Application Of Granulocyte Colony-stimulating Factor Research Articles

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.

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. 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. 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. 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.

Granulocyte colony-stimulating factor effects on neurological and motor function in animals with spinal cord injury: a systematic review and meta-analysis.

Spinal cord injury (SCI) is a severe neurological injury for which no effective treatment exists. Granulocyte colony-stimulating factor (G-CSF) is used to treat autologous bone marrow transplantation, chemotherapy-induced granulocytopenia, Acquired Immune Deficiency Syndrome (AIDS), etc. Recent research has revealed the potential application of G-CSF on neuroprotective effectiveness. In central nervous system diseases, G-CSF can be used to alleviate neuronal injury. To investigate the effects of G-CSF on Basso, Beattie, and Bresnahan (BBB) scale score, inclined plane test, electrophysiologic exam, quantitative analysis of TUNEL-positive cells, and quantitative analysis of glial fibrillary acidic protein (GFAP) immunostaining images in animal models of SCI. We searched PubMed, Web of Science, and Embase databases for all articles on G-CSF intervention with animal models of SCI reported before November 2022. A total of 20 studies met the inclusion criteria. Results revealed that G-CSF intervention could improve the BBB scale score in both groups at 3, 7, 14, 28, and 35 days [at 35 days, weighted mean differences (WMD) = 2.4, 95% CI: 1.92-2.87, p < 0.00001, I2 = 69%]; inclined plane test score; electrophysiologic exam; quantitative analysis of TUNEL-positive cell numbers; quantitative analysis of GFAP immunostaining images in animal models of SCI. Subgroup analysis revealed that treatment with normal saline, phosphate-buffered saline, and no treatment resulted in significantly different neurological function effectiveness compared to the G-CSF therapy. SD rats and Wistar rats with SCI resulted in significant neurological function effectiveness. C57BL/6 mice showed no difference in the final effect. The T9-T10 or T10 segment injury model and the T8-T9 or T9 segment injury model resulted in significant neurological function effectiveness. The BBB score data showed no clear funnel plot asymmetry. We found no bias in the analysis result (Egger's test, p = 0.42). In our network meta-analysis, the SUCRA ranking showed that 15 mg/kg-20 mg/kg was an optimal dose for long-term efficacy. Our meta-analysis suggests that G-CSF therapy may enhance the recovery of motor activity and have a specific neuroprotective effect in SCI animal models.Systematic review registration: PROSPERO, identifier: CRD42023388315.

Application of G-CSF in high-leukocyte acute myeloid leukemia is a poor prognostic factor

ABSTRACTObjectiveTo analyze the effect of granulocyte colony-stimulating factor (G-CSF) on outcomes in patients with acute myeloid leukemia (AML).MethodsA total of 526 patients with AML in the Haematology Department were enrolled. They were divided into a G-CSF treatment group and a no G-CSF group according to whether G-CSF was administered in the induction chemotherapy period, with 355 cases in the G-CSF group and 171 cases in the no G-CSF group. Cox regression analysis and Kaplan-Meier curve analysis were used to analyze the effect of G-CSF on the first complete remission (CR1) phase and overall survival (OS). In addition, further analysis was performed based on an initial white blood cell count of 50 * 10^9/L.ResultsThe application of G-CSF significantly shortened the CR1 phase and OS in patients with high leukocytes.ConclusionsG/GM-CSF should be used with caution in patients with AML, especially those with high leukocytes.

Early granulocyte colony stimulating factor administration increases the risk of cytokine release syndrome in acute lymphoblastic leukemia patients receiving anti-CD19 chimeric antigen receptor T-cell therapy.

Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and neutropenia are common toxicities associated with chimeric antigen receptor T (CAR-T) cell therapy. The role of granulocyte colony stimulating factor (G-CSF) in CAR-T-cell-treated patients remains unclear. To explore the efficacy and safety of early G-CSF administration in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) who were receiving autologous anti-CD19 CAR-T cells, we retrospectively collected and summarized clinical data to compare patients receiving G-CSF within 14days (early G-CSF group) to patients receiving later or no G-CSF (control group) after their CART infusion. The results showed that there was no significant difference in the incidence and duration of neutropenia between the early G-CSF group and the control group (77% vs. 63%, p=0.65; 8 vs. 4days, p=0.37, respectively). However, the incidence and duration of CRS were significantly higher in the early G-CSF group than in the control group (81% vs. 38%, p=0.03; 3 vs. 0days, p=0.004, respectively). Moreover, early G-CSF application had no significant effect on the expansion and efficacy of CAR-T cells. In conclusion, our study suggested that early G-CSF administration did not reduce the incidence and duration of neutropenia but rather increased the incidence and duration of CRS.

