Role Of Granulocyte Colony-stimulating Factor Research Articles

Granulocyte colony-stimulating factor protects against arthritogenic alphavirus pathogenesis in a type I IFN-dependent manner.

Arthritogenic alphaviruses cause disease characterized by fever, rash, and incapacitating joint pain. Alphavirus infection stimulates robust inflammatory responses in infected hosts, leading to the upregulation of several cytokines, including granulocyte colony-stimulating factor (G-CSF). G-CSF is secreted by endothelial cells, fibroblasts, macrophages, and monocytes and binds to colony stimulating factor 3 receptor (CSF3R, also known as G-CSFR) on the surface of myeloid cells. G-CSFR signaling initiates proliferation, differentiation, and maturation of myeloid cells, especially neutrophils. Importantly, G-CSF has been found at high levels in both the acute and chronic phases of chikungunya disease; however, the role of G-CSF in arthritogenic alphavirus disease remains unexplored. Here, we sought to test the effect of G-CSF on chikungunya virus (CHIKV) and Mayaro virus (MAYV) infection using G-CSFR-deficient mice (G-CSFR-/-). We observed sustained weight loss in G-CSFR-/- mice following viand MAYV infection compared to wild-type mice. Furthermore, G-CSFR-/- mice had a significantly higher percentage of inflammatory monocytes and reduction in neutrophils throughout infection. The difference in weight loss in G-CSFR-/- mice induced by alphavirus infection was corrected by blocking type I IFN signaling. In summary, these studies show that type I IFN signaling contributes to G-CSFR mediated control of arthritogenic alphavirus disease.

Single Dose of Granulocyte-Colony Stimulating Factor Use to Improve Intracytoplasmic Sperm Injection Outcomes

Receptive endometrium is essential for successful embryo implantation and is created by the synergistic activities of estrogen and progesterone, as well as support from other endocrine, paracrine, and autocrine pathways. Granulocyte Colony Stimulating Factor (G-CSF) may play a crucial role in modulating the immune response to enhance implantation. To estimate the role of granulocyte-colony stimulating factor on the clinical intracytoplasmic sperm injection (ICSI) outcome parameters. A prospective comparative study with random sample selection was carried out from 2021 to 2023 at the High Institute for Infertility Diagnosis and Assisted Reproductive Technologies, Al-Nahrain University. It included 80 women with infertility, with or without previous failure trials of intracytoplasmic sperm injection, who completed IVF and ICSI protocols and reached the day of embryo transfer. On the day of embryo transfer, patients were divided into two groups: 49 patients received no additional treatment (group 1), and 31 patients received granulocyte-colony stimulating factor subcutaneous injection within one hour of embryo transfer (group 2). The implantation rate was 13.3% in group 2 compared to 7.6% in group 1. The chemical and clinical pregnancy rates were 29.0% and 25.8% in group 2, while group 1 had 18.4% for both chemical and clinical pregnancy rates. The pregnancy and implantation rates were slightly higher in group 2, but the difference was not significant. More research is needed to support the use of G-CSF as a standard treatment in ICSI patients.

Granulocyte colony-stimulating factor does not improve mortality in severe alcoholic hepatitis: a single-center experience from the United States.

To assess the role of granulocyte colony-stimulating factor (GCSF) in the patients with severe alcoholic hepatitis (SAH) using real world experience in the United States. There are few effective treatments for severe alcoholic hepatitis, which has a significant fatality rate. GCSF has been associated with improved survival in a small number of Indian studies, while there is a dearth of information from other parts of the globe. We performed a single-center retrospective study of consecutive patients admitted to a tertiary care, liver transplant center with severe alcoholic hepatitis from May 2015 to February 2019. The patients receiving GCSF (5μg/kg subcutaneously every 12 hours for 5 consecutive days) (n=12) were compared to the patients receiving standard of care (n=42). Thirty-day, 90-day and 1-year mortality rates was similar among groups (25% vs. 17%, P=0.58; 41% vs 29%, P=0.30; 41% vs 47%, P=0.44, respectively). There was no difference in liver transplant listing and orthotopic transplantation among groups. In this real-world, United States-based study, GCSF does not improved survival in the patient with several alcoholic hepatitis compared to standard of care.

