Low-dose Granulocyte Colony-stimulating Factor Research Articles

Granulocyte colony-stimulating factor protected against brain injury in a rat cerebral hemorrhage model by modulating inflammation.

Granulocyte colony-stimulating factor (G-CSF) has been reported to exert a protective effect against secondary brain damage, but the underlying mechanisms remain unknown. We explored the ability of G-CSF to protect the brain from injury in a rat autologous blood-induced model of intracerebral hemorrhage (ICH), with a special focus on the anti-inflammation effect. An ICH was induced in 8-week-old male rats by an infusion of autologous blood, and the rats were then randomly assigned to five treatment groups: sham, ICH, and ICH+ low-dose (25 µg/kg), middle-dose (50 µg/kg), and high-dose (75 µg/kg) G-CSF. We then evaluated the levels of brain inflammation-related genes and proteins. The levels of tumor-necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) mRNA increased between days 1 and 14 post-ICH, with the highest expression on day 3. These changes were rectified by G-CSF in a dose-dependent manner. At day 3 post-injury, an elevation of the nuclear factor-kappa B (NF-κB) p65 protein level and a reduction of the inhibitor of NF-κB alpha (IκBα) protein level were observed; G-CSF treatment exerted a beneficial effect on both protein expressions. The expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins were increased; these changes were rectified by the highest dose of G-CSF. The brain-protecting effects of G-CSF are likely to be attributable, at least in part, to attenuation of the TNF-α, IL-6, iNOS, and COX-2 expressions induced by NF-κB activation in the brain tissues of this autologous blood-induced ICH rat model.

Clinical Outcomes and Mutation Clearance in Children with Acute Myeloid Leukemia Treated with Low-Dose Chemotherapy Plus G-CSF for Remission Induction

▪Background: The treatment of pediatric acute myeloid leukemia (AML) generally consists of near-myeloablative therapy to induce remission. However, the benefit of higher doses of induction therapy is not clearly established and has been recently challenged. The clinical impact of reducing the intensity of induction therapy for children with AML remains unknown.Methods: 140 children younger than 15 years of age with de novo AML were enrolled in this study. Forty-six patients received low-dose chemotherapy (LDC) concurrently with granulocyte colony-stimulating factor (G-CSF) for the first induction course while 94 patients received standard-dose chemotherapy (SDC). All patients received similar standard postremission treatment. The median age of the 82 males and 58 females was 81 months (5-170 months). Clinical outcomes of children were compared between the two groups, and molecular response was assessed by whole-exome and targeted sequencing.Results: Complete remission (CR) after 2 courses of induction was achieved in 87.0% (40 of 46) and 85.1% (80 of 94) of patients receiving LDC/G-CSF and SDC at first induction, respectively (P=0.80). There were no significant differences in the 3-year event-free survival (65.5% vs. 66.9%; P=0.99) and overall survival (78.8% vs. 72.6%, P=0.96) of patients receiving LDC/G-CSF or SDC at first induction, respectively. Risk of relapse and treatment with hematopoietic stem cell transplantation, but not type of regimen used in induction, were significantly associated with outcome. Recovery of white blood cell (WBC) and platelet counts was significantly faster in patients receiving LDC/G-CSF than those receiving SDC [11.5 vs. 18.5 days for WBC count (P <0.001); 15.5.0 vs. 22.0 days for platelet count (P <0.001)].Of 191 leukemia cell mutations identified by exome sequencing at diagnosis in 23 patients achieving CR, 95.8% (93 of 97) and 91.7% (55 of 60) were cleared [variant allele frequency (VAF)<2.5%] after 2 courses of LDC/G-CSF or SDC, respectively (P=0.45). All 51 of the reported leukemia-associated recurrently mutated genes were cleared after 2 induction courses, regardless of the regimen received. Notably, of all mutations detected at diagnosis, all but 1 mutation were undetectable (VAF<1%) in follow-up samples (0-19 months off therapy). The persistent mutation (CACNA1G; VAF, 1.1%) was detected in the follow-up sample of a child receiving the SDC regimen at the 11-month off-therapy visit, who relapsed 4 months later.Conclusions: Children with AML receiving LDC/G-CSF for remission induction had similar outcomes but experienced significantly less toxicity than those receiving SDC. Genome-wide mutational clearance in CR patients revealed that both regimens resulted in similar levels of molecular remission. Thus, we recommend LDC/G-CSF as an alternative approach to remission induction in pediatric AML. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

