Serum Granulocyte Colony-stimulating Factor Concentrations Research Articles

Neonatal Leukemoid Reaction with Fetal Inflammatory Response Syndrome Is Associated with Elevated Serum Granulocyte Colony Stimulating Factor and Interleukin-6.

Leukemoid reaction (LR) is a reactive disease that exhibits abnormal blood values similar to leukemia, but not due to leukemia. One report showed that neonatal LR (NLR) was associated with elevated serum granulocyte colony stimulating factor (G-CSF) in only 30% of the study neonates. NLR is not always associated with the elevation of serum G-CSF. NLR was defined as a white blood cell count of ≥ 40 × 103/μL and/or blast cell concentration of > 2%. We have focused on NLR with fetal inflammatory response syndrome (FIRS), defined as a fetal systemic inflammatory reaction triggered by intrauterine infection. FIRS was diagnosed based on a cord serum interleukin-6 (IL-6) concentration ≥ 17.5 pg/mL and histopathological chorioamnionitis. Because NLR is highly associated with FIRS, we have hypothesized that NLR is associated with the elevation of both G-CSF and IL-6. This is the first report to measure multiple cytokines in NLR at the same time. The study comprised 19 preterm infants with FIRS: 8 with NLR (study group) and 11 without NLR (control group). Serum G-CSF and IL-6 concentrations were significantly higher in the study group than the control group. There was a positive correlation between G-CSF and IL-6 levels in the study group but not in the control group. These results suggest that elevated serum G-CSF and IL-6 may underlie NLR. Thus, G-CSF and IL-6 concentrations may be predictive of the onset of NLR. Measuring these cytokines is useful for judging the prognosis of preterm infants and for their post-natal clinical management.

Granulocyte-colony stimulating factor producing mucinous cystic neoplasm with an associated invasive carcinoma of the pancreas

The present case study documents an autopsy case of granulocyte-colony stimulating factor (G-CSF)-producing mucinous cystic neoplasm (MCN), with an associated invasive carcinoma of the pancreas. A 65-year-old woman presented to Omuta City Hospital (Omuta Japan) with a primary complaint of abdominal pain. Multiple liver nodules and a pancreatic cyst were detected upon abdominal computed tomography. Initially, liver abscess was suspected as the patient exhibited leukocytosis and elevated C-reactive protein level. However, the serum concentration of G-CSF was 98.8 pg/ml (normal, <39.0 pg/ml). At 6 weeks after admission, the patient succumbed to liver failure. At autopsy, a cystic lesion was identified in the pancreatic tail that contained bloody necrotic fluid. Microscopically, the cystic lesion was composed of columnar and mucin-producing epithelium associated with ovarian-type subepithelial stroma. The stroma exhibited positive immunostaining for vimentin, estrogen receptor and progesterone receptor. Calcification on the cystic wall was observed. The tumor invaded the pancreatic parenchyma and metastasized to the liver and lungs. The lesion was diagnosed as invasive adenocarcinoma arising in MCN. By contrast, liver nodules predominantly consisted of pleomorphic cancer cells with small foci of adenocarcinoma. Pancreatic and hepatic cancer cells were confirmed to be positive for G-CSF staining. The present case report indicates that G-CSF-producing MCNs may be associated with an aggressive clinical course, particularly when anaplastic changes are observed.

G-CSF producing oral carcinoma with diffuse uptake of FDG in the bone marrow: A case report.

A 78-year-old male patient was referred to the Department of Oral Surgery, Hokuto Hospital (Obihiro, Japan) for painless swelling on the left neck and tongue. Histopathological examination of a biopsy specimen resulted in a diagnosis of squamous cell carcinoma of the tongue. Imaging examinations revealed cervical lymph node metastases on both sides, along with diffuse uptake of 18F-fluorodeoxyglucose (FDG) in the bone marrow of the spine and pelvis. Hematologic tests revealed an increased white blood cell (WBC) count and serum concentrations of granulocyte colony stimulating factor (G-CSF). These findings suggested a G-CSF producing tumor, with fluctuations of WBC count, serum G-CSF concentration, and FDG uptake in the bone marrow, associated with tumor shrinkage and enlargement, an indicator of tumor status.