Granulocyte Colony-Stimulating Factor Accelerates the Recovery of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure by Promoting M2-Like Transition of Monocytes.

Background and AimAcute-on-chronic liver failure (ACLF) has a high mortality rate. The role of granulocyte colony-stimulating factor (G-CSF) in ACLF remains controversial. Monocytes/macrophages are core immune cells, which are involved in the initiation and progression of liver failure; however, the effect of G-CSF on monocytes/macrophages is unclear. The study aimed to verify the clinical efficacy of G-CSF and explore the effect of it on monocytes in hepatitis B virus (HBV)-related ACLF (HBV-ACLF) paitents.MethodsWe performed a large randomized controlled clinical trial for the treatment of HBV-ACLF using G-CSF. A total of 111 patients with HBV-ACLF were prospectively randomized into the G-CSF group (5 μg/kg G-CSF every day for 6 days, then every other day until day 18) or the control group (standard therapy). All participants were followed up for at least 180 days. The relationship between monocyte count and mortality risk was analyzed. The effect of G-CSF on the phenotype and function of monocytes from patients with HBV-ACLF was evaluated using flow cytometry in vivo and in vitro experiments.ResultsThe survival probability of the G-CSF group at 180 days was higher than that of the control group (72.2% vs. 53.8%, P = 0.0142). In the G-CSF-treated group, the monocyte counts on days 0 and 7 were independently associated with an evaluated mortality risk in the fully adjusted model (Model 3) [at day 0: hazard ratio (HR) 95% confidence interval (CI): 15.48 (3.60, 66.66), P = 0.0002; at day 7: HR (95% CI): 1.10 (0.50, 2.43), P=0.8080]. Further analysis showed that after treatment with G-CSF in HBV-ACLF patients, the expression of M1-like markers (HLA-DR and CD86) in monocytes decreased (HLA-DR: P = 0.0148; CD86: P = 0.0764). The expression of MerTK (M2-like marker) increased (P = 0.0002). The secretion of TNF-α, IL-6, and IL-10 from monocytes decreased without lipopolysaccharide (LPS) stimulation (TNF-α: P < 0.0001; IL-6: P= 0.0025; IL-10: P = 0.0004) or with LPS stimulation (TNF-α: P = 0.0439; P = 0.0611; IL-10: P = 0.0099). Similar effects were observed in vitro experiments.ConclusionG-CSF therapy confers a survival benefit to patients with HBV-ACLF. G-CSF can promote the anti-inflammatory/pro-restorative phenotype (M2-like) transition of monocytes, which may contribute to the recovery of ACLF.Clinical Trial Registration NumberClinicalTrials.gov, identifier (NCT02331745).

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Improving early breast cancer treatment: the role of granulocyte colony-stimulating factor

Breast cancer is still the leading cause of death in patients with malignant tumors. Among women with breast cancer, standard combination chemotherapy with anthracyclines and taxanes reduces mortality from this disease by about one third compared to patients not receiving chemotherapy and is the standard for neoadjuvant or adjuvant chemotherapy of breast cancer. Understanding the patterns of tumor growth has made it possible to improve the current paradigms of the treatment of early forms of breast cancer and to use dose-dense chemotherapy regimens to achieve better treatment results. Nowadays, chemotherapy in a dose-dense regimen for breast cancer is the preferred option in all world and Russian clinical guidelines. However, the use of such chemotherapy regimens significantly increases the incidence of side effects, primarily febrile neutropenia. The appearance of more effective methods of supportive care, particularly short-acting and long-acting granulocyte colony-stimulating factor, in clinical practice has made it possible to use dose-dense chemotherapy regimens to increase the effectiveness of the treatment.

Insights into the Role of Granulocyte Colony-Stimulating Factor in Severe Alcoholic Hepatitis.

