Granulocyte Colony-stimulating Factor Group Research Articles

Efficacy and Safety of Granulocyte-Colony Stimulating Factor Therapy in Chagas Cardiomyopathy: A Phase II Double-Blind, Randomized, Placebo-Controlled Clinical Trial.

AimPrevious studies showed that granulocyte-colony stimulating factor (G-CSF) improved heart function in a mice model of Chronic Chagas Cardiomyopathy (CCC). Herein, we report the interim results of the safety and efficacy of G-CSF therapy vs. placebo in adults with Chagas cardiomyopathy.MethodsPatients with CCC, New York Heart Association (NYHA) functional class II to IV and left ventricular ejection fraction (LVEF) 50% or below were included. A randomization list using blocks of 2 and 4 and an allocation rate of 1:1 was generated by R software which was stratified by functional class. Double blinding was done to both arms and assessors were masked to allocations. All patients received standard heart failure treatment for 2 months before 1:1 randomization to either the G-CSF (10 mcg/kg/day subcutaneously) or placebo group (1 mL of 0.9% saline subcutaneously). The primary endpoint was either maintenance or improvement of NYHA class from baseline to 6–12 months after treatment, and intention-to-treat analysis was used.ResultsWe screened 535 patients with CCC in Salvador, Brazil, of whom 37 were randomized. Overall, baseline characteristics were well-balanced between groups. Most patients had NYHA class II heart failure (86.4%); low mean LVEF was 32 ± 7% in the G-CSF group and 33 ± 10% in the placebo group. Frequency of primary endpoint was 78% (95% CI 0.60–0.97) vs. 66% (95% CI 0.40–0.86), p = 0.47, at 6 months and 68% (95% CI 0.43–0.87) vs. 72% (95% CI 0.46–0.90), p = 0.80, at 12 months in placebo and G-CSF groups, respectively. G-CSF treatment was safe, without any related serious adverse events. There was no difference in mortality between both arms, with five deaths (18.5%) in treatment vs. four (12.5%) in the placebo arm. Exploratory analysis demonstrated that the maximum rate of oxygen consumption during exercise (VO2 max) showed an improving trend in the G-CSF group.ConclusionG-CSF therapy was safe and well-tolerated in 12 months of follow-up. Although prevention of symptom progression could not be demonstrated in the present study, our results support further investigation of G-CSF therapy in Chagas cardiomyopathy patients.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT02154269].

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).

Intrauterine administration of G-CSF for promoting endometrial growth after hysteroscopic adhesiolysis: a randomized controlled trial.

Does intrauterine infusion of granulocyte colony-stimulating factor (G-CSF) prevent adhesion reformation and promote endometrial growth after hysteroscopic adhesiolysis? Intrauterine perfusion of G-CSF can increase endometrial thickness but does not prevent the recurrence of intrauterine adhesions (IUAs) in patients with Asherman syndrome (AS) after surgery. Intrauterine infusion of G-CSF has been used in attempts to treat patients with recurrent miscarriage and an idiopathic thin endometrium for either fresh or frozen-thawed embryo transfer cycles but without uniform efficacy. There have been no reports on the effect of G-CSF on the recurrence of IUAs, endometrial regrowth or pregnancy results in specific populations with AS. This two-center prospective double-blind randomized controlled trial ran between April 2016 and August 2021. In it, 245 patients with moderate to severe AS were randomized to G-CSF and control groups at a 1:1 ratio; 229 women were included in the adhesion recurrence analysis; and 164 patients were analyzed for pregnancy outcomes. All eligible patients received the first hysteroscopic adhesion separation and balloon placement procedure. Patients who met our inclusion and exclusion criteria were randomized after surgery. These patients returned for balloon removal and underwent intrauterine perfusion with 300 µg (1.8 ml) G-CSF or 1.8 ml normal saline according to randomization at 7 days after surgery. A second-look hysteroscopy was carried out 1-2 months later. The primary outcome was the rate of formation of new adhesions at the second hysteroscopy. The secondary outcomes included endometrial thickness in the periovulatory period after surgery, as well as the clinical pregnancy and live birth rates. Age, menstrual cycle characteristics, pregnancy history and IUA score before surgery were similar between groups. There were no statistically significant differences in the adhesion reformation rate or median adhesion score reduction. However, G-CSF perfusion significantly improved endometrial thickness (7.91 ± 2.12 mm vs 7.22 ± 2.04 mm; P = 0.019, 95% CI for difference: -1.26 to -0.12), as well as cumulative pregnancy and live birth rate over time (P = 0.017 and P = 0.042). Furthermore, multivariate logistic regression analysis showed that postoperative endometrial thickness was an independent prognostic factor for pregnancy and live birth rates. These results cannot be extended to older patients or those without AS, as our subjects had moderate or severe AS and were aged <40 years. The low number of patients included in the fertility analysis could lead to biased results. Intrauterine perfusion of G-CSF could be an effective adjuvant therapy for patients with AS to increase endometrial thickness. This study was supported by grants from the National Key Research and Development Program of China (2018YFC1004800), the National Natural Science Foundation of China (82001624 and 81871209), the Natural Science Foundation of Zhejiang Province (LQ20H040004) and the provincial and ministerial construction project of Zhejiang Province (2017 WKJ-ZJ-1721). The authors declare that they have no conflicts of interest regarding this work. ClinicalTrials.gov (NCT02855632). 4 March 2016. 13 April 2016.