Direct Potential Modulation of Neurogenic Differentiation Markers by Granulocyte-Colony Stimulating Factor (G-CSF) in the Rodent Brain.

The hematopoietic granulocyte-colony stimulating growth factor (G-CSF, filgrastim) is an approved drug in hematology and oncology. Filgrastim’s potential in neurodegenerative disorders is gaining increasingly more attention, as preclinical and early clinical studies suggest it could be a promising treatment option. G-CSF has had a tremendous record as a safe drug for more than three decades; however, its effects upon the central nervous system (CNS) are still not fully understood. In contrast to conceptual long-term clinical application with lower dosing, our present pilot study intends to give a first insight into the molecular effects of a single subcutaneous (s.c.) high-dose G-CSF application upon different regions of the rodent brain. We analyzed mRNA—and in some instances—protein data of neurogenic and non-neurogenic differentiation markers in different regions of rat brains five days after G-CSF (1.3 mg/kg) or physiological saline. We found a continuous downregulation of several markers in most brain regions. Remarkably, cerebellum and hypothalamus showed an upregulation of different markers. In conclusion, our study reveals minor suppressive or stimulatory effects of a single exceptional high G-CSF dose upon neurogenic and non-neurogenic differentiation markers in relevant brain regions, excluding unregulated responses or unexpected patterns of marker expression.

The Efficacy and Safety of Diyushengbai Tablet on Preventing and Treating Leukopenia Caused by Radiotherapy and Chemotherapy Against Tumor: A Systematic Review and Meta-Analysis

Background: Leukopenia is one of the side effects of radiotherapy and chemotherapy. Diyushengbai tablet (DYT) is used to prevent and treat leukopenia caused by various reasons. A meta-analysis was performed to systematically analyze the therapeutic effects of DYT on preventing and treating leukopenia caused by radiotherapy and chemotherapy. Objectives: This study aimed to systematically evaluate the efficacy and safety of DYT in preventing and treating leukopenia caused by radiotherapy and chemotherapy. Methods: We performed a comprehensive literature search of electronic databases such as PubMed, The Cochrane Library, China Knowledge Network (CNKI), China Biomedical Literature Database (CBM), Wanfang Data Knowledge Service Platform, and VIP, through November of 2021. The scanning reports deadline is until November 2021. The bias risk evaluation criteria developed by the Cochrane collaborative organization were used to evaluate the literature quality of the included studies. The RevMan5.4 software was used to analyze the data, and the Stata16.0 was used to perform the Egger test. Results: After selecting all the databases, a total of 41 reports which involved 3,793 cases were analyzed. Meta-analysis showed that DYT could significantly reduce the white blood cell (WBC) suppression caused by radiotherapy and chemotherapy and improve the patients’ WBC counts and neutrophils, compared with the efficacy of other oral WBC-elevating drugs such as Leucogen tablets and Batilol tablets and additional utilization of granulocyte colony-stimulating factor (G-CSF). The results of meta-analysis showed that for preventive medication purpose, the overall incidence of leukocyte suppression was [RR = 0.74, 95%CI (0.59, 0.92), p = 0.006], and the white blood cell count was [MD = 1.12, 95%CI (0.95, 1.29), p < 0.00001]; while for therapeutic purpose, the incidence of overall leukocyte suppression was [RR = 0.61, 95%CI (0.38, 0.95), p = 0.03], and the white blood cell count was [MD = 1.20, 95%CI (0.77, 1.62), p < 0.00001]. More importantly, the additional use of DYT can reduce the application amount of G-CSF. The results showed that the application of G-CSF can be reduced by an average of 1.57 from the beginning of treatment to return normal white blood cells around 2.23 in two cycles of chemotherapy. Conclusion: DYT is more effective in preventing and treating leukopenia caused by radiotherapy and chemotherapy than other oral WBC-elevating drugs, which have a high clinical value.

Granulocyte colony-stimulating factor in reproductive-related disease: Function, regulation and therapeutic effect

Granulocyte colony-stimulating factor (G-CSF) is one of the cytokines which plays important roles in embryo implantation and normal pregnancy. At the maternal-fetal interface, G-CSF can be synthesized by multiple cells, and participates in regulation of trophoblast development, endometrial decidualization, placental metabolism and angiogenesis. Moreover, as an important medium of intercellular communication, G-CSF has also been shown to exert key roles in crosstalk between cellular components at the maternal-fetal interface. Recently, our study demonstrated that G-CSF derived from M2 macrophage could promote trophoblasts invasion and migration through activating PI3K/AKT/Erk1/2 pathway, thereby involving in normal pregnancy program. Herein, we will summarize the role and regulation of G-CSF in normal pregnancy and reproductive-related disease, and the clinical applications of G-CSF in patients undergoing in vitro fertilization with thin endometrium, repeated implantation failure, and women suffered with recurrent spontaneous abortion.

