Granulocyte Colony Research Articles

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

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

Survival and Hematologic Benefits of Romiplostim After Acute Radiation Exposure Supported FDA Approval Under the Animal Rule

Patients exposed to acute high doses of ionizing radiation are susceptible to dose-dependent bone marrow depression with resultant pancytopenia. Romiplostim (RP; Nplate) is a recombinant thrombopoietin receptor agonist protein that promotes progenitor megakaryocyte proliferation and platelet production and is an approved treatment for patients with chronic immune thrombocytopenia. The goal of our study was to evaluate the postirradiation survival and hematologic benefits of a single dose of RP with or without pegfilgrastim (PF; Neulasta, granulocyte colony stimulating factor) by conducting a well-controlled, treatment-concealed, good laboratory practice-compliant study in rhesus macaques that was compliant with the United States Food and Drug Administration Animal Rule regulatory approval pathway. Irradiated male and female rhesus macaques (20/sex in each of 3 groups: control, RP, and RP+PF) were subcutaneously administered vehicle or RP (5 mg/kg, 10 mL/kg) on day 1 in the presence or absence of 2 doses of PF (0.3 mg/kg, 0.03 mL/kg, days 1 and 8). Total body radiation (680 cGy, 50 cGy/min from cobalt-60 gamma ray source) occurred 24 ± 2 hours previously at a dose targeting 70% lethality for the control cohort over 60 days. The study examined 60-day survival postirradiation as the primary endpoint. Secondary endpoints included incidence, severity, and duration of thrombocytopenia and neutropenia, other hematology parameters, coagulation parameters, and body weight change to provide insights into potential mechanisms of action. Compared with sham-treated controls, treated animals demonstrated a 40% to 55% survival benefit compared with controls, less severe clinical signs, reduced incidence of thrombocytopenia and/or neutropenia, earlier hematologic recovery, and reduced morbidity from bacterial infection. These results were pivotal in obtaining Food and Drug Administration approval in January 2021 for RP's new indication as a single administration therapy to increase survival in adults and pediatric patients acutely exposed to myelosuppressive doses of radiation.

The role of plerixafor in conditioning regimens before unmanipulated bone marrow transplantation in patients with Wiscott–Aldrich syndrome

Our previous experience of using plerixafor and granulocyte colony stimulating factor (G-CSF) in addition to treosulfan-based conditioning in patients with Wiscott–Aldrich syndrome (WAS) demonstrated efficacy and a decreased risk of severe graft failure after hematopoietic stem cell transplantation (HSCT) with TCRab + /CD19 + graft depletion. Because of the remaining risk of graft failure in WAS patients following HSCT with unmanipulated grafts reported in a number of large-scale retrospective studies, we used plerixafor and G-CSF in conditioning regimens in 6 WAS patients who received native bone marrow as a graft source. None of the patients developed severe organ toxicity in the early post-transplantation period. All of them had long-term full donor chimerism in whole blood and the CD3 + line and a good graft function. At the last follow-up, 5 patients are alive at 3.7 to 74.7 months after HSCT (median follow-up time: 24.0 months). One patient died of chronic lung graft-versus-host-disease at 18 months after the transplantation. Despite limited experience, we believe that additional hematopoietic stem cell mobilization with plerixafor and G-CSF in treosulfan-based conditioning regimens may be effective in WAS patients undergoing HSCT with an unmanipulated graft. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Key words: plerixafor, conditioning regimen, hematopoietic stem cell transplantation, Wiscott–Aldrich syndrome, unmanipulated graft

Reparative, Neuroprotective and Anti-neurodegenerative Effects of Granulocyte Colony Stimulating Factor in Radiation-Induced Brain Injury Model.

