G-CSF Research Articles

Pexidartinib and standard neoadjuvant therapy in the adaptively randomized I-SPY2 trial for early breast cancer.

We investigated the small-molecule receptor tyrosine kinase-inhibitor of colony-stimulating factor-1 receptor pexidartinib in the stage II/III breast cancer in the I-SPY2 platform trial. I-SPY2 is an adaptive platform trial that features multiple arms of experimental agents administered on a background of standard neoadjuvant therapy with paclitaxel and adriamycin/cyclophosphamide, followed by definitive surgery. The adaptive randomization engine preferentially assigns patients based upon cumulative performance of each agent in a given breast cancer subtype based on hormone receptor and HER2 receptor status. The study endpoint is pathologic complete response. A total of 9 participants were randomized to receive pexidartinib with neoadjuvant paclitaxel before enrollment was halted due to a serious adverse event of vanishing bile duct syndrome. No participants received a full course of the study drug. Although there remains interest in agents targeting CSF-1, hepatic toxicity appears to be a limiting factor for their use in early breast cancer. NCT01042379 ( www. gov/ct2/show/NCT01042379 ).

Factors influencing white blood cell mobilisation in healthy granulocyte donors.

Granulocyte transfusions represent a therapeutic option for severely neutropenic patients with bacterial or fungal infections that are otherwise unresponsive to conventional therapy. Prior clinical studies suggest that patients receiving higher granulocyte doses achieve superior outcomes. Consequently, suboptimal donor stimulation and collection leading to lower granulocyte doses likely correlate with worse clinical outcomes. A retrospective analysis was conducted on mobilisation data from 312 granulocyte collections from healthy donors between January 2020 and May 2023. This study was performed in a single blood donor center exclusively supporting a comprehensive cancer center. Donors underwent stimulation with 480 mcg of filgrastim (granulocyte colony stimulating factor [G-CSF]) subcutaneously and 8 mg of dexamethasone orally administered 12 to 14 h before collection. The correlation between donor characteristics (age, gender, body weight (BW), body mass index (BMI), baseline haemoglobin (Hgb), and platelet (PLT) counts) and mobilisation efficiency (Δ WBC, defined as post-mobilisation WBC count-baseline WBC count) was examined to identify factors associated with enhanced mobilisation efficiency. Additionally, the impact of multiple donations on Δ WBC in repeat donors was assessed. The median donor age was 43 years (range 18-81), with 224 male and 88 female donors. Female donors exhibited significantly higher baseline PLT counts and post-mobilisation WBC counts. However, donor gender did not significantly affect Δ WBC. A negative correlation was observed between Δ WBC and age (r = -0.235, p = 0.001), with older donors (61-81 years) exhibiting significantly lower mobilisation efficiency. BW and BMI differences had no significant effect on Δ WBC. A positive correlation was identified between baseline PLT count and Δ WBC (r = 0.140, p = 0.014), with females having significantly higher baseline PLT counts (p = 0.0004). No correlation was found between Δ WBC and baseline Hgb (r = 0.004, p = 0.477). Repeat donors showed no statistically significant change in Δ WBC with subsequent donations, with a mean interval of 136.5 days between collections. Mobilisation efficiency was not impacted by donor BW or BMI suggesting that BW-based G-CSF stimulation is not essential for optimising WBC mobilisation. Rather, a fixed single dose of 480 mcg of G-CSF and 8 mg of dexamethasone was sufficient to mobilise donors, thus reducing the procedural costs and the potential risks for medication-related side effects. The positive correlation found between baseline PLT count and Δ WBC suggests that PLT count could be used as a potential predictor of mobilisation efficiency. Mobilisation response in up to four collections in repeat granulocytes donors was not affected in subsequent donations. However, sample size is a limitation, and more data is needed for a meaningful conclusion of whether frequent granulocyte donations are safe and effective.

Venetoclax plus D-CAG (decitabine, cytarabine, aclarubicin, G-CSF) for elderly or unfit patients with newly diagnosed acute myeloid leukemia: a multicenter, prospective study.