Analysis of the Safety of Pegfilgrastim Addition in Bleomycin, Etoposide, and Cisplatin Treatment Patients With Germ Cell Tumors.

It has been reported that chemotherapy drugs and granulocyte colony-stimulating factor (G-CSF) administered on the same day can aggravate neutropenia. In the present study, we investigated the safety of pegfilgrastim during bleomycin, etoposide, and cisplatin (BEP) therapy. This single-center retrospective study, including 137 cycles of BEP therapy for germ cell tumors between January 2008 and April 2021, investigated safety. Short-acting G-CSF was used for 84 cycles and pegfilgrastim was used for 53 cycles. In the pegfilgrastim group, neutrophil count at nadir was significantly higher than in the G-CSF group (median 1,650/μl and 680/μl, respectively). The incidence of grade 3–4 neutropenia was significantly higher and the duration longer in the G-CSF group. Also, there was no significant difference in the incidence of febrile neutropenia. In conclusion, concomitant use of pegfilgrastim during BEP therapy did not increase neutropenia and was effective in terms of safety.

Effectiveness of granulocyte colony-stimulating factor for patients with acute-on-chronic liver failure: a meta-analysis.

BACKGROUND: The safety and efficacy of granulocyte colony-stimulating factor (G-CSF) for the treatment of acute-on-chronic liver failure (ACLF) remain uncertain. Therefore, we conducted a meta-analysis to draw a firmer conclusion.METHODS: We searched the Cochrane library, PubMed, Embase, and China Biology Medicine disc to identify relevant RCTs performed before January 2020. Risk ratios (RRs) and their 95% confidence intervals (95% CIs) were calculated using a random effects model.MAIN OUTCOME MEASURES: RRs (95% CI) for 1-, 2-, and 3-month survival rates.SAMPLE SIZE: Six RCTs, including three open-label studies.RESULTS: The six studies included 246 subjects (121 in a G-CSF group and 125 in a control group). G-CSF administration significantly improved the 1-, 2-, and 3-month survival rates in patients with ACLF. The pooled RRs (95% CI, P) were 0.43 (0.27–0.69, P=.0004), 0.44 (0.32–0.62, P<.00001), and 0.39 (0.22–0.68, P=.0009), respectively.CONCLUSION: G-CSF may be beneficial and effective in the treatment of ACLF, but further studies are needed to verify this conclusion.LIMITATIONS: The sample size was small, and studies were restricted to countries in Asia.PROSPERO REGISTRATION NUMBER: CRD42021225681CONFLICT OF INTEREST: None.

Does granulocyte-colony stimulating factor stimulate peripheral nerve regeneration? An experimental study on traumatic lesion of the sciatic nerve in rats.

To analyse the therapeutic potential of granulocyte-colony stimulating factor (G-CSF) treatment using a rat model of traumatic sciatic nerve lesion. G-CSF has proven strong neurotrophic properties in various models of ischaemic and traumatic brain injury. Fewer studies exist regarding the influence of G-CSF on posttraumatic peripheral nerve regeneration. Currently, the possibilities of pharmacological prevention or treatment of mechanical nerve injury are limited, and there is an urgent need to find new treatment strategies applicable in clinical situations. A controlled traumatic right sciatic nerve lesion was set using a waterjet device. Three treatment groups were created. In the first group, G-CSF was administered after sciatic nerve injury. The second group received G-CSF before and after trauma, while the third group was treated with glucose 5%-solution. Sciatic nerve function was assessed clinically and electrophysiologically at day 1, and after weeks 1, 2, 4 and 6. Additionally, α-motoneurons of the spinal cord and sciatic nerve fibres were counted at week 6. Clinically, rats in both G-CSF groups improved faster compared to the control group. Additionally, animals treated with G-CSF had a significantly better improvement of motor potential amplitude and motor nerve conduction velocity at week 6 (p < 0.05). Histologically, G-CSF treatment resulted in a significantly higher number of α-motoneurons and small myelinated nerve fibres compared to placebo treatment (p < 0.05). Under G-CSF treatment, the recovery of motor nerve conduction velocity and amplitude was enhanced. Further, signs of nerve regeneration and preservation of α-motoneurons were observed. These results indicate that G-CSF might accelerate and intensify the recovery of injured nerves. Thus, treatment with G-CSF may be beneficial for patients with peripheral nerve damage, and should be explored in further clinical studies.

