1.5 years, P = 0.03) and female gender (P ≤ 0.02), but not CYP2B6 or CYP2C19 metabolizer phenotypes appeared as significant prognostic factors in treatment outcomes. Our results may contribute to a better understanding of the impact of CYP2B6 variability on cyclophosphamide-induced side effects.
Topics: Humans; Child; Female; Child, Preschool; Infant; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cyclophosphamide; Neuroblastoma; Drug-Related Side Effects and Adverse Reactions
PubMed: 37479763
DOI: 10.1038/s41598-023-38983-0 -
Emerging Infectious Diseases Nov 2014Cancer patients are at risk for candidemia, and increasing Candida spp. resistance poses an emerging threat. We determined rates of antifungal drug resistance,...
Cancer patients are at risk for candidemia, and increasing Candida spp. resistance poses an emerging threat. We determined rates of antifungal drug resistance, identified factors associated with resistance, and investigated the correlation between resistance and all-cause mortality rates among cancer patients with ≥1 C. glabrata-positive blood culture at MD Anderson Cancer Center, Houston, Texas, USA, during March 2005-September 2013. Of 146 isolates, 30 (20.5%) were resistant to fluconazole, 15 (10.3%) to caspofungin, and 10 (6.8%) to multiple drugs (9 caspofungin-resistant isolates were also resistant to fluconazole, 1 to amphotericin B). Independently associated with fluconazole resistance were azole preexposure, hematologic malignancy, and mechanical ventilation. Independently associated with caspofungin resistance were echinocandin preexposure, monocytopenia, and total parenteral nutrition. Fluconazole resistance was highly associated with caspofungin resistance, independent of prior azole or echinocandin use. Caspofungin resistance was associated with increased 28-day all-cause mortality rates. These findings highlight the need for good stewardship of antifungal drugs.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Candida glabrata; Candidiasis; Cause of Death; Child; Drug Resistance, Fungal; Drug Resistance, Multiple, Fungal; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Neoplasms; Risk Factors; Young Adult
PubMed: 25340258
DOI: 10.3201/eid2011.140685 -
Frontiers in Immunology 2023Patients with septic shock caused by have mortality rates exceeding 50%, despite appropriate antibiotic therapy. Our objectives were to establish a rabbit model of...
Monoclonal antibodies neutralizing alpha-hemolysin, bicomponent leukocidins, and clumping factor A protected against -induced acute circulatory failure in a mechanically ventilated rabbit model of hyperdynamic septic shock.
BACKGROUND
Patients with septic shock caused by have mortality rates exceeding 50%, despite appropriate antibiotic therapy. Our objectives were to establish a rabbit model of septic shock and to determine whether a novel immunotherapy can prevent or halt its natural disease progression.
METHODS
Anesthetized rabbits were ventilated with lung-protective low-tidal volume, instrumented for advanced hemodynamic monitoring, and characterized for longitudinal changes in acute myocardial dysfunction by echocardiography and sepsis-associated biomarkers after intravenous challenge. To demonstrate the potential utility of this hyperdynamic septic shock model for preclinical drug development, rabbits were randomized for prophylaxis with anti-Hla/Luk/ClfA monoclonal antibody combination that neutralizes alpha-hemolysin (Hla), the bicomponent pore-forming leukocidins (Luk) including Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysin, and clumping factor A (ClfA), or an irrelevant isotype-matched control IgG (c-IgG), and then challenged with .
RESULTS
Rabbits challenged with , but not those with saline, developed a hyperdynamic state of septic shock characterized by elevated cardiac output (CO), increased stroke volume (SV) and reduced systemic vascular resistance (SVR), which was followed by a lethal hypodynamic state characterized by rapid decline in mean arterial pressure (MAP), increased central venous pressure, reduced CO, reduced SV, elevated SVR, and reduced left-ventricular ejection fraction, thereby reproducing the hallmark clinical features of human staphylococcal septic shock. In this model, rabbits pretreated with anti-Hla/Luk/ClfA mAb combination had 69% reduction in mortality when compared to those pretreated with c-IgG (<0.001). USA300-induced acute circulatory failure-defined as >70% decreased in MAP from pre-infection baseline-occurred in only 20% (2/10) of rabbits pretreated with anti-Hla/Luk/ClfA mAb combination compared to 100% (9/9) of those pretreated with c-IgG. Prophylaxis with anti-Hla/Luk/ClfA mAb combination halted progression to lethal hypodynamic shock, as evidenced by significant protection against the development of hyperlactatemia, hypocapnia, hyperkalemia, leukopenia, neutropenia, monocytopenia, lymphopenia, as well as biomarkers associated with acute myocardial injury.