Induction regimens with satisfactory remission rates are limited for patients with acute myeloid leukemia (AML) who are elderly or ineligible for intensive chemotherapy. This study is a single-arm, multicenter, prospective phase I/II study (registered with the Chinese Clinical Trial Registry as ChiCTR 2200059694 on May 8, 2022), aiming to evaluate the efficacy and safety of venetoclax plus decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (VD-CAG) for newly diagnosed AML patients who are elderly or ineligible for intensive chemotherapy. The primary endpoint was composite complete remission (CRc) after 1 cycle of induction chemotherapy. The secondary endpoints were measurable residual disease (MRD) by flow cytometry and adverse events. Forty patients(n = 40) received 1 cycle of the VD-CAG regimen for induction chemotherapy. The median age of the patients was 64 (55-81) years, and 10 patients (25%) had secondary AML. Our results showed that 1 cycle of VD-CAG had a high overall response rate of 97.5% and CRc of 95%, and all 10 patients with secondary AML achieved CRc. Moreover, the patients who achieved CRc had deep remission, with MRD-negativity of 71.1% and 54.2% by flow cytometry and molecular assessment, respectively. In addition, blood cell recovery was quick, with a median time to absolute neutrophil count ≥ 1.0 × 109/L and platelet count ≥ 100 × 109/L at 19 days and 15.5 days, respectively. In conclusion, VD-CAG demonstrates high efficacy as an induction treatment for elderly or unfit patients with newly diagnosed AML, and it could be an alternative upfront therapy for this subpopulation, Trials with large-scale subjects are needed for further validation, especially for secondary AML.

A strategy to design protein-based antagonists against type I cytokine receptors.

Excessive cytokine signaling resulting from dysregulation of a cytokine or its receptor can be a main driver of cancer, autoimmune, or hematopoietic disorders. Here, we leverage protein design to create tailored cytokine receptor blockers with idealized properties. Specifically, we aimed to tackle the granulocyte-colony stimulating factor receptor (G-CSFR), a mediator of different types of leukemia and autoinflammatory diseases. By modifying designed G-CSFR binders, we engineered hyper-stable proteins that function as nanomolar signaling antagonists. X-ray crystallography showed atomic-level agreement with the experimental structure of an exemplary design. Furthermore, the most potent design blocks G-CSFR in acute myeloid leukemia cells and primary human hematopoietic stem cells. Thus, the resulting designs can be used for inhibiting or homing to G-CSFR-expressing cells. Our results also demonstrate that similarly designed cytokine mimics can be used to derive antagonists to tackle other type I cytokine receptors.

Dorsal root ganglia CSF1+ neuronal subtypes have different impact on macrophages and microglia after spared nerve injury.

Colony-stimulating factor 1 (CSF1) is a growth factor secreted by dorsal root ganglia (DRG) neurons important for DRG macrophages and spinal cord (SC) microglia injury-induced proliferation and activation, specifically released after spared nerve injury (SNI). In this study, we investigated if SNI-induced CSF1 expression and perineuronal rings of macrophages around mouse DRG neurons vary between L3-L5 DRG and with the neuronal type, and if the CSF1+ neuronal projections at the SC dorsal horns were associated with an increased microglial number in the corresponding laminae. Seven days after surgery, L3-L5 DRG as well as their corresponding segments at the SC level were collected, frozen, and cut. DRG sections were double-immunostained using antibodies against CSF1 and NF200, CGRP or IB4, while SC sections were immunostained using a fluorescent Nissl Stain and analyzed for CX3CR1-GFP microglia number and distribution by an in-house ImageJ Plug-in. Our results showed that SNI-induced CSF1 expression was common for all subtypes of mouse DRG neurons, being responsible for attracting more resident macrophages around them in a DRG-dependent manner, with L4 showing the stronger response and CSF1+/NF200+ neurons showing the highest incidence. Even though the total number of microglia in the SC ipsilateral dorsal horns increased after SNI, the increase at their specific laminar projection sites did not mirror the incidence of DRG neuronal subtypes among CSF1+ neurons. Taken together, these results contribute to a more comprehensive understanding of the connection between CSF1 and macrophage/microglia response after SNI and emphasize the importance of considering L3-L5 DRG individually when investigating SNI-neuropathic pain pathogenesis in mice.

Mesenchymal stem cells treated with Interleukin-1 beta for mediation of an inflammatory response in human tissues.

