Drug Analysis of Voriconazole Combined with Granulocyte Colony Stimulating Factor.

BACKGROUND: The aim of the study was to improve the clinical cognition of leukemia-like reaction caused by voriconazole and granulocyte colony-stimulating factor and to avoid misdiagnosis or delayed diagnosis. METHODS: A case of drug analysis of Voriconazole combined with granulocyte colony stimulating factor was retrospectively analyzed and related literature was reviewed. RESULTS: Blood routine of the patient on July 29: WBC 13.48 x 109/L, neutrophil 85.3%, lymphocyte 13.4%, hemoglobin 111 g/L, platelet 285 x 109/L. Vancomycin was given to prevent intracranial infection. Lumbar puncture was performed on July 30, cerebrospinal fluid was sent for routine and biochemical examination, leukocytes were 0.15 x 109/L, monocytes 45%, polynuclear cells 55%, protein 1.172 g/L, Acinetobacter baumannii and Candida clorbicus were detected in sputum culture, vancomycin and meropenem static sites were given to prevent intracranial secondary infection. Fungi were detected in urine culture, and voriconazole was given to prevent fungal infection. Blood routine: White blood cell 0.61 x 109/L, neutrophil 23%, lymphocyte 73.8%, red blood cell 2.65 x 1012/L, hemoglobin 77 g/L, platelet 17 x 109/L, bone marrow was extracted after medication. Bone marrow images show poor myelodysplasia, with granulocytes dominated by protoearly cells. Subsequent flow cytometry, chromosomal karyotype, and fusion gene analysis were performed to exclude the possibility of leukemia. Flow cytometry showed that the proportion of myeloid primordial cells was not high, the granulocytes were mainly at the early and young stage, no abnormal phenotype was observed in erythrocytes, monocytes and NK cells, no obvious mature B lymphocytes were observed, and the ratio of CD4+/CD8+ was decreased. Karyotype results showed that there was no mitotic phase. The results of fusion gene analysis showed that the fusion gene was negative or lower than the detection sensitivity. Voliconazole was stopped first, and granulocyte colony stimulating factor was stopped 3 days later. Two weeks later, blood and bone marrow images basically recovered, white blood cell 7.88 x 109/L, neutrophil 46.3%, lymphocyte 48.2%, hemoglobin 126 g/L, platelet 142 x 109/L, bone marrow hyperplasia active. The proportion of three series is roughly normal. CONCLUSIONS: The reason for the occurrence of leukemia-like reaction in this patient was considered to be related to voriconazole and granulocyte colony stimulating factor, cessation of voriconazole and granulocyte colony stimulating factor, and recovery of blood and bone marrow images. In the clinical use of voriconazole and granulocyte colony stimulating factor, close attention should be paid to the drug interaction and individualized medication should be carried out to ensure the safety of medication.

Decitabine as epigenetic priming with CLAG induce improved outcome of relapsed or refractory acute myeloid leukemia in children.