Alcohol use disorder is the predominant cause of chronic liver disease globally. The standard of care for the treatment of alcoholic hepatitis, corticosteroids, has been shown to provide a therapeutic response in ∼60% of carefully selected patients with a short-term survival benefit. The patients who do not respond to steroids, or are ineligible due to infections or very severe disease, have little options other than liver transplantation. There is, thus, a large unmet need for new therapeutic strategies for this large and sick group of patients. Granulocyte colony stimulating factor (G-CSF) has been shown to favorably modulate the intrahepatic immune milieu and stimulate the regenerative potential of the liver. Initial studies have shown encouraging results with G-CSF in patients with severe alcoholic hepatitis. It has also been found to help steroid nonresponsive patients. There is, however, a need for careful selection of patients, regular dose monitoring and close observation for adverse events of G-CSF. In this review, we analyze the basis of the potential benefits, clinical studies, cautions and challenges in the use of G-CSF in alcoholic hepatitis.

Contrasting Immunopathogenic and Therapeutic Roles of Granulocyte Colony-Stimulating Factor in Cancer.

Tumor cells are particularly adept at exploiting the immunosuppressive potential of neutrophils as a strategy to achieve uncontrolled proliferation and spread. Recruitment of neutrophils, particularly those of an immature phenotype, known as granulocytic myeloid-derived suppressor cells, is achieved via the production of tumor-derived granulocyte colony-stimulating factor (G-CSF) and neutrophil-selective chemokines. This is not the only mechanism by which G-CSF contributes to tumor-mediated immunosuppression. In this context, the G-CSF receptor is expressed on various cells of the adaptive and innate immune systems and is associated with induction of T cell polarization towards the Th2 and regulatory T cell (Treg) phenotypes. In contrast to the potentially adverse effects of sustained, endogenous production of G-CSF by tumor cells, stringently controlled prophylactic administration of recombinant (r) G-CSF is now a widely practiced strategy in medical oncology to prevent, and in some cases treat, chemotherapy-induced severe neutropenia. Following an overview of the synthesis, structure and function of G-CSF and its receptor, the remainder of this review is focused on: (i) effects of G-CSF on the cells of the adaptive and innate immune systems; (ii) mechanisms by which this cytokine promotes tumor progression and invasion; and (iii) current clinical applications and potential risks of the use of rG-CSF in medical oncology.

Treatment induced leucopenia in hepatitis C and Role of G-CSF in its management.

To determine the frequency and severity of leucopenia during antiviral treatment in patients with hepatitis C and the effectiveness of G-CSF (Granulocyte-Colony Stimulating Factor) in its management. An observational study. Shafi Clinic, Rawalpindi, from July 2005 to July 2007. Patients with Polymerase Chain Reaction (PCR) positive for Hepatitis C Virus-Ribonucleic Acid (HCVRNA) by Enzyme Linked Immunosorbent Assay (ELISA) method were included in the study. Standard combination therapy was given to all i.e. interferon and ribavirin. Those with total leukocyte count (TLC)<4000/cmm were given injection Granulocyte-Colony Stimulating Factor (G-CSF) according to severity of leucopenia. Response to therapy was noted and dose titration was done accordingly. A total of 208 patients were enrolled in the study with 99 (48%) males and 109 (52%) females. Total leukocyte count (TLC)<4000/cmm was observed in 78 (37.5%) cases. Conventional interferon induced leucopenia was seen in 60 out of 172 (35%) cases. Pegylated interferon induced leucopenia was seen in 18 out of 36 (50%) cases. Patients on Pegylated interferon had more severe leucopenia as compared to those on conventional interferon. Granulocyte-Colony Stimulating Factor (G-CSF) administration resulted in an increase in mean total leukocyte count from 2300 to 5200/cmm. No patient required antiviral dose reduction or discontinuation. Recombinant Granulocyte-Colony Stimulating Factor (G-CSF) administration tends to manage leucopenia, which is a common adverse effect of antiviral treatment for hepatitis C.