Effect of intrauterine granulocyte-colony stimulating factor administration on in vitro fertilization outcome in women with moderate-to-severe endometriosis: An RCT.

BackgroundNearly 25-50% of infertile women have endometriosis. There are reports of disorders in the expression of granulocyte colony-stimulating factor (G-CSF) receptors in women with endometriosis.ObjectiveTo examine the effect of intrauterine administration of G-CSF in in vitro fertilization (IVF) cycles on the fertility rate of infertile women with moderate-to-severe endometriosis.Materials and Methods This clinical trial was conducted on 66 infertile women with moderate-to-severe endometriosis, undergoing IVF and intracytoplasmic sperm injection (ICSI). The participants were allocated into two groups via simple randomization: the G-CSF (n = 27) and control (n = 39) groups. In the G-CSF intervention group, on the oocyte pick-up day, immediately after an ovarian puncture, 300 μg of G-CSF was injected through a transcervical catheter under abdominal ultrasound guide to visualize flushing into the uterine cavity. Women in the control group received no intervention. The two groups were evaluated for clinical pregnancy.ResultsNo significant difference was noted in the demographic characteristics of the two groups. The rate of clinical pregnancy was 28.2% in the control group and 25.9% in the G-CSF group, indicating no significant difference (p = 0.83).ConclusionThe results showed that the intrauterine injection of G-CSF had no effects on pregnancy in women with stage-3/4 endometriosis undergoing IVF.

P–309 Effectiveness of intrauterine infusion of platelet-rich plasma (PRP) vs. granulocyte colony-stimulating factor (G-CSF) in women with thin endometrium undergoing assisted reproduction

Abstract Study question To compare the effect of intrauterine infusion of platelet-rich plasma (PRP) and granulocyte colony-stimulating factor (G-CSF) on endometrial thickness, clinical pregnancy rate and live-birth rate. Summary answer According to our research, PRP-therapy has more positive results in pregnancy rates. Nevertheless, there is still limited data to answer all questions completely. What is known already Thin endometrium is defined as endometrium thickness &amp;lt;7 mm or &amp;lt; 8 mm on the day of human chorionic gonadotropin (HCG) administration, which negatively affects the onset of pregnancy during natural fertilization and in assisted reproduction. Endometrial thickness may impact pregnancy and live-birth rates in fresh and frozen IVF cycles but, currently, there is minimal evidence to support any specific protocol to significantly improve pregnancy outcomes in patients with thin endometrium. Therefore, we decided to compare effects of two methods: transvaginal intrauterine perfusion of G-CSF for infertile women with thin endometrium in IVF cycles and intrauterine infusion of PRP. Study design, size, duration We conducted a systematic review and meta-analysis by PRISMA checklist. PubMed, The Cochrane Library, ClinicalTrials.gov and Google Scholar were searched electronically until 2021 using key words: “G-CSF”, “PRP”, “endometrium”. We included published and unpublished randomized clinical trials (RCT) and non-randomized clinical trials in English which include min.10 patients. Participants/materials, setting, methods Participants: female infertile patients of reproductive age with thin endometrium (≤ 7 mm) in embryo transfer cycles. Exclusion criteria: history of any chromosomal or genetic abnormalities and hematological disorders. Outcomes – endometrial thickness, pregnancy and live-birth rates.Risk of bias assessment was held using The Cochrane Handbook and The Cochrane collaboration tools. RoB 2 tool was used for randomized trials and ROBINS-I tool for non-randomized trials. For quantitative synthesis RevMan 5.4 was used to conduct meta-analysis. Main results and the role of chance Literature search resulted in 144 potentially relevant publications initially (Google Scholar: 126, PubMed: 1, Clinicaltrials: 14, Cochrane: 3). These publications were checked for titles and abstracts, duplicates were removed and 7 publications were selected. After evaluating the selection criteria, 2 articles were excluded. As a result, 5 articles remained for qualitative and quantitative synthesis, including 2 randomized controlled trials (RCT), 2 retrospective cohort studies, and 1 prospective cohort study. 403 patients participated in selected studies (the PRP group included 205 patients, and the G-CSF group - 198 patients). The primary quantitative analysis (meta-analysis) is aimed at comparison of endometrial thickness in patients receiving PRP therapy and patients receiving G-CSF. Two RCTs were included in this meta-analysis. (RR = 1.07, 95% CI: 0.81 to 1.43, P = 0.63). The heterogeneity for this comparison was 0%. Consequently, both options are equally altered by the thickness of endometrium. The secondary analysis compared clinical pregnancy rates in patients receiving PRP therapy and G-CSF. 4 studies were eligible for this synthesis. (RR = 1.36, 95% Cl: 1.06 to 1.76, P = 0.02). The heterogeneity for this comparison was 55%. PRP was significantly more effective. Limitations, reasons for caution Firstly, only 5 publications were found for the entire time. There are not enough well-conducted studies for more accurate analysis. Secondly, according to risk of bias assessment most of included studies had moderate concerns. Finally, there is no sufficient data to judge about live-birth rates after both types of treatment. Wider implications of the findings: Thin endometrium negatively affects the onset of pregnancy in assisted reproduction.Based on our meta-analysis, PRP therapy has a considerable effect on pregnancy rates in patients with thin endometrium in comparison with G-CSF.Currently, there is minimal evidence to support any specific protocol for improving IVF outcomes in women with thin endometrium. Trial registration number PROSPERO 2020 CRD42020222075