The present study examined the functional activities of the human bone marrow mesenchymal stem cells (hBM-MSCs) under the effects of various concentrations of the inflammatory mediator interleukin 1 beta (IL-1β). The effects of IL-1β on the functional properties of hBM-MSCs were measured using functional assays (adhesion, proliferation, and migration). hBM-MSCs expressions of colony-stimulating factors 1 and 2 (CSF1, CSF2), C-C chemokine receptor type 2 (CCR2), C-X-C chemokine receptor type 1 and 3 (CXCL1, CXCL3), were examined using real-time polymerase chain reaction (RT‒PCR). The pro-inflammatory cytokine IL-1β did not disrupt hBM-MSCs adhesion, but it improved proliferation and migration only up to 50 ng/ml. However, in response to 100 ng/ml IL-1β, cell growth, proliferation, and migration were reduced significantly. The expression of CSF1, CCR2, CXCL3, and IL-1β genes increased with the increase in the concentration of IL-1β. CSF2 and CXCL1 gene expression increased in the 50ng/ml group compared with the 10ng/ml group to be higher than the control group in the 100ng/ml IL-1β group which might facilitate the differentiation, and homing of MSCs to the site of injury and augment their activities in the inflamed microenvironment. The study corroborates the advantages of prior stimulation of mesenchymal stem cells (MSCs) with the cytokine IL-1β, demonstrating an upregulation of key chemokines and cytokines. This upregulation potentially enhances MSCs' ability to differentiate and migrate to injury sites, while also augmenting their functional role within an inflamed microenvironment, thereby amplifying their therapeutic potential.

Optimization of T-cell replete haploidentical hematopoietic stem cell transplantation: the Chinese experience.

Haploidentical-related donor (HID) hematopoietic stem cell transplantation (HSCT) has undergone significant advances in recent decades. Granulocyte colony-stimulating factor- and antithymocyte globulin-based protocols and post-transplantation cyclophosphamide-based regimens represent two of the current T-cell-replete protocols in HID HSCT. Recently, the optimization of several critical transplant techniques has further improved hematopoietic reconstitution, decreased the incidence of relapse and graft-versus-host disease after HID HSCT, and extended the application of HID HSCT to older patients and those with non-malignant hematologic disorders. Particularly, combining this approach with novel immunotherapy would further improve the efficacy and safety of HID HSCT. This review focuses on recent progress in the optimization of HID HSCT.

Different impacts of granulocyte colony-stimulating factor administration on allogeneic hematopoietic cell transplant outcomes for adult acute myeloid leukemia according to graft type.

We retrospectively evaluated the impacts of using granulocyte colony-stimulating factor (G-CSF) and its timing on posttransplant outcomes for 9766 adults with acute myeloid leukemia (AML) between 2013 and 2022 using a Japanese database. We separately evaluated three distinct cohorts based on graft type: 3248 received bone marrow transplantation (BMT), 3066 received peripheral blood stem cell transplantation (PBSCT), and 3452 received single-unit cord blood transplantation (CBT). Multivariate analysis showed that G-CSF administration significantly accelerated neutrophil recovery after BMT, PBSCT, and CBT. However, it was associated with a higher risk of grades II-IV acute graft-versus-host disease (GVHD) across all graft types. Moreover, an increased incidence of overall chronic GVHD was observed with G-CSF administration in BMT and CBT patients, but not in PBSCT patients. G-CSF administration significantly improved overall survival (OS) and leukemia-free survival (LFS) only following CBT. Regarding the timing of G-CSF, in comparison with late initiation of G-CSF (Days 5-10), early initiation (Days 0-4) did not provide benefits for hematopoietic recovery regardless of graft type. In contrast, late initiation was significantly associated with a lower risk of grades II-IV acute GVHD and better OS and LFS in CBT patients. These data demonstrated that G-CSF administration accelerated neutrophil recovery and increased the risk of grades II-IV acute GVHD across all graft types, but significantly improved survival outcomes but only following CBT. Therefore, routine use of G-CSF should be considered for CBT in adult patients with AML.

Long term outcomes of intracarotid arterial transfusion of circulatory-derived autologous CD34 + cells for acute ischemic stroke patients—A randomized, open-label, controlled phase II clinical trial