BACKGROUND: Decitabine (DAC), a DNA methyltransferase inhibitor, has shown efficacy combined with chemotherapy for relapsed or refractory (R/R) acute myeloid leukemia (AML) in adults, but less is known about its efficacy in children. Accordingly, we conducted a study which involved a priming regimen consisting of DAC with cladribine, cytarabine, and granulocyte-stimulating factor (DAC-CLAG) and compared the efficacy and safety of this regimen with CLAG alone. METHODS: A total of 39 R/R AML children who received the CLAG or DAC-CLAG regimen in Shanghai Children's Hospital were retrospectively enrolled in this non-randomized study. These regimens were studied sequentially over time. Twenty-two patients received CLAG from 2015, while 17 patients were administered epigenetic priming with DAC before CLAG from 2020. Patients were subsequently bridged to stem cell transplantation (SCT) or consolidation chemotherapy. Complete remission (CR) and adverse effects were analyzed by Fisher's exact test, and survival was analyzed by the Kaplan-Meier method. RESULTS: DAC-CLAG conferred a numerically higher CR compared to CLAG (70.59% vs 63.64%; P = 0.740). High CR rates occurred in patients with good cytogenetics (P = 0.029) and prior induction without cladribine (P = 0.099). The 1-year event-free survival (EFS) was 64.71% ± 11.59% and 63.31% ± 10.35% in the DAC-CLAG and CLAG group (P = 0.595), and 1-year overall survival (OS) was 81.45% ± 9.72% and 77.01% ± 9.04%, respectively (P = 0.265). The 1-year OS and EFS after SCT were higher in the DAC-CLAG than in the CLAG cohort (100% vs 92.31% ± 7.39%, P = 0.072; 92.31% ± 7.39% vs 85.71% ± 9.35%, P = 0.158). Univariate analysis revealed that a good prognosis included good cytogenetics (P = 0.002), non-complex karyotype (P = 0.056), CR on reinduction (P < 0.0001), and bridging to SCT (P = 0.0007). Use of a hypomethylating agent (P = 0.049) and bridging to SCT (P = 0.011) were independent prognostic factors. Grade 3/4 hematologic toxicity and infection were the main adverse events. CONCLUSIONS: DAC prior to the CLAG regimen improved remission in pediatric R/R AML, and was feasible and well tolerated. CLAG ± DAC as a salvage therapy prior to SCT induced improved survival.

The value of G-CSF in women experienced at least one implantation failure: a systematic review and meta-analysis.

Objective: Despite the developments of in vitro fertilization (IVF) protocols, implantation failure remains a challenging problem, owing to the unbalance between the embryo, endometrium, and immune system interactions. Effective treatments are urgently required to improve successful implantation. Recently, many researchers have focused on granulocyte colony-stimulating factor (G-CSF) to regulate immune response and embryo-endometrium cross-talk. However, previous studies have reported inconsistent findings on the efficacy of G-CSF therapy on implantation failure. The objective of this review was to further explore the effects of G-CSF according to administration dosage and timing among women who experienced at least one implantation failure. Methods: We systematically searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Scopus, and Web of Science for randomized controlled trials of G-CSF on implantation failure up to July 21, 2023. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated and the heterogeneity of the studies with the I2 index was analyzed. Results: We identified a total of 2031 studies and finally included 10 studies in the systematic review and meta-analysis. G-CSF administration improved the clinical pregnancy rate (CPR), implantation rate (IR), biochemical pregnancy rate (BPR), and live birth rate (LBR) in women with at least one implantation failure. Subgroup analyses showed that G-CSF treatment could exert good advantages in improving CPR [OR=2.49, 95%CI (1.56, 3.98), I2 = 0%], IR [OR=2.82, 95%CI (1.29, 6.15)], BPR [OR=3.30, 95%CI (1.42, 7.67)] and LBR [OR=3.16, 95%CI (1.61, 6.22), I2 = 0%] compared with the blank control group. However, compared with placebo controls, G-CSF showed beneficial effects on CPR [OR=1.71, 95%CI (1.04, 2.84), I2 = 38%] and IR [OR=2.01, 95%CI (1.29, 3.15), I2 = 24%], but not on LBR. In addition, >150µg of G-CSF treatment increased CPR [OR=2.22, 95%CI (1.47, 3.35), I2 = 0%], IR [OR=2.67, 95%CI (1.47, 4.82), I2 = 0%] and BPR [OR=2.02, 95%CI (1.17, 3.47), I2 = 22%], while ≤150µg of G-CSF treatment improved miscarriage rate (MR) [OR=0.14, 95%CI (0.05, 0.38), I2 = 0%] and LBR [OR=2.65, 95%CI (1.56, 4.51), I2 = 0%]. Moreover, G-CSF administration on the day of embryo transfer (ET) could increase CPR [OR=2.81, 95%CI (1.37, 5.75), I2 = 0%], but not on the day of ovum pick-up (OPU) or human chorionic gonadotropin (HCG) injection. Conclusion: G-CSF has a beneficial effect on pregnancy outcomes to some extent among women who experienced at least one implantation failure, and the administration dosage and timing influence the effect size.Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023447046.