Role of G-CSF after High-Dose Post-Transplantation Cyclophospamide

<h3>Background</h3> High-dose post-transplantation cyclophosphamide (PTC) has proven to be a valuable treatment modality for the prevention of graft-versus-host disease (GVHD) after stem cell transplant (SCT). Granulocyte colony stimulating factor (G-CSF) is routinely given after PTC to improve time to engraftment. Historically, G-CSF is given on Day +5 post-SCT. However, this strategy has not been vigorously compared to other dosing strategies. We sought to assess the effect of delayed (Day +10) or omitted administration of G-CSF on various post-SCT outcomes. <h3>Methods</h3> Allogeneic SCT patients receiving PTC at standard dosing of 50 mg/kg daily on Days +3 and +4 were included in this retrospective analysis. G-CSF was given at the labeled dose of 5 mcg/kg (rounded to nearest vial) on Day +10 for 15 consecutive patients then omitted entirely for 31 consecutive patients. These results were compared to historical controls that received G-CSF beginning Day +5 after PTC. All patients received antimicrobial prophylaxis with levofloxacin, acyclovir and posaconazole. The primary outcome was to determine time to engraftment, defined as an absolute neutrophil count ≥500, in each group. A complete list of secondary outcomes is below and includes febrile neutropenia and infection rates, incidence of acute GVHD, as well as survival and relapse rates. <h3>Results</h3> Sixty-eight patients were included in the final analysis. Patient characteristics and outcomes are described in Table 1. There were no significant differences between the three groups with the exception of cells infused (p=0.04). Patients not receiving G-CSF post-transplant were associated with a statistically significant longer time to engraftment than those receiving G-CSF (22 vs. 18 days; p=0.04). There were no significant differences in all other outcomes. First year relapse and mortality were unable to be determined at this time for patients not receiving G-CSF due to this population not reaching these endpoints at time of submission. <h3>Conclusion</h3> Administration of G-CSF after post-transplant cyclophosphamide is associated with earlier neutrophil engraftment (22 vs. 18 days; p=0.04). There was no difference in time to neutrophil engraftment in patients receiving G-CSF on Day +5 vs. 10. Secondary endpoints including platelet engraftment, aGVHD, incidence of febrile neutropenia, or infections were similar among all groups. A larger, randomized study is needed to confirm these results.

Role of Granulocyte Colony Stimulating Factor on the Short-Term Outcome of Children with Acute on Chronic Liver Failure

Acute-on-chronic liver failure (ACLF) results in very high mortality in children. We aimed to evaluate the role of granulocyte colony-stimulating factor (GCSF) on short-term outcome of children with ACLF in a nontransplant unit. Children (aged>1 year) diagnosed with ACLF over a 15 month period were randomised. Group A was given GCSF therapy along with standard medical care (SMC - details in supplementary data) and group B was given only SMC. The outcome was evaluated as survival at 30 and 60 days of therapy. Thirty-one children with ACLF were enrolled, with a mean age of 6.92±4.3yrs. A total of 15 patients were randomised to group A and 16 to group B. The overall mortality was 54.83%. The intervention group showed survival rates of 80%, 66.67% and 53.3%, whereas the control group had survival rates of 43.75%, 37.5% and 37.5% at 14, 30 and 60 days, respectively. A significant survival benefit was noted on day 14 (p= 0.043) of therapy in group A with significant difference in Child-Turcotte-Pugh (CTP) and pediatric end-stage liver disease (PELD) scores in the two groups. After an initial rise in group A, the granulocyte counts fell to become comparable in the two groups by day 30 and 60, indicating that the effect of GCSF therapy wears off over time. There was no significant difference in the overall survival, median/mean CTP, PELD and MCS (Modified Cliff sequential organ failure assesment (SOFA)) scores on day 30 and 60. Mean (%) CD 34+cells level showed a rise on day 7 in group Abut was statistically insignificant. The present study shows that GCSF therapy at 5 mcg/kg/day for 5 days seems to be ineffective in improving the survival outcome on day 30 and 60 of therapy. Studies with larger number of children enrolled and longer duration of therapy are required. (CTRI/2017/11/010420).