BackgroundThis phase II randomized controlled trial tested whether the intracarotid arterial administration (ICAA) of autologous CD34 + cells to patients within 14 ± 7 days after acute ischemic stroke (IS) could be safe and further improve short- and long-term outcomes.MethodsBetween January 2018 and March 2022, 28 consecutive patients were equally randomly allocated to the cell-treated group (CD34 + cells/3.0 × 107/patient) or the control group (receiving optimal medical therapy). CD34 + cells were transfused into the ipsilateral brain infarct zone of cell-treated patients via the ICAA in the catheterization room.ResultsThe results demonstrated 100% safety and success rates for the procedure, and no long-term tumorigenesis was observed in cell-treated patients. In cell-treated patients, the angiogenesis capacity of circulating endothelial progenitor cells (EPCs)/Matrigel was significantly greater after treatment than before treatment with granulocyte colony-stimulating factor (all p < 0.001). Blood samples from the right internal jugular vein of the cell-treated patients presented significantly greater levels of the stromal cell-derived factor 1α/EPC at 5, 10 and 30 min compared with 0 min (all p < 0.005). The National Institute of Health Stroke Scale scores were similar upon presentation, but a greater response was observed by Days 30 and 90 in the cell-treated group than in the control group. Tc-99 m brain perfusion was significantly greater at 180 days in the cell-treated group than in the control group (p = 0.046). The combined long-term end points (defined as death/recurrent stroke/or severe disability) were notably lower in the control group compared with the cell-treated group (14.3% vs. 50.0%, p = 0.103).ConclusionIntracarotid transfusion of autologous CD34 + cells is safe and might improve long-term outcomes in patients with acute IS.Trial registration ISRCTN, ISRCTN15677760. Registered 23 April 2018- Retrospectively registered, https://doi.org/10.1186/ISRCTN15677760

G-CSF resistance of ELANE mutant neutropenia depends on SERF1 containing truncated neutrophil elastase aggregates.

Severe congenital neutropenia (SCN) is frequently associated with dominant point mutations in ELANE, the gene encoding neutrophil elastase (NE). Chronic administration of granulocyte colony-stimulating factor (G-CSF) is a first-line treatment of ELANE-mutant (ELANEmut) SCN. However, some ELANEmut patients including patients with ELANE start codon mutations do not respond to G-CSF. Here, through directed granulopoiesis of gene-edited isogenic normal and patient-derived iPSCs, we demonstrate that ELANE start codon mutations suffice to induce G-CSF resistant granulocytic precursor cell death and refractory SCN. ELANE start codon mutated neutrophil precursors express predominantly nuclear N-terminal truncated alternate NE. Unlike G-CSF sensitive ELANE mutations that induce endoplasmic reticulum and unfolded protein response stress, we found that the mutation of the ELANE translation initiation codon resulted in NE aggregates and activated pro-apoptotic aggrephagy as determined by downregulated BAG1 expression, decreased BAG1/BAG3 ratio, NE co-localization with BAG3, and localized expression of autophagic LC3B. We found that SERF1, an RNA-chaperone protein, known to localize in misfolded protein aggregates in neurodegenerative diseases, was highly upregulated and interacted with cytoplasmic NE of mutant neutrophil precursors. Silencing of SERF1 enhanced survival and differentiation of iPSC-derived neutrophil precursors, restoring their responsiveness to G-CSF. These observations provide a mechanistic insight of G-CSF-resistant ELANEmut SCN, revealing targets for therapeutic intervention.

Ribosomal protein S3A (RPS3A), as a transcription regulator of colony-stimulating factor 1 (CSF1), promotes glioma progression through regulating the recruitment and autophagy-mediated M2 polarization of tumor-associated macrophages.