Effects of Prophylactic Administration of Granulocyte Colony-Stimulating Factor on Peripheral Leukocyte and Neutrophil Counts Levels After Chemotherapy in Patients With Early-Stage Breast Cancer: A Retrospective Cohort Study.

BackgroundBoth chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) frequently occur and can lead to dose-limiting toxicity and even fatal chemotherapy side effects. The prophylactic use of recombinant human granulocyte colony-stimulating factor (rhG-CSF), including pegylated rhG-CSF (PEG-rhG-CSF), significantly reduces the risks of CIN and FN during chemotherapy in early-stage breast cancer (ESBC) patients. However, whether the prophylactic use of granulocyte colony-stimulating factor (G-CSF), especially PEG-rhG-CSF, can influence white blood cell (WBC) counts and absolute neutrophil counts (ANCs) after finishing the chemotherapy remains unknown. Therefore, exploring the development and recovery tendency of WBC counts and ANCs during and after chemotherapy is crucial.ObjectiveWe aimed to investigate the variation tendency and recovery of WBC counts and ANCs during and after chemotherapy and evaluate the independent factors influencing leukopenia and neutropenia lasting longer after chemotherapy. We also aimed to provide individualized prophylactically leukocyte elevation therapy for breast cancer patients.MethodsThis single-center retrospective cohort study evaluated 515 ESBC patients who received rhG-CSF or PEG-G-CSF for prophylaxis after adjuvant or neoadjuvant chemotherapy. Blood test reports were analyzed during chemotherapy, and on a 12-month follow-up period after finishing the chemotherapy. The WBC counts and ANCs were measured to assess their variation tendency characteristics and to identify independent factors that influenced the occurrence of leukopenia and neutropenia lasting longer than 12 months after chemotherapy.ResultsProphylaxis with rhG-CSF or PEG-rhG-CSF kept the mean values of WBC counts and ANCs within the normal range during chemotherapy, but a significant difference in WBC levels was detected before the end of the last chemotherapy compared to the prechemotherapy period (baseline) (p < 0.001). During the 12-month follow-up after the end of the last chemotherapy, WBC counts and ANCs gradually recovered, but the group that used only PEG-rhG-CSF (long-acting group, p WBC = 0.012) or rhG-CSF (short-acting group, p WBC = 0.0005) had better leukocyte elevation effects than the mixed treatment group (PEG-rhG-CSF mixed rhG-CSF). Besides, the short-acting group had a better neutrophil elevation effect than the longer-acting (p ANC = 0.019) and mixed (p ANC = 0.002) groups. Leukopenia was still present in 92 (17.9%) patients and neutropenia in 63 (12.2%) 12 months after the end of the last chemotherapy. The duration of leukopenia over 12 months was closely associated with the baseline WBC level (p < 0.001), G-CSF types (p = 0.027), and surgical method (p = 0.041). Moreover, the duration of neutropenia over 12 months was closely related to the baseline ANC (p < 0.001), G-CSF types (p = 0.043), and molecular typing (p = 0.025).ConclusionThe prophylactic application of G-CSF effectively stabilized the WBC counts and ANCs during chemotherapy in ESBC patients. Nevertheless, the recovery of WBC counts and ANCs after chemotherapy varied between different G-CSF treatment groups. The risk of leukopenia and neutropenia persisting for more than 12 months after chemotherapy was associated with G-CSF types, the baseline level of WBC count/ANCs, surgical method, and molecular typing.

The effects of granulocyte-colony stimulating factor on chronic liver disease: a meta-analysis.

The clinical application of granulocyte-colony stimulating factor on chronic liver disease is still controversial. The study aimed to evaluate the effects of granulocyte-colony stimulating factor on chronic liver disease. A systematic literature search was performed in PubMed, Embase, Cochrane Library and Chinese Biomedical Literature database. Randomized-controlled trials assessing the efficacy of granulocyte-colony stimulating factor were selected. Granulocyte-colony stimulating factor was associated with an increasing long-term survival (RR 1.54; 95% CI 1.22 to 1.94; p = 0.0003; heterogeneity: Q = 0.26, I2 = 25%) and an increasing short-term survival (RR 1.44; 95% CI 1.16 to 1.78; p = 0.0009; heterogeneity: Q < 0.00001, I2 = 80%). Granulocyte-colony stimulating factor failed to lower mortality secondary to multiple organ failure (RR 0.65; 95% CI 0.34 to 1.21; p = 0.17; heterogeneity: Q = 0.45; I2 = 0%), gastrointestinal bleeding mortality (RR 0.97; 95% CI 0.61 to 1.56; p = 0.91; heterogeneity: Q = 0.35; I2 = 11%) and sepsis mortality (RR 0.27; 95% CI 0.06 to 1.12; p = 0.07; heterogeneity: Q < 0.00001; I2 = 90%). It significantly lowered the Child-Turcotte-Pugh (MD=-0.97, 95% CI -1.48 to -0.45; p = 0.0003; heterogeneity: Q = 0.25; I2 = 28%). No serious adverse events were observed. Granulocyte-colony stimulating factor resulted in significantly improved 12-month survival and reduced Child-Turcotte-Pugh score with relative safety. Establishment of guidelines and protocols in future clinical trials will promote granulocyte-colony stimulating factor as an effective and safe therapy for chronic liver disease.