Neuroprotective effects of low-dose G-CSF plus meloxicam in a rat model of anterior ischemic optic neuropathy

Non-arteritic anterior ischemic optic neuropathy (NAION) causes a sudden loss of vision and lacks effective treatment. Granulocyte colony-stimulating factor (G-CSF) provides neuroprotection against the experimental optic nerve injuries but also induce leukocytosis upon typical administration. We found synergetic neuroprotective effects of meloxicam and low dose G-CSF without leukocytosis in a rat model of anterior ischemic optic neuropathy (rAION). The WBC counts in the low-dose G-CSF-plus meloxicam-treated group were similar to the sham-operated group. Combination treatment of low-dose G-CSF plus meloxicam preserved RGCs survival and visual function, reduced RGC apoptosis and the macrophages infiltration, and promote more M2 phenotype of macrophage/microglial transition than the low-dose GCSF treatment or the meloxicam treatment. Moreover, the combination treatment induced higher serine/threonine kinase 1 (Akt1) expression. The combination treatment of low-dose G-CSF plus meloxicam lessened the leukocytotic side effect and provided neuroprotective effects via Akt1 activation in the rAION model. This approach provides crucial preclinical information for the development of alternative therapy in AION.

Plerixafor on-demand in association with low-dose cyclophosphamide and G-CSF in the mobilization of patients with multiple myeloma: High effectiveness, low toxicity, and affordable cost

In CD34+ cells mobilization of patients with multiple myeloma (MM), the use of Cyclophosphamide (CTX) at a dose of 2 g/m2 has low efficacy although also lower toxicity. The suboptimal mobilizing effect of low-dose CTX, however, may be overcome by plerixafor (PLX) on demand.We conducted a prospective multicenter study in 138 patients with MM to evaluate CTX 2 g/m2 in association with granulocyte-colony stimulating factor (G-CSF) and on-demand PLX. We compared results with a historical group of MM patients (n = 138) mobilized using CTX at a dose of 4 g/m2.CD34+ cells greater than 2 × 106/kg in max three aphereses were harvested in 98.6% of patients in the on-demand PLX study group while in 84.0% in the historical group, (p = 0.0001). In the on-demand-PLX study group, a successful harvest greater than 5 × 106/kg in max three aphereses was observed in 85.5% of patients versus 62.3% of patients in the historical control group, (p=0.0001). In the on-demand-PLX study group, 4.3% (6/138) of patients had febrile complications. Salvage mobilization in the on-demand PLX study group was 1.4%.In conclusions, on-demand PLX + CTX 2 g/m2 + G-CSF 10 μg/kg has higher efficacy and lower toxicity compared with CTX 4 g/m2 + G-CSF. An analysis of costs is presented.

Severe Chronic Neutropenia in the Large Granular Lymphocyte Syndrome: Outcomes in Response to Granulocyte Colony Stimulating Factor (G-CSF) and Immunosuppressive Therapies