Associations of systemic inflammatory regulators with CKD and kidney function: evidence from the bidirectional mendelian randomization study.

BACKGROUND: Previous observational studies have reported that systemic inflammatory regulators are related to the development of chronic kidney disease (CKD); however, whether these associations are causal remains unclear. The current study aimed to investigate the potential causal relationships between systemic inflammatory regulators and CKD and kidney function. METHOD: We performed bidirectional two-sample Mendelian randomization (MR) analyses to infer the underlying causal associations between 41 systemic inflammatory regulators and CKD and kidney function. The inverse-variance weighting (IVW) test was used as the primary analysis method. In addition, sensitivity analyses were executed via the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test and the weighted median test. RESULTS: The findings revealed 12 suggestive associations between 11 genetically predicted systemic inflammatory regulators and CKD or kidney function in the forward analyses, including 4 for CKD, 3 for blood urea nitrogen (BUN), 4 for eGFRcrea and 1 for eGFRcys. In the other direction, we identified 6 significant causal associations, including CKD with granulocyte-colony stimulating factor (GCSF) (IVW ß = 0.145; 95% CI, 0.042 to 0.248; P = 0.006), CKD with stem cell factor (SCF) (IVW ß = 0.228; 95% CI, 0.133 to 0.323; P = 2.40 × 10- 6), eGFRcrea with SCF (IVW ß =-2.90; 95% CI, -3.934 to -1.867; P = 3.76 × 10- 8), eGFRcys with GCSF (IVW ß =-1.382; 95% CI, -2.404 to -0.361; P = 0.008), eGFRcys with interferon gamma (IFNg) (IVW ß =-1.339; 95% CI, -2.313 to -0.366; P = 0.007) and eGFRcys with vascular endothelial growth factor (VEGF) (IVW ß =-1.709; 95% CI, -2.720 to -0.699; P = 9.13 × 10- 4). CONCLUSIONS: Our findings support causal links between systemic inflammatory regulators and CKD or kidney function both in the forward and reverse MR analyses.

Killer Function of Circulating Neutrophils in Relation to Cytokines in Uterine Myoma and Endometrial Cancer.

The study presents the killer functions of circulating neutrophils: myeloperoxidase activity, the ability to generate ROS, phagocytic activity, receptor status, NETosis, as well as the level of cytokines IL-2, IL-4, IL-6, IL-17A, and IL-18, granulocyte CSF, monocyte chemotactic protein 1, and neutrophil elastase in the serum of patients with uterine myoma and endometrial cancer (FIGO stages I-III). The phagocytic ability of neutrophils in uterine myoma was influenced by serum levels of granulocyte CSF and IL-2 in 54% of the total variance. The degranulation ability of neutrophils in endometrial cancer was determined by circulating IL-18 in 50% of the total variance. In uterine myoma, 66% of the total variance in neutrophil myeloperoxidase activity was explained by a model dependent on blood levels of IL-17A, IL-6, and IL-4. The risk of endometrial cancer increases when elevated levels of monocyte chemotactic protein 1 in circulating neutrophils are associated with reduced ability to capture particles via extracellular traps (96% probability).

Establishment of human hematopoietic organoids for evaluation of hematopoietic injury and regeneration effect.