Systemic chemotherapy with pronounced efficacy and neutropenia in a granulocyte-colony stimulating factor-producing advanced gastric neuroendocrine carcinoma.

An advanced granulocyte-colony stimulating factor (G-CSF)-producing tumor is rare, and it exhibits leukocytosis in association with high serum G-CSF levels. A 67-year-old male with a 1-month history of bloody emesis and black stools was revealed to exhibit leukocytosis, anemia and a high serum concentration of G-CSF. During a gastrointestinal endoscopy, an ulcerating tumor was identified in the stomach. Computed tomography and a fluorodeoxyglucose-positron emission tomography scan demonstrated direct invasion of the gastric tumor into the transverse colon, regional lymphadenopathy, lung nodules and diffuse high uptake of FDG in bone marrow. The histological diagnosis was a G-CSF-producing neuroendocrine carcinoma (NEC) (tumor 4b, node 2, metastasis 1, pulmonary, clinical stage IV). Systemic chemotherapy consisting of cisplatin and irinotecan was started. Common terminology criteria of adverse events grade 3 tumor lysis syndrome and gastric penetration appeared. Grade 4 neutropenia lasted for 10 days despite intensive G-CSF administration. Prominent shrinkage of the primary and the metastatic tumors was observed subsequent to 3 cycles of chemotherapy. Total gastrectomy and resection of the transverse colon were subsequently performed. Systemic chemotherapy was effective for a G-CSF-producing advanced gastric NEC with careful monitoring and appropriate supportive care for severe adverse events.

Granulocyte-colony stimulating factor producing anaplastic carcinoma of the pancreas treated by distal pancreatectomy and chemotherapy: report of a case.

Granulocyte-colony stimulating factor (G-CSF) producing pancreatic cancers are extremely rare. These tumors have an aggressive clinical course but no established treatment. We encountered a patient with a G-CSF-induced pancreatic cancer who was treated by surgical resection, followed by steroid treatment and chemotherapy. A 68-year-old Asian male presented at a local hospital with a 3-month history of fever, loss of appetite, and 10-kg weight loss. Laboratory data showed leukocytosis and elevation of C-reactive protein. Computed tomography (CT) revealed a 50-mm mass in the tail of the pancreas, but no signs of infective foci. He was transferred to our hospital for further evaluation. Contrast-enhanced CT showed rapid growth of this tumor over 1 week, and 18 F-2-fluoro-2-deoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) showed FDG accumulation in the tail of the pancreas (SUV max, 17.1) but at no other sites in his body. Magnetic resonance imaging showed a heterogeneous mass, similar to that observed by CT. Three weeks later, the patient underwent a distal pancreatectomy with splenectomy. The resected specimen was 154 mm in diameter, a threefold increase from the initial image. Histopathological examination identified the tumor as an anaplastic carcinoma of the pancreas. Following surgery, his leukocyte count and body temperature were reduced. He recovered well and was discharged from our hospital on postoperative day 18. Immunohistochemical expression of G-CSF in the resected specimen and elevated serum G-CSF concentration confirmed that the mass was a G-CSF producing anaplastic carcinoma of the pancreas. Subsequently, the patient experienced a high fever and loss of appetite. CT showed recurrence of cancer in the abdominal cavity, for which he was started immediately on tegafur-gimeracil-oteracil potassium combination S-1 and steroid. Unfortunately, he died on postoperative day 83. To our knowledge, this patient was the first with a G-CSF producing anaplastic carcinoma of the pancreas to be treated by surgical resection, steroid and adjuvant chemotherapy.

G-CSF-producing esophageal cancer with induction of intense bone marrow FDG uptake

We report the first case of esophageal squamous cell carcinoma (SCC) producing granulocyte colony-stimulating factor (G-CSF) with induction of high uptake of (18)F-fluorodeoxyglucose (FDG) throughout the bone marrow. A close relationship between tumor status and serum G-CSF concentration was also seen. A 65-year-old man was admitted to our hospital because of esophageal SCC with leukocytosis and pyrexia. His leukocyte count and serum G-CSF concentration were 15900/μl and 140 pg/ml, respectively. Positron emission tomography/computed tomography (PET/CT) showed focal intense bone marrow (18)F-FDG uptake. Hypermetabolic activity in the bone marrow was suspected to be an effect of G-CSF. Under the diagnosis of G-CSF-producing esophageal SCC, the patient underwent minimally invasive esophagectomy in the prone position with 2-field lymph node dissection. After removal of the tumor, the leukocyte count and serum G-CSF concentration rapidly normalized. Immunohistochemically, G-CSF expression was found in the cytoplasm of tumor cells. High uptake of (18)F-FDG throughout the bone marrow decreased. The patient left the hospital on postoperative day 10 without any complications. Changes in bone marrow PET/CT findings and serum G-CSF concentration should be helpful in the definitive diagnosis of G-CSF-producing esophageal SCC and serve as an indicator of therapeutic effect.

