Uterine infusion strategies for infertile patients with recurrent implantation failure: a systematic review and network meta-analysis.

BACKGROUND: Intra-uterine infusion treatments were reported to be beneficial to embryo implantation and pregnancy outcomes, and considered as potential therapies for infertile patients with recurrent implantation failure (RIF). Nevertheless, their efficiencies were controversial and there lack of consensus on which intrauterine treatment is the most effective. METHODS: All prospective trials (in Chinese or English) were searched in Databases PubMed, Cochrane, Web of Science, and CNKI from July 2013 to July 2023. We included studies that investigated various uterine infusions, including chorionic gonadotropin, granulocyte colony-stimulating factor, monocytes, platelet-rich plasma, etc. during IVF treatment and reported subsequent pregnancy outcomes. RESULTS: We finally included 56 researches, including 40 randomized controlled trials, 14 non-randomized controlled trials, and 3 prospective cohort studies. This study included a total of 11 uterine perfusion methods: Placebo, Human Chorionic Gonadotropin (HCG), Granulocyte Colony-Stimulating Factor (G-CSF), platelet-rich plasma (PRP), Peripheral Blood Mononuclear Cell (PBMC), Growth hormone (GH), dexamethasone (DEX), Embryo culture supernatant (ESC), PRP combined with G-CSF (PRP + G-CSF), RPR combined with subcutaneous injection of G-CSF (RPR + G-CSFsc), G-CSF combined with subcutaneous injection of AXaIU (G-CSF + AXaIUsc). Intrauterine infusion of HCG, PBMC, G-CSF, and PRP significantly improves pregnancy outcomes in patients with repeated implantation failure compared with blank controls or placebo, and PRP improved the clinical pregnancy and live birth most. GH and ESC infusion might improve the pregnancy outcomes, but uterine infusion of DEX was shown with high miscarriage. The combination therapy did not show a significant advantage over the mono-therapy. CONCLUSIONS: Intrauterine infusion of HCG, PBMC, G-CSF, and PRP are promising strategies for improving pregnancy outcomes for infertile patients with recurrent implantation failure. Among these treatments, PRP may be the best. More researches are required to explore the effect of drug combinations and less commonly used drugs as well. TRIAL REGISTRATION: Our study was registered in PROSPERO and the ID was CRD42023467188.

Shorter donor leukocyte telomere length is associated with poor peripheral blood stem cell mobilization induced by granulocyte colony-stimulating factor.

BACKGROUND/PURPOSE: Insufficient numbers of peripheral blood stem cells (PBSC) after granulocyte colony-stimulating factor (G-CSF) mobilization occurs in a significant proportion of PBSC collections, often from older age donors. Telomere length (TL) is often used as an indicator of an individual's biological age. This study aimed to investigate the relationship between donors' leukocyte TL and the outcome of G-CSF-induced PBSC mobilization in healthy unrelated donors. METHODS: Donors' leukocyte TLs and the outcome of G-CSF-induced PBSC mobilization, as assessed by pre-harvest CD34+ cell counts, were analyzed in 39 healthy PBSC donors. TL in a non-mobilized general population (n = 90) was included as a control group. G-CSF mobilization effect was categorized into three groups according to pre-harvest CD34+ cell count: poor (≤25/µL, PMD), intermediate (between 25 and 180/µL), and good (≥180/µl, GMD). RESULTS: Leukocyte TL of PBSC donors correlated well with pre-harvest CD34+ cell counts (r = 0.645, p < 0.001). Leukocyte TLs of PMDs (n = 8) were significantly shorter than those of GMDs (n = 9) and non-mobilization controls (p < 0.05). Moreover, all PMD TLs were below the 50th percentile, and 62.5% of PMDs had TLs below the 10th percentile of age-matched control participants. In contrast, no GMD TLs were below the 10th percentile; in fact, 33.3% (3/9) of them were above the 90th percentile. CONCLUSION: Our results indicate that shorter donor leukocyte TL is associated with poor G-CSF-induced PBSC mobilization. TL, which represents a donor's biological age, could be a potential predictor for mobilization outcome.