This animal model aimed to compare the rat group that received brain irradiation and did not receive additional treatment (only saline) and the rat group that underwent brain irradiation and received Granulocyte colony stimulating factor (G-CSF) treatment. In addition, the effects of G-CSF on brain functions were examined by magnetic resonance (MR) imaging and histopathologically. This study used 24 female Wistar albino rats. Drug administration (saline or G-CSF) was started at the beginning of the study and continued for 15 days after whole-brain radiotherapy (WBRT). WBRT was given on day 7 of the start of the study. At the end of 15 days, the behavioral tests, including the three-chamber sociability test, open field test, and passive avoidance learning test, were done. After the behavioral test, the animals performed the MR spectroscopy procedure. At the end of the study, cervical dislocation was applied to all animals. G-CSF treatment positively affected the results of the three-chamber sociability test, open-space test and passive avoidance learning test, cornu Ammonis (CA) 1, CA3, and Purkinje neuron counts, and the brain levels of brain-derived neurotrophic factor and postsynaptic density protein-95. However, G-CSF treatment reduced the glial fibrillary acidic protein immunostaining index and brain levels of malondialdehyde, tumor necrosis factor-alpha, nuclear factor kappa-B, and lactate. In addition, on MR spectroscopy, G-CSF had a reversible effect on brain lactate levels. In this first designed brain irradiation animal model, which evaluated G-CSF effects, we observed that G-CSF had reparative, neuroprotective and anti-neurodegenerative effects and had increased neurotrophic factor expression, neuronal counts, and morphology changes. In addition, G-CSF had a proven lactate-lowering effect in MR spectroscopy and brain materials.

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

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

Increased renal dysfunction and neutrophil infiltration in a mouse model of psoriasis

Psoriasis is a chronic inflammatory skin disease affecting 2-5% of the global population. As an autoimmune disease, psoriasis is characterized by T cell-mediated hyperproliferation of epidermal keratinocytes. Interestingly, most of the morbidity and mortality from psoriasis is related to increased risk of cardiovascular and renal disease. For example, moderate to severe psoriasis is associated with an approximately 1.5-fold increased risk of chronic kidney disease. Neutrophils are increased in the skin and circulation of patients with psoriasis, and markers of neutrophil activation are associated with extra-cutaneous manifestations of psoriasis including vascular inflammation. However, the molecular mechanisms linking psoriasis and kidney disease remain unclear. We hypothesized that increased neutrophil infiltration of the kidney through enhanced granulopoiesis promotes renal dysfunction in psoriasis. Using a KC-Tie2 mouse model of psoriasis with keratinocyte-specific overexpression of the angiopoietin receptor Tie2, we found that KC-Tie2 mice compared to littermate controls exhibit significantly increased urine albumin, suggestive of renal dysfunction. KC-Tie2 mice also exhibit significantly increased kidney/body weight and heart/body weight ratios compared to littermate controls. To determine a mechanism for the increased renal dysfunction in these mice, we assessed skin and renal immune cell content using flow cytometry. KC-Tie2 mice had increased neutrophils in the skin, as well as an approximately 10-fold increase in neutrophils in the kidneys. This increase in renal neutrophils in KC-Tie2 mice was relatively selective as there were no differences in the number of renal dendritic cells, lymphocytes, or monocytes and a modest but significant increase in macrophages. We also observed a selective increase in neutrophils in the spleen of KC-Tie2 mice. Given these findings and prior reports of increased circulating neutrophils in KC-Tie2 mice, we assessed mediators of granulopoiesis in the serum and found a significant increase in granulocyte colony stimulating factor (GCSF) in KC-Tie2 mice. Taken together, these results provide evidence for increased renal dysfunction in a mouse model of psoriasis coincident with marked increases in renal neutrophils that may represent a novel mechanism linking skin inflammation to renal dysfunction through enhanced granulopoiesis. MRA is funded by NIH K08HL153786-01. JM is funded by 2T32GM007569. NW is funded by NIH R01 AR075777, NIH R01 AR073196, NIH P50 CORT AR070590, and National Psoriasis Foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Incidence, predictors, and outcomes of febrile neutropenia and neutropenia in patients with metastatic castrate-resistant prostate cancer receiving docetaxel.