Granulocyte colony-stimulating factor (G-CSF) enhances cocaine effects in the nucleus accumbens via a dopamine release-based mechanism.

Cocaine use disorder is associated with alterations in immune function including altered expression of multiple peripheral cytokines in humans-several of which correlate with drug use. Individuals suffering from cocaine use disorder show altered immune system responses to drug-associated cues, highlighting the interaction between the brain and immune system as a critical factor in the development and expression of cocaine use disorder. We have previously demonstrated in animal models that cocaine use upregulates the expression of granulocyte colony-stimulating factor (G-CSF)-a pleiotropic cytokine-in the serum and the nucleus accumbens (NAc). G-CSF signaling has been causally linked to behavioral responses to cocaine across multiple behavioral domains. The goal of this study was to define whether increases in G-CSF alter the pharmacodynamic effects of cocaine on the dopamine system and whether this occurs via direct mechanisms within local NAc microcircuits. We find that systemic G-CSF injection increases cocaine effects on dopamine terminals. The enhanced dopamine levels in the presence of cocaine occur through a release-based mechanism, rather than through effects on the dopamine transporter-as uptake rates were unchanged following G-CSF treatment. Critically, this effect could be recapitulated by acute bath application of G-CSF to dopamine terminals, an effect that was occluded by prior G-CSF treatment, suggesting a similar mechanistic basis for direct and systemic exposures. This work highlights the critical interaction between the immune system and psychostimulant effects that can alter drug responses and may play a role in vulnerability to cocaine use disorder.

Addition of Plerixafor Overcomes Poor Mobilization in Autologous and Allogeneic Stem Cell Grafts and Leads to Efficient and Sustained Engraftment