Granulocyte colony-stimulating factor priming improves embryos and pregnancy rate in patients with poor ovarian reserve: a randomized controlled trial.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) administration increased ovarian preantral follicles and anti-Müllerian hormone (AMH) in animal models with diminished ovarian reserve. We investigated whether G-CSF priming before treatment with assisted reproductive technology (ART) improved embryo development and pregnancy rate while increasing serum AMH in patients with poor ovarian reserve. METHODS: In this prospective randomized open-label controlled trial, 100 patients 20 to 42 years old with AMH below 2 ng/mL were randomized to priming or control groups (50 patients each). None had over 1 ART failure, day-3 follicle-stimulating hormone (FSH) above 30 IU/L, uterine anomalies, or a partner with azoospermia. All patients initially underwent conventional infertility treatment for 2 consecutive cycles in which the priming group but not controls received a subcutaneous G-CSF priming injection during the early luteal phase. Each group then underwent 1 cycle of in vitro fertilization/intracytoplasmic sperm injection and fresh embryo transfer (IVF/ICSI-fresh ET), followed by cryopreserved ET if needed until live birth or embryo depletion. AMH was measured before and after priming. RESULTS: Fertilization rate, embryonic development, and implantation rate by fresh ET were significantly improved by priming. Clinical and ongoing pregnancy rates by IVF/ICSI-fresh ET were significantly higher with priming (30% and 26% in 47 ART patients; 3 delivered with conventional treatment) than in controls (12% and 10% in 49 ART patients; 1 dropped out). With priming, significantly more patients achieved cryopreservation of redundant blastocysts. The cumulative live birth rate was 32% in 50 patients with priming, significantly higher than 14% in 49 controls (relative risk, 2.8; 95% confidence interval, 1.04-7.7). Infants derived from priming had no congenital anomalies, while infant weights, birth weeks, and Apgar scores were similar between groups. Among 4 variables (age, day-3 FSH, AMH, and priming), logistic regression significantly associated age and priming with cumulative live birth. Priming significantly increased serum AMH. No adverse effects of priming were observed. CONCLUSION: G-CSF priming improved embryonic development and pregnancy rate during ART treatment and increased AMH in patients with poor ovarian reserve. Enhanced preantral follicle growth likely was responsible. TRIAL REGISTRATION: UMIN registration in Japan (UMIN000013956) on May 14, 2014.  https://www.umin.ac.jp/ctr/index.htm .

Recurrent distal cholangiocarcinoma and humoral hypercalcemia of malignancy: report of a rare case and literature review.

A 61-year-old Japanese woman presented with epigastric pain and jaundice. Imaging showed the presence of primary distal cholangiocarcinoma (DCC). A subtotal stomach-preserving pancreaticoduodenectomy was performed, followed by chemotherapy using S-1. However, second-line chemotherapy with gemcitabine and cis-diamminedichloroplatinum was required for the treatment of hepatic metastasis of the DCC 3 months following the surgery. Nine months after the surgery, the serum calcium and parathyroid hormone-related peptide concentrations were high, at 16.5 mg/dL and 28.7 pmol/L, respectively, which suggested the presence of humoral hypercalcemia of malignancy (HHM) secondary to the DCC. Moreover, marked leukocytosis, with a white blood cell count of 40,400/µL, was also present. The patient died 11 months after the diagnosis of DCC. Because hypercalcemia of malignancy is associated with a poor prognosis, and HHM and leukocytosis caused by DCC are very rare, we have presented the present case in detail and provide a review of the existing literature.

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

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

A Spotlight on Drug-Induced Vasculitis.