The incidence of febrile neutropenia (FN) in adults with castrate-resistant metastatic prostate cancer (mCRPC) receiving docetaxel in real-world settings has not been well studied since the expanded role of hormonal treatments. The study objective was to determine the incidence of FN and neutropenia among adults with mCRPC receiving docetaxel. Secondary objectives were to quantify outcomes of patients who develop FN and to identify predictors for FN in this population. A single-center retrospective cohort study was conducted which included adults with mCRPC receiving docetaxel at the Ottawa Hospital over a 5-year period. Charts were reviewed to collect clinical data to determine the incidence of FN and neutropenia. A multiple logistic regression was used to identify predictors of FN. In patients receiving docetaxel for mCRPC, the incidence of FN and neutropenia was 34/137 (25%) and 45/137 (33%), respectively. Among 34 patients who developed FN, 94% required hospitalization for FN for a mean of 5days (± 2.8) and 6% died. Following FN, 53% required at least 1 treatment delay and 71% had at least 1 dose reduction. Age category (OR 2.025, 95% CI 1.13-3.627) and presence of multiple comorbidities (OR 1.466, 95% CI 1.01-2.258) increased the risk of FN. The incidence of FN and neutropenia in the clinical setting in patients receiving docetaxel for mCRPC is higher than previously reported and high enough to consider primary prophylaxis with granulocyte colony stimulating factors in high-risk groups. Age and multiple comorbidities were identified as risk factors.

Inflammation biomarkers in OSA, chronic obstructive pulmonary disease, and chronic obstructive pulmonary disease/OSA overlap syndrome.

The coexistence of obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD) in a single individual, also known as overlap syndrome (OVS), is associated with higher cardiovascular risk and mortality than either OSA or COPD alone. However, the underlying mechanisms remain unclear. We hypothesized that patients with OVS have elevated systemic inflammatory biomarkers relative to patients with either disease alone, which could explain greater cardiovascular risk observed in OVS. We included 255 participants in the study, 55 with COPD alone, 100 with OSA alone, 50 with OVS, and 50 healthy controls. All participants underwent a home sleep study, spirometry, and a blood draw for high-sensitivity C-reactive protein and total blood count analysis. In a randomly selected subset of 186 participants, inflammatory protein profiling was performed using Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assays. Biomarker level differences across groups were identified using a mixed linear model. Levels of interleukin 6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and granulocyte colony stimulating factor (G-CSF) were higher in participants with OVS and COPD compared with healthy controls and participants with OSA. Furthermore, participants with OVS had higher circulating levels of leukocytes and neutrophils than those with COPD, OSA, and controls. COPD and OVS are associated with higher systemic inflammation relative to OSA and healthy controls. This work proposes the potential utilization of interleukin 6, granulocyte colony stimulating factor, and high-sensitivity C-reactive protein as screening biomarkers for COPD in patients with OSA. Inflammatory pathways may not fully explain the higher cardiovascular risk observed in OVS, indicating the need for further investigation. Sanchez-Azofra A, Gu W, Masso-Silva JA, etal. Inflammation biomarkers in OSA, chronic obstructive pulmonary disease, and chronic obstructive pulmonary disease/OSA overlap syndrome. J Clin Sleep Med. 2023;19(8):1447-1456.

Cytopenias in pediatric kidney transplant recipients: preceding factors and clinical consequences.

Kidney trans plantation is associated with secondary complications, including the risk of developing posttransplant cytopenias. This study aimed to evaluate the characteristics, identify predictors, and assess the management and consequences of cytopenias in the pediatric kidney transplant population. This is a single-center retrospective analysis of 89 pediatric kidney transplant recipients. Possible factors preceding cytopenias were compared with the goal of recognizing predictors for posttransplant cytopenias. Posttransplant neutropenias were analyzed for the total study period and separately for the period beyond 6months posttransplant (late neutropenias), to rule out confounding influences of induction and initial intensive therapy. Sixty patients (67%) developed at least one episode of posttransplant cytopenia. All episodes of posttransplant thrombocytopenias were mild or moderate. Posttransplant infections and graft rejection were found to be significant predictors for thrombocytopenia (HR 6.06, 95% CI 1.6-22.9, and HR 5.82, 95% CI 1.27-26.6, respectively). A total of 30% of posttransplant neutropenias were severe (ANC ≤ 500). Pretransplant dialysis and posttransplant infections were significant predictors for late neutropenias (HR 11.2, 95% CI 1.45-86.4, and HR 3.32, 95% CI 1.46-7.57, respectively). Graft rejection occurred in 10% of patients with cytopenia, all following neutropenia, within 3months from cytopenia appearance. In all such cases, mycophenolate mofetil dosing had been held or reduced prior to rejection. Posttransplant infections are substantial contributors to developing posttransplant cytopenias. Preemptive transplantation appears to reduce risk of late neutropenia, the accompanying reduction in immunosuppressive therapy, and the ensuing risk of graft rejection. An alternative response to neutropenia, possibly using granulocyte colony stimulating factor, may diminish graft rejection. A higher resolution version of the Graphical abstract is available as Supplementary information.