Granulocyte Colony-Stimulating Factor Does Not Influence Clostridium Perfringens α-Toxin-Induced Myonecrosis in Mice.

Clostridium perfringens type A causes gas gangrene characterized by myonecrosis and development of an effective therapy for treating affected patients is of clinical importance. It was recently reported that the expression of granulocyte colony-stimulating factor (G-CSF) is greatly up-regulated by C. perfringens infection. However, the role of G-CSF in C. perfringens-mediated myonecrosis is still unclear. Here, we assessed the destructive changes in C. perfringens-infected skeletal muscles and tested whether inhibition of G-CSF receptor (G-CSFR) signaling or administration of recombinant G-CSF affects the tissue injury. Severe edema, contraction of muscle fiber diameter, and increased plasma creatine kinase activity were observed in mice intramuscularly injected with C. perfringens type A, and the destructive changes were α-toxin-dependent, indicating that infection induces the destruction of skeletal muscle in an α-toxin-dependent manner. G-CSF plays important roles in the protection of tissue against damage and in the regeneration of injured tissue. However, administration of a neutralizing antibody against G-CSFR had no profound impact on the destructive changes to skeletal muscle. Moreover, administration of recombinant human G-CSF, filgrastim, imparted no inhibitory effect against the destructive changes caused by C. perfringens. Together, these results indicate that G-CSF is not beneficial for treating C. perfringens α-toxin-mediated myonecrosis, but highlight the importance of revealing the mechanism by which C. perfringens negates the protective effects of G-CSF in skeletal muscle.

Granulocyte Colony Stimulating Factor in Burn Patients with Neutropenia.

To assess the role of granulocyte-colony stimulating factor (G-CSF) for improving neutropenia in burns patients with neutropenia. Experimental study. Jinnah Burn and Reconstructive Surgery Centre, Lahore, from May to October 2017. Patients with burn injury, having absolute neutrophil count (ANC) <500 / μL or where it was expected to decrease to <500/μL within the next 48 hours, were recruited in the study. A detailed demographic profile of patients was taken, burn site was evaluated, and sample collection by phlebotomy was done in the complete blood count (CBC) vial. Samples were run in a CBC analyser and verification of neutrophil count on the neubuar chamber was done. ANC was taken for 3 days for each patient. Injection Filgrastim was given 300 μg subcutaneous (S/C) or intravenous (I/V) once daily until the neutropenia improved. Improvement was categorised as good, moderate and poor, depending on the number of days for improvement in ANC. The response was further stratified on the basis of age, gender and percentage of burn. A total of 39 patients with mean age of 32.1±14.4 years included 84.6% (n=33) males and 15.4% (n=6) females. Mean percentage of burn was 40.5±15.7%. In 12-40 years of age, there were 30/39 (76.9%) patients. Among them, 11/30 (36.6%) were good, 13/30 (43.3%) were moderate, and 6/30 (20%) were poor responders. In 41-70 years of age, there were 9/39 (23.1%) patients. Among them, 2/9 (22.2%) were good, 4/9 (44.44%) were moderate, and 3/9 (33.3%) were poor responders (p = 0.616). The addition of G-CSF injections to the standard treatment of burn injury markedly improve the neutrophil counts in burn patients with neutropenia.