Dysregulated expression of ribosomal protein S3A (RPS3A) is associated with the tissue infiltration of immune-related cells in a variety of cancers. However, the role of RPS3A in immune cell infiltration in glioma remains unclear. This study aimed to explore the role of RPS3A in the glioma immune microenvironment.RPS3A expression was detected in tumor tissues from patients with glioma. U251 cells were transfected with RPS3A shRNA (sh-RPS3A) and overexpression vector (pcDNA-RPS3A) and then co-cultured with PMA-induced THP-1 cells. Cell viability, invasion, and apoptosis were detected by Edu staining, Transwell, and flow cytometry, respectively. The expression of tumor-associated macrophage (TAM) M1 and M2 markers was detected with RT-qPCR. Next, the interaction between RPS3A and E4 transcription factor 1 (E4F1) was verified by Co-IP analysis, and the binding of E4F1 to colony-stimulating factor 1 (CSF1) promoter was verified by ChIP analysis. Overexpression vectors of CSF1 and E4F1 were used to treat sh-RPS3A-transfected U251 cells for reversal experiments. Finally, U251 cells transfected with sh-RPS3A adenovirus vectors were subcutaneously injected into nude mice to construct a xenograft tumor model, and the growth and metastasis of glioma in vivo were monitored.RPS3A was significantly upregulated in glioma tissues. Overexpression of RPS3A promoted glioma cell proliferation and invasion and inhibited apoptosis. Moreover, overexpression of RPS3A promoted TAM proliferation, invasion, and M2 polarization. Silencing RPS3A had the opposite effect. Silencing RPS3A inhibited autophagy in U251 cells, whereas rapamycin, an activator of autophagy, reversed the inhibitory effect of RPS3A silencing on TAM M2 polarization. Meanwhile, RPS3A promoted its expression by interacting with E4F1, and E4F1 promoted CSF1 transcriptional activation. Overexpression of CSF1 promoted the proliferation and invasion of U251 cells and reversed the inhibitory effect of RPS3A silencing on TAM proliferation and invasion, but had no effect on TAM M2 polarization. The results of in vivo experiments showed that knockdown of RPS3A significantly inhibited glioma tumor growth and metastasis in vivo.This study revealed that RPS3A recruited TAMs by upregulating E4F1-mediated transcription activation of CSF1, and promoted the M2 polarization of TAMs through autophagy, promoting glioma cell malignant growth and tumor progression.

Treatment Intensification With Either Fludarabine, AraC, G-CSF and Idarubicin, or Cladribine Plus Daunorubicin and AraC on the Basis of Residual Disease Status in Older Patients With AML: Results From the NCRI AML18 Trial.

To evaluate the survival benefit of chemotherapy intensification in older patients with AML who have not achieved a measurable residual disease (MRD)-negative remission. Five hundred twenty-three patients with AML (median age, 67 years; range, 51-79) without a flow cytometric MRD-negative remission response after a first course of daunorubicin and AraC (DA; including 165 not in remission) were randomly assigned between up to two further courses of DA or intensified chemotherapy-either fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (FLAG-Ida) or DA with cladribine (DAC). Overall survival (OS) was not improved in the intensification arms (DAC v DA: hazard ratio [HR], 0.74 [95% CI, 0.55 to 1.01]; P = .054; FLAG-Ida v DA: HR, 0.86 [95% CI, 0.66 to 1.12]; P = .270); OS at 3 years was 34%, 46%, and 42% for DA, DAC, and FLAG-Ida, respectively. Early deaths and other adverse events were more frequent with FLAG-Ida (9% day 60 deaths v 4% after DA or DAC; P = .032). Of patients entering random assignment, 131 had MRD unknown status. In this subgroup of patients lacking evidence of residual leukemia by flow cytometry, there was no detectable survival advantage from intensification. A planned sensitivity analysis excluding these patients demonstrated a survival benefit for both DAC (HR, 0.66 [95% CI, 0.46 to 0.93]; P = .018) and FLAG-Ida (HR, 0.72 [95% CI, 0.53 to 0.98]; P = .035); OS at 3 years was 30%, 46%, and 46% for DA, DAC, and FLAG-Ida, respectively. There was a concordant reduction in relapse (DAC v DA: HR, 0.66 [95% CI, 0.45 to 0.98]; P = .039; FLAG-Ida v DA: HR, 0.70 [95% CI, 0.49 to 0.99]; P = .042). DAC benefit was maintained when survival was censored for transplant (P = .042). In this study of older patients with AML considered fit and with evidence of residual disease after first induction, chemotherapy intensification improved survival. DAC intensification was better tolerated than FLAG-Ida.

Effect of an Add-On Multi-Strain Probiotic Formulation in the Prevention of Recurrent Urinary Tract Infections: A Double-Blind Randomized Placebo-Controlled Trial

Urinary tract infections (UTIs) present a significant health challenge for women globally, particularly due to high recurrence rates. This randomized, double-blinded, placebo-controlled study conducted at AIIMS Bhubaneswar, India, evaluated the effectiveness of a multi-strain lactobacilli probiotic formulation as an adjunct to standard antibiotic therapy in preventing recurrent UTIs. Fifty-one adult women (18–50 years) with recurrent UTIs received either the probiotic or a placebo for 24 weeks. The primary outcome was UTI recurrence, while secondary outcomes included the number of UTI episodes and changes in urinary nerve growth factor (NGF) and serum macrophage colony-stimulating factor (M-CSF) levels. The results showed a significant reduction in UTI recurrence in the probiotic group, with 75% remaining recurrence-free, compared to 33% in the placebo group (p = 0.007). The relative risk for recurrence absence was 2.67 (95% CI: 1.19–5.99). Although the mean number of UTI episodes decreased in the probiotic group, the difference was not statistically significant (p = 0.379). The urinary NGF and serum M-CSF levels significantly decreased from baseline in both groups, but there were no significant differences between them. This study suggests probiotics may be a valuable adjunct therapy for preventing recurrent UTIs.