BACKGROUND: Human hematopoietic organoids have a wide application value for modeling human bone marrow diseases, such as acute hematopoietic radiation injury. However, the manufacturing of human hematopoietic organoids is an unaddressed challenge because of the complexity of hematopoietic tissues. METHODS: To manufacture hematopoietic organoids, we obtained CD34+ hematopoietic stem and progenitor cells (HSPCs) from human embryonic stem cells (hESCs) using stepwise induction and immunomagnetic bead-sorting. We then mixed these CD34+ HSPCs with niche-related cells in Gelatin-methacryloyl (GelMA) to form a three-dimensional (3D) hematopoietic organoid. Additionally, we investigated the effects of radiation damage and response to granulocyte colony-stimulating factor (G-CSF) in hematopoietic organoids. RESULTS: The GelMA hydrogel maintained the undifferentiated state of hESCs-derived HSPCs by reducing intracellular reactive oxygen species (ROS) levels. The established hematopoietic organoids in GelMA with niche-related cells were composed of HSPCs and multilineage blood cells and demonstrated the adherence of hematopoietic cells to niche cells. Notably, these hematopoietic organoids exhibited radiation-induced hematopoietic cell injury effect, including increased intracellular ROS levels, γ-H2AX positive cell percentages, and hematopoietic cell apoptosis percentages. Moreover, G-CSF supplementation in the culture medium significantly improved the survival of HSPCs and enhanced myeloid cell regeneration in these hematopoietic organoids after radiation. CONCLUSIONS: These findings substantiate the successful manufacture of a preliminary 3D hematopoietic organoid from hESCs-derived HSPCs, which was utilized for modeling hematopoietic radiation injury and assessing the radiation-mitigating effects of G-CSF in vitro. Our study provides opportunities to further aid in the standard and scalable production of hematopoietic organoids for disease modeling and drug testing.

Leveraging G-CSF prescribing in the outpatient setting: considerations beyond clinical factors-a questionnaire study.

PURPOSE: This study aims to delineate G-CSF treatment practices, assess decision criteria, and measure their implementation in ambulatory settings for patients with breast (BC), lung (LC), or gastrointestinal cancers (GIC), beyond standard recommendations. METHODS: In this non-interventional, cross-sectional, multicenter study, clinical cases were presented using conversational interfaces (chatbots), simulating a conversation with one or more virtual interlocutors through voice or text exchange. The clinical simulations were configured by four parameters: types of cancer, risk of FN related to chemotherapy and comorbidities, access to care, and therapy setting (adjuvant/neoadjuvant/metastatic). RESULTS: The questionnaire was completed by 102 physicians. Most practitioners (84.5%) reported prescribing G-CSF, regardless of tumor type. G-CSF was prescribed more frequently for adjuvant/neoadjuvant therapy than for metastatic cases. The type of chemotherapy was cited as the first reason for prescribing G-CSF, with access to care being the second. Regarding the type of chemotherapy, physicians do not consider this factor alone, but combined with comorbidities and age (56.7% of cases). Pegfilgrastim long-acting was prescribed in most cases of BC and LC (70.1% and 86%, respectively), while filgrastim short-acting was named in the majority of cases of GIC (61.7%); 76.3% of physicians prescribed G-CSF as primary prophylaxis. CONCLUSIONS: Our findings suggest that recommended practices are broadly followed. In the majority of cases, G-CSF is prescribed as primary prophylaxis. In addition, physicians seem more inclined to prescribe G-CSF to adjuvant/neoadjuvant patients rather than metastatic patients. Finally, the type of chemotherapy tends to be a more significant determining factor than the patient's background.

Balancing Benefits and Risks: A Literature Review on Hypersensitivity Reactions to Human G-CSF (Granulocyte Colony-Stimulating Factor).

Human granulocyte colony-stimulating factor (G-CSF) is a granulopoietic growth factor used in the treatment of neutropenia following chemotherapy, myeloablative treatment, or healthy donors preparing for allogeneic transplantation. Few hypersensitivity reactions (HRs) have been reported, and its true prevalence is unknown. We aimed to systematically characterize G-CSF-induced HRs while including a comprehensive list of adverse reactions. We reviewed articles published before January 2024 by searching in the PubMed, Embase, Cochrane Library, and Web of Science databases using a combination of the keywords listed, selected the ones needed, and extracted relevant data. The search resulted in 68 entries, 17 relevant to our study and 7 others found from manually searching bibliographic sources. A total of 40 cases of G-CSF-induced HR were described and classified as immediate (29) or delayed (11). Immediate ones were mostly caused by filgrastim (13 minimum), with at least 9 being grade 5 on the WAO anaphylaxis scale. Delayed reactions were mostly maculopapular exanthemas and allowed for the continuation of G-CSF. Reactions after first exposure frequently appeared and were present in at least 11 of the 40 cases. Only five desensitization protocols have been found concerning the topic at hand in the analyzed data. We believe this study brings to light the research interest in this topic that could benefit from further exploration, and propose regular updating to include the most recently published evidence.