Granulocyte-colony stimulating factor (G-CSF) to treat acute-on-chronic liver failure: A multicenter randomized trial (GRAFT study)

Based on positive results from small single center studies, granulocyte-colony stimulating factor (G-CSF) is being widely used for the treatment of patients with acute-on-chronic liver failure (ACLF). Herein, we aimed to evaluate the safety and efficacy of G-CSF in patients with ACLF. In this multicenter, prospective, controlled, open-label phase II study, 176 patients with ACLF (EASL-CLIF criteria) were randomized to receive G-CSF (5 μg/kg daily for the first 5 days and every third day thereafter until day 26) plus standard medical therapy (SMT) (n= 88) or SMT alone. The primary efficacy endpoint was 90-day transplant-free survival analyzed by Cox regression modeling. The key secondary endpoints were overall and transplant-free survival after 360 days, the development of ACLF-related complications, and the course of liver function scores during the entire observation period. Patients treated with G-CSF had a 90-day transplant-free survival rate of 34.1% compared to 37.5% in the SMT group (hazard ratio [HR] 1.05; 95% CI 0.711-1.551; p= 0.805). Transplant-free and overall survival at 360 days did not differ between the 2 arms (HR 0.998; 95% CI 0.697-1.430; p= 0.992 and HR 1.058; 95% CI 0.727-1.548; p= 0.768, respectively). G-CSF did not improve liver function scores, the occurrence of infections, or survival in subgroups of patients without infections, with alcohol-related ACLF, or with ACLF defined by the APASL criteria. Sixty-one serious adverse events were reported in the G-CSF+SMT group and 57 were reported in the SMT group. In total, 7 drug-related serious adverse reactions occurred in the G-CSF group. The study was prematurely terminated due to futility after conditional power calculation. In contrast to previous findings, G-CSF had no significant beneficial effect on patients with ACLF in this multicenter controlled trial, which suggests that it should not be used as a standard treatment for ACLF. CLINICALTRIALS. NCT02669680 LAY SUMMARY: Granulocyte-colony stimulating factor was considered as a novel treatment for acute-on-chronic liver failure (ACLF). We performed the first randomized, multicenter, controlled phase II trial, which showed that G-CSF did not improve survival or other clinical endpoints in patients with ACLF. Therefore, G-CSF should not be used to treat liver disease outside clinical studies.

Impact of granulocyte-colony stimulating factor on docetaxel-induced febrile neutropenia in patients with breast cancer.

Febrile neutropenia (FN) is a life-threatening complication of Docetaxel-based chemotherapy regimens (DBRs). Prophylactic granulocyte-colony stimulating factor (G-CSF) can reduce the risk of FN. This study investigated the effect of G-CSF on FN in patients receiving DBRs for breast cancer. Patients treated between 2015 and 2017 were identified from the hospital's pharmacy database and their medical records were examined retrospectively. Data from patients' first four cycles of DBR were collected. FN rate, FN associated length of hospital stay (FN-LOS), and chemotherapy dose modification/delay due to FN were compared between patients who did (G-CSF group) or did not (non-GCSF group) receive prophylactic G-CSF. Of the 276 included patients, 83.3% received a DBR as adjuvant or neoadjuvant therapy, and 50% received docetaxel as combination therapy. Prophylactic G-CSF was administered with the first cycle of a DBR in 69.9% of patients who were significantly less likely to experience FN compared to the non-G-CSF group (6.2% vs. 15.7%; odds ratio: 0.36 [95% CI: 0.16-0.82]; p = 0.020). Collectively and after the 4 DBR treatment cycles, FN rate (4.8 vs. 8.5; odds ratio: 0.54 [95% CI: 0.30-0.97]; p = 0.043) and the mean FN-LOS (3.55 vs. 5.28 days; t = -2.22; p = 0.037) were reduced in the G-CSF group. There was no difference in DBR dose delay/reduction between both groups in cycles 2-4. In patients receiving DBRs for breast cancer, prophylactic G-CSF significantly reduced both the rate of FN and duration of hospitalization for FN.

Effect of Systemic Administration of Granulocyte Colony-Stimulating Factor on a Chronic Partial-Thickness Cartilage Defect in a Rabbit Knee Joint.