Role of G-CSF after High-Dose Post-Transplantation Cyclophospamide

BackgroundHigh-dose post-transplantation cyclophosphamide (PTC) has proven to be a valuable treatment modality for the prevention of graft-versus-host disease (GVHD) after stem cell transplant (SCT). Granulocyte colony stimulating factor (G-CSF) is routinely given after PTC to improve time to engraftment. Historically, based on the Johns Hopkins regimen, G-CSF is given on Day +5 post-SCT. However, this strategy has not been vigorously compared to other dosing strategies. We sought to assess the effect of delayed (Day +10) or omitted administration of G-CSF on various post-SCT outcomes.MethodsAllogeneic SCT patients receiving PTC at standard dosing of 50 mg/kg daily on Days +3 and +4 were included in this retrospective analysis. G-CSF was given at the labeled dose of 5 mcg/kg (rounded to nearest vial) on Day +10 for 15 consecutive patients then omitted entirely for ten consecutive patients. These results were compared to historical controls that received G-CSF beginning Day +5 after PTC. All patients received antimicrobial prophylaxis with levofloxacin, acyclovir and posaconazole. The primary outcome was to determine time to engraftment defined, as an absolute neutrophil count ≥500, in each group. A complete list of secondary outcomes is below and includes febrile neutropenia and infection rates, incidence of acute GVHD, as well as survival and relapse rates.ResultsForty-eight patients receiving PTC were included in the final analysis. Patient characteristics and outcomes are described in Table 1. There were no significant differences between the three groups with the exception of cells infused (p=0.03). While there was a longer time to ANC engraftment for patients not receiving GCSF after PTC, this was not statistically significant. Acute GVHD and first year outcomes were unable to be determined at this time for patients not receiving GCSF due to this population not reaching these endpoints at time of submission.ConclusionAdministration of G-CSF after post transplant cyclophosphamide is not associated with earlier neutrophil engraftment. Secondary endpoints including platelet engraftment, aGVHD, incidence of febrile neutropenia, or infections were similar among all groups. A larger, randomized study is needed to confirm these results. [Display omitted] DisclosuresBachier:Sanofi: Speakers Bureau; Seattle Genetics: Speakers Bureau.

G-CSF associates with neurogenesis and predicts prognosis and sensitivity to chemotherapy in pancreatic ductal adenocarcinoma.

BackgroundRecent studies demonstrated that granulocyte colony-stimulating factor (G-CSF), regularly used for the prevention of neutropenia, is engaged in cancer progression. However, the role of G-CSF in pancreatic ductal adenocarcinoma (PDAC) is not clear. The aim of the present study was to investigate the expression and prognostic value of G-CSF in patients with PDAC.Materials and methodsThe localization and expression of G-CSF in PDAC were examined by immunohistochemistry (IHC). The analysis of the levels of G-CSF in plasma was evaluated using ELISA kit. The correlation between G-CSF expression and patients’ survival was assessed by Kaplan–Meier analysis.ResultsIn IHC specimens, G-CSF was discovered predominantly in the cell cytoplasm and expressed in most of PDAC, while in plasma, the systemic level of G-CSF is no different between normal patients and pancreatic cancer patients. In 100 PDAC cases with IHC, patients with grades 2 and 3 were defined as the high expression group (41 patients, 41%), and those with grades 0 and 1 as the low expression group (59 patients, 59%). Significant correlation was noted between high G-CSF expression and neural invasion (P = 0.042) or early recurrence (P < 0.001). G-CSF appeared to be an independent adverse prognostic factor (hazard ratio = 1.774, 95% confidence interval 1.150–2.737, P = 0.010) in addition to N stage (P = 0.002). Specifically, adjuvant chemotherapy consisting of gemcitabine prolongs survival of patients with high G-CSF expression (median survival time 14 months vs 7.5 months). Morphologically, high G-CSF expression cells demonstrate the association with neurogenesis.ConclusionHigh expression of G-CSF is a prognostic marker and an indicator to chemotherapy response in PDAC.

Role of granulocyte colony-stimulating factor in human reproduction

As new research reveals, granulocyte colony-stimulating factor (G-CSF) plays an effective role in pregnancy success, considering that it not only affects the embryo implantation and ovarian function but also it promotes endometrial thickening and improves the pathophysiology of endometriosis, which all fundamentally lead to reducing pregnancy loss. In this review, we focus on the role of G-CSF in human reproduction. We summarized its role in ovulation, luteinized unruptured follicle syndrome, poor responders, improving repeated in vitro fertilization failure, endometrial receptivity and treatment of thin endometrium, and recurrent spontaneous abortion.