The Effect of Granulocyte Colony Stimulating Factor (G-CSF) on the Outcome of Assisted Reproduction Technology in Thin Endometrium Women: A Meta-Analysis

The Effect of Granulocyte Colony Stimulating Factor (G-CSF) on the Outcome of Assisted Reproduction Technology in Thin Endometrium Women: A Meta-Analysis

Efficacy and safety of dexcitabine combined with HAAG regimen in the treatment of recurrent acute myeloid leukemia

Objective: To investigate the efficacy and safety of dexithabine (DAC) combined with HAAG regimen [harringtonine (HHT), cytarabine (Ara-C), aclarubicin (Acla) and recombinant human granulocyte colony stimulating factor (G-CSF)] in the treatment of acute myeloid leukemia (AML). Methods: The clinical data of 89 AML patients in People's Hospital Affiliated to Shandong First Medical University from January 2019 to January 2021 were retrospectively analyzed. The patients were divided into observation group (n=48) and control group (n=41) according to the treatment plan. The observation group included 25 males and 23 females, aged (44.4±9.3) years old, and was treated with DAC combined with HAAG. The control group included 24 males and 17 females, aged (42.2±10.1) years old, and was treated with DAC regimen. After 3 cycles of treatment, the treatment efficacy of the two groups was judged, including complete remission, partial remission and no remission. The level of serum P-glycoprotein (P-gp) in the two groups was detected by direct immunofluorescence-labeled monoclonal antibody flow cytometry. The enzyme-linked immunosorbent assay was used to detect the level of soluble urokinase-type plasminogen activator receptor (suPAR). Meanwhile, the incidence of adverse reactions such as digestive tract reaction, liver and kidney dysfunction, hemorrhage and infection during treatment were recorded. Results: After 3 cycles of treatment, the observation group had complete remission, partial remission and no remission in 10 cases, 21 cases and 17 cases, respectively, and the control group had 3 cases, 11 cases and 27 cases, respectively. The overall efficacy of the observation group was better than that of the control group (Z=-2.919, P=0.004). The levels of serum P-gp and suPAR in the observation group were (5.2±1.8) % and (464.4±103.4) ng/L, respectively, which were significantly lower than those in the control group [(8.8±1.9) % and (660.6±110.4) ng/L, respectively] (both P<0.05). During the treatment, the incidence of digestive tract reaction, liver and kidney dysfunction, hemorrhage and infection in the observation group was 29.2% (14/48), 22.9% (11/48), 16.7% (8/48) and 33.3% (16/48), respectively, while in the control group was 26.8% (11/41), 21.9% (9/41), 14.6% (6/41) and 24.4% (10/41), respectively, with no statistically significant difference (all P>0.05). Conclusions: The overall efficacy of DAC combined with HAAG in the treatment of AML is better than that of DAC alone. Moreover, the incidence of adverse reactions in DAC combined with HAAG is similar to that of DAC alone, with a high safety profile.

Evaluation of Trends in Treatment of Metastatic Hormone Sensitive Prostate Cancer (mHSPC) Across Canada During the COVID-19 Pandemic.