Granulocyte‐colony stimulating factor‐producing cervical cancers treated with carbon‐ion irradiation

Granulocyte-colony stimulating factor (G-CSF)-producing tumor is a rare condition. It has an aggressive nature and shows resistance to conventional treatments. We report two cases of G-CSF-producing uterine cervical cancer who were successfully treated with carbon-ion radiotherapy (C-ion RT). The first case was a 76-year-old woman with stage IIIB uterine cervical cancer, and the second was a 75-year-old woman with bulky stage IIB disease. Prior to treatment, both patients presented severe granulocytosis and elevated serum G-CSF concentrations. After C-ion RT, their cervical tumors completely disappeared, and their granulocytosis and elevated serum G-CSF levels improved as well. C-ion RT has been reported to be effective for various aggressive tumors, and it may be a good treatment option for this rare aggressive tumor.

Increased Circulation of Galectin-3 in Cancer Induces Secretion of Metastasis-Promoting Cytokines from Blood Vascular Endothelium

Cytokines such as interleukin (IL)-6 and granulocyte colony-stimulating factor (G-CSF) are important metastasis promoters. This study has investigated the functional significance of the increased circulation of galectin-3, a common feature in patients with cancer and in particular those with metastasis, on cytokine secretion from the blood vascular endothelium in cancer. The effects of galectin-3 on secretion of cytokines from human microvascular lung endothelial cells were assessed in vitro by cytokine array and in vivo in mice. The consequences of galectin-3-induced cytokine secretion on endothelial cell behaviors were determined, and the relationship between the levels of circulating galectin-3 and cytokines in patients with colorectal cancer with and without metastasis was investigated. Galectin-3 at pathologic concentrations found in patients with cancer induces secretion of IL-6, G-CSF, sICAM-1, and granulocyte macrophage colony-stimulating factor from blood vascular endothelial cells in vitro and in mice. These cytokines autocrinely/paracrinely interact with the vascular endothelium to increase the expressions of endothelial cell surface adhesion molecules integrinα(v)β(1), E-selectin, ICAM-1, and VCAM-1, resulting in increased cancer cell-endothelial adhesion and increased endothelial cell migration and tubule formation. In patients with metastatic colon cancer, higher serum galectin-3 levels correlated significantly with increased serum G-CSF, IL-6, and sICAM1 concentrations. The increased circulation of galectin-3 in patients with cancer induces secretion of several metastasis-promoting cytokines from the blood vascular endothelium that enhances endothelial cell activities in metastasis. Targeting the actions of circulating galectin-3 in patients with cancer therefore represents a promising therapeutic strategy to reduce metastasis and improve survival.

Acute pyelonephritis with anaplastic thyroid carcinoma producing granulocyte colony-stimulating factor

Paraneoplastic leukocytosis was defined as elevated white blood cell (WBC) levels caused by cytokines, likely produced by the tumor itself, without evidence of infection or myeloproliferative disease. We report a case of anaplastic thyroid carcinoma with leukocytosis caused by elevated production of granulocyte colony-stimulating factor (G-CSF) by the carcinoma. Initially, acute pyelonephritis (APN) was diagnosed and treatment for APN was ongoing, but the WBC count steadily increased to 68.8×109/L. She was diagnosed with anaplastic thyroid carcinoma on her neck mass, and the serum concentration of G-CSF was found to be markedly increased at 1,010 pg/mL. In spite of supportive care, the patient's condition rapidly deteriorated and the patient died on day 23 of hospital stay. Leukocytosis without definite evidence of infection could be a paraneoplastic manifestation in patients with malignant tumors, and paraneoplastic leukocytosis may be related to poor prognosis.