Mechanism of Astragalus polysaccharides (APS) improving myelosuppression and exerting anti-tumor effects during radiotherapy and chemotherapy

Abstract. Chemoradiotherapy, as a routine method of anti-tumor treatment, is accompanied by severe adverse reactions such as myelosuppression. It not only hinders the treatment process but also reduces the quality of life of patients. Therefore, effective prevention and treatment of myelosuppression during radiotherapy and chemotherapy is an extremely important issue that needs to be addressed in clinical practice. The commonly used method for preventing and treating myelosuppression during radiotherapy and chemotherapy is medication intervention. Human granulocyte colony stimulating factor(Human G-CSF) is the preferred drug, while modern Chinese medicine preparations are used as adjunctive therapy. There are still certain limitations in the clinical use of Human G-CSF, so research on the unique role of modern Chinese medicine in this regard has gradually received attention. By consulting literature, we took Astragalus polysaccharide (APS), a traditional Chinese medicine extract that has been proven to have relevant preventive and curative effects in existing studies, as an entry point to explore the mechanisms involved in the modulation of the signaling pathway by APS to play a role in improving the myelosuppressive and anti-tumour effects. This study aims to explore the mechanism by which APS participates in regulating signaling pathways to improve myelosuppression and anti-tumor effects. Some of its mechanisms are closely related to traditional Chinese medicine theory. This article will briefly discuss them in order to provide some inspiration for expanding drug selection in clinical practice and further conducting related research.

Prognostic factors of immunosuppression therapy combined with eltrombopag in the treatment of childhood severe aplastic anemia

Objective: To analyze the influence factors on the efficacy of immunosuppression therapy (IST) combined with eltrombopag and IST alone in the treatment of childhood severe aplastic anemia (SAA). Methods: A retrospective cohort study. A total of 124 children with SAA who were initially treated with IST in Beijing Children's Hospital from March 2017 to May 2020 were enrolled. Clinical characteristics, laboratory examination and prognosis data were collected at the time of enrollment. According to the treatment plan, the children were divided into the eltrombopag combined with IST group (eltrombopag group) and the IST group. Binary Logistic regression model was used to analyze the factors affecting the efficacy of the two groups at 6 months of treatment, and the factors affecting the efficacy of the eltrombopag group at the end of follow-up. Results: There were 75 cases (45 males and 30 females) in the eltrombopag group. The age of diagnosis was 5.9 (3.5, 8.5) years. There were 49 patients in the IST group, including 23 males and 26 females, whose age at diagnosis was 6.2 (4.4, 8.8) years. The absolute lymphocyte count before treatment in the eltrombopag group was significantly lower than that in the IST group (1.1 (0.4, 1.6)×109 vs. 2.1 (1.4, 2.8)×109/L). Absolute reticulocyte count in the eltrombopag group was significantly higher than that of IST group (26.9 (8.7, 54.2)×109 vs. 9.5 (4.0, 19.0)×109/L) (both P<0.05). Influencing factors of 6-month response: a comparison between response and un-response groups in the eltrombopag treated patients showed that, before treatment, hemoglobin (69 (61, 78) vs. 64 (59, 68) g/L), platelet (10 (6, 16)×109 vs. 6 (3, 8)×109/L), absolute reticulocyte count (ARC) (34.0 (15.8, 57.3)×109 vs. 6.5 (4.6, 16.8)×109/L) and the response rate to granulocyte colony stimulating factor (G-CSF) after treatment (82.4% (47/57) vs. 9/18) were significantly different (all P<0.05). Logistic regression model analysis showed that ARC (OR=1.09, 95%CI 1.02-1.18) and absolute neutrophil count were independent influencing factors of 6-month response rate in the eltrombopag group (OR=0.00, 95%CI 0.00-0.89). ARC was also the independent influencing factors of the end of follow-up response rate in the eltrombopag group (OR=1.04, 95%CI 1.01-1.07). Conclusions: Pre-treatment blood count and response to G-CSF were predictors of overall response to eltrombopag combined with IST. The higher the ARC before treatment, the higher the total response rate and complete response.

