Granulocyte Colony-stimulating Factor Levels Research Articles

Pentraxin 3 as a clinical marker in children with lower respiratory tract infection

SummaryBackgroundPentraxin 3 (PTX‐3) is an acute‐phase protein that increases in the plasma during inflammation.ObjectiveWe aimed to evaluate the usefulness of PTX‐3 as a clinical marker in children with lower respiratory tract infection (LRTI) and examine the correlation of PTX‐3 with other biomarkers such as C‐reactive protein (CRP) and procalcitonin (PCT).MethodsWe enrolled 117 consecutive patients admitted to Seoul St. Mary's Hospital with LRTI using the WHO criteria. We recorded data on fever duration and peak temperature before admission, duration of fever after admission, respiratory rate, heart rate, oxygen saturation upon admission, duration of oxygen supplementation, and duration of hospital stay. Upon admission, white blood cell (WBC) count, erythrocyte sedimentation rate, CRP level were measured. Multiplex respiratory virus polymerase chain reaction was performed using nasal swabs. PTX‐3, PCT, and various cytokines were measured after the study had been completed.ResultsWe found that there was no significant difference in the level of PTX‐3 according to the type of viral infection. PTX‐3 levels showed a significant correlation with PCT levels, but not with levels of CRP. The level of PTX‐3 showed a significant correlation with peak temperature and duration of fever before admission as well as interleukin (IL)‐6 levels. PCT levels showed a significant correlation with IL‐6 and granulocyte‐colony stimulating factor levels, peak temperature, and duration of fever before admission, and duration of hospital stay. CRP levels showed a significant correlation with duration of fever before admission, total WBC count, and neutrophil count. PCT levels significantly predicted a hospital stay of 7 days or more. PTX‐3, PCT, and CRP levels showed no correlation with any other clinical features.ConclusionPTX‐3 reflected disease severity but failed to predict length of hospital stay. Further studies evaluating the use of PTX‐3 as a biomarker in mild LRTI would be useful. Pediatr Pulmonol. 2016;51:42–48. © 2015 Wiley Periodicals, Inc.

Mobilization of sca1/flk-1 positive endothelial progenitor cells declines in apolipoprotein E-deficient mice with a high-fat diet

BackgroundAtherosclerosis features a deterioration of the endothelial layer in all stages. Restoration of the endothelium is associated with circulating stem cell antigen 1 (sca1) and vascular endothelial growth factor receptor type 2 (flk-1) positive endothelial progenitor cells (EPCs). We investigated whether EPC production and/or a mobilization from bone marrow are reduced in severe atherosclerosis. Methods and resultsEPCs in peripheral blood were diminished in ApoE−/− mice with high-fat diet (HFD) whereas bone marrow levels of these cells were not significantly altered compared to controls.In situ perfusion of the hind limbs demonstrated that EPC mobilization was reduced compared to ApoE−/− mice with normal chow, although increased plasma stromal cell-derived factor (SDF) 1α and responsivity suggested a mobilizing stimulus. The proliferation of sca1/flk-1 positive cells showed no functional impairment.EPCs could not only be significantly mobilized from the bone marrow through the application of granulocyte colony stimulating factor (GCSF), but also led by trend to a depletion of the bone marrow pool. GCSF levels in plasma were equal in ApoE−/− mice with normal chow or HFD, which excluded a decline in GCSF production. ConclusionThe capability of the bone marrow pool to adapt the proliferation and mobilization of sca1/flk-1 positive EPCs seems overstrained in ApoE−/− mice with a HFD.