Protection of neutrophils by bone marrow mesenchymal stromal cells is enhanced by tumor-associated inflammatory cytokines.

Mesenchymal stromal/stem cells (MSCs), which are distributed in many tissues including bone marrow, have been reported to play a critical role in tumor development. While bone marrow, the primary site for hematopoiesis, is important for establishing the immune system, whether MSCs in the bone marrow can promote tumor growth via influencing hematopoiesis remains unclear. We observed that the numbers of MSCs and neutrophils were increased in bone marrow in tumor-bearing mice. Moreover, co-culture assay showed that MSCs strongly protected neutrophils from apoptosis and induced their maturation. G-CSF and GM-CSF have been well-documented to be associated with neutrophil formation. We found a remarkably increased level of G-CSF, but not GM-CSF, in the supernatant of MSCs and the serum of tumor-bearing mice. The G-CSF expression can be enhanced with inflammatory cytokines (IFNγ and TNFα) stimulation. Furthermore, we found that IFNγ and TNFα-treated MSCs enhanced their capability of promoting neutrophil survival and maturation. Our results indicate that MSCs display robustly protective effects on neutrophils to contribute to tumor growth in bone niches.

Revolutionizing Stroke Recovery: Unveiling the Promise of Stem Cell Therapy.

Stem cells, renowned for their unique regenerative capabilities, present significant hope in treating stroke, a major cause of disability globally. This review offers a detailed analysis of stem cell applications in stroke (ischemic and hemorrhagic) recovery. It examines therapies based on autologous (patient-derived), allogeneic (donor-derived), and Granulocyte-Colony Stimulating Factor (G-CSF) based stem cells, focusing on cell types such as Mesenchymal Stem/Stromal Cells (MSCs), Bone Marrow Mononuclear Stem Cells (BMMSCs), and Neural Stem/Progenitor Cells (NSCs). The paper compiles clinical trial data to evaluate their effectiveness and safety and addresses the ethical concerns of these innovative treatments. By explaining the mechanisms of stem cell-induced neurological repair, this review underscores stem cells' potential in revolutionizing stroke rehabilitation and suggests avenues for future research.

Evaluation of the hematological and immunological markers after the first and second doses of BNT162b2 mRNA vaccine.

OBJECTIVE: Both humoral and cellular immunity can be significantly influenced by the immunological responses to vaccination, and both responses are essential. Vaccination is the most consistent, safe, and cost-efficient practice for controlling the COVID-19 pandemic. PATIENTS AND METHODS: Blood samples were collected from participants who received two vaccine doses of COVID-19 Pfizer/BioNTech (BNT162b2) before and on days 7 and 10 after the first and second immunization. We evaluated some hematological and immunological markers responses to the 1st and 2nd doses of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine. RESULTS: In healthy subjects' neutrophil and WBC counts significantly increased compared to those after the first dose. The results of all first-group participant categories demonstrated no discernible variations in lymphocyte counts. There was no change in IgM or IgG in all second-group cohorts, except for a considerable rise in IgG levels in people with a history of coronavirus infection following the second dosage compared to baseline. After the second dose, CD4+ T-cell and CD8+ T-cell levels rose in all groups compared to before the immunization and after the first dosage. Data demonstrated a substantial rise in neutrophil-lymphocyte ratio (NLR) after the second dose of the vaccine. Individuals who had previously had COVID-19 disease experienced a considerable increase in C3 and C4 levels after the first and second dosages compared to baseline. Additionally, compared to their levels after the first dosage, C4 levels increased significantly following the second dosage. Interleukin (IL)-6, IL-15, macrophage colony-stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), interferon gamma-induced protein 10 (IP-10/CXCL10), and macrophage inflammatory protein-1 alpha (MIP-1α/CCL3) levels were increased after boost correlated with Spike antibody levels, supporting their utility as indicators of successful humoral immunity development in response to vaccination. CONCLUSIONS: We can conclude that the Pfizer/BioNTech vaccine produced a more potent T-cell response than humoral ones.