Use of Granulocyte Transfusions in the Management of Severe Infections Among Children with Neutropenia.

Background/Objectives: Infections remain the leading cause of mortality among neutropenic patients with haematologic malignancies, making effective infection management crucial. Achieving a sufficient neutrophil count is essential for the elimination of pathogens. Granulocyte concentrate (GC) can be a treatment option for neutropenic patients with severe infections. This study aimed to evaluate the efficacy, safety, and impact on survival of GC transfusions in neutropenic children with severe infections treated over the past 13 years in a single centre. Methods: The retrospective study analysed clinical data from 60 children (median age 9.5 years) who received GC transfusions at our centre. Granulocytes were collected by apheresis from donors stimulated with granulocyte colony-stimulating factor. The majority of the patients (70%) were diagnosed with acute leukaemia. The main indications for GC were severe pneumonia (45%) and bacterial sepsis (38.33%). Results: The patients received 1 to 29 GC transfusions for 1 to 70 days, with a median time of administration of 3 days. Neutrophil counts increased to >1000/µL within a median of 5 days. GCs were well tolerated by most patients. One patient presented symptoms of anaphylaxis, the other acute lung injury related to transfusions, and alloimmunisation was reported in one patient. Of the patients analysed, 78.33% survived the infection that justified GC administration. We did not observe significant differences in survival depending on the aetiology of the infection. Conclusions: Based on our research, GC appears to be a beneficiary for neutropenic children with severe infections and reduces infection mortality rates. However, further well-designed randomised trials are needed to define its role in this setting.

The efficacy and safety of the prophylactic application of PEG-rhG-CSF in radiotherapy with weekly concurrent chemotherapy for cervical cancer

ObjectiveTo evaluate the efficacy and safety of pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in preventing neutropenia during concurrent radiotherapy combined with weekly chemotherapy in patients with cervical cancer.MethodsFrom September 2019 to November 2020, 180 patients with cervical cancer who required concurrent chemoradiotherapy (CCRT) were enrolled in this study. The patients were randomly divided into the following three groups at a ratio of 1:1:1: Group A (PEG-rhG-CSF), Group B (PEG-rhG-CSF + rhG-CSF) and the control group (rhG-CSF). Cisplatin or carboplatin was administered weekly. The primary endpoint was the incidence of grade 3/4 neutropenia. The secondary endpoints were the incidence of febrile neutropenia (FN), delay of radiotherapy, chemotherapy dose reduction, rate of PFS at 2 years and 3 years, and incidence of adverse reactions.ResultsSixty patients were randomly assigned to each group. Two patients in Group B withdrew from the trial for personal reasons. The incidence of grade 1/2 neutropenia in the Control group was significantly lower than that in Group A and Group B (P < 0.001). However, the incidence of grade 3/4 neutropenia in the Control group was significantly greater than that in Group A and Group B (P < 0.001). There was no significant difference in the incidence of FN among the three groups (P = 0.771). The rate of platinum dose reduction in Group A (6.7%) and Group B (5.2%) was significantly lower than that in the Control group (30.0%) (P < 0.001). The delay rate of radiotherapy in Group A (10%) and Group B (13.8%) was obviously inferior to that in the Control group (31.7%) (P = 0.006). The 2-year PFS rates of Group A, Group B, and the Control group were 93.3%, 98.3%, and 91.7%, respectively, with no statistically significant difference (P = 0.270). The 3-year PFS rates were 89.8%, 94.1%, and 84.9%, respectively, with no statistically significant difference (P = 0.178). No treatment-related serious adverse events occurred in any of the patients.ConclusionIn Group A and Group B, The prophylactic application of PEG-rhG-CSF during conventional chemoradiotherapy combined with weekly chemotherapy for patients with cervical cancer can reduce the incidence of grade 3/4 neutropenia and does not increase the incidence of adverse reactions when compared to Control group.Trial registrationchictr.org.cn, ChiCTR1900026309, registered 29 September 2019-prospectively registered.