In metastatic hormone sensitive prostate cancer (mHSPC), treatment intensification with either docetaxel or an androgen-receptor-axis targeted therapy (ARAT), added to androgen deprivation therapy (ADT) is the new standard of care. To better understand patterns of treatment intensification in Canada and specifically how it has been influenced by the COVID-19 pandemic, we conducted a national survey of genitourinary medical oncologists from across Canada. Using SurveyMonkey, we conducted an online survey of 119 medical oncologists in Canada from January 15 to January 27, 2021. The survey consisted of 16 questions, including demographics, and asked specifically about their approach to managing mHSPC before and during the pandemic. Overall there were 50/119 (42%) respondents. Most were male (65%), from Ontario (35%), practicing in academic centers (71%), with 45% reporting their practices focused primarily on genitourinary malignancies and one other tumor site. The majority were in practice 1 to 5 years (34%). Overall 65% indicated their practice patterns had changed since the pandemic, with 51% offering more ARATs and less docetaxel chemotherapy. In low volume mHSPC, the use of ARATs increased from 73% to 79%, while the use of docetaxel remained unaltered at 2%. In high volume disease, the use of ARATs increased from 63% to 84%, while the use of docetaxel decreased from 37% to 14%. Use of granulocyte colony stimulating factor (G-CSF) with docetaxel chemotherapy increased by 35%. Post-pandemic, 45% reported they intend to maintain these changes. Only 18% reported they had prostate cancer patients test positive for COVID-19, and all patients recovered. Management of patients with mHSPC in Canada has changed during the pandemic, with increased uptake of ARATs and reduced use of docetaxel, a trend expected to continue beyond the pandemic. How this trend will impact uptake of triplet therapy (ADT+ARAT+Docetaxel), downstream treatment choices and overall outcomes remains to be seen.

Severe congenital neutropenia type 4 with early-onset inflammatory bowel disease attributed to a G6PC3 variant (not previously associated with disease): A case report and a literature review

Severe congenital neutropenia type 4 is an extremely rare autosomal recessive disorder due to biallelic loss-of-function mutations affecting the glucose-6-phosphatase catalytic subunit 3 (G6PC3). It encompasses a complex heterogeneous spectrum of clinical presentations with many extra-hematological complications. In this report, we present a case of a 6-year-old Mediterranean female patient with repeated admissions due to recurrent infections, arthritis and chronic diarrhea. Thorough investigations reveled significant neutropenia, thrombocytosis, hepatosplenomegaly, delayed bone age, and Crohn's disease. Whole exome sequencing showed an extremely rare homozygous frameshift mutation affecting the penultimate exon (c.765_766del/ p.Ala257CysfsTer129); the mutation was not associated with disease previously. The patient's symptoms were controlled using antibiotics, steroids, granulocyte colony stimulating factor and infliximab. Although the latter showed marked control of both the recurrent arthritis and the inflammatory bowel disease symptoms, this was unfortunately short lived and required dose escalation and more frequent infusions.

In vitro study to evaluate the effect of granulocyte colony stimulating factor on colorectal adenocarcinoma and on mesenchymal stem cells trans differentiation into cancer stem cells by cancer cells derived exosomes

BackgroundColorectal cancer (CRC) is a common and lethal malignancies with poor prognosis. CRC cells release extracellular vesicles called exosomes to facilitate tumor progression by passing bioactive molecules such as proteins and nucleic acids between cells of the tumor and their microenvironment. Granulocyte colony stimulating factor (G-CSF) is a hematopoietic growth factor which mainly affects the lineage of neutrophil and exerts direct anti-tumor effects on various tumor types. The purpose of our study is to investigate the effect of G-CSF on CRC cells and to evaluate its capability to attenuate the potentiality of CRC cells derived exosomes to induce bone marrow-derived mesenchymal stem cells (BM-MSCs) malignant transformation into cancer stem cells (CSCs).ResultsThe level of both lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT-1) (p = 0.014) & β-catenin (p = 0.01) was significantly decreased, whereas programmed cell death 4 (PDCD4) (p = 0.018) was increased in CRC exosomes pre-treated with G-CSF compared to untreated CRC exosomes. Additionally, there was a significant decrease in the cell proliferation in CRC cells pre-treated with G-CSF compared to untreated CRC cells (p = 0.008). Flow cytometric analysis of BM-MSCs showed that G-CSF could attenuate their transformation into CSCs.ConclusionG-CSF can be a promising therapeutic agent for CRC treatment.