Associations of granulocyte colony-stimulating factor with toxicities and efficacy of chimeric antigen receptor T-cell therapy in relapsed or refractory B-cell acute lymphoblastic leukemia.

Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We present a retrospective study of 67 patients with R/R B-ALL who received anti-CD19 CAR T-cell therapy, 41 (61.2%) patients received G-CSF (G-CSF group), while 26 (38.8%) did not (non-G-CSF group). Patients had similar duration of grade 3-4 neutropenia between the two groups. The incidences of CRS and NEs were higher in G-CSF group, while no differences in severity were found. Further stratified analysis showed that the incidence and severity of CRS were not associated with G-CSF administration in patients with low bone marrow (BM) tumor burden. None of the patients with low BM tumor burden developed NEs. However, there was a significant increase in the incidence of CRS after G-CSF administration in patients with high BM tumor burden. The duration of CRS in patients who used G-CSF was longer. There were no significant differences in response rates at 1 and 3 months after CAR T-cell infusion, as well as overall survival (OS) between the two groups. In conclusion, our results showed that G-CSF administration was not associated with the incidence or severity of CRS in patients with low BM tumor burden, but the incidence of CRS was higher after G-CSF administration in patients with high BM tumor burden. The duration of CRS was prolonged in G-CSF group. G-CSF administration was not associated with the efficacy of CAR T-cell therapy.

Survivors of polymicrobial sepsis are refractory to G-CSF-induced emergency myelopoiesis and hematopoietic stem and progenitor cell mobilization.

Sepsis survivors exhibit immune dysfunction, hematological changes, and increased risk of infection. The long-term impacts of sepsis on hematopoiesis were analyzed using a surgical model of murine sepsis, resulting in 50% survival. During acute disease, phenotypic hematopoietic stem and progenitor cells (HSPCs) were reduced in the bone marrow (BM), concomitant with increased myeloid colony-forming units and extramedullary hematopoiesis. Upon recovery, BM HSPCs were increased and exhibited normal function in the context of transplantation. To evaluate hematopoietic responses in sepsis survivors, we treated recovered sham and cecal ligation and puncture mice with a mobilizing regimen of granulocyte colony-stimulating factor (G-CSF) at day 20 post-surgery. Sepsis survivors failed to undergo emergency myelopoiesis and HSPC mobilization in response to G-CSF administration. G-CSF is produced in response to acute infection and injury to expedite the production of innate immune cells; therefore, our findings contribute to a new understanding of how sepsis predisposes to subsequent infection.

[Clinical Analysis of PEG-rhG-CSF in Mobilization of Autologous Hematopoietic Stem Cells in Hematological Tumors].

OBJECTIVE: To investigate the efficiency and optimal time of stem cell apheresis mobilized by pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in autologous stem cell transplantation (ASCT) for hematological malignancies without monitoring pre-collection CD34+ cells. METHODS: Forty-six patients underwent stem cell mobilization were retrospectively analyzed between August 2017 and January 2022 at the First Affiliated Hospital of Fujian Medical University. 27 patients using high dose chemotherapy combined with PEG-rhG-CSF mobilization were enrolled in the PEG-rhG-CSF group, and other 19 patients mobilized with recombinant human granulocyte colony stimulating factor (G-CSF) were enrolled in G-CSF group. The mobilization and collection effects of the patients in two groups were compared. RESULTS: A total of 46 patients underwent 86 apheresis procedures, the median amount of mononuclear cell (MNC) in the PEG-rhG-CSF group and G-CSF group was 6.54（3.85-12.61）×108/kg and 6.15（1.13-11.58）×108/kg, respectively (P >0.05), the total CD34+ cells of the grafts were 11.44(1.33-65.02)×106/kg and 4.95(0.30-24.02)×106/kg (P < 0.05), with harvest timing of 14(10-20) days and 14(4-22) days, respectively (P >0.05). In the PEG-rhG-CSF group, there was a significant difference between the number of CD34+ cells collected when white blood cells (WBC) ≥10×109/L and WBC<10×109 /L, 19.04(2.85-65.02)×106/kg and 6.22(0.81-34.86)×106/kg, respectively (P < 0.05). CONCLUSION: Stem cells mobilization with PEG-rhG-CSF was highly efficient with a median mobilization time of 14 days. In the absence of peripheral blood CD34 monitoring, peripheral blood WBC≥10×109/L can be considered as a threshold for a single stem cell apheresis to collect sufficient stem cells.