Granulocyte-colony stimulating factor-producing squamous cell carcinoma arising in ovarian mature cystic teratoma: A case report

Granulocyte-colony stimulating factor (G-CSF)-producing cancer has been reported to occur in various organs. It has an aggressive nature and shows resistance to conventional treatments, however, its clinical features are not well known because of the small number or reported cases. We report G-CSF-producing squamous cell carcinoma arising in malignant-transformed ovarian mature cystic teratoma. An 80-year-old woman underwent suboptimal surgical excision of stage IIIC ovarian cancer. Prior to the treatment, the patient presented severe granulocytosis and elevated serum G-CSF concentration. With the help of histopathological and immunohistochemical studies, we diagnosed this case to be a poorly differentiated squamous cell carcinoma developed in ovarian mature cystic teratoma, which highly expressed G-CSF. During radiation therapy, the patient died from rapid growth of residual tumor and peritoneal dissemination 2 months after surgery. This is the first case of G-CSF-producing squamous cell carcinoma arising in malignant-transformed ovarian mature cystic teratoma, and its prognosis was very poor.

Alterations of Circulating Endothelial Cell and Endothelial Progenitor Cell Counts around the Ovulation

Circulating endothelial cells (CECs) and progenitor cells (CEPs) have been intensively studied as a promising tool for treating ischemic diseases and monitoring cancer treatments, but how the menstrual cycle affects the variation in their counts remains unclear. The aims of the study were to determine the influence of the menstrual cycle on the number of CECs and CEPs and to investigate the association of their counts with circulating hormones and angiogenesis-associated factors. CEP and CEC counts by flow cytometry and the CellSearch system and circulating factor levels were measured eight times during the menstrual cycle in 18 volunteers. The menstrual cycle was divided into six phases based on hormone concentrations. CEP counts peaked in the periovulatory and middle luteal phases with a drop in the early luteal phase. CEC counts showed no significant variation. There were significant correlations between the CEP counts and the serum concentrations of estradiol (E2), LH, and granulocyte colony-stimulating factor (G-CSF) (P < 0.0001, P < 0.0001, and P = 0.01, respectively). The difference in CEP counts between two adjacent phases was significantly correlated with that in E2, LH, G-CSF, and serum vascular endothelial growth factor (P < 0.0001, P < 0.0001, P = 0.02, and P = 0.006, respectively). CEP counts peaked in the periovulatory and middle luteal phases, with a drop in the early luteal phase, and were correlated with serum E2, LH, and G-CSF concentrations. Consideration of the variation in CEP counts would be important for the clinical application of CEPs.

Deciduosis can cause remarkable leukocytosis and obscure abdominal pain

Remarkable leukocytosis with obscure abdominal pain during pregnancy is clinically challenging for obstetricians. A 31-year-old pregnant woman developed persistently elevated white blood cell (approximately 30 000/µL) and C-reactive protein (3.0 mg/dL) with occasional moderate abdominal pain. At 29 gestational weeks, she underwent emergency cesarean section due to suspected abruptio placentae. Hemoperitoneum was observed with extensive hemorrhagic nodules on the peritoneal and omental surfaces. White blood cells rose 87200/µL, and C-reactive protein peaked at 44.9mg/dL after surgery. Pathologically, biopsies showed deciduosis, and decidual cells on the omental surface showed immunohistochemical staining for granulocyte colony-stimulating factor (G-CSF). Serum G-CSF concentration was 339 pg/mL at 28 weeks, and that of ascites was 312 000 pg/mL at cesarean section. G-CSF-producing deciduosis can induce leukocytosis as well as abdominal pain during pregnancy and postpartum.