Cartilage lesions in the knee joint can lead to joint mechanics changes and cause knee pain. Bone marrow stimulation (BMS) promotes cartilage regeneration by perforating the subchondral bone just below the injury and inducing bone marrow cells. This study aimed to investigate whether systemic administration of granulocyte colony-stimulating factor (G-CSF) with BMS improves repair of chronic partial-thickness cartilage defects (PTCDs). Eighteen 6-month-old New Zealand white rabbits were divided into 3 groups: control (C, n = 6), BMS alone (n = 6), and BMS + G-CSF (n = 6). Partial cartilage defects with 5 mm diameter were created in the trochlear region of both knees; after 4 weeks, the BMS alone and BMS + G-CSF groups underwent BMS; G-CSF (50 µg/kg) or saline was administered subcutaneously for 5 days starting from 3 days before BMS. At 8 and 16 weeks after cartilage defect creation, the area of cartilage defects was macroscopically and histologically evaluated. International Cartilage Repair Society (ICRS) grades for macroscopic assessment were 0, 0.7, and 0.7 at 8 weeks and 0, 1.2, and 1.3 at 16 weeks in the C, BMS, and BMS + G-CSF groups, respectively. Wakitani scores for histological assessment were 9.8, 8.7, and 8.2 at 8 weeks and 9.5, 9, and 8.2 at 16 weeks in the C, BMS, and BMS + G-CSF groups, respectively. The BMS + G-CSF group showed significantly more repair than the C group, but there was no difference from the BMS group. The effect of BMS and G-CSF on chronic PTCDs in mature rabbit knees was limited.

Can granulocyte colony stimulating factor (G-CSF) ameliorate acetaminophen-induced hepatotoxicity?

Acetaminophen (APAP) is often used as an antipyretic and analgesic agent. Overdose hepatotoxicity, which often results in liver cell failure and liver transplantation, is a severe complication of APAP usage. To save the liver and save lives from acute liver damage caused by APAP, the search for new strategies for liver defense is important. Wistar rats have been used for the induction of APAP hepatotoxicity. Elevated levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were evaluated for liver toxicity. In addition, the levels of hepatic tissue oxidative markers such as malondialdehyde (MDA), nitric oxide (NO) increased while glutathione (GSH) was depleted and catalase (CAT) activity was curtailed. The biochemical findings were consistent with the changes in histology that suggested liver damage and inflammation. Treated rats with N-acetylcysteine (N-AC) and granulocyte colony stimulating factor (G-CSF) showed a decrease in serum levels of ALT, AST and LDH, while the level of ALP in the G-CSF group was still high. After administration of APAP, treatment with N-AC or G-CSF substantially reduced the level of MDA and NO while maintaining the GSH content and CAT activity. Treatment with N-AC and G-CSF after administration of APAP has also attenuated inflammation and hepatocytes necrosis. The results of this study showed that G-CSF could be viewed as an alternative hepatoprotective agent against APAP-induced acute liver injury compared to N-AC.

POS-711 GRAFT FUNCTION AND ACUTE REJECTION AFTER G-CSF USE IN KIDNEY TRANSPLANT PATIENTS: A RETROSPECTIVE COHORT STUDY

Neutropenia is a commonly seen complication following kidney transplantation1,2 and is often managed with granulocyte colony-stimulating factor (G-CSF) which stimulates white blood cell (WBC) proliferation. Published data on solid organ graft outcomes following G-CSF treatment is limited and reports on the rates of graft rejection following treatment are contradictory2-5. The records of 310 consecutive kidney-only transplants between 2011 and 2019 were examined. From this a cohort of patients who received G-CSF for neutropenia was identified and matched 1:1 with patients from the same era who did not receive G-CSF. Variables including donor type, HLA mismatch, CMV status, induction agent and immunosuppressive regimen were matched as closely as possible. Outcome data was recorded including eGFR at 12 and 18 months post-transplantation, episodes of rejection at 12 and 18 months (biopsy-proven), graft loss at 12 and 18 months, or death. Fifty-two patients were included in the analysis, with twenty-six patients in each group (G-CSF vs. non G-CSF). Median eGFR in the G-CSF group was 42mL/min/1.73 m2 vs 51mL/min/1.73 m2 in the non G-CSF group at 12 months (p=0.25) and 42mL/min/1.73 m2 vs 48 mL/min/1.73 m2 at 18 months (p=0.33). There were 2/26 patients who had an episode of rejection in the G-CSF group vs 6/26 patients with an episode of rejection in the non G-CSF group at 12 months (p=0.24), and 2/26 patients with an episode of rejection vs 8/26 patients with an episode of rejection at 18 months (p=0.08). In the G-CSF group 1/26 patient had graft loss vs 2/26 patients in the non G-CSF group at 12 months (p=0.55), and 1/26 graft losses vs 2/26 graft losses at 18 months (p=0.55). 1 patient in each group died due to unrelated causes.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT) In this small cohort of patients, treatment with G-CSF was not associated with any significant increase in rates of rejection or graft loss, with comparable graft function at 12 and 18 months. While other studies have had relatively short periods of follow up and no comparator, this study is strengthened by its long follow-up and the presence of a control group. Nonetheless, while these results are reassuring, larger prospective studies are needed in order to provide greater certainty that there is no association between G-CSF use and rates of acute rejection in kidney transplant recipients.