Granulocyte colony-stimulating factor blockade enables dexamethasone to inhibit lipopolysaccharide-induced murine lung neutrophils.

Glucocorticoids promote neutrophilic inflammation, the mechanisms of which are poorly characterized. Using a lipopolysaccharide (LPS)-induced acute murine lung injury model, we determined the role of granulocyte colony-stimulating factor (G-CSF) in mouse lung neutrophil numbers in the absence and presence of dexamethasone, a potent glucocorticoid. G-CSF was blocked using a neutralizing antibody. Airway neutrophil numbers, cytokine levels, and lung injury parameters were measured. Glucocorticoid treatment maintained LPS-induced airway G-CSF while suppressing TNF and IL-6. The addition of anti-G-CSF antibodies enabled dexamethasone to decrease airway G-CSF, neutrophils, and lung injury scores. In LPS-challenged murine lungs, structural cells and infiltrating leukocytes produced G-CSF. In vitro using BEAS 2B bronchial epithelial cells, A549 lung epithelial cells, human monocyte-derived macrophages, and human neutrophils, we found that dexamethasone and proinflammatory cytokines synergistically induced G-CSF. Blocking G-CSF production in BEAS 2B cells using shRNAs diminished the ability of BEAS 2B cells to protect neutrophils from undergoing spontaneous apoptosis. These data support that G-CSF plays a role in upregulation of airway neutrophil numbers by dexamethasone in the LPS-induced acute lung injury model.

Efficacy of G-CSF Primed DLI Using Cells Reserved at the Time of Harvest in Patients with Hematologic Malignancies Who Lately Relapsed after Allogeneic PBSCT

IntroductionThere is no standard therapeutic approach for the relapse after allogeneic hematopoietic cell transplantation (allo-HCT). The aim of this paper is to confirm the role of granulocyte colony-stimulating factor (G-CSF) primed donor lymphocyte infusion (DLI) according to the timing of relapse after allo-HCT with limited CD34+ cell dose (<6x106/kg)MethodsOne hundred ten patients who had relapsed after allo-HCT at Kyungpook National University Hospital from November 2001 to December 2014, including 40 patients who received DLI from cryopreserved cells derived from the original G-CSF primed graft, were retrospectively reviewed. The patients were classified into early relapse or late relapse group by the median time of relapse after transplant.ResultsThe median age at transplant was 38.5 years (range, 17-67 years) and male was 69 patients (62.2%). Primary diseases for allo-HCT included AML/MDS (n=63, 57.3%), ALL (n=32, 29.1%), CML (n=8, 7.3%), and NHL (n=7, 6.4%). Fifty four patients (49.1%) were in CR1 (complete remission), 16 (14.5%) in CR2, and 40 (36.4%) in relapsed and refractory status at the time of HCT. Sixty nine patients (62.2%) received myeloablative conditioning regimen. The median dose of CD34+ cells was 5.06x106/kg (range, 1~20.6x106/kg). Ninety nine percent of patients achieved the neutrophil recovery (> 500x103/mm3 for 3 days) at a median time of 13 days (range 9-24 days). The median time from HCT to relapse was 139 days (range, 21~1801 days). The median relapse free survival (RFS) since HCT was not significantly different according to the dose of CD34+ cells: median 147 days (range, 122-171) and 157 days (range, 87-227) in CD34+ < 6x106/kg and > 6x106/kg, respectively (p=0.249). The median overall survival (OS) since HCT was not significantly different according to the dose of CD34+ cells: median 324 days (range, 272-375) and 262 days (range, 235-288) in CD34+ < 5.06x106/kg and > 5.06x106/kg, respectively (p=0.554).The incidence of chronic GVHD was more frequent in higher CD34+ group (32.9% vs. 48.2%, P=0.042). After relapse, 57 patients (51.8%) were treated with salvage chemotherapy, 13 patients (11.8%) with second allo-HCT, and 40 patients (36.4%) with G-CSF primed DLI. The median number of CD3+T cell was 2.95x107/kg (range, 0.1~5.43x107/kg). Fourteen patients (23.6%) achieved DLI-induced CR, 20 patients progressed, and 6 patients were not evaluable for response. DLI-induced acute GVHD was observed in 25 patients (62.5%) and chronic GVHD developed in 4 patients (10%). The 1-year overall survival (OS) since relapse was not significantly different according to the use of DLI in early relapse group (11.7 +/- 5.3% and 10.0 +/- 6.7%, p=0.663), but in late relapse group, significantly higher in DLI than non-DLI (43.3 +/- 11.3% and 17.1 +/- 6.9%, p=0.021). The patients treated with DLI showed significantly higher RFS in late relapse group (286 days vs. 165 days, p=0.004). The incidence of DLI-induced GVHD did not differ between two groups.ConclusionsG-CSF primed DLI after allo-HCT with limited CD34+ cell dose can be feasible and effective option in terms of response, donor convenience and its cost. In the late relapse group, it may replace the second transplantation for the patients with hematologic malignancies lately relapsed after first allo-HCT. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The role of G-CSF in recurrent implantation failure: A randomized double blind placebo control trial