The large granular lymphocyte (LGL) syndrome and large granular lymphocytic leukemia (LGLL) are rare hematological disorders. Through the Severe Chronic Neutropenia International Registry (SCNIR) we have followed the clinical course and treatment responses of 27 LGL patients presenting with severe chronic neutropenia without evidence of leukemia, rheumatoid arthritis or autoimmune diseases. This report focuses on their treatment responses to G-CSF and outcomes with and without other immunosuppressive therapies. Methods: Patients with severe chronic neutropenia and a diagnosis of LGL syndrome (at least 3 ANC values &amp;lt; 0.5 x 109/L over a 3 month period) were enrollment in the SCNIR if they do not have concomitant systemic autoimmune disease, myeloid or lymphoid malignancy or drug-induced neutropenia. Findings: The 27 LGL patients (8 males, median age 53; 19 females, median age 57) had chronic neutropenia for approximately 4 years (range 0.4 - 25.6 years) before enrollment. Diagnoses were primarily based on FACS analysis (12 bone marrow [50%]; 11 blood and bone marrow [46%]; 1 blood only [4%]). None of these patients presented with lymphocytosis, i.e., ALC &amp;gt; 5.0 x 109/L. Before enrollment, 7 patients had anti-neutrophil antibody tests (3 positive, 4 negative), 4 patients had antinuclear antibody tests (2 positive, 2 negative), and ANCA was positive for the one patient tested. After enrollment, additional results were: 1 patient had a negative anti-neutrophil antibody, 8 patients had antinuclear antibody tests (2 positive, 6 negative), and ANCA was positive in two additional patients. The diagnosis of LGL was based on increased LGL cells in the blood or bone marrow, most frequently increased CD 3+, CD 8+, CD 57+ cells. Increases in lymphocytes in the marrow, often in clusters were a common finding; lymphocytes in the marrow ranged from 6-79%. The range of CD 57+ in blood 11-19%, bone marrow 19-61%; CD 56+/NK cells in blood 0.06-14%, bone marrow &amp;lt;1-76.8%; increased CD 8+/CD 3+ in blood 1.5-90%, bone marrow &amp;lt;1-91%. Ten patients have gene rearrangement studies, 7 prior to enrollment (3 negative, 4 positive) and 3 patients had these studies after enrollment, all positive. Because most patients had neutropenia, fevers and infections we evaluated the effectiveness and safety of G-CSF therapy. Treatments were G-CSF alone (13), G-CSF with prednisone (5), G-CSF with methotrexate and prednisone (4), G-CSF with methotrexate alone (2), G-CSF with cyclosporine (1), G-CSF with cyclosporine and prednisone (1), and G-CSF with prednisone, methotrexate and cyclosporine (1). Prior to G-CSF treatment the median ANC was 0.54 x 109/L, mean 1.48 +/- 0.35 SEM. The ALC median was 1.67 x 109/L, mean 2.74 +/- 0.74. The G-CSF dosing median was 1.44 mcg/kg/day, mean 2.27 +/- 0.31. All responded to G-CSF alone or in combination therapy to achieve a mean ANC greater than 1.0 x 109/L. After G-CSF treatment the median ANC was 2.23 x 109/L, mean 3.78 +/- 0.40. The ALC median was 2.24 x 109/L, mean 3.17 +/- 0.48. Time period for SCNIR observation median years is 9.6 years; mean 10.0 +/- 1.2, range 0.4 to 23.1 years. There was a total 270 years of observation in the SCNIR and 307 years of G-CSF administration in this group of 27 patients. The increase in neutrophils was consistently associated with fewer episodes of fever, infections and antibiotic use. One of 27 patients had episodic thrombocytopenia (&amp;lt;50 x 109/L) before G-CSF and continued while on G-CSF. Seven of 26 patients reported episodic thrombocytopenia after starting G-CSF. There were no report episodes of significant bleeding. Fourteen of 27 are now living, ages 17 to 72, and all have continued on treatment. Over the 24 year observation period, 5 patients developed Hodgkin disease (1) or non-Hodgkin lymphoma (5); and 5/6 died. Five other LGL patients died of sepsis or pneumonia. Other deaths were attributed to a T-cell lymphoproliferative disorder (1), chronic pancreatitis (1) and lung cancer (1). There were no myeloid malignancies. Conclusions: Our long term observations suggests that the combination of low dose G-CSF plus methotrexate or cyclosporine appears to be more effective than either drug alone, titrated each to minimal effective doses, and continued indefinitely. There was no increased frequency of opportunistic infections. The expected course is a long period of normal ANCs without other autoimmune diseases. Evolution to lymphoid, not myeloid, malignancies is the greatest concern. Disclosures Dale: Coherus: Consultancy; x4pharma: Consultancy, Honoraria, Research Funding; Athelas: Equity Ownership; Prolong: Consultancy; Cellerant: Other: Scientific Advisory Board; Hospira: Consultancy; Amgen: Consultancy, Research Funding; Sanofi Aventis: Consultancy, Honoraria; Beheringer/Ingelheim: Consultancy. Newburger:TransCytos LLC: Consultancy; X4 Pharmaceuticals: Consultancy, Honoraria.