Identification of cancer chemotherapy regimens and patient cohorts in administrative claims: challenges, opportunities, and a proposed algorithm

BackgroundReal-world evidence is a valuable source of information in healthcare. This study describes the challenges and successes during algorithm development to identify cancer cohorts and multi-agent chemotherapy regimens from claims data to perform a comparative effectiveness analysis of granulocyte colony stimulating factor (G-CSF) use.MethodsUsing the Biologics and Biosimilars Collective Intelligence Consortium’s Distributed Research Network, we iteratively developed and tested a de novo algorithm to accurately identify patients by cancer diagnosis, then extract chemotherapy and G-CSF administrations for a retrospective study of prophylactic G-CSF.ResultsAfter identifying patients with cancer and subsequent chemotherapy exposures, we observed only 12% of patients with cancer received chemotherapy, which is fewer than expected based on prior analyses. Therefore, we reversed the initial inclusion criteria to identify chemotherapy receipt, then prior cancer diagnosis, which increased the number of patients from 2,814 to 3,645, or 68% of patients receiving chemotherapy had diagnoses of interest. Additionally, we excluded patients with cancer diagnoses that differed from those of interest in the 183 days before the index date of G-CSF receipt, including early-stage cancers without G-CSF or chemotherapy exposure. By removing this criterion, we retained 77 patients who were previously excluded. Finally, we incorporated a 5-day window to identify all chemotherapy drugs administered (excluding oral prednisone and methotrexate, as these medications may be used for other non-malignant conditions) as patients may fill oral prescriptions days to weeks prior to infusion. This increased the number of patients with chemotherapy exposures of interest to 6,010. The final cohort of included patients, based on G-CSF exposure, increased from 420 from the initial algorithm to 886 using the final algorithm.ConclusionsMedications used for multiple indications, sensitivity and specificity of administrative codes, and relative timing of medication exposure must all be evaluated to identify patient cohorts receiving chemotherapy from claims data.

Neonatal cytokines associated with infant overweight and obesity at 1 year of age

ObjectiveThe incidence of childhood overweight and obesity has been increasing in recent years. Immune dysregulation has been demonstrated as a condition related to childhood obesity. Whether the neonatal immune status is related to infant overweight and obesity at 1 year of age is unclear. MethodsTo explore the relationship between neonatal cytokines and infant overweight and obesity, we conducted a prospective study in Suzhou Municipal Hospital Affiliated to Nanjing Medical University from 2015 to 2016. 514 neonates were recruited and their dried blood spots were collected after birth. Infants were grouped into normal size groups and overweight and obesity groups based on BMI at 1 year of age. 27 neonatal cytokines levels were compared between the two groups. Results370 infants were included in final analysis. Granulocyte colony stimulating factor (GCSF), interleukin-17A (IL17A) and platelet derived growth factor-BB (PDGF-BB) levels were independently associated with childhood overweight and obesity (OR =1.27, 95%CI 1.03, 1.57; OR =1.29, 95%CI: 1.06, 1.60; OR =0.69, 95%CI: 0.49, 0.96). Additionally, neonatal GCSF and IL17A levels were positively associated with increased BMI (β = 0.11, 95%CI: 0.02, 0.19; β = 0.07, 95%CI 0.01, 013) and BMI z-scores (β = 0.10, 95%CI: 0.02, 0.18; β = 0.06, 95%CI 0.01, 0.13). Neonatal PDGF-BB levels were negatively associated with BMI (β = −0.12, 95%CI: −0.23, −0.01) and BMI z-scores (β = −0.12, 95%CI: −0.23, −0.01). The inverse probability weighting (IPW) was performed to account for potential selection bias of this study, and the results were consistent with the above mentioned findings. ConclusionsNeonatal GCSF, IL17A and PDGF-BB levels were correlated with infant overweight and obesity at 1 year of age, suggesting that early life immune status play a significant role of late obesity.