PROGRESSION OF PULMONARY HYPERTENSION IS ATTENUATED BY COMBINED TREATMENT WITH GRANULOCYTE COLONY-STIMULATING FACTOR AND BONE MARROW-DERIVED MESENCHYMAL STEM CELLS

<h3>Background</h3> Pulmonary arterial hypertension (PAH) is a cardiovascular disease characterized by increased resting pulmonary pressure levels. The prognosis remains poor, with a 5-years mortality rate estimated at 40%. Mesenchymal stem cells (MSCs) transplantation has demonstrated promising therapeutic effects in the treatment of pulmonary hypertensive rodents, as well as the administration of CXCR4/SDF inhibitor granulocyte-colony-stimulating factor (G-CSF). However, it remains unclear whether the association of MSCs and G-CSF therapies provides additional salutary effects in the treatment of PAH compared to the isolated treatments. <h3>Methods</h3> PAH was induced in adult male Wistar rats (Protocol number 087/15) by intraperitoneal injection of monocrotaline (MCT, 60mg/kg IP), while the Control group (CTL) received vehicle. Two weeks after the MCT injection, a subset of MCT-treated rats was treated with vehicle, MSCs (5 × 106 cells), G-CSF (50 µg/kg/d for 14 days), or the combination of both, totaling five groups (CTL n=8, MCT n=7, MSCs n=10, G-CSF n=13, and MSCs+G-CSF n=13). Electrocardiographic, echocardiographic, and hemodynamic recordings were performed. Blood samples were collected for the characterization of circulating bone marrow-derived hematopoietic stem cells (HSC). Data were analyzed with One-way and Two-way ANOVA (Prism®, GraphPad) and were expressed as mean ± SEM. <h3>Results</h3> Compared to the CTL group, the MCT group exhibited a decreased pulmonary acceleration time/pulmonary ejection time (CTL 0.46±0.01 vs MCT 0.22±0.02, <i>p</i><0.05), while it was not affected by neither therapeutic approach (<i>p</i>>0.05). Whereas the MCT group exhibited a decreased velocity-time index versus the CTL group, it was improved by the MSCs+G-CSF therapy (CTL 4±0.2 vs MCT 2.1±0.4 vs MSCs 2.5±0.5 vs G-CSF 3.1±0.4 vs MSCs+G-CSF 4.9±0.5 cm, p<0.05). The G-CSF group exhibited decreased levels of RV systolic pressure versus the MCT group (MCT 39.4±3.15 vs G-CSF 28.7±1.1, <i>p</i><0.05). The QTc interval was prolonged in groups versus CTL group (CTL 164.2±7.2 vs MCT 198.6±5.5 vs MSCs 190.7±6.4 vs G-CSG 193.4±7.1 vs MSCs+G-CSF 183.9±9.6 ms, <i>p</i><0.05). Furthermore, the relative cardiac weight was significantly decreased by the MSCs therapy versus the MCT group (CTL 3.6±0.3 vs MCT 4.7±0.3 vs MSCs 3.1±0.2 G-CSF 4.2±0.2 vs MSCs+G-CSF 3.9±0.3, <i>p</i><0.05). <h3>Conclusion</h3> Our study indicates that G-CSF and MSCs have therapeutic potential in the treatment of PAH either when administered isolated or combined.

G-CSF reduces loss of dopaminergic neurons by inhibiting TNF-α and IL-1β in mouse model of Parkinson’s disease

Purpose of the study granulocyte-colony stimulating factor (G-CSF) is a hematopoietic growth factor existing in neutrophils, glial cells and neurons. Increasing researches discovered that G-CSF improved cell survival in neurodegenerative diseases by its anti-inflammatory effect. However, the effect of G-CSF in suppressing inflammation in Parkinson’s disease (PD) remains unclear. Thus, the purpose of this study is to explored the anti-inflammatory effect of G-CSF in mouse model of PD. Materials and methods G-CSF was administrated in the PD model induced by MPTP. Subsequently, the protein of tyrosine hydroxylase (TH), ionized calcium-binding adaptor molecule 1 (Iba-1) and the inflammatory cytokines including tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) in the midbrain were examined. In addition, the phosphorylated mitogen-activated protein kinases (MAPK) including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 MAPK in the midbrain were investigated. Results Compared with the MPTP group, the protein of TH in the midbrain was increased, while the Iba-1 and the inflammatory factors were decreased. In addition, the expression of phosphorylated JNK (p-JNK) in the midbrain of the MPTP + G-CSF group was decreased, while the phosphorylated ERK (p-ERK) levels were elevated. Conclusions These findings emphasize that G-CSF inhibited the degradation of DA neurons. The protective effect is associated with the reduction of the inflammatory factors caused by the inhibition of the microglial activation. Moreover, G-CSF may decrease the inflammatory factors through the decrease of P-JNK and the increase of P-ERK.