Recurrent implantation failure (RIF) is the absence of implantation after three consecutive In Vitro Fertilization (IVF) cycles with transferring at least four good quality embryos in a minimum of three fresh or frozen cycles in a woman under 40 years. The definition and management of RIF is under constant scrutiny. To investigate the effects of Granulocyte colony stimulating factor (G-CSF) on RIF, pregnancy rate, abortion rate and implantation rates. A double blind placebo controlled randomized trial was conducted at two tertiary university based hospitals. One hundred patients with the history of RIF from December 2011 until January 2014 were recruited in the study. G-CSF 300µg/1ml was administered at the day of oocyte puncture or day of progesterone administration of FET cycle. Forty patients were recruited at G-CSF group, 40 in saline and 20 in placebo group. The mean age for whole study group was 35.3±4.2 yrs (G-CSF 35.5±4.32, saline 35.3±3.98, placebo 35.4±4.01, respectively). Seventeen patients had a positive pregnancy test after embryo transfer [10 (25%) in G-CSF; 5 (12.5%) in saline; and 2 (10%) in placebo group]. The mean of abortion rates was 17.6% (3), two of them in G-CSF, one in saline group. The implantation rate was 12.3% in G-CSF, 6.1% in saline and 4.7% in placebo group. G-CSF may increase chemical pregnancy and implantation rate in patients with recurrent implantation failure but clinical pregnancy rate and abortion rate was unaffected.

Phenotypic Heterogeneity of Neutropenia and Gastrointestinal Illness Associated with G6PC3 Founder Mutation.

Severe congenital neutropenia type IV (SCN IV) is a syndrome of severe neutropenia, cardiac and urogenital defects, prominent superficial veins, facial dysmorphism, failure to thrive (FTT), and intermittent thrombocytopenia, caused by a glucose-6-phosphatase catalytic subunit 3 (G6PC3) gene mutation. SCN IV has been linked to glycogen storage disease type 1b as both disorders involve disruption of the glucose-6-phosphatase/glucose-6-phosphate transporter complex, leading to arrested neutrophil maturation. Emerging evidence suggests that neutrophil function plays an important role in intestinal integrity, evidenced by inflammatory bowel disease in certain neutropenic patients. Here, we report 3 unrelated Hispanic males from the Dominican Republic with classic features of SCN IV found to share an identical inherited canonical splice-site mutation of the G6PC3 gene (c.218+1G>A). All 3 patients presented with severe FTT and gastrointestinal manifestations. Two of the patients had significant improvement in growth and resolution of gastrointestional symptoms with initiation of granulocyte colony-stimulating factor. We hypothesize that the gene variant described represents a founder mutation in the Dominican Republic, the first to be described in this geographical region. We discuss the potential associations between neutropenia and gastrointestinal disease with FTT and the role of granulocyte colony-stimulating factor in improving neutrophil count and intestinal integrity and growth.