Treatment of Leg Ischemia With Biodegradable Gelatin Hydrogel Microspheres Incorporating Granulocyte Colony-stimulating Factor

Granulocyte colony-stimulating factor (G-CSF) is a potent angiogenic factor. We hypothesized that G-CSF-immersed gelatin hydrogel microspheres (G-CSF-GHMs) injected into the ischemic legs might continuously release a small amount of G-CSF to locally stimulate angiogenesis without unfavorable systemic effects. Just after ligation of the right femoral artery of BALB/c mice, recombinant human G-CSF (100-μg/kg)-immersed GHM was injected into the right hindlimb muscles; the controls included a saline-injected group, an intramuscularly injected G-CSF group, a subcutaneously injected G-CSG group, and an empty GHM-injected group. Eight weeks later, improvement of blood perfusion to the ischemic limb was significantly augmented in the G-CSF-GHM group compared with any of the control groups. Despite there being no increase in the serum concentration of G-CSF, in peripheral granulocytes, or in circulating endothelial progenitor cells, not only capillary but also arteriolar density was significantly increased in this group. Next, we started treatment with G-CSF-GHM 4 weeks after ligation to examine whether the treatment is effective if performed during the chronic stage of ischemia. The late treatment was also found to effectively improve blood flow in the ischemic leg. In conclusion, G-CSF-GHM administration is suggested to be a promising and readily usable approach to treating peripheral artery disease, applicable even during the chronic stage.

Bioequivalence of two recombinant granulocyte colony-stimulating factor products after subcutaneous injection in healthy volunteers

The objective of the study was the demonstration of bioequivalence of two recombinant human granulocyte colony-stimulating factor (G-CSF) formulations after subcutaneous administration of 5 microg/kg and 10 microg/kg comparing their pharmacokinetic and pharmacodynamic profiles in healthy subjects. This was a randomized, single dose, two-period cross-over, two-arm study with a 14 days wash-out period. In total 56 subjects were included, 28 in each dosage cohort (5 microg/kg and 10 microg/kg). Using a 1 : 1 : 1 : 1 randomization ratio, subjects were randomly assigned to one of four possible treatment-sequence groups. A single dose of test formulation (XM02) and reference product (Neupogen, F. Hoffmann - La Roche, Ltd.) were injected. The serum G-CSF concentrations were measured by enzyme-linked immunosorbent assay (ELISA) during 48 hours after injection. The absolute Neutrophil Count (ANC) was determined by automated hematology analyzer Coulter STKSTM (Beckman Coulter, Inc.) up to 96 hours after injection. The primary pharmacokinetic (AUC0-48, AUC0- yen and Cmax) and pharmacodynamic (ANC AUC0-96, ANC AUC0- yen and ANCmax) variables were considered bioequivalent if the 90% confidence intervals (CI) were in the bioequivalence range of 80 - 125%. 50 subjects completed the study: 24 subjects in 5 microg/kg and 26 in 10 microg/kg dosage groups. The pharmacokinetic and pharmacodynamic parameters in 5 mg/kg and 10 mg/kg group for both formulations were very close to each other. Single doses of test and reference formulations were well tolerated. The most frequent AEs were: headache, erythrocyturia and myalgia. The incidence of AEs was equally distributed across dosage and treatment groups. The study results demonstrated the bioequivalence of two body weight-dependent doses of XM02, a new formulation of filgrastim, and the reference product Neupogen after administration of a 5 microg/kg b.w. and 10 microg/kg b.w. with respect to pharmacokinetic, pharmacodynamic and safety profiles.

Conditioning of Monocytes in the Bone Marrow by Inflammatory Cytokines Inhibits Their Angiogenic Potential at Peripheral Sites of Ischemia