Effects of granulocyte colony-stimulating factor therapy for osteogenesis imperfecta: a case report

Introduction: Osteogenesis imperfecta (OI) is a genetic disorder of increased bone fragility and low bone mass. OI type IV. Materials and methods: We examined the safety and effectiveness of a low dose of analog granulocyte colony-stimulating factor (G-CSF) in a 15-year-old girl OI type IV. G-CSF 5 μg/kg was given subcutaneously, for 5 days/month for 3, 6 and 12 months. Laboratory tests, including blood, biochemical tests were performed, in addition to clinical examination.Results: Clinical examination revealed an increase of muscle strength in the upper and lower limbs between base line and day 6 and 12 months. We found no serious adverse events. Leukocyte levels remained below 38,000/μL. Low dose G-CSF was safe and well tolerated by the patient. Conclusions: A significant increase in muscle strength in this patient may indicate beneficial effects of G-CSF factor in this disorder. These results are inspiring and warrant further studies.

The effect of systemic administration of G-CSF on a full-thickness cartilage defect in a rabbit model MSC proliferation as presumed mechanism: G-CSF for cartilage repair.

ObjectivesThe aim of this study was to investigate the effect of granulocyte-colony stimulating factor (G-CSF) on mesenchymal stem cell (MSC) proliferation in vitro and to determine whether pre-microfracture systemic administration of G-CSF (a bone marrow stimulant) could improve the quality of repaired tissue of a full-thickness cartilage defect in a rabbit model.MethodsMSCs from rabbits were cultured in a control medium and medium with G-CSF (low-dose: 4 μg, high-dose: 40 μg). At one, three, and five days after culturing, cells were counted. Differential potential of cultured cells were examined by stimulating them with a osteogenic, adipogenic and chondrogenic medium.A total of 30 rabbits were divided into three groups. The low-dose group (n = 10) received 10 μg/kg of G-CSF daily, the high-dose group (n = 10) received 50 μg/kg daily by subcutaneous injection for three days prior to creating cartilage defects. The control group (n = 10) was administered saline for three days. At 48 hours after the first injection, a 5.2 mm diameter cylindrical osteochondral defect was created in the femoral trochlea. At four and 12 weeks post-operatively, repaired tissue was evaluated macroscopically and microscopically.ResultsThe cell count in the low-dose G-CSF medium was significantly higher than that in the control medium. The differentiation potential of MSCs was preserved after culturing them with G-CSF.Macroscopically, defects were filled and surfaces were smoother in the G-CSF groups than in the control group at four weeks. At 12 weeks, the quality of repaired cartilage improved further, and defects were almost completely filled in all groups. Microscopically, at four weeks, defects were partially filled with hyaline-like cartilage in the G-CSF groups. At 12 weeks, defects were repaired with hyaline-like cartilage in all groups.ConclusionsG-CSF promoted proliferation of MSCs in vitro. The systemic administration of G-CSF promoted the repair of damaged cartilage possibly through increasing the number of MSCs in a rabbit model.Cite this article: T. Sasaki, R. Akagi, Y. Akatsu, T. Fukawa, H. Hoshi, Y. Yamamoto, T. Enomoto, Y. Sato, R. Nakagawa, K. Takahashi, S. Yamaguchi, T. Sasho. The effect of systemic administration of G-CSF on a full-thickness cartilage defect in a rabbit model MSC proliferation as presumed mechanism: G-CSF for cartilage repair. Bone Joint Res 2017;6:123–131. DOI: 10.1302/2046-3758.63.BJR-2016-0083.