PURPOSE OF REVIEW: Drug-induced vasculitis (DIV) is a rare form of vasculitis related to the use of various drugs. DIV primarily affects small to medium size vessels, but it can potentially involve vessels of any size. Differentiating between primary systemic vasculitis and DIV can be challenging; however, it is crucial, so that the offending agent can be discontinued promptly. RECENT FINDINGS: The clinical phenotype of DIV is protean and depends on the size of the affected vessels. It ranges from arthralgias, to an isolated cutaneous rash, to severe single or multi-organ involvement. While withdrawal of the offending drug is the most important step in management, a significant number of patients require immunosuppressive therapy for varying periods of time. DIV can affect any vascular bed size, leading to protean vasculitic syndromes. Increased awareness among general practitioners, specialty, and subspecialty physicians is crucial for early recognition, and withdrawal of drug for better outcomes.

The therapeutic effect of granulocyte colony stimulating factor (G-CSF) on potential biochemical pregnancy in patients with unexplained repeated transplantation failure (RIF): a case series and literature review.

BACKGROUND: Biochemical pregnancy is a type of embryo transfer failure, patients with unexplained repeated implantation failure (RIF) also have higher biochemical pregnancy rate. Our study intends to evaluate the effect of granulocyte colony-stimulating factor (G-CSF) in patients with unexplained RIF with low hCG levels in early pregnancy. METHODS: Unexplained RIF patients with low hCG levels after embryo transfer were allocated. G-CSF were administrated from the ninth days after embryo transfer. Clinical pregnancy, miscarriage and live birth rates were evaluated. RESULTS: The clinical pregnancy and live birth rates were 52.5% and 30%. CONCLUSION: G-CSF is an effective treatment for potential biochemical pregnancy in unexplained RIF patients.

Mesenchymal stem cells microvesicles versus granulocytes colony stimulating factor efficacy in ameliorating septic induced acute renal cortical injury in adult male albino rats (Histological and Immunohistochemical Study).

Sepsis is the most common cause of acute kidney injury in ICU patients, with increasing mortalities. Treatment septic AKI is unsatisfactory; therefore, more effective therapies must be investigated. MSCs-MVs have the same effectiveness in tissue repair as their original cells. Granulocyte colony-stimulating factor (G-CSF) is considered a simple and convenient tool in regenerative medicine. This study aimed to compare the probable therapeutic effect of MSCs-MVs versus G-CSF on septic AKI in rats. Forty-eight adult male rats were divided into four groups; I control group (IA-ID), II induced-sepsis group, III G-CSF, and IV MSC-MVs groups. Sepsis was induced in groups II, III, IV through a single IV injection of 10 mg/ kg of E.Coli-LPS dissolved in 1 ml saline. Four hours later, group IV received a single IV injection of MSCs-MVs, while group III received a SC injection of Neupogen for 5 days. All animals were sacrificed 7 days from the start. Serum and tissue samples of each group were used for biochemical study. Sections from all groups were subjected to light and electron microscopic examination. A fluorescent microscope examination for subgroup ID and group IV was done. Morphometric and statistical analyses were performed. Group II showed features of acute tubular injury. Group III showed some improvement (biochemically, LM & EM level) however, group IV showed more improvement. MVs injection caused a marked improvement in septic AKI; G-CSF can also meliorate the degenerative effect of sepsis on renal cortex, but to a lesser extent than MSCs-MVs.

Emerging challenges in the evaluation of fever in cancer patients at risk of febrile neutropenia in the era of COVID-19: a MASCC position paper.

Patients with cancer are at higher risk of more severe COVID-19 infection and have more associated complications. The position paper describes the management of cancer patients, especially those receiving anticancer treatment, during the COVID-19 pandemic. Dyspnea is a common emergency presentation in patients with cancer with a wide range of differential diagnoses, including pulmonary embolism, pleural disease, lymphangitis, and infection, of which SARS-CoV-2 is now a pathogen to be considered. Screening interviews to determine whether patients may be infected with COVID-19 are imperative to prevent the spread of infection, especially within healthcare facilities. Cancer patients testing positive with no or minimal symptoms may be monitored from home. Telemedicine is an option to aid in following patients without potential exposure. Management of complications of systemic anticancer treatment, such as febrile neutropenia (FN), is of particular importance during the COVID-19 pandemic where clinicians aim to minimize patients' risk of infection and need for hospital visits. Outpatient management of patients with low-risk FN is a safe and effective strategy. Although the MASCC score has not been validated in patients with suspected or confirmed SARS-CoV-2, it has nevertheless performed well in patients with a range of infective illnesses and, accordingly, it is reasonable to expect efficacy in the clinical setting of COVID-19. Risk stratification of patients presenting with FN is a vital tenet of the evolving sepsis and pandemic strategy, necessitating access to locally formulated services based on MASCC and other national and international guidelines. Innovative oncology services will need to utilize telemedicine, hospital at home, and ambulatory care services approaches not only to limit the number of hospital visits but also to anticipate the complications of the anticancer treatments.