CONCLUSION
These results demonstrate the potential utility of a mechanically ventilated rabbit model that reproduced hallmark clinical features of hyperdynamic septic shock and the translational potential of immunotherapy targeting virulence factors for the prevention of staphylococcal septic shock.
Topics: Humans; Animals; Rabbits; Staphylococcus aureus; Antibodies, Monoclonal; Hemolysin Proteins; Leukocidins; Shock, Septic; Respiration, Artificial; Stroke Volume; Ventricular Function, Left; Staphylococcal Infections; Shock; Immunoglobulin G
PubMed: 37781371
DOI: 10.3389/fimmu.2023.1260627 -
Cancer Medicine Apr 2015Guanine-adenine-thymine-adenine 2 (GATA2) mutated disorders include the recently described MonoMAC syndrome (Monocytopenia and Mycobacterium avium complex infections),... (Review)
Review
Guanine-adenine-thymine-adenine 2 (GATA2) mutated disorders include the recently described MonoMAC syndrome (Monocytopenia and Mycobacterium avium complex infections), DCML (dendritic cell, monocyte, and lymphocyte deficiency), familial MDS/AML (myelodysplastic syndrome/acute myeloid leukemia) (myeloid neoplasms), congenital neutropenia, congenital lymphedema (Emberger's syndrome), sensorineural deafness, viral warts, and a spectrum of aggressive infections seen across all age groups. While considerable efforts have been made to identify the mutations that characterize this disorder, pathogenesis remains a work in progress with less than 100 patients described in current literature. Varying clinical presentations offer diagnostic challenges. Allogeneic stem cell transplant remains the treatment of choice. Morbidity, mortality, and social costs due to the familial nature of the disease are considerable. We describe our experience with the disorder in three affected families and a comprehensive review of current literature.
Topics: Adult; Child; Female; GATA2 Transcription Factor; Genetic Counseling; Germ-Line Mutation; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Deficiency Syndromes; Male
PubMed: 25619630
DOI: 10.1002/cam4.384 -
Turkish Journal of Haematology :... Dec 2010Parvovirus-B19 (PV-B19) is a member of Parvoviridae, which is one of the smallest DNA viruses. PV-B19-associated diseases usually serve as a good representation of the...
Parvovirus-B19 (PV-B19) is a member of Parvoviridae, which is one of the smallest DNA viruses. PV-B19-associated diseases usually serve as a good representation of the balance of virus, host response and the immune system. The diseases manifested with PV-B19 are erythema infectiosum, which is common in children, hydrops fetalis, transient pure red cell aplasia in patients with chronic hemolytic anemia, arthralgia - mostly observed in women, and chronic pure red cell aplasia in immunocompromised individuals. Cytopenia (bicytopenia, monocytopenia or pancytopenia) may also accompany the diseases mentioned above. On the other hand, there are many diseases, including neurologic, vasculitic, hepatic, rheumatoid, nephritic, autoimmune, myocardial, and others in which the mechanisms of the diseases are not clear, which may be associated with PV-B19. The virus may manifest with unexpected and unexplained clinical pictures and lead to misdiagnosis. Therefore, hematologic disorders in any unestablished clinical diagnosis should be investigated for PV-B19 infection. However, serologic examination for PV-B19 diagnosis is not sufficient in immunocompromised status. The virus can be determined with polymerase chain reaction (PCR) in the serum or tissue samples. Supportive therapy, blood transfusion and immunoglobulin are the conventional therapeutic interventions for PV-B19 today. Vaccination studies are under examination.
PubMed: 27263735
DOI: 10.5152/tjh.2010.43 -
Blood Jan 2015Germ-line GATA2 gene mutations, leading to haploinsufficiency, have been identified in patients with familial myelodysplastic syndrome/acute myeloid leukemia,... (Comparative Study)
Comparative Study
Germ-line GATA2 gene mutations, leading to haploinsufficiency, have been identified in patients with familial myelodysplastic syndrome/acute myeloid leukemia, monocytopenia and mycobacterial infections, Emberger syndrome, and dendritic cell, monocyte, B-, and NK-cell deficiency. GATA2 mutations have also been reported in a minority of patients with congenital neutropenia and aplastic anemia (AA). The bone marrow (BM) from patients with GATA2 deficiency is typically hypocellular, with varying degrees of dysplasia. Distinguishing GATA2 patients from those with AA is critical for selecting appropriate therapy. We compared the BM flow cytometric, morphologic, and cytogenetic features of 28 GATA2 patients with those of 32 patients being evaluated for idiopathic AA. The marrow of GATA2 patients had severely reduced monocytes, B cells, and NK cells; absent hematogones; and inverted CD4:CD8 ratios. Atypical megakaryocytes and abnormal cytogenetics were more common in GATA2 marrows. CD34(+) cells were comparably reduced in GATA2 and AA. Using these criteria, we prospectively identified 4 of 32 patients with suspected AA who had features suspicious for GATA2 mutations, later confirmed by DNA sequencing. Our results show that routine BM flow cytometry, morphology, and cytogenetics in patients who present with cytopenia(s) can identify patients for whom GATA2 sequencing is indicated.