There is considerable interest in the potential of cell-based approaches to mediate therapeutic angiogenesis for a number of acute and chronic vascular syndromes. Accumulating evidence suggests that monocytes play a key role in the regulation of angiogenesis at sites of ischemia. Our laboratory has recently demonstrated that the adoptive transfer of a small number of bone marrow monocytes significantly enhanced revascularization in a murine model of acute hindlimb ischemia (Capoccia, 2008). However, the number of donor monocytes recruited to sites of ischemia was small compared to recipient (endogenous) monocytes; only 1% of the total monocytes in the ischemic muscle were of donor origin. This observation suggested that the angiogenic capacity of endogenous monocytes in the ischemic recipient was impaired. To test this hypothesis, we harvested monocytes from the bone marrow of ischemic or control mice, adoptively transferred them into recipient mice 24 hours after surgical induction of hindlimb ischemia, and measured revascularization using laser Doppler imaging. Compared with control cells, monocytes harvested from ischemic mice had markedly reduced capacity to stimulate revascularization [ratio of blood flow in ischemic versus nonischemic limb: 0.92 ± 0.04 (control) and 0.60 ± 0.10 (ischemic) on day 14; p < 0.05]. Interestingly, the ischemia-conditioned and control monocytes were recruited to the ischemic tissue equally. We next performed RNA expression profiling on monocytes harvested from the bone marrow of ischemic and control mice. The expression of a number of STAT3 target genes was induced, including SOCS3. Accordingly, using a phosphoflow assay, we observed a significant increase in STAT3 phosphorylation in ischemia-conditioned monocytes (mean fluorescent intensity: 34 ± 4) compared with control monocytes (17 ± 2; p<0.05). Major activators of STAT3 in monocytes are granulocyte-colony stimulating factor (G-CSF) and interleukin-6 (IL-6), two cytokines often elevated in inflammatory conditions. Indeed, the serum concentration of G-CSF and IL-6 was markedly increased in ischemic mice [850 ± 40 pg/mL (G-CSF); 1660 ± 540 pg/mL (IL-6)] compared with control mice [123±40 pg/mL (G-CSF); undetectable (IL-6) p<.05 for both]. Interestingly, monocytes obtained from ischemic IL-6−/− or ischemic G-CSFR−/− mice and adoptively transferred into ischemic recipients were competent to accelerate revascularization in contrast to monocytes obtained from ischemic wild type controls. These observations demonstrate that loss of either G-CSF or IL-6 signaling is sufficient to restore the ability of ischemia-conditioned monocytes to enhance revascularization. Taken together these data provide evidence that the ischemic environment generates signals, including G-CSF and IL-6, which inhibit the angiogenic potential of monocytes that reside in the bone marrow. This “conditioning” of bone marrow monocytes provides a novel mechanism by which systemic cytokines regulate angiogenesis and tissue repair.

A case of maxillary gingival squamous cell carcinoma producing granulocyte colony-stimulating factor (G-CSF)

A case of gingival squamous cell carcinoma producing G-CSF is reported.A 78-year-old man presented with a granulated mass in the right upper gingiva. Pathological examination of a biopsy specimen revealed a welldifferentiated squamous cell carcinoma. Laboratory ndings on admission showed marked leukocytosis (12.3×103/μl).We had planned a partial resection of the maxilla under general anesthesia. However, the operation was canceled on the originally scheduled day, because of fever and leukocytosis (13.6×103/μl).After 10 days, tumor resection was performed under general anesthesia, despite fever and leukocytosis (18.3×103/μl). Postoperatively, the patient's white blood cell count soon decreased, and the fever disappeared.Immunohistochemically staining with monoclonal anti-G-CSF antibody was positive. The serum G-CSF concentration reached an abnormally high level preoperatively, which soon decreased to the normal range postoperatively.We diagnosed the disease as gingival squamous cell carcinoma producing G-CSF.

Granulocyte colony-stimulating factor-producing malignant pleural mesothelioma with the expression of other cytokines

We report a 65-year-old man with malignant pleural mesothelioma that produced granulocyte colony-stimulating factor (G-CSF) and other cytokines. At the first presentation, the WBC count was 8600 cells/microl and C-reactive protein (CRP) was 0.6 mg/dl. Seventeen months later, the WBC count had increased to 53,600 cells/microl (93% neutrophils) and CRP to 27.1 mg/dl. The serum concentration of G-CSF had increased to 36.0 pg/dl (normal range, <5.0 pg/dl), interleukin 1beta (IL-1beta) to 46.0 pg/dl (normal range, <10 pg/dl), and IL-6 to 197 pg/dl (normal range, <4.0 pg/dl). The patient died 19 months after the first presentation, and 6 weeks after sudden leukocytosis. At autopsy, a diagnosis of malignant pleural mesothelioma was made. The tumor cells were positive for anti-human G-CSF, granulocyte-macrophage colony-stimulating factor, IL-1beta, and IL-6 antibodies. Malignant mesothelioma may produce G-CSF and other cytokines. Mesothelial cells may have the potential to produce G-CSF and other cytokines in the progress of malignant formation, and this may be a factor influencing the poor prognosis.