▪Poor hematopoietic stem cell (HSC) mobilization upon granulocyte-colony stimulating factor (G-CSF) remains a significant problem for autologous and allogeneic hematopoietic cell transplantation (HCT). In up to 20% of patients, no sufficient autografts can be collected. The chemokine receptor CXCR4 plays a pivotal role in the homing of HSCs to the bone marrow. CXCR4 inhibition by the bicyclam derivative plerixafor can lead to improved HSC yields. We here evaluated the effects of plerixafor supported HSC apheresis in order to enable otherwise impossible HCT and with regard to graft quality and transplantation outcomes in both the autologous and allogeneic setting.Data retrospectively obtained from all 2,257 leukaphereses between 2014 and 2017 (588 for autologous and 1,669 for allogeneic transplantation) were analyzed. 48 individuals (31 male and 17 female, median age 52 years, range 31-72 years) were identified who received plerixafor due to insufficient HSC mobilization upon G-CSF stimulation. 44 patients (non-hodgkin lymphoma n=19, multiple myeloma n=19, systemic sclerosis n=3, Ewing sarcoma n=2, germinal cell cancer n=1) collected HSC for autologous, 4 HLA-identical siblings for allogeneic transplantation representing a low rate of poor mobilizers of 7% (44/588) and 0.2% (4/1669) autologous and allogeneic donors, respectively.A median of 1 dose plerixafor (range, 1-3 doses) was applied. Aphereses after addition of plerixafor were performed at a median of 2 days (range, 1-651 days) after insufficient attempts (median CD34+ cells 13/µl; range, 0-46/µl). 4 patients received a second mobilization chemotherapy before plerixafor application. 2 donors received plerixafor despite collection of >3.0x106 HSC per kilogram recipient body weight (kg BW) to enable in vitro graft manipulation or more than one HCT.Patients collecting HSC for autologous HCT received a median of 7 therapy cycles (range, 3-25 cycles) before HSC mobilization. Allogeneic donors tended to be older (median age of 54 years; range, 49-69 years).HSC mobilization was improved in 38/44 patients and 4/4 allogeneic donors. Before and after plerixafor application, median CD34+ cell counts were 0.6x106 (0.1-4.1 x106) cells/kg BW in 51 aphereses (range, 1-3 per patient) and 2.0x106 (range, 0.1-23.3 x106) cells/kg BW in 94 aphereses (range, 1-4 per patient), respectively (p<0.0001).Autologous HCT was performed in 32/44 patients. In the remaining, no HCT was performed due to further insufficient HSC mobilization despite plerixafor application (n=6), death due to progressive disease (n=3) or due to infection (n=1) before HCT. Two recent patients did not undergo autologous HCT, yet. All patients received G-CSF during autologous HCT. Median neutrophil (>500/µl) and platelet (>20,000/µl) engraftment was reached on day 12 (range, days 9-21) and 14 (range, days 10-23), respectively. No primary or secondary graft failure or poor graft function (PGF) was observed.The collected allogeneic grafts were applied to the patients in all 4 cases. Allogeneic HCT patients did not receive G-CSF. Median neutrophil and platelet engraftment was noted on days 13 (range, days 11-20) and 15 (range, days 11-23), respectively. Again, neither primary or secondary graft failure nor PGF was noted.Median overall survival after HCT for patients receiving autologous and allogeneic grafts was 31 (range, 1-72) and 7 (range, 5-53) months, respectively.For both autologous and allogeneic grafts, addition of plerixafor improved HSC yields in most poor mobilizers and therefore enabled for an otherwise impossible HCT including in vitro manipulation of allogeneic grafts and repetitive HCT. Of note, using G-CSF and plerixafor mobilization resulted in insufficient cell counts in only 0.3% of donors (6/2,257; for patients 6/588: 1%; for allogeneic donors 0/1,669: 0%) allowing HCT for almost every patient. Of note, poor mobilizers overall appeared to be seldom. Since plerixafor application was successful in most patients, these data might also help to reduce G-CSF application especially to patients who should not suffer from additional pulmonal toxicity (e.g. in systemic sclerosis). Hematopoietic engraftment after HCT of plerixafor mobilized grafts was rapid and sustained without observation of graft failure or PGF. The time to engraftment was comparable to G-CSF mobilized grafts showing that the quality of plerixafor mobilized grafts is to be estimated equal. DisclosuresBethge:Miltenyi Biotech GmbH: Consultancy, Honoraria, Research Funding; Neovii GmbH: Honoraria, Research Funding.

Randomized, double blind, placebo-controlled, safety and efficacy study of dutogliptin in combination with filgrastim in early recovery post-MI: rationale, design and first interim analysis

Abstract Background Regenerative therapies offer new approaches to improve cardiac function after acute ST-elevation myocardial infarction (STEMI). Mobilization of stem cells and homing within the infarcted area have been identified as the key mechanisms for successful treatment. Application of granulocyte-colony stimulating factor (G-CSF) is the least invasive way to mobilize stem cells while DDP4-inhibitor facilitates homing via stromal cell-derived factor 1 alpha (SDF-1α). Dutogliptin, a novel DPP4 inhibitor, combined with stem cell mobilization using G-CSF significantly improved survival and reduced infarct size in a murine model. Purpose We initiated a phase II, multicenter, randomized, placebo-controlled efficacy and safety study (N=140) analyzing the effect of combined application of G-CSF and dutogliptin, a small molecule DPP-IV-inhibitor for subcutaneous use after acute myocardial infarction. Methods The primary objective of the study is to evaluate the safety and tolerability of dutogliptin (14 days) in combination with filgrastim (5 days) in patients with STEMI (EF &amp;lt;45%) following percutaneous coronary intervention (PCI). Preliminary efficacy will be analyzed using cardiac magnetic resonance imaging (cMRI) to detect &amp;gt;3.8% improvement in left ventricular ejection fraction (LV-EF). 140 subjects will be randomized to filgrastim plus dutogliptin or matching placebos. Results Baseline characteristics of the first 26 patients randomized (24 treated) in this trial reveal a majority of male patients (70.8%) and a medium age of 58.4 years (37 to 84). During the 2-week active treatment period, 35 adverse events occurred in 13 patients, with 4 rated as serious (hospitalization due to pneumonia N=3, hospitalization due to acute myocardial infarction N=1), and 1 adverse event was rated as severe (fatal pneumonia), 9 moderate, and 25 as mild. 6 adverse events were considered possibly related to the study medication, including cases of increased hepatic enzymes (N=3), nausea (N=1), subcutaneous node/suffusion (N=1) and syncope (N=1). Conclusions Our data demonstrate that the combined application of dutogliptin and G-CSF appears to be safe on the short term and feasible after acute myocardial infarction and may represent a new therapeutic option in future. Funding Acknowledgement Type of funding source: Other. Main funding source(s): This research is funded by the sponsor RECARDIO, Inc., 1 Market Street San Francisco, CA 94150, USA. RECARDIO Inc. is funding the complete study. The Scientific Board of RECARDIO designed the study. Data Collection is at the participating sites. Interpretation of the data by the Scientific Board and Manuscript written by the authors and approved by the Sponsor