Commentary - A comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars and Intended Copy Biologics in treating chemotherapy associated febrile neutropenia.

Filgrastim, human white cell growth factor, Granulocyte colony-stimulating factor (G-CSF), is a core medicine in the WHO list of Essential Medicines. For this reason, recent reporting of statistically significant safety and efficacy differences between reference and Biosimilar brands of filgrastim by Rastogi and the Indian Pharmacopoeia Commission in Toxicology and Applied Pharmacology in 2020 is of great concern [Shruti Rastogi et al. Towards a comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars in treating chemotherapy associated febrile neutropenia: Trends from decades of data. Toxicology and Applied Pharmacology Volume 395, 15 May 2020, 114,976. https://doi.org/10.1016/j.taap.2020.114976]. This commentary shows that the alarming report is a result of incorrect statistical tests misapplied to inappropriate data sets compounded by a further problem relating to the strict regulatory definition of a Biosimilar Medicine as opposed that of an Intended Copy Biologic. In contrast, the body of evidence from more than seven and a half thousand participants in Confirmatory Clinical Studies and Post Approval Clinical Studies as well as the Periodic Safety Update Reports confirms that European approved filgrastim Biosimilars show no meaningful difference in quality, safety or efficacy compared to the reference brand.

Towards a comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars in treating chemotherapy associated febrile neutropenia: Trends from decades of data.

Filgrastim, a biopharmaceutical listed on WHO model list of essential medicines, was approved in USA in 1991 for patients with non-myeloid malignancies associated with severe neutropenia and fever. Several filgrastim biosimilars have now been approved in USA, Europe and elsewhere since 2008, based on the reference product which has lost patent exclusivity; however their immunogenicity and safety is controversial. We conducted a retrospective, post market study between 1991 and May 2018 using VigiBase®. The study included all adverse events with case reports ≥150. Overall, 11,183 adverse drugs reaction reports were identified during observation period; of which 5764; 51.5% reports concerned to Neupogen®, the originator, and rest consists of Leucostim® (N = 680), Zarzio® (N = 622), Grasin® (N = 545), Nivestim® (N = 359) and Tevagrastim® (N = 152) biosimilars. When compared with the originator, Grasin® was associated with higher reporting of pyrexia (11.5% vs 7.9%, ROR 1.52, IC025 1.12), myalgia (37% vs 2.2%, ROR 25.94, IC025 2.11) and back pain (11.3% vs 4%, ROR 3.09, IC025 2.32). Zarzio® was associated with increased reporting of arthralgia (4.5% vs 2.9%, ROR 1.59, IC025 1.25) and neutropenia (11.4% vs 4%, ROR 2.59, IC025 3.07). Bone pain was reported more often with Nivestim® (14.4% vs 8.3%, ROR 1.87, IC025 5.30). Drug ineffectiveness was reported in cases with Zarzio® (35.9%), Nivestim® (19.4%) and Tevagrastim® (42.2%). Authors observed significant differences among originator and biosimilars in particular to efficacy, adverse events reported and time to onset of occurrences. Large epidemiologic studies are needed to further confirm these finding and provide additional insights.

Granulocyte-colony stimulating factor gene therapy as a novel therapeutics for stroke in a mouse model.