Granulocyte colony stimulating factor (GCSF) treatment in neuropathic pain

&lt;p&gt;Granulocyte colony stimulating factor (GCSF) is an endogenous growth factor that can stimulate granulocyte formation and is used widely in hematogenous disease without significant clinical side effects. Several clinical and animal studies had showed that both a single high-dose and repeated low-dose systemic GCSF treatment can attenuate neuropathic pain after central or peripheral nerve injury. GCSF treatment can recruit more opioid containing neutrophils to injured tissue, up-regulate opioid receptors (mu opioid receptor) on the injured nerve, which decreased nociceptive signals from injured nerve to the spinal dorsal horn. Thereafter, activated microglia, increased phosphorylated-p38 (p-p38) and pro-inflammatory cytokines on the spinal dorsal horn are suppressed, which further attenuated neuropathic pain. The systemic GCSF administration may avoid the addiction side effect induced by repeated exogenous opioid exposure and provide a new therapeutic strategy to treat neuropathic pain.&lt;/p&gt;

Blood graft cellular composition and posttransplant outcomes in myeloma patients mobilized with or without low-dose cyclophosphamide: a randomized comparison.

Autologous stem cell transplantation is a standard treatment in multiple myeloma (MM). Blood grafts are usually collected after mobilization with granulocyte-colony-stimulating factor (G-CSF) alone or in a combination with cyclophosphamide (CY). There is limited knowledge of the possible effects of different mobilization regimens on blood graft characteristics and posttransplant outcomes. Thirty-eight patients with MM were included in this study. The patients were randomly assigned at registration to mobilization with either low-dose CY plus G-CSF (Arm A) or G-CSF alone (Arm B) and received three cycles of lenalidomide, bortetzomib, and dexamethasone induction. Flow cytometry analysis of lymphocyte subsets in the blood grafts after cryopreservation was performed. Hematologic and immune recovery were evaluated up to 12 months posttransplant. The blood grafts in Arm A contained significantly more CD34+ cells but in Arm B there was a greater proportion of CD34+CD38- cells and higher numbers of T and B lymphocytes as well as natural killer (NK) cells. The engraftment was comparable but lymphocyte count at 15 days posttransplant was higher in Arm B (0.8 × 10(9) /L vs. 0.5 × 10(9) /L, p = 0.033). At 3 and 6 months posttransplant the total number of NK cells was also higher in G-CSF-mobilized patients. There was no difference in progression-free survival between the study arms. CY plus G-GSF yields more CD34+ cells but seems to diminish lymphocyte and NK cell counts in the grafts and hampers immune recovery after transplantation. Thus G-CSF alone might be a preferred mobilization method due to more rapid immune recovery posttransplant.

Phase II Trial of Intravenous Low-Dose Granulocyte Colony-Stimulating Factor in Acute Ischemic Stroke

Granulocyte colony-stimulating factor (G-CSF) has shown neuroprotective and neurogenerative activities in experimental studies, and our previous phase I clinical study suggested the safety and potential efficacy of low-dose G-CSF in acute ischemic stroke patients. The present phase II trial is aimed to evaluate the effect of G-CSF administration on neurological function and infarct volume, compared with a placebo group. Forty-nine acute ischemic stroke patients (29 males, 20 females; 71 ± 10 years) within 24 hours after onset were recruited. Eligible patients were randomized 2:2:1 to receive G-CSF 150 µg/body/day, G-CSF 300 µg/body/day, and placebo, respectively. We evaluated clinical outcome in terms of the National Institutes of Health Stroke Scale, the modified Rankin Scale, and the Barthel Index at 90 days after onset, together with changes in infarct volume on magnetic resonance imaging. We found no serious adverse event, including change in leukocyte levels, which remained below 31,000/µL, at 150 and 300 µg G-CSF/body/day. Clinical outcome scores did not show any significant difference among the 3 groups. Chronological changes in infarct volume also showed no significant difference. G-CSF was well-tolerated at 150 and 300 µg/body/day in patients with acute ischemic stroke. However, administration of G-CSF at both 150 and 300 µg/body/day neither contributed to functional recovery nor reduced infarct volume at 3 months after onset, compared with the control group. The apparent lack of effectiveness may have been due to the small sample size. A trial of combination therapy with recombinant tissue plasminogen activator and G-CSF is planned.