Exogenous versus Endogenous Stem Cells Impacts on Knee Articular Cartilage Repair, Pain Sensation and Gait in a Rat Model of Osteoarthritis; Structural and Functional Assessment

Osteoarthritis (OA) is a joint disease with a very limited available curative option. Stem cells-based therapy revealed a promising regenerative capability in cartilage repair. We aimed to compare the sole and the combined effects of bone marrow derived mesenchymal stem cells (BM-MSCs) and the granulocyte colony stimulating factor (G-CSF) mobilized endogenous stem cells in articular cartilage repair, pain and gait improvement in monoiodoacetat (MIA)-induced rat model of osteoarthritis. OA was induced by a single intra articular injection 1 mg MIA. BM-MSCs-treated and the combined groups received a single intra-articular of injection of BM-MSCs. G-CSF-treated and the combined groups received subcutaneous injections of G-CSF. The articular cartilage repair, total leucocytic count, nociception behavior and gait parameters were assessed. The results revealed an increase in total leucocytic count on the 5th day after G-CSF injection and returned to normal on day 35. All treated groups showed comparable improvement in nociception behavior and gait parameters. Histopathological evaluation showed enhanced cartilage repair in the combined group compared to the two other treated groups. In conclusion The concomitant application of BM-MSCs and G-CSF have a promising comparable effect of exogenous and mobilized endogenous stem cells on pain, gait and the structural improvements.

Impact of Granulocyte Colony-Stimulating Factor (G-CSF) and Epoetin (EPO) on Hematologic Toxicities and Quality of Life in Patients During Adjuvant Chemotherapy in Early Breast Cancer: Results From the Multi-Center Randomized ADEBAR Trial

BackgroundHematologic toxicities are one of the greatest challenges in adjuvant chemotherapy for breast cancer. This analysis of the ADEBAR trial aims to evaluate application and effect of granulocyte colony-stimulating factor (G-CSF) and epoetin alfa (EPO) on hematologic parameters and fatigue in patients with breast cancer during chemotherapy. Patients and MethodsIn the ADEBAR trial, 1493 patients with node-positive primary breast cancer were randomized to either 6 × 5-fluorouracil, epirubicin, and cyclophosphamide (FEC120) or 4 × epirubicin and cyclophosphamide followed by 4 × docetaxel (EC-DOC). Co-medication with G-CSF or EPO was applied to treat chemotherapy-induced leukopenia or anemia. Fatigue was assessed at baseline and after one-half of the chemotherapy. ResultsIn total, 899 patients could be included in the analysis. There was no evidence for an association between leucocyte or hemoglobin levels and application of G-CSF and EPO in the preceding cycle, respectively. Hemoglobin levels (B = −0.41; P < .001) were affected by treatment regimen. Fatigue during chemotherapy was mostly affected by the level of fatigue before the start of chemotherapy (B = 0.41; P < .001). Patients with G-CSF application in the preceding cycle showed an increased fatigue score (B = 5.43; P = .02). ConclusionWe showed that fatigue during adjuvant chemotherapy was mostly affected by the level of fatigue present before the start of chemotherapy. This result suggests that the level of fatigue before the start of treatment should be included as an important factor when deciding on type and toxicity of chemotherapy in early breast cancer.

Effects of Granulocyte Colony-Stimulating Factor on Proliferation and Apoptosis of B Cells in Bone Marrow of Healthy Donors

Background and ObjectiveThe aim of this study was to investigate the effects of granulocyte colony-stimulating factor (G-CSF) on the proliferation and apoptosis of bone marrow (BM) B cells from healthy donors and its mechanism. Materials and MethodsThe proliferation ability and apoptosis of BM cells from healthy donors before and after in vivo G-CSF application were determined by multiparameter flow cytometry. The gene expression of B cells was detected by RNA-Seq. In vitro experiments were performed to investigate the effects of G-CSF on the proliferation and apoptosis of BM B cells through which gene. ResultsTreating healthy donors with G-CSF significantly decreased proliferation and increased apoptosis of BM B cells. The proliferation of CD19+CD27- B cell subgroup and CD19+CD24hiCD38hi B cell subset were also decreased. G-CSF also significantly altered proapoptotic genes, cell cycle arrest genes, and DNA replication and cell cycle genes, especially significantly increased SOCS1 expression of BM B cells. In vitro experiments showed that SOCS1 overexpression did not affect B cell proliferation ability and apoptosis. ConclusionsOur results suggest that extensive effects of G-CSF on BM B cells, such as inhibiting proliferation, inducing apoptosis, and altering a series of gene expression.