BACKGROUND: Global ischemia is the resulting effect of a cardiopulmonary arrest (CPA). Presently there is no effective treatment to address neurological deficits in patients who survived a CPA. Granulocyte-colony stimulating factor is a growth factor (G-CSF) with a plethora of beneficial effects, including neuroprotection. Clinical application of human G-CSF (hG-CSF) is limited due to its plasma half-life of 4 h. Therefore, novel approaches need to be investigated that would (1) enable prolonged manifestation of hG-CSF and (2) demonstrate G-CSF efficacy from studying the underlying protective mechanisms of hG-CSF. In our previous work, we used the self-complementary adeno-associated virus (stereotype2: scAAV2) as a vector to transfect the hG-CSF gene into the global ischemic brain of a mouse. As an extension of that work, we now seek to elucidate the protective mechanisms of hG-CSF gene therapy against endoplasmic reticulum induced stress, mitochondrial dynamics and autophagy in global ischemia. METHOD: A single drop of either AAV-CMV-hG-CSF or AAV-CMV-GFP was dropped into the conjunctival sac of the Swiss Webster mouse's left eye, 30-60 min after bilateral common artery occlusion (BCAO). The efficacy of the expressed hG-CSF gene product was analyzed by monitoring the expression levels of endoplasmic reticulum stress (ER), mitochondrial dynamics and autophagic proteins over 4- and 7-days post-BCAO in vulnerable brain regions including the striatum, overlying cortex (frontal brain regions) and the hippocampus (middle brain regions). Statistical analysis was performed using mostly One-Way Analysis of variance (ANOVA), except for behavioral analysis, which used Repeated Measures Two-Way ANOVA, post hoc analysis was performed using the Tukey test. RESULTS: Several biomarkers that facilitated cellular death, including CHOP and GRP78 (ER stress) DRP1 (mitochondrial dynamics) and Beclin 1, p62 and LC3-ll (autophagy) were significantly downregulated by hG-CSF gene transfer. hG-CSF gene therapy also significantly upregulated antiapoptotic Bcl2 while downregulating pro-apoptotic Bax. The beneficial effects of hG-CSF gene therapy resulted in an overall improvement in functional behavior. CONCLUSION: Taken together, this study has substantiated the approach of sustaining the protein expression of hG-CSF by eye drop administration of the hG-CSF gene. In addition, the study has validated the efficacy of using hG-CSF gene therapy against endoplasmic reticulum induced stress, mitochondrial dynamics and autophagy in global ischemia.

Mode of action of granulocyte-colony stimulating factor (G-CSF) as a novel therapy for stroke in a mouse model.

BACKGROUND: The FDA approved drug granulocyte-colony stimulating factor (G-CSF) displays anti-apoptotic and immunomodulatory properties with neurogenesis and angiogenic functions. It is known to demonstrate neuroprotective mechanisms against ischemic global stroke. Autophagy is a method for the degradation of intracellular components and in particular, unrestrained autophagy may lead to uncontrolled digestion of affected neurons as well as neuronal death in cerebral ischemia. Mitochondrial dynamics is vital for the regulation of cell survival and death after cerebral ischemia and an early upstream event in neuronal death is mitochondrial fission. We examined the pro-survival mechanisms of G-CSF against apoptosis resulting from autophagy, mitochondrial stress and endoplasmic reticulum (ER) stress. METHODS: Male Swiss Webster mice (20 weeks of age) were subjected to bilateral common carotid artery occlusion (BCAO) for 30 min. After occlusion, mice were injected with G-CSF (50 µg/kg) subcutaneously for 4 days. Behavioral analysis was carried out using the corner test and locomotor activity test before animals were sacrificed on day 4 or day 7. Key proteins in ER stress, autophagy and mitochondrial stress induced apoptosis were analyzed by immunoblotting. RESULTS: G-CSF improved neurological deficits and improved behavioral performance on corner and locomotor test. G-CSF binds to G-CSF receptors and its activation leads to upregulation of Akt phosphorylation (P-Akt) which in turn decreases levels of the ER stress sensor, GRP 78 and expression of proteins involved in ER stress apoptosis pathway; ATF6, ATF4, eIF2α, XBP1, Caspase 12 and CHOP. G-CSF treatment significantly decreased Beclin-1, an autophagy marker, and decreased mitochondrial stress biomarkers DRP1 and P53. G-CSF also up-regulated the mitochondrial fusion protein, OPA1 and anti-apoptotic protein Bcl-2 while down-regulating the pro-apoptotic proteins Bax, Bak and PUMA. CONCLUSIONS: G-CSF is an endogenous ligand in the CNS that has a dual activity that is beneficial both in reducing acute neuronal degeneration and adding to long-term plasticity after cerebral ischemia. G-CSF treatment exerts neuroprotective effects on damaged neurons through the suppression of the ER stress and mitochondrial stress and maintains cellular homeostasis by decreasing pro-apoptotic proteins and increasing of anti-apoptotic proteins.