Comparison of two autologous hematopoietic stem cell mobilization strategies in patients with multiple myeloma: CE plus G-CSF versus G-CSF only: A single-center retrospective analysis.

BACKGROUND: Despite recent advances in the treatment of multiple myeloma, high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) remains an essential therapeutic keystone. As for the stem cell mobilization procedure, different regimens have been established, usually consisting of a cycle of chemotherapy followed by application of granulocyte-colony stimulating factor (G-CSF), although febrile neutropenia is a common complication. Following national guidelines, our institution decided to primarily use G-CSF only mobilization during the COVID-19 pandemic to minimize the patients' risk of infection and to reduce the burden on the health system. STUDY DESIGN AND METHODS: In this retrospective single-center analysis, the efficacy and safety of G-CSF only mobilization was evaluated and compared to a historic control cohort undergoing chemotherapy-based mobilization by cyclophosphamide and etoposide (CE) plus G-CSF. RESULTS: Although G-CSF only was associated with a higher need for plerixafor administration (p < .0001) and a higher number of apheresis sessions per patient (p = .0002), we were able to collect the target dose of hematopoietic stem cells in the majority of our patients. CE mobilization achieved higher hematopoietic stem cell yields (p = .0015) and shorter apheresis sessions (p < .0001) yet was accompanied by an increased risk of febrile neutropenia (p < .0001). There was no difference in engraftment after ASCT. DISCUSSION: G-CSF only mobilization is a useful option in selected patients with comorbidities and an increased risk of serious infections, especially in the wintertime or in future pandemics.

Blocking OLFM4/galectin-3 axis in placental polymorphonuclear myeloid-derived suppressor cells triggers intestinal inflammation in newborns.

Fetal growth restriction (FGR) is a major cause of premature and low-weight births, which increases the risk of necrotizing enterocolitis (NEC); however, the association remains unclear. We report a close correlation between placental polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and NEC. Newborns with previous FGR exhibited intestinal inflammation and more severe NEC symptoms than healthy newborns. Placental PMN-MDSCs are vital regulators of fetal development and neonatal gut inflammation. Placental single-cell transcriptomics revealed that PMN-MDSCs populations and olfactomedin-4 gene (Olfm4) expression levels were significantly increased in PMN-MDSCs in later pregnancy compared to those in early pregnancy and non-pregnant females. Female mice lacking Olfm4 in myeloid cells mated with wild-type males showed FGR during pregnancy, with a decreased placental PMN-MDSCs population and expression of growth-promoting factors (GPFs) from placental PMN-MDSCs. Galectin-3 (Gal-3) stimulated the OLFM4-mediated secretion of GPFs by placental PMN-MDSCs. Moreover, GPF regulation via OLFM4 in placental PMN-MDSCs was mediated via hypoxia inducible factor-1α (HIF-1α). Notably, the offspring of mothers lacking Olfm4 exhibited intestinal inflammation and were susceptible to NEC. Additionally, OLFM4 expression decreased in placental PMN-MDSCs from pregnancies with FGR and was negatively correlated with neonatal morbidity. These results revealed that placental PMN-MDSCs contributed to fetal development and ameliorate newborn intestinal inflammation.

How to manage poor mobilisers.