Growth factor release by vesicular phospholipid gels: in-vitro results and application for rotator cuff repair in a rat model

BackgroundBiological augmentation of rotator cuff repair is of growing interest to improve biomechanical properties and prevent re-tearing. But intraoperative single shot growth factor application appears not sufficient to provide healing support in the physiologic growth factor expression peaks. The purpose of this study was to establish a sustained release of granulocyte-colony stimulating factor (G-CSF) from injectable vesicular phospholipid gels (VPGs) in vitro and to examine biocompatibility and influence on histology and biomechanical behavior of G-CSF loaded VPGs in a chronic supraspinatus tear rat model.MethodsG-CSF loaded VPGs were produced by dual asymmetric centrifugation. In vitro the integrity, stability and release rate were analyzed. In vivo supraspinatus tendons of 60 rats were detached and after 3 weeks a transosseous refixation with G-CSF loaded VPGs augmentation (n = 15; control, placebo, 1 and 10 μg G-CSF/d) was performed. 6 weeks postoperatively the healing site was analyzed histologically (n = 9; H&E by modified MOVIN score/Collagen I/III) and biomechanically (n = 6).ResultsIn vitro testing revealed stable proteins after centrifugation and a continuous G-CSF release of up to 4 weeks. Placebo VPGs showed histologically no negative side effects on the healing process. Histologically in vivo testing demonstrated significant advantages for G-CSF 1 μg/d but not for G-CSF 10 μg/d in Collagen III content (p = 0.035) and a higher Collagen I/III ratio compared to the other groups. Biomechanically G-CSF 1 μg/d revealed a significant higher load to failure ratio (p = 0.020) compared to control but no significant differences in stiffness.ConclusionsBy use of VPGs a continuous growth factor release could be obtained in vitro. The in vivo results demonstrate an improvement of immunohistology and biomechanical properties with a low dose G-CSF application via VPG. The VPG itself was well tolerated and had no negative influence on the healing behavior. Due to the favorable properties (highly adhesive, injectable, biocompatible) VPGs are a very interesting option for biologic augmentation. The study may serve as basis for further research in growth factor application models.

Controlled Release of Granulocyte Colony-Stimulating Factor Enhances Osteoconductive and Biodegradable Properties of Beta-Tricalcium Phosphate in a Rat Calvarial Defect Model

Autologous bone grafts remain the gold standard for the treatment of congenital craniofacial disorders; however, there are potential problems including donor site morbidity and limitations to the amount of bone that can be harvested. Recent studies suggest that granulocyte colony-stimulating factor (G-CSF) promotes fracture healing or osteogenesis. The purpose of the present study was to investigate whether topically applied G-CSF can stimulate the osteoconductive properties of beta-tricalcium phosphate (β-TCP) in a rat calvarial defect model. A total of 27 calvarial defects 5 mm in diameter were randomly divided into nine groups, which were treated with various combinations of a β-TCP disc and G-CSF in solution form or controlled release system using gelatin hydrogel. Histologic and histomorphometric analyses were performed at eight weeks postoperatively. The controlled release of low-dose (1 μg and 5 μg) G-CSF significantly enhanced new bone formation when combined with a β-TCP disc. Moreover, administration of 5 μg G-CSF using a controlled release system significantly promoted the biodegradable properties of β-TCP. In conclusion, the controlled release of 5 μg G-CSF significantly enhanced the osteoconductive and biodegradable properties of β-TCP. The combination of G-CSF slow-release and β-TCP is a novel and promising approach for treating pediatric craniofacial bone defects.