Systemic Administration of G-CSF Accelerates Bone Regeneration and Modulates Mobilization of Progenitor Cells in a Rat Model of Distraction Osteogenesis.

Granulocyte colony-stimulating factor (G-CSF) was shown to promote bone regeneration and mobilization of vascular and osteogenic progenitor cells. In this study, we investigated the effects of a systemic low dose of G-CSF on both bone consolidation and mobilization of hematopoietic stem/progenitor cells (HSPCs), endothelial progenitor cells (EPCs) and mesenchymal stromal cells (MSCs) in a rat model of distraction osteogenesis (DO). Neovascularization and mineralization were longitudinally monitored using positron emission tomography and planar scintigraphy. Histological analysis was performed and the number of circulating HSPCs, EPCs and MSCs was studied by flow cytometry. Contrary to control group, in the early phase of consolidation, a bony bridge with lower osteoclast activity and a trend of an increase in osteoblast activity were observed in the distracted callus in the G-CSF group, whereas, at the late phase of consolidation, a significantly lower neovascularization was observed. While no difference was observed in the number of circulating EPCs between control and G-CSF groups, the number of MSCs was significantly lower at the end of the latency phase and that of HSPCs was significantly higher 4 days after the bone lengthening. Our results indicate that G-CSF accelerates bone regeneration and modulates mobilization of progenitor cells during DO.

The combination of G-CSF and AMD3100 mobilizes bone marrow-derived stem cells to protect against cisplatin-induced acute kidney injury in mice

BackgroundSeveral studies have confirmed that mobilizing bone marrow-derived stem cells (BMSCs) ameliorates renal function loss following cisplatin-induced acute kidney injury (AKI). The aim of this study was to explore whether the combination of granulocyte-colony stimulating factor (G-CSF) and plerixafor (AMD3100) exerts beneficial effects on renal function recovery in a model of cisplatin-induced nephrotoxicity.MethodsC57BL/6J mice received intraperitoneal injections of G-CSF (200 μg/kg/day) for 5 consecutive days. On the day of the last injection, the mice received a single subcutaneous dose of AMD3100 (5 mg/kg) 1 h before cisplatin 20 mg/kg injection. Ninety-six hours after cisplatin injection, the mice were euthanized, and blood and tissue samples were collected to assess renal function and tissue damage. Cell mobilization was assessed by flow cytometry (FCM).ResultsMice pretreated with G-CSF/AMD3100 exhibited longer survival and lower serum creatinine and blood urea nitrogen (BUN) levels than mice treated with only G-CSF or saline. Combinatorial G-CSF/AMD3100 treatment attenuated tissue injury and cell death, enhanced cell regeneration, and mobilized a higher number of stem cells in the peripheral blood than G-CSF or saline treatment. Furthermore, the mRNA expression of proinflammatory factors was lower, whereas that of anti-inflammatory factors was higher, in the G-CSF/AMD3100 group than in the G-CSF or saline group (all P < 0.05).ConclusionsThese results suggest that combinatorial G-CSF/AMD3100 therapy mobilizes BMSCs to accelerate improvements in renal functions and prevent cisplatin-induced renal tubular injury. This combinatorial therapy may represent a new therapeutic option for the treatment of AKI and should be further investigated in the future.

Don't Go Breakin’ My Heart: Lack of Association between Granulocyte Colony Stimulating Factor and Development of Acute Cellular Rejection

Purpose Neutropenia commonly occurs after heart transplantation (HT) and granulocyte colony-stimulating factor (GCSF) may be used for treatment of neutropenia in this setting. Published data is lacking on the incidence and etiology of neutropenia, and the safety of GCSF with respect to subsequent risk of acute rejection. Methods This was a retrospective study in adult HT recipients from 2012-2018 at a single institution. All patients who received at least one dose of GCSF were identified and compared with patients without a history of therapy in the first year of HT. Patients were evaluated for acute cellular rejection (ACR) ≥2R within 3 and 12 months after GCSF. This was compared with the incidence of ACR in the non-GCSF group starting 4.5 months after HT (as the mean time to first neutropenic episode was 142 days in the GCSF group). Categorical variables were compared using the chi-square test. Results Of the 211 recipients included in the overall cohort, 71.1% were male, 58.3% were Caucasian, and 24.2% had ischemic cardiomyopathy. Mean age was 52.5 ± 12.1 years. In this cohort, 71 (33.6%) developed 136 episodes of neutropenia (mean 1.9 episodes/patient) requiring at least one dose of GCSF. Moderate (ANC 501-999/mcL) and severe (ANC ≤500/mcL) neutropenia was seen in 41.9% and 25% of cases, respectively. 78.9% of neutropenic cases were thought to be medication related based on chart review. Nearly all patients were induced with ATG (94.3%) and 24.6% were primary mismatch for cytomegalovirus. Each cycle of GCSF required on average 3.4 doses, with a mean total dose of 18.8 mcg/kg. The mean ANC nadir and peak was 850 ± 580/mcL and 7,520 ± 5,210/mcL, respectively. The mean time from HT to first neutropenic episode was 142 ± 100 days. Incidence of ACR ≥2R within the first 3 and 12 months was not significantly different between the GCSF (3 mo.: 9.9% and 12 mo.: 14.1%) and non-GCSF groups (3 mo.: 4.3% and 12 mo.: 18.6%) (p>0.05). Conclusion In this study, GCSF treated neutropenia occurred in one-third of patients within the first year after HT. GCSF does not appear to increase subsequent risk of ACR within the first year after GCSF administration.