Large vessel vasculitis secondary to granulocyte-colony stimulating factor.

Aortitis is a rare entity that may cause fever of unknown origin. This entity has a wide various etiologies, which main cause is rheumatologic, but not only. Iatrogenia has also been described, including chemotherapy and supporting treatment (like granulocyte-colony stimulating factor in oncological patients. The evidence in favour of this pharmacological link is growing. The differential diagnosis of fever, in febrile neutropenia setting, can be difficult to itemize.

Two-Faced Roles of Tumor-Associated Neutrophils in Cancer Development and Progression.

Neutrophils are the most abundant circulating leukocytes in humans. Neutrophil infiltration into tumor tissues has long been observed but its roles have been ignored due to the presumed short life cycle and metabolic incompetence of neutrophils. Recent advances in neutrophil biology research have revealed that neutrophils have a longer life cycle with a potential to express various bioactive molecules. Clinical studies have simultaneously unraveled an increase in the neutrophil-lymphocyte ratio (NLR), a ratio of absolute neutrophil to absolute lymphocyte numbers in cancer patient peripheral blood and an association of higher NLR with more advanced or aggressive disease. As a consequence, tumor-associated neutrophils (TANs) have emerged as important players in tumor microenvironment. The elucidation of the roles of TANs, however, has been hampered by their multitude of plasticity in terms of phenotypes and functionality. Difficulties are further enhanced by the presence of a related cell population-polymorphonuclear leukocyte (PMN)-myeloid-derived suppressor cells (MDSCs)-and various dissimilar aspects of neutrophil biology between humans and mice. Here, we discuss TAN biology in various tumorigenesis processes, and particularly focus on the context-dependent functional heterogeneity of TANs.

Neurological manifestations of COVID-19 and other coronaviruses: A systematic review.

OBJECTIVE: To describe the main neurological manifestations related to coronavirus infection in humans. METHODOLOGY: A systematic review was conducted regarding clinical studies on cases that had neurological manifestations associated with COVID-19 and other coronaviruses. The search was carried out in the electronic databases PubMed, Scopus, Embase, and LILACS with the following keywords: "coronavirus" or "Sars-CoV-2" or "COVID-19" and "neurologic manifestations" or "neurological symptoms" or "meningitis" or "encephalitis" or "encephalopathy," following the Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Seven studies were included. Neurological alterations after CoV infection may vary from 17.3% to 36.4% and, in the pediatric age range, encephalitis may be as frequent as respiratory disorders, affecting 11 % and 12 % of patients, respectively. The Investigation included 409 patients diagnosed with CoV infection who presented neurological symptoms, with median age range varying from 3 to 62 years. The main neurological alterations were headache (69; 16.8 %), dizziness (57, 13.9 %), altered consciousness (46; 11.2 %), vomiting (26; 6.3 %), epileptic crises (7; 1.7 %), neuralgia (5; 1.2 %), and ataxia (3; 0.7 %). The main presumed diagnoses were acute viral meningitis/encephalitis in 25 (6.1 %) patients, hypoxic encephalopathy in 23 (5.6 %) patients, acute cerebrovascular disease in 6 (1.4 %) patients, 1 (0.2 %) patient with possible acute disseminated encephalomyelitis, 1 (0.2 %) patient with acute necrotizing hemorrhagic encephalopathy, and 2 (1.4 %) patients with CoV related to Guillain-Barré syndrome. CONCLUSION: Coronaviruses have important neurotropic potential and they cause neurological alterations that range from mild to severe. The main neurological manifestations found were headache, dizziness and altered consciousness.