Topics: Adult; Anemia, Aplastic; Antigens, CD34; Bone Marrow; Bone Marrow Diseases; Cohort Studies; Cytogenetics; Female; Flow Cytometry; GATA2 Transcription Factor; Humans; Immunohistochemistry; Male; Middle Aged; Mutation; Sequence Analysis, DNA; Young Adult
PubMed: 25359990
DOI: 10.1182/blood-2014-06-580340 -
Acta Informatica Medica : AIM : Journal... Mar 2023Coronavirus disease 2019 (COVID-19) can cause a wide clinical spectrum, ranging from asymptomatic to severe disease with a high mortality rate. In view of the current...
BACKGROUND
Coronavirus disease 2019 (COVID-19) can cause a wide clinical spectrum, ranging from asymptomatic to severe disease with a high mortality rate. In view of the current pandemic and the increasing influx of patients into healthcare facilities, there is a need to identify simple and reliable tools for stratifying patients.
OBJECTIVE
Study aimed to analyze whether hemogram-derived ratios (HDRs) can be used to identify patients with a risk of developing a severe clinical form and admission to hospital.
METHODS
This cross-sectional and observational study included 500 patients with a confirmed diagnosis of COVID-19. Data on clinical features and laboratory parameters were collected from medical records and 13 HDRs were calculated and analyzed. Descriptive and inferential statistics were included in the analysis.
RESULTS
Of the 500 patients, 43.8% had a severe form of the disease. Lymphocytopenia, monocytopenia, higher C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were found in severe patients ( < 0.05). Significantly higher neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), neutrophil-to-platelet ratio (NPR), neutrophil-to-lymphocyte-to-platelet ratio (NLPR) and CRP-to-lymphocyte ratio (CRP/Ly) values were found in severe patients ( < 0.001). In addition, they have statistically significant prognostic potential ( < 0.001). The area under the curve (AUC) for CRP/Ly, dNLR, NLPR, NLR, and NPR were 0.693, 0.619, 0.619, 0.616, and 0.603, respectively. The sensitivity and specificity were 65.7% and 65.6% for CRP/Ly, 51.6% and 70.8 for dNLR, 61.6% and 57.3% for NLPR, 40.6% and 80.4% for NLR, and 48.8% and 69.1% for NPR.
CONCLUSION
The results of the study suggest that NLR, dNLR, CRP/Ly, NPR, and NLPR can be considered as potentially useful markers for stratifying patients with a severe form of the disease. HDRs derived from routine blood tests results should be included in common laboratory practice since they are readily available, easy to calculate, and inexpensive.
PubMed: 37038490
DOI: 10.5455/aim.2023.31.41-47 -
Infection, Genetics and Evolution :... Dec 2021Inborn errors of immunity (IEIs) result from mutations in genes involved in host immune defense and immune regulation. Herein, we report the identification of a novel...
Inborn errors of immunity (IEIs) result from mutations in genes involved in host immune defense and immune regulation. Herein, we report the identification of a novel IRF8 mutation in a neonate with an IEI. DNA samples from both the neonate and her parents were subjected to DNA sequencing, and the immune status of the patient was assessed. We identified a mutation (c.331C > T, p. Arg111*) in the interferon regulatory factor 8 (IRF8) gene that manifested as sever dysfunctional neutrophilia (96.53 × 10/l) and monocytopenia (0.02 × 10/l). The patient's CD3 T cell and CD8 T cell counts were decreased. Her levels of IFN-γ were low even during severe infection. The mRNA expression levels of IRF8 were lower than normal. Her clinical manifestations included a recurrent and progressively fatal infection. Since IRF8 plays a key role in the differentiation and development of immune cells, we suspected that the novel mutation (c.331C > T, p. Arg111*) may be consistent with a severe loss of IRF8 function and result in a failure of immune cells to differentiate and maturation, and lead to a severe infection with early onset.
Topics: China; Fatal Outcome; Female; Humans; Infant, Newborn; Interferon Regulatory Factors; Leukocyte Disorders; Mutation
PubMed: 34666172
DOI: 10.1016/j.meegid.2021.105121 -
Annals of Intensive Care May 2022The reports of an early and profound acquired immunodepression syndrome (AIDs) in ICU patients had gained sufficient credence to modify the paradigm of acute...