Efficacy and safety of lenalidomide in HIV-associated cryptococcal meningitis patients with persistent intracranial inflammation: an open-label, single-arm, prospective interventional study

BackgroundPatients with human immunodeficiency virus-associated cryptococcal meningitis (HIV-CM) have persistent intracranial inflammation despite negative cerebrospinal fluid (CSF) fungal cultures after optimal treatment for CM, which could be devastating for the central nervous system. However, a definitive treatment strategy for persistent intracranial inflammation despite optimal antifungal therapies is undefined.MethodsWe identified 14 HIV-CM patients with persistent intracranial inflammation and conducted a 24-week, prospective, interventional study. All participants received lenalidomide (25 mg, p.o.) on days 1 to 21 of a 28-day cycle. Follow-up lasted for 24 weeks with visits at baseline and weeks 4, 8, 12, and 24. The primary endpoint was the change in clinical manifestations, routine CSF parameters, and MRI findings after lenalidomide treatment. An exploratory analysis was made on changes in cytokine levels in CSF. Safety and efficacy analyses were undertaken in patients who received at least one dose of lenalidomide.ResultsOf 14 participants, 11 patients completed the 24 weeks of follow-up. Rapid clinical remission following lenalidomide therapy was observed. Clinical manifestations (fever, headache, altered mentation) were reversed fully by week-4 and remained stable during follow-up. A significant reduction in white blood cell (WBC) count in CSF was noted occurred at week-4 (P = 0.009). The median protein concentration in CSF decreased from 1.4 (0.7–3.2) g/L at baseline to 0.9 (0.6–1.4) at week-4 (P = 0.004). The median albumin concentration in CSF decreased from 79.2 (48.4–149.8) mg/L at baseline to 55.3 (38.3–89.0) mg/L at week-4 (P = 0.011). The WBC count, protein level, and albumin level in CSF remained stable and approached a normal range through week-24. There was no significant change in immunoglobulin-G, intracranial pressure (ICP), or chloride-ion concentration at each visit. Brain MRI demonstrated multiple lesions to be absorbed post-therapy. Levels of tumor necrosis factor-α granulocyte colony stimulating factor, interleukin (IL)-6, and IL-17A decreased significantly during 24-week follow-up. Two (14.3%) patients had mild skin rash, which resolved spontaneously. Lenalidomide-related serious adverse events were not observed.ConclusionLenalidomide could improve persistent intracranial inflammation in HIV-CM patients significantly and was well tolerated without serious adverse events observed. And the additional randomized controlled study is required to further validate the finding.

Pegbovigrastim use in periparturient embryo-recipient cows: Effects on health and reproduction

The objective of this randomized clinical study was to evaluate the effects of periparturient administration of pegbovigrastim (recombinant bovine granulocyte colony stimulating factor; PEG) on postpartum health and reproductive outcomes in dairy cows carrying transferred embryos. A total of 60 multiparous Jersey cows (second parity n = 21, >second parity n = 39) that were in vitro-fertilized embryo recipients were enrolled. Animals were selected from a commercial herd and assigned to 1 of 2 treatments: (1) PEG (n = 31), which received a subcutaneous injection of 15 mg of PEG 7 d before expected calving and a second dose within 1 h of parturition; or (2) CON, untreated control (n = 29). Parturition was induced pharmacologically in all cows at 280 d of pregnancy with 500 μg of cloprostenol and 25 mg of dexamethasone intramuscularly. Cow health was monitored daily during the periparturient period and included assessment for retained fetal membranes within 24 h after calving and metritis until 20 d in milk. Descriptive statistics were calculated, to determine the incidence of postpartum diseases, causes of culling, and early-lactation reproductive outcomes, including number of inseminations, days to first heat, days to first service, and interval from calving to conception. The Wilcoxon rank sum test was used to assess treatment effects on early-lactation reproductive performance outcomes. The overall incidence of metritis in this cohort of cows was 17.14%. Animals treated with PEG tended to have more cases of metritis (25%) compared with CON (8.8%). Mastitis incidence in PEG was 19.35% compared with CON at 27.59%. These data suggest that in this dairy, with embryo-recipient cows induced to calve at 280 d of pregnancy, the administration of 2 doses of PEG tended to increase postpartum metritis but had no effect on mastitis incidence, culling rate, or early-lactation reproductive outcomes.