Granulocyte colony-stimulating factor-associated aortitis in the Japanese Adverse Drug Event Report database.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) is the standard-of-care therapy for chemotherapy-associated neutropenia in patients with malignancies. Recent case reports have implied that G-CSF treatment may be associated with the development of aortitis, but the precise nature of the relationship is unclear. We investigated the association between G-CSF and risk for aortitis in patients with various malignancies. METHODS: We performed an observational study of 102,014 subjects with malignant neoplasms documented in the Japanese Adverse Drug Event Report (JADER) database between April 2004 and February 2018. The adjusted odds ratio (OR) and 95% confidence interval (CI) for aortitis in patients treated and not treated with G-CSF were estimated using multivariate logistic regression with R software. RESULTS: Among the 102,014 subjects, 25 developed aortitis. Of the 3409 and 98,630 subjects treated and not treated with G-CSF, 16 (0.47% [95% CI; 0.27, 0.76]) and 9 (0.01% [0.00, 0.02]) developed aortitis, respectively. Multivariate logistic regression indicated an association between G-CSF and aortitis (adjusted OR 45.87 [19.16, 109.8], p < 0.001). The values for filgrastim, pegfilgrastim, and lenograstim were 0.25% (0.07, 0.63), 1.58% (0.79, 2.81), and 0.24% (0.05, 0.69), respectively. CONCLUSION: G-CSF treatment was associated with a signal of increased risk for aortitis among patients with malignant neoplasms. Three different G-CSF agents were associated with such risk, implying that it is a class effect. However, we do not recommend changing G-CSF prescriptions, because our results may have been influenced by the limitations of the JADER database and because the benefit of G-CSF treatment outweighs the potential risk.

Effects of continuous high-dose G-CSF administration on hematopoietic stem cell mobilization and telomere length in patients with amyotrophic lateral sclerosis - a pilot study.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of complex and still poorly understood etiology. Loss of upper and lower motoneurons results in death within few years after diagnosis. Recent studies have proposed neuroprotective and disease-slowing effects of granulocyte-colony stimulating factor (G-CSF) treatment in ALS mouse models as well as humans. In this study, six ALS patients were monitored up to 3.5 years during continuous high-dose G-CSF administration. Repetitive analyses were performed including blood count parameters, CD34+ hematopoietic stem and progenitor cell (HSPC) and colony forming cell (CFC) counts, serum cytokine levels and leukocyte telomere length. We demonstrate that continuous G-CSF therapy was well tolerated and safe resulting in only mild adverse events during the observation period. However, no mobilization of CD34+ HSPC was detected as compared to baseline values. CFC mobilization was equally low and even a decrease of myeloid precursors was observed in some patients. Assessment of telomere length within ALS patients' leukocytes revealed that G-CSF did not significantly shorten telomeres, while those of ALS patients were shorter compared to age-matched healthy controls, irrespective of G-CSF treatment. During G-CSF stimulation, TNF-alpha, CRP, IL-16, sVCAM-1, sICAM-1, Tie-2 and VEGF were significantly increased in serum whereas MCP-1 levels decreased. In conclusion, our data show that continuous G-CSF treatment fails to increase circulating CD34+ HSPC in ALS patients. Cytokine profiles revealed G-CSF-mediated immunomodulatory and proteolytic effects. Interestingly, despite intense G-CSF stimulation, telomere length was not significantly shortened.

Granulocyte-colony stimulating factor-associated aortitis in a woman with advanced breast cancer: a case report and review of the literature.