Use of Human Granulocyte Colony-Stimulating Factor (G-CSF) in Consolidation Chemotherapy in Adult Acute Myeloid Leukaemia (AML)

Acute myeloid leukaemia (AML) is treatable and potentially curable disease. Significant morbidity is related to the prolonged, severe neutropenia resulting from the disease as well as the intensive chemotherapy. The administration of granulocyte - colony stimulating factor (G-CSF) is recommended to reduce the neutropenic period. But the current information and guidelines are insufficient about the most appropriate time to start G-CSF and the optimum duration of treatment after chemotherapy in consolidation phase. This study explores better timing to start G-CSF after completion of chemotherapy in consolidation phase of AML patient. This prospective study was conducted in the department of Haematology, Bangabandhu Sheikh Mujib Medical University among AML patients, who received consolidation chemotherapy (high dose cytarabine). Samples were grouped into two arms. Arm-A (Absolute Neutrophil Count &gt;1000/cmm) received prophylactic G-CSF and Arm-B (Absolute Neutrophil Count &lt;1000/cmm) received G-CSF during neutropenia. Filgrastim was used as G-CSF and daily 300 micrograms were given subcutaneously according to study protocol. Statistical analysis was done by parametric (t test) test and appropriate using computer based SPSS (21) Program. Total sample was 19, out of which 6 in prophylactic G-CSF group (Arm-A) and 13 in delayed G-CSF group (Arm-B). Most of the patients were male (63.16%), male to female ratio 1.7:1 and mean age of sample 35 years. Mean ANC at the 1st day of G-CSF application in Arm-A 1170.5/cmm &amp; in Arm-B 272.6/cmm (p=&lt;0.001); mean requirements of G-CSF accordingly 11.5 and 5.9 (p=0.0014), mean 1st day of G-CSF application 9.5th day and 14.5th day (p=0.001). Outcomes in Arm-A and Arm-B were accordingly, mean duration of ANC recovery 10 and 9.85 days (p=0.913), febrile neutropenia 2.67 and 2.57 days (p=0.961), hospital stay 20 and 20.3 days (p=0.259), red cell concentrate transfusion 1.83 and 1.46 units (p=0.550), platelets concentrate transfusion 11.83 and 7.77 bags (p=0.2405), and there was no death case in two arms. Differences of timing to start G-CSF and its requirements between two groups were significant, but the outcomes did not show any statistically significant difference.&#x0D; Bangladesh Med J. 2018 May; 47 (2): 23-28

Therapeutic effect of human umbilical cord blood mesenchymal stem cells combined with G-CSF on rats with acute liver failure

Human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) have been used to facilitate healing in animal models of liver injury, while granulocyte colony-stimulating factor (G-CSF) has been shown to stimulate stem cell mobilization and these cells may contribute to liver repair. hUCB-MSCs were characterized by flow cytometry, and transplanted into rats with d-galactosamine (D-GalN)/lipopolysaccharides (LPS)-induced acute liver failure (ALF) together with granulocyte colony-stimulating factor (G-CSF). Liver function, oxidative stress and pro-inflammatory cytokines expressions were examined using enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was used to observe the morphological changes. Apoptosis was investigated by terminal dUTP nick end labeling (TUNEL) staining. Bromodeoxyuridine (BrdU) cell proliferation assay was analyzed by immunofluorescence and immunohistochemistry. In the results, cultured hUCB-MSCs displayed proliferation and adipogenic and osteogenic differentiation potentials. hUCB-MSCs in combination with G-CSF significantly attenuated ALF-induced liver function injury. Furthermore, hUCB-MSCs and G-CSF treatment remarkably suppressed the secretions of pro-inflammatory cytokines and MDA activation induced by ALF. In addition, inflammation, lesions and cell apoptosis in liver tissues were obviously ameliorated by application of hUCB-MSCs and G-CSF. In conclusion, hUCB-MSCs, alone or co-treatment with G-CSF could ameliorate ALF in rats by inhibiting liver function injury, production of pro-inflammatory cytokines, oxidative stress, and liver cell apoptosis.

Combination of BMSCs-laden acellular nerve xenografts transplantation and G-CSF administration promotes sciatic nerve regeneration.