Low-Dose Cyclophosphamide versus Intermediate-High-Dose Cyclophosphamide versus Granulocyte Colony-Stimulating Factor Alone for Stem Cell Mobilization in Multiple Myeloma in the Era of Novel Agents: A Multicenter Retrospective Study

The optimal stem cell (SC) mobilization strategy for patients with multiple myeloma (MM) remains a matter of debate. Possible approaches include low or high doses of cyclophosphamide (Cy), other chemotherapeutic agents, or granulocyte colony-stimulating factor (G-CSF) alone. The scope of the study was to compare low-dose Cy plus G-CSF versus intermediate-high-dose Cy plus G-CSF versus G-CSF alone for SC mobilization in MM, in terms of efficacy and safety. We retrospectively analyzed 422 MM patients undergoing SC mobilization in 6 Italian centers, including 188 patients who received low-dose Cy (LD-Cy group, defined as 2 g/m2), 163 patients who received intermediate-high-dose Cy (HD-Cy group, defined as ≥ 3 g/m2), and 71 patients who received G-CSF alone (G-CSF group). The median peak of circulating CD34+ cells was 77/µL in the LD-Cy group, 92/µL in the HD-Cy group, and 55/µL in the G-CSF group (P=.0001). The median amount of SCs collected was 9.1×106/kg, 9.7×106/kg, and 5.6×106/kg in the 3 groups, respectively (P=.0001). The rate of mobilization failure (defined as failure to collect ≥2×106/kg) was 3.7% in the LD-Cy group, 3.4% in the HD-Cy group, and 4.3% in the G-CSF group (P=.9). The target SC dose of at least 4×106/kg was reached in 90.4%, 91.1%, and 78.6% of the patients in these 3 groups, respectively (P=.014). The "on demand" use of plerixafor was higher in the G-CSF group (76%) compared with the LD-Cy group (19%) and the HD-Cy group (6%). In multivariate analysis, G-CSF mobilization and previous use of melphalan or radiotherapy were independently associated with failure to collect the target SC dose of ≥4×106/kg. No impacts of age, blood counts, or previous treatment with lenalidomide, bortezomib, or carfilzomib were observed. Our results suggest that LD-Cy may be considered for successful SC mobilization in patients with MM.

Prophylactic granulocyte-colony stimulating factor in patients with lung neuroendocrine carcinoma receiving platinum agents plus etoposide

BackgroundThe clinical utility of prophylactic granulocyte-colony stimulating factor (G-CSF) in patients receiving platinum agents plus etoposide for neuroendocrine carcinoma (NEC) is unknown. MethodsChemotherapy-naïve patients with NEC who received platinum agents plus etoposide were retrospectively evaluated. The occurrence of severe neutropenia and febrile neutropenia (FN) and efficacy of chemotherapy were compared between patients who did (G-CSF group) and did not receive prophylactic G-CSF (non-G-CSF group). ResultsAmong 58 patients, 51 (87.9%) and 7 (12.1%) had small-cell lung cancer and large-cell NEC, respectively, and 24 (41.4%) and 34 (58.6%) received cisplatin and carboplatin, respectively. The G-CSF and non-G-CSF groups included 32 and 26 patients, respectively. The non-G-CSF group displayed significantly higher rates of grade 3–4 neutropenia {88.5% [95% confidence interval (CI) = 69.8% – 97.6%] vs. 56.2% [95% CI = 37.7% – 73.6%], P = 0.009} and FN [50.9% (95% CI = 30% – 70%) vs. 18.8% (95% CI = 7.2% – 36.4%), P = 0.023] than the G-CSF group. In multivariate analysis, non-G-CSF was an independent risk factor for grade 3–4 neutropenia and FN. The rate of treatment delay was significantly higher in the non-G-CSF group (69.2% vs. 31.2%, P = 0.001). The relative dose intensity was significantly higher in the G-CSF group (86.7% vs. 74.1%, P < 0.001). The overall response rate, progression-free survival, and overall survival were comparable between the two groups. ConclusionsIn patients with NEC receiving platinum agents plus etoposide, prophylactic G-CSF significantly reduced the risks of severe neutropenia and FN.