白血球機能制御による新たなる抗炎症治療戦略 Ｇｒａｎｕｌｏｃｙｔｅ ｃｏｌｏｎｙ‐ｓｔｉｍｕｌａｔｉｎｇ ｆａｃｔｏｒ （Ｇ‐ＣＳＦ）療法

Granulocyte colony-stimulating factor (G-CSF) is a naturally occurring glycosylated protein that was originally identified as a granulopoietic growth factor. It has been shown that G-CSF stimulates the proliferation and maturation of neutrophil precursor cells as well as increases such neutrophil functions as chemotaxis, phagocytosis, and bactericidal activity. G-CSF has drawn recent attention as a therapeutic drug for sepsis, because studies show that G-CSF not only selectively stimulates the proliferation of neutrophils but also plays an important role as a multipotent modulator of acute inflammation.We previously reported an increased serum G-CSF concentration concomitant with an elevated absolute neutrophil count showing a left shift toward more immature forms, and that neutrophil phagocytic and bactericidal activity is maintained in patients with trauma or sepsis. We suggested that G-CSF plays an important role in neutrophil maturation and the maintenance of neutrophil function in inflammatory response associated with trauma and sepsis.We also investigated the clinical effects of recombinant human G-CSF (rhG-CSF) administration in patients with sepsis who lack appropriate neutrophilia. We concluded that rhG-CSF administration attenuates inflammatory responses without inducing tissue injury. In addition, we found the difference in responses after rhG-CSF in each patients with sepsis. In the good response group, rhG-CSF administration markedly improved the severity of illness and produced a good outcome. The endogenous G-CSF level in blood showed lower than that in the poor response patients before rhG-CSF administration. Immature neutrophils was significantly higher in poor response group than those in good response group. Those results suggest that rhG-CSF was effective in septic patients with a low percentage of immature neutrophils and insufficient endogenous G-CSF.Some recent reports, however, have suggested that rhG-CSF treatment in patients receiving cytotoxins can be associated with pulmonary toxicity. However, we revealed that rhG-CSF causes leukocyte stiffness but attenuates inflammatory response without inducing lung injury in septic patients.This review will provide an overview of our current understanding of the role of G-CSF as an anti-inflammatory modulator in patients with sepsis.

DIFFERENCES IN THE EXPRESSION OF CD64 AND mCD14 ON POLYMORPHONUCLEAR CELLS AND ON MONOCYTES IN PATIENTS WITH SEPTIC SHOCK

The present study was performed to clarify the time course of the expression of CD64, the Fc gamma receptor type I (FcγR1), and membrane-bound CD14 (mCD14), one of the major receptors for endotoxin, on polymorphonuclear leukocytes (PMN) and monocytes in 22 postoperative/post-traumatic patients with septic shock. Therefore, the expression of CD64 and mCD14, and serum concentrations of granulocyte colony-stimulating factor (G-CSF) and interferon-γ (IFN-γ) were determined by flow cytometric analysis and enzyme-linked immunosorbent assay (ELISA), respectively, from the first day of septic shock onwards over a period of 14 days. When compared to the values of 12 healthy controls, CD64 expression was elevated significantly on PMN and monocytes of the patients, whereas the expression of mCD14 was decreased significantly at all days. The initially increased expression of CD64 on PMN and monocytes decreased within the first days of septic shock. The already initially decreased mCD14 expression decreased further on PMN, but not on monocytes. Serum concentrations of G-CSF and IFN-γ during the study period were significantly higher than those of the control group. The differences in the kinetics of CD64 and mCD14 expression in patients with septic shock may be explained by different regulatory effects of cytokines, such as G-CSF and IFN-γ.

Malignant Fibrous Histiocytoma of Soft Tissue Producing Granulocyte Colony-Stimulating Factor.

We treated a rare case of malignant fibrous histiocytoma (MFH) of soft tissue that produced granulocyte colony-stimulating factor (G-CSF). The patient, an 80-year-old woman, was admitted because of a feeling of abdominal fullness and leg edema. An elastic, hard, tender tumor was palpated in the right thigh. Histopathological examinations of the tumor revealed atypical and prominent pleomorphic spindle-shaped cells with funicular arrangement, which were compatible with the diagnosis of MFH. Prominent leukocytosis (up to 84,300/microl), a high serum G-CSF concentration (82 pg/ml) and positive immunohistochemical staining of the tumor tissue for G-CSF indicated that G-CSF was produced by the MFH.