Autologous hematopoietic progenitor cell transplantation (ASCT) has been used for more than five decades to treat malignant and non-malignant diseases. Successful engraftment after high-dose chemotherapy relies on the ability to collect sufficient CD34 + hematopoietic progenitor cells (HPCs), typically from peripheral blood after mobilization. Commonly, either granulocyte colony-stimulating factor (G-CSF) alone as a single agent (i.e. steady-state mobilization) or G-CSF after chemotherapy is administered to collect adequate numbers of HPCs (minimum ≥2 × 106 CD34 + cells/kg for one ASCT; optimal up to 5 × 106 CD34 + cells/kg). However, a significant proportion of patients fail successful HPC mobilization, which is commonly defined as a CD34+ cell count below 10-15/µL after at least 4 days of 10 µg/kg b.w. G-CSF alone, or after chemo-mobilization in combination with 5-10 µg/kg b.w. G-CSF. In these situations plerixafor, a chemokine receptor inhibitor (CXCR4) can be used to enhance HPC collection in patients with multiple myeloma and malignant lymphoma whose cells mobilize poorly. Risk factors for poor mobilization have been evaluated and several strategies (e.g. plerixafor to rescue the mobilization approach or pre-emptive use) have been suggested to optimize mobilization, especially in patients at risk. This manuscript discusses the risk factors of poor CD34+ mobilization and summarizes the current strategies to optimize mobilization and HPC collection.

IL-23 regulation of myeloid cell biology during inflammation.

Interleukin (IL)-23 is implicated in the pathogenesis of several inflammatory diseases and is usually linked with helper T cell (Th17) biology. However, there is some data linking IL-23 with innate immune biology in such diseases. We therefore examined the effects of IL-23p19 genetic deletion and/or neutralization on in vitro macrophage activation and in an innate immune-driven peritonitis model. We report that endogenous IL-23 was required for maximal macrophage activation by zymosan as determined by pro-inflammatory cytokine production, including a dramatic upregulation of granulocyte-colony stimulating factor (G-CSF). Furthermore, both IL-23p19 genetic deletion and neutralization in zymosan-induced peritonitis (ZIP) led to a specific reduction in the neutrophil numbers, as well as a reduction in the G-CSF levels in exudate fluids. We conclude that endogenous IL-23 can contribute significantly to macrophage activation during an inflammatory response, mostly likely via an autocrine/paracrine mechanism; of note, endogenous IL-23 can directly up-regulate macrophage G-CSF expression, which in turn is likely to contribute to the regulation of IL-23-dependent neutrophil number and function during an inflammatory response, with potential significance for IL-23 targeting particularly in neutrophil-associated inflammatory diseases.

[The Role of NK Cells in Allogeneic Hematopoietic Stem Cell Micro-Transplantation for Acute Myeloid leukemia].

OBJECTIVE: To explore the role of NK cells in allogeneic hematopoietic stem cell micro-transplantation(MST) in the treatment of patients with acute myeloid leukemia(AML). METHODS: Data from 93 AML patients treated with MST at our center from 2013-2018 were retrospectively analyzed. The induction regimen was anthracycline and cytarabine combined with peripheral blood stem cells transplantation mobilization by granulocyte colony stimulating factor (GPBSC), followed by 2-4 courses of intensive treatment with medium to high doses of cytarabine combined with GPBSC after achieving complete remission (CR). The therapeutic effects of one and two courses of MST induction therapy on 42 patients who did not reach CR before transplantation were evaluated. Cox proportional hazards regression analysis was used to analyze the impact of donor NK cell dose and KIR genotype, including KIR ligand mismatch, 2DS1, haplotype, and HLA-Cw ligands on survival prognosis of patients. RESULTS: Forty-two patients received MST induction therapy, and the CR rate was 57.1% after 1 course and 73.7% after 2 courses. Multivariate analysis showed that, medium and high doses of NK cells was significantly associated with improved disease-free survival (DFS) of patients (HR=0.27, P =0.005; HR=0.21, P =0.001), and high doses of NK cells was significantly associated with improved overall survival (OS) of patients (HR=0.15, P =0.000). Donor 2DS1 positive significantly increases OS of patients (HR=0.25, P =0.011). For high-risk patients under 60 years old, patients of the donor-recipient KIR ligand mismatch group had longer DFS compared to the nonmismatch group (P =0.036); donor 2DS1 positive significantly prolonged OS of patients (P =0.009). CONCLUSION: NK cell dose, KIR ligand mismatch and 2DS1 influence the therapeutic effect of MST, improve the survival of AML patients.