脳梗塞を標的とした低用量G-CSF の臨床応用

脳梗塞を標的とした低用量G-CSF の臨床応用

Phase I Study of Intravenous Low-dose Granulocyte Colony-stimulating Factor in Acute and Subacute Ischemic Stroke

Granulocyte colony-stimulating factor (G-CSF; filgrastim) may be useful for the treatment of acute ischemic stroke because of its neuroprotective and neurogenesis-promoting properties, but an excessive increase of neutrophils may lead to brain injury. We examined the safety and tolerability of low-dose G-CSF and investigated the effectiveness of G-CSF given intravenously in the acute phase (at 24 hours) or subacute phase (at 7 days) of ischemic stroke. Three intravenous dose regimens (150, 300, or 450 μg/body/day, divided into 2 doses for 5 days) of G-CSF were examined in 18 patients with magnetic resonance imaging (MRI)-confirmed infarct in the territory of the middle cerebral artery. Nine patients received the first dose at 24 hours poststroke (acute group) and 9 patients received the first dose on day 7 poststroke (subacute group; n = 3 at each dose in each group). A scheduled administration of G-CSF was skipped if the patient's leukocyte count exceeded 40,000/μL. Patients received neurologic and MRI examinations. We found neither serious adverse event, drug-related platelet reduction nor splenomegaly. Leukocyte levels remained below 40,000/μL at 150 and 300 μg G-CSF/body/day, but rose above 40,000/μL at 450 μg G-CSF/body/day. Neurologic function improvement between baseline and day 90 was more marked after treatment in the acute phase versus the subacute phase (Barthel index 49.4 ± 28.1 v 15.0 ± 22.0; P < .01). Low-dose G-CSF (150 and 300 μg/body/day) was safe and well tolerated in ischemic stroke patients, and leukocyte levels remained below 40,000/μL.

Granulocyte colony stimulating factor in chronic angina to stimulate neovascularisation: a placebo controlled crossover trial

BackgroundExperimental studies demonstrate that granulocyte colony stimulating factor (G-CSF) promotes neovascularisation and confers cardioprotection.ObjectiveTo assess the efficacy of repeated low dose G-CSF plus exercise on myocardial ischaemia in patients with...

Effects of granulocyte-colony stimulating factor on chromosome aneuploidy and replication asynchrony in healthy peripheral blood stem cell donors

AbstractAs peripheral blood has surpassed bone marrow as a predominant source of stem cells for transplantation, use of the cytokine granulocyte colony-stimulating factor (G-CSF) to mobilize peripheral blood stem cells (PBSCs) is increasing. Issues regarding potential genotoxic effects of even short-term, low-dose G-CSF treatment for the healthy donors have been raised. To address the question of chromosomal instability, we used FISH to evaluate the peripheral blood lymphocytes of 22 PBSC donors and 22 matched controls at 5 time points over a 12-month period. The specimens obtained were a pre-G-CSF, followed by collections at the time of PBSC harvest (days 5-7) and at 2, 6, and 12 months after donation. Eight additional PBSC donors provided a single sample at 12 months. Nine loci (mapped to chromosomes 7, 8, 9, 17, 21, and 22) were evaluated for aneuploidy, including 3 mapped to chromosome 7 because of the specific relevance of monosomy 7. Replication timing was evaluated for chromosome 15 and 17 loci. No evidence was found of G-CSF–induced chromosomal instability. This work supports the epidemiologic data that have demonstrated no increased risk for hematologic malignancies in G-CSF–primed PBSC donors.

Low-dose and long-term G-CSF treatment can improve severe myocardial ischemia in patients with severe coronary artery disease