Peripheral nerve gaps often lead to interrupted innervation, manifesting as severe sensory and motor dysfunctions. The repairs of the nerve injuries have not achieved satisfactory curative effects in clinic. The transplantation of bone marrow stromal cells (BMSCs)-laden acellular nerve xenografts (ANX) has been proven more effective than the acellular nerve allografting. Besides, granulocyte colony-stimulating factor (G-CSF) can inhibit inflammation and apoptosis, and thus is conducive to the microenvironmental improvement of axonal regeneration. This study aims to investigate the joint effect of BMSCs-seeded ANX grafting and G-CSF administration, and explore the relevant mechanisms. Adult SD rats were divided into five groups randomly: ANX group, ANX combined with G-CSF group, BMSCs-laden ANX group, BMSCs-laden ANX combined with G-CSF group, and autograft group. Eightweeks after transplantation, the detection of praxiology and neuroelectrophysiology was conducted, and then the morphology of the regenerated nerves was analyzed. The inflammatory response and apoptosis in the nerve grafts as well as the expression of the growth-promoting factors in the regenerated tissues were further assayed. G-CSF intervention and BMSCs implanting synergistically promoted peripheral nerve regeneration and functional recovery following ANX bridging, and the restoration effect was matchable with that of the autologous nerve grafting. Moreover, local inflammation was alleviated, the apoptosis of the seeded BMSCs was decreased, and the levels of the neuromodulatory factors were elevated. In conclusion, the union application of BMSCs-implanted ANX and G-CSF ameliorated the niche of neurotization and advanced nerve regeneration substantially. The strategy achieved the favorable effectiveness as an alternative to the autotransplantation.

Application of G-CSF in Congestive Heart Failure Treatment.

Introduction: Congestive Heart Failure (CHF) is a disorder in which the heart is unable to supply enough blood for body tissues. Since heart is an adaptable organ, it overcomes this condition by going under remodeling process. Considering cardiac myocytes are capable of proliferation after MI, stimulation of neovascularization as well as their regeneration might serve as a novel target in cardiac remodeling prevention and CHF treatment. Granulocyte Colony-Stimulating Factor (G-CSF), is a hematopoietic cytokine that promotes proliferation and differentiation of neutrophils and is in-volved in cardiac repair after MI. So far, this is the first review to focus on GCSF as a novel treat-ment for heart failure.Methods: We conducted a search of some databases such as PubMed for articles and reviews pub-lished between 2003 and 2017, with different keywords including “G-CSF”, “congestive heart fail-ure”, “new therapies for CHF”, “filgrastim”, “in vivo study”.Results: GCSF exerts its beneficial effects on cardiac repair through either stem cell mobilization or direct angiogenesis promotion. All of which are capable of promoting cardiac cell repair.Conclusion: GCSF is a promising target in CHF-therapy by means of cardiac repair and remodeling prevention through multiple mechanisms, which are effective enough to be used in clinical practice.

Biomarker Supervised G-CSF (Filgrastim) Response in ALS Patients.

Objective: To evaluate safety, tolerability and feasibility of long-term treatment with Granulocyte-colony stimulating factor (G-CSF), a well-known hematopoietic stem cell factor, guided by assessment of mobilized bone marrow derived stem cells and cytokines in the serum of patients with amyotrophic lateral sclerosis (ALS) treated on a named patient basis.Methods: 36 ALS patients were treated with subcutaneous injections of G-CSF on a named patient basis and in an outpatient setting. Drug was dosed by individual application schemes (mean 464 Mio IU/month, range 90-2160 Mio IU/month) over a median of 13.7 months (range from 2.7 to 73.8 months). Safety, tolerability, survival and change in ALSFRS-R were observed. Hematopoietic stem cells were monitored by flow cytometry analysis of circulating CD34+ and CD34+CD38− cells, and peripheral cytokines were assessed by electrochemoluminescence throughout the intervention period. Analysis of immunological and hematological markers was conducted.Results: Long term and individually adapted treatment with G-CSF was well tolerated and safe. G-CSF led to a significant mobilization of hematopoietic stem cells into the peripheral blood. Higher mobilization capacity was associated with prolonged survival. Initial levels of serum cytokines, such as MDC, TNF-beta, IL-7, IL-16, and Tie-2 were significantly associated with survival. Continued application of G-CSF led to persistent alterations in serum cytokines and ongoing measurements revealed the multifaceted effects of G-CSF.Conclusions: G-CSF treatment is feasible and safe for ALS patients. It may exert its beneficial effects through neuroprotective and -regenerative activities, mobilization of hematopoietic stem cells and regulation of pro- and anti-inflammatory cytokines as well as angiogenic factors. These cytokines may serve as prognostic markers when measured at the time of diagnosis. Hematopoietic stem cell numbers and cytokine levels are altered by ongoing G-CSF application and may potentially serve as treatment biomarkers for early monitoring of G-CSF treatment efficacy in ALS in future clinical trials.