Pimicotinib Significantly Improves Outcomes for Patients with Tenosynovial Giant Cell Tumor

Results from the Phase 3 MANEUVER trial (NCT05804045) of pimicotinib (ABSK021), an investigational orally administered, highly selective, and potent small-molecule inhibitor of colony-stimulating factor-1 receptor (CSF-1R) being developed by Abbisko Therapeutics, met its primary endpoint, demonstrating significant improvement in objective response rate (ORR) in patients with tenosynovial giant cell tumor (TGCT). The ORR for pimicotinib at week 25 was 54.0% compared with 3.2% for placebo (p&lt;0.0001).

Abstract 4116714: Macrophage Colony Stimulating Factor as a Causal Metabolic Mediator of Cardiovascular Disease: An Observational and Mendelian Randomization Analysis

Background: Macrophage biology plays a key role in the pathogenesis of atherosclerosis and circulating macrophage colony-stimulating factor (M-CSF) is a marker of macrophage activity. However, there is conflicting evidence regarding its role as a mediator of cardiovascular disease. Methods: We evaluated the association between plasma M-CSF concentration with myocardial infarction, stroke, heart failure and mortality in a large substudy involving 9992 participants drawn from 14 countries and followed for a median period of 9.8 years (Interquartile Range 8.9 years - 11.4 years) utilizing a nested case-cohort design in the Prospective Urban Rural Epidemiology (PURE) study. We then conducted a two-sample Mendelian randomization (MR) analysis to evaluate the upstream determinants (using genome wide association data from the PURE biobank and publicly available consortia) and downstream effects on clinical events.. Results: The strongest causal upstream determinant of M-CSF concentration was body mass index (BMI), which showed a positive association with plasma M-CSF concentration (Beta: 0.17 SD increase; 95% CI: 0.08 - 0.27). In a survival analysis, M-CSF was independently associated with increased incident myocardial infarction (HR: 1.25 per 1 SD M-CSF increase; 95% CI: 1.13-1.38), stroke (HR: 1.17; 95% CI:1.04-1.32), and heart failure (HR: 1.34; 95% CI: 1.15-1.56) and other cardiovascular disease risk factors. Circulating M-CSF concentration also showed a strong association with long-term risk of overall mortality (HR: 1.44; 95% CI: 1.39-1.60). Mendelian randomization analyses confirmed that increased M-CSF was associated with increased risk of MI, heart failure, and ischemic stroke (specifically large artery atherosclerotic and cardioembolic stroke). Conclusions: M-CSF is a strong causal driver of cardiovascular disease morbidity whose concentration is causally influenced by body mass index. Our analysis suggests a role for macrophage activity in mediating the relationship between body mass index and cardiovascular disease outcomes.

Clinicopathological Characteristics of Neutrophil-Rich Hepatocellular Carcinoma: An Uncommon Subtype of Primary Liver Cancer.

Introduction. Neutrophil-rich hepatocellular carcinoma (HCC) is an extremely uncommon subtype of HCC with an overall incidence of <1%. Neutrophil-rich HCC shows poor cellular differentiation and sarcomatoid transformation in most patients. There is prominent neutrophilic inflammatory cell infiltration in the tumor. These tumors are associated with poor prognosis, high rate of recurrence, and metastasis. Methods. Herein, we investigated 4 patients with neutrophil-rich HCC reported at our center. Clinical, radiological, and pathological findings were reviewed. Immunophenotypic characterization of the tumors were done. Granulocyte colony-stimulating factor (G-CSF), programmed cell death ligand 1 (PD-L1), and mismatch repair immunostains were performed in all 4 tumors. Results. We report 4 neutrophil-rich HCCs in 3 male patients and one female patient with an age range of 43 to 64 years. Three underwent living donor liver transplantation and one underwent right hepatectomy. Tumor measured 0.5 cm to 12 cm in maximum dimension. Histologically, tumors demonstrated moderate to marked cellular pleomorphism. Spindle cell transformation was noted in 3 tumors. Three tumors showed vascular invasion, and one tumor showed bile duct invasion. Immunopositivity for Hep Par-1, arginase-1, and glypican-3 was present in all tumors. Tumors also expressed stemness markers including KRT19 and EpCAM. Cytoplasmic positivity for G-CSF and immunoexpression of PD-L1 was demonstrated. We also report proficient mismatch repair by immunohistochemistry in all tumors. Conclusion. Neutrophil-rich HCC is an aggressive primary liver cancer which demonstrates stemness-related features. Programmed cell death ligand 1 expression in tumor cells suggests distinct immunogenic features and potential role of anti-PD-L1 therapies in inoperable disease.