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) is increasingly been used to prevent febrile neutropenia (FN) associated with the administration of chemotherapy for various cancers. The most common adverse effects of G-CSF are bone pain and injection-site reactions and aortitis has rarely been reported. We report herein a rare case of G-CSF associated with aortitis in a woman with advanced breast cancer. CASE PRESENTATION: A 72-year-old woman with estrogen receptor-negative human epidermal growth factor 2-positive breast cancer with distant metastases in the lung was admitted. Her treatment was initiated with docetaxel in combination with trastuzumab and pertuzumab followed by the supportive use of a long-acting G-CSF, pegfilgrastim. After administration of pegfilgrastim on day 5, the patient had an intermittent fever (body temperature up to 39.6 °C) on day 9 which continued irrespective of taking levofloxacin. She visited our outpatient clinic on day 13 with no objective symptoms other than fever. Laboratory tests revealed a high neutrophil count (15,000/µl) and a high C-reactive protein (CRP) level (46.35 mg/dl) without any other abnormalities. There was no response upon administration of antimicrobial agents. An 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed thickening of the wall of the descending thoracic aorta and left pleural effusion. Therefore, thoracic aortitis induced by pegfilgrastim was suspected. On day 19, the fever resolved spontaneously followed by a gradual reduction in the neutrophil count and CRP level. In the follow-up CT, the aortic wall thickness and pleural effusion had disappeared. CONCLUSIONS: G-CSF may cause aortitis due to stimulation of the production of inflammatory cytokines. In case of high continuous fever after administration of pegfilgrastim, aortitis should be suspected unless there are other infectious findings.

Vigorous exercise mobilizes CD34+ hematopoietic stem cells to peripheral blood via the ß2-adrenergic receptor.

Acute dynamic exercise mobilizes CD34+ hematopoietic stem cells (HSCs) to the bloodstream, potentially serving as an economical adjuvant to boost the collection of HSCs from stem cell transplant donors. The mechanisms responsible for HSC mobilization with exercise are unknown but are likely due to hemodynamic perturbations, endogenous granulocyte-colony stimulating factor (G-CSF), and/or ß2-adrenergic receptor (ß2-AR) signaling. We characterized the temporal response of HSC mobilization and plasma G-CSF following exercise, and determined the impact of in vivo ß-AR blockade on the exercise-induced mobilization of HSCs. Healthy runners (n = 15) completed, in balanced order, two single bouts of steady state treadmill running exercise at moderate (lasting 90-min) or vigorous (lasting 30-min) intensity. A separate cohort of healthy cyclists (n = 12) completed three 30-min cycling ergometer trials at vigorous intensity after ingesting: (i) 10 mg bisoprolol (ß1-AR antagonist); (ii) 80 mg nadolol (ß1 + ß2-AR antagonist); or (iii) placebo, in balanced order with a double-blind design. Blood samples collected before, during (runners only), immediately after, and at several points during exercise recovery were used to determine circulating G-CSF levels (runners only) and enumerate CD34+ HSCs by flow cytometry (runners and cyclists). Steady state vigorous but not moderate intensity exercise mobilized HSCs, increasing the total blood CD34+ count by ∼4.15 ±â€¯1.62 Δcells/µl (+202 ±â€¯92%) compared to resting conditions. Plasma G-CSF increased in response to moderate but not vigorous exercise. Relative to placebo, nadolol and bisoprolol lowered exercising heart rate and blood pressure to comparable levels. The number of CD34+ HSCs increased with exercise after the placebo and bisoprolol trials, but not the nadolol trial, suggesting ß2-AR signaling mediated the mobilization of CD34+ cells [Placebo: 2.10 ±â€¯1.16 (207 ±â€¯69.2%), Bisoprolol 1.66 ±â€¯0.79 (+163 ±â€¯29%), Nadolol: 0.68 ±â€¯0.54 (+143 ±â€¯36%) Δcells/µL]. We conclude that the mobilization of CD34+ HSCs with exercise is not dependent on circulating G-CSF and is likely due to the combined actions of ß2-AR signaling and hemodynamic shear stress.