Xuanhusuo powder has an anti-breast cancer effect by inhibiting myeloid-derived suppressor cell differentiation in the spleen of mice through down-regulating granulocyte colony stimulating factor.

To investigate the mechanism of Xuanhusuo powder (XHSP) inhibiting the differentiation of spleen myeloid-derived suppressor cells (MDSCs) in breast cancer mice. Forty-eight BALB/c female mice aged 4-5 weeks were selected, 6 of them were in normal control group, while others were in tumor-bearing models established by orthotopic injection of 4T1 cells into the subcutaneous fat pad of the second pair of left mammary glands. The tumor-bearing mice were divided into granulocyte colony stimulating factor (G-CSF) control group, G-CSF knock-down group, model control group, XHSP small dose group, XHSP medium dose group, XHSP high dose group, and cyclophosphamide (CTX) group, with 6 mice in each group. G-CSF control group and G-CSF knock-down group were constructed by stably transfecting 4T1 cells established by shRNA lentivirus combined with puromycin selection. 48 h after the model was established, XHSP small, medium, high dose group were given 2, 4, 8 g·kg－1·d－1 intragastric administration once a day, respectively. CTX was given 30 mg/kg by intraperitoneal injection, once every other day. The other groups were given an equal volume of 0.5% hydroxymethylcellulose sodium. The drugs in each group were continuously administered for 25 d. Histological changes in spleen were observed by HE staining, the proportion of MDSCs subsets in the spleen were detected by flow cytometry, the co-expression of CD11b and Ly6G in the spleen was detected by immunofluorescence, and the concentration of G-CSF in peripheral blood was detected by ELISA. The spleen of tumor-bearing mice was co-cultured with 4T1 stably transfected cell lines in vitro, treated with XHSP (30 μg/mL) for 24 h, and the co-expression of CD11b and Ly6G in the spleen was detected by immunofluorescence. 4T1 cells were treated by XHSP (10, 30, 100 μg/mL) for 12 h. The mRNA level of G-CSF was detected by realtime RT-PCR. Compared with normal mice, the red pulp of the spleen in tumor-bearing mice was widened with megakaryocyte infiltration. The proportion of spleen polymorphonucleocyte-like MDSCs (PMN-MDSCs) was significantly increased (P<0.01) and the co-expression of CD11b and Ly6G was increased, and the concentration of G-CSF in peripheral blood was significantly increased (P<0.01). However, XHSP could significantly reduce the proportion of PMN-MDSCs (P<0.05) and the co-expression of CD11b and Ly6G in the spleen, down-regulate the mRNA level of G-CSF in 4T1 cells (P<0.01). The concentration of G-CSF in peripheral blood of tumor-bearing mice also decreased (P<0.05) and tumor volume was reduced and splenomegaly was improved (all P<0.05). XHSP may play an anti-breast cancer role by down-regulating G-CSF, negatively regulating the differentiation of MDSCs, and reconstruct the spleen myeloid microenvironment.

The therapeutic effects and optimal timing of granulocyte colony stimulating factor intrauterine administration during IVF-ET

Most of embryos fail to produce live offspring during In Vitro Fertilization-Embryo Transfer (IVF-ET) procedure. There is a dearth of research activity addressing this problem despite the significant population of women suffering from repeated implantation failure after transfer of high-quality of embryos. As a clinically accessible option, granulocyte colony stimulating factor (G-CSF) is often used for the treatment to improve the rates of embryo implantation. However, there are currently no evidence-based standardized protocol for the clinical use of G-CSF. G-CSF was administered into one side of mouse uterine horns and saline was infused into the other side of horns as a control. Intrauterine G-CSF administration showed maximal effects 24 h after administration in enhancing endometrial receptivity and subsequent increase of angiogenesis by demonstrating elevated integrin β3 and OPN and reduced cytotoxicity of NK cells. Furthermore, G-CSF administration 24 h prior to embryo transfer promoted the stability of attached embryos at the early stage of implantation in vitro. Our findings suggest as new consensus criteria providing a potential therapeutic strategy of the clinical use of G-CSF to achieve maximal effects of IVF-ET for patients who are suffering from repeated implantation failure with the problems with endometrial receptivity.