INTRODUCTION
The reports of an early and profound acquired immunodepression syndrome (AIDs) in ICU patients had gained sufficient credence to modify the paradigm of acute inflammation. However, despite several articles published on AIDs and its assessment by monocytic HLA-DR monitoring, several missing informations remained: 1-Which patients' are more prone to benefit from mHLA-DR measurement, 2-Is the nadir or the duration of the low mHLA-DR expression the main parameter to consider? 3-What are the compared performances of leukocytes' count analyses (lymphocyte, monocyte).
MATERIAL AND METHOD
We conducted an observational study in a surgical ICU of a French tertiary hospital. A first mHLA-DR measurement (fixed flow cytometry protocol) was performed within the first 3 days following admission and a 2nd, between day 5 and 10. The other collected parameters were: SAPS II and SOFA scores, sex, age, comorbidities, mortality and ICU-acquired infections (IAI). The associations between mHLA-DR and outcomes were tested by adjusted Fine and Gray subdistribution competing risk models.
RESULTS
1053 patients were included in the study, of whom 592 had a 2nd mHLA-DR measurement. In this cohort, 223 patients (37.7%) complicated by IAI. The initial decrement in mHLA-DR was not associated with the later occurrence of IAI, (p = 0.721), however, the persistence of a low mHLA-DR (< 8000 AB/C), measured between day 5 and day 7, was associated with the later occurrence of IAI (p = 0.01). Similarly, a negative slope between the first and the second value was significantly associated with subsequent IAI (p = 0.009). The best performance of selected markers was obtained with the combination of the second mHLA-DR measurement with SAPSII on admission. Persisting lymphopenia and monocytopenia were not associated with later occurrence of IAI.
CONCLUSION
Downregulation of mHLA-DR following admission is observed in a vast number of patients whatever the initial motif for admission. IAI mostly occurs among patients with a high severity score on admission suggesting that immune monitoring should be reserved to the most severe patients. The initial downregulation did not preclude the later development of IAI. A decreasing or a persisting low mHLA-DR expression below 8000AB/C within the first 7 days of ICU admission was independently and reliably associated with subsequent IAI among ICU patients with performances superior to leukocyte subsets count alone.
PubMed: 35526199
DOI: 10.1186/s13613-022-01010-y -
Frontiers in Immunology 2018Infection with causes a chronic parasitic disease that progress to severe liver and gastrointestinal damage, and eventually death. During its development into mammalian...
Infection with causes a chronic parasitic disease that progress to severe liver and gastrointestinal damage, and eventually death. During its development into mammalian hosts, immature schistosomula transit through the lung vasculature before they reach the liver to mature into adult worms. A low grade inflammatory reaction is induced during this process. However, molecules that are required for efficient leukocyte accumulation in the lungs of -infected subjects are unknown. In addition, specific leukocyte subsets that mediate pulmonary response during migration through the lung remain to be elucidated. β integrins are fundamental regulators of leukocyte trans-endothelial migration and function. Therefore, we investigated their role during experimental schistosomiasis. Mice that express low levels of CD18 (the common β integrin subunit) and wild type C57BL/6 mice were subcutaneously infected with cercariae. Cellular profiles of lungs and livers were evaluated in different time points after infection by flow cytometry. Low levels of CD18 affected the accumulation of patrolling Ly6C, intermediate Ly6C monocytes, monocyte-derived macrophages and monocyte-derived dendritic cells in the lungs 7 days after infection. This correlated with increased TNF-α levels. Strikingly, low CD18 expression resulted in monocytopenia both in the peripheral blood and bone marrow during acute infection. After 48 days, worm burdens were higher in the hepatic portal system of CD18 mice, which also displayed reduced hepatic accumulation of patrolling Ly6C and intermediate Ly6C, but not inflammatory Ly6C monocytes. Higher parasite burden resulted in increased granulomatous lesions in the liver, increased egg deposition and enhanced mortality. Overall, our data point for a fundamental role of CD18 for monocyte hematopoiesis during infection, which promotes an efficient host response against experimental schistosomiasis.
Topics: Animals; Antigens, Ly; CD18 Antigens; Cell Movement; Disease Resistance; Hematopoiesis; Humans; Immunity, Innate; Leukocytes, Mononuclear; Lung; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Models, Animal; Mutation; Parasite Egg Count; Schistosoma mansoni; Schistosomiasis mansoni
PubMed: 30233576
DOI: 10.3389/fimmu.2018.01970