BackgroundIt has been reported that granulocyte colony-stimulating factor (G-CSF) can promote angiogenesis by mobilizing bone marrow stem cells to blood vessels. The purpose of this study is to clarify whether low-dose and long-term G-CSF treatment can improve severe myocardial ischemia. MethodsWe studied 40 patients (M/F = 29/11, age = 68 ± 9 years) who had severe coronary artery disease (7 with and 5 without old myocardial infarction; 3VD/2VD/1VD = 17/17/6) and severe myocardial ischemia with no indication for revascularization. G-CSF (1.5 μg/kg) was injected for 14 consecutive days. All patients were evaluated using stress myocardial scintigraphy, the Canadian Cardiovascular Society (CCVS) score, and cardiopulmonary exercise testing before and after 3 months of treatment. On 17 SPECT segments, the total defect score (TDS) and delta TDS (TDS (stress) minus TDS (resting)) were evaluated to assess the severity of myocardial ischemia. ResultsThe changes in stress TDS, delta TDS, and regional wall motion score were significantly greater in the G-CSF group than the control group (P < .0001). The CCVS score improved significantly from baseline to the 3-month follow-up assessment in the G-CSF group (P < .0001). The increase of peak VO2 was significantly larger in the G-CSF group than the control group (P = .015). ConclusionLow-dose and long-term G-CSF treatment can improve severe ischemia in patients with severe coronary artery disease.

Safety and feasibility of autologous umbilical cord blood transfusion in 2 toddlers with cerebral palsy and the role of low dose granulocyte-colony stimulating factor injections

Cerebral palsy (CP) with a prevalence of 2.1 per 1,000 live births generates variable degrees of incurable developmental disability. The aim of the present report was to provide insight in the safety and feasibility of autologous umbilical cord blood (UCB) transfusion with low dose Granulocyte Colony Stimulating Factor (G-CSF) injections in improving the functional outcome of children with cerebral palsy. Two toddlers with diagnosed CP were given autologous umbilical cord blood (UCB) transfusion accompanied by low dose subcutaneous granulocyte colony stimulating factor (G-CSF) injections. Gross Motor Function Classification System (GMFCS) improvements were seen in both without any side effects being noted to date. In this first report, autologous UCB based intervention in tandem with low dose sc G-CSF administration seems to be feasible and safe with encouraging functional outcome improvements in children with CP.

Combined Low-Dose Homoharringtonine, Cytarabine and Granulocyte Colony-Stimulating Factor for Patients with Advanced Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia Transformed From MDS

AbstractAbstract 4004A pilot study of the efficacy and toxicity of the low-dose cytarabine and homoharringtonine in combination with granulocyte colony-stimulating factor (G-CSF) (CHG protocol) in patients with advanced myelodysplastic syndromes (MDS) or MDS-transformed acute myeloid leukaemia (t-AML) was conducted. A total of 50 patients (31, advanced MDS; 19, t-AML) were enrolled in this study. All patients were administered the CHG regimen comprising low-dose cytarabine (25 mg/d, intravenous continuous infusion, days 1 C14), homoharringtonine (1 mg/d, intravenous continuous infusion, days 1 C14) and G-CSF (300 μg/d, subcutaneous injection, days 0 C14, intermitted when the peripheral WBC count reached >20 °Á 109/L). This regimen was followed by conventional chemotherapy as post-remission therapy when complete remission (CR) was achieved. The overall response rate was 68.0% after one course of the CHG regimen was applied. Of the total 50 patients, 24 (48.0%) achieved CR and 9 (18.0%) achieved partial remission (PR). The median overall survival (OS) was 14.1 months. Among the patients aged ≥ 70 years, the response rate was 81.0% (71.4% CR and 9.6% PR), while in patients aged < 70 years, the response rate was 55.2% (31.0% CR and 24.1% PR) (P < 0.01). There were no statistically significant differences for CR, PR and OS when the patients were grouped by blast percentage in bone marrow and karyotypes, respectively. 8 of the 24 CR patients who just received post-remission regimens of HA (homoharringtonine and cytarabine) and DA (daunorubicin and cytarabine) relapsed rapidly and just kept a mean CR of 4.3 months. Otherwise, the other 14 CR patients alternatively received succeeded chemotherapy, which combined mitoxantrone, idarubicin, pirarubicin or aclarubicin with cytarabine or decitabine. The mean CR duration of these 14 patients reached 15.5 months with 4 still maintaining continuous CR. No treatment-related deaths were observed. Myelosuppression was mild to moderate, and no severe non-haematological toxicity was observed. Thus, CHG priming regimen as an induction therapy is well tolerated and effective in advanced MDS or t-AML patients. Disclosures:No relevant conflicts of interest to declare.