Elevated chemokine levels during adult but not pediatric Crimean–Congo hemorrhagic fever

BackgroundCrimean–Congo hemorrhagic fever (CCHF) is a tick-borne viral zoonosis. Clinical reports indicate the severity of CCHF is milder in children than adults. The chemokines are important chemo-attractant mediators of the host immune system. ObjectivesThe main aim of the study was to identify whether or not there were any differences in chemokine levels between the pediatric and adult patients and control groups, and whether there was any correlation with disease severity. Study designThe serum levels of select chemokines including chemokine (C-C) ligand 2 (CCL2), CCL3, CCL4, chemokine (C-X-C) ligand 8 (CXCL8), CXCL9, and granulocyte-colony stimulating factor (G-CSF) in 29 adult and 32 pediatric CCHF patients and in 35 healthy children and 40 healthy adult control groups were studied by flow cytometric bead immunoassay method. ResultsGreat variability was detected in the serum levels of the chemokines for both the adult and pediatric patients and controls. With the exception of G-CSF, the median serum levels of CCL2, CCL3, CCL4, CXCL8, and CXCL9 were found to be significantly higher in the adult patients compared to adult controls (2364.7 vs. 761pg/ml; 714.1 vs. 75.2pg/ml; 88.6 vs. 25.5pg/ml; 217.9 vs. 18.3pg/ml; 875 vs. 352.2pg/ml, respectively, p<0.0001 for all comparisons). Among the chemokines the median CCL4 and G-CSF levels were significantly higher in the pediatric patients compared to pediatric controls (40.3 vs. 7.1pg/ml, p<0.0001; 0.1 vs. 0.1pg/ml, p=0.049, respectively). ConclusionThe results of this study showed prominent chemokine raising in adult CCHF patients compared to children CCHF patients.

Coordinate expansion of murine hematopoietic and mesenchymal stem cell compartments by SHIPi.

Promoting the expansion of adult stem cell populations offers the potential to ameliorate radiation or chemotherapy-induced bone marrow failure and allows for expedited recovery for patients undergoing these therapies. Previous genetic studies suggested a pivotal role for SH2 domain-containing inositol-5-phosphatase 1 (SHIP1) in limiting the size of the hematopoietic stem cell (HSC) compartment. The aim of this study was to determine whether our recent development of small molecule SHIP1 inhibitors offers the potential for pharmacological expansion of the HSC compartment in vivo. We show here that treatment of mice with aminosteroid inhibitors of SHIP1 (SHIPi) more than doubles the size of the adult mesenchymal stem cell (MSC) compartment while simultaneously expanding the HSC pool sixfold. Consistent with its ability to target SHIP1 function in vivo, SHIPi also significantly increases plasma granulocyte colony-stimulating factor (G-CSF) levels, a growth factor that supports proliferation of HSC. Here, we show that SHIPi-induced G-CSF production mediates HSC and MSC expansion, as in vivo neutralization of G-CSF abrogates the SHIPi-induced expansion of both the HSC and MSC compartments. Due to its expansionary effect on adult stem cell compartments, SHIPi represents a potential novel strategy to improve declining stem cell function in both therapy induced and genetically derived bone marrow failure syndromes.

Enhanced inflammation in aged mice following infection with Streptococcus pneumoniae is associated with decreased IL-10 and augmented chemokine production.

Streptococcus pneumoniae is the most common cause of severe pneumonia in the elderly. However, the impact of aging on the innate inflammatory response to pneumococci is poorly defined. We compared the innate immune response in old vs. young adult mice following infection with S. pneumoniae. The accumulation of neutrophils recovered from bronchoalveolar lavage fluid and lung homogenates was increased in aged compared with young adult mice, although bacterial outgrowth was similar in both age groups, as were markers of microvascular leak. Aged mice had similar levels of IL-1β, TNF, IFN-γ, IL-17, and granulocyte colony-stimulating factor following S. pneumoniae infection, compared with young mice, but increased levels of the chemokines CXCL9, CXCL12, CCL3, CCL4, CCL5, CCL11, and CCL17. Moreover, levels of IL-10 were significantly lower in aged animals. Neutralization of IL-10 in infected young mice was associated with increased neutrophil recruitment but no decrease in bacterial outgrowth. Furthermore, IL-10 neutralization resulted in increased levels of CCL3, CCL5, and CXCL10. We conclude that aging is associated with enhanced inflammatory responses following S. pneumoniae infection as a result of a compromised immunomodulatory cytokine response.

Gastric metastasis from esophageal squamous cell carcinoma producing granulocyte colony-stimulating factor: report of a case and literature review

We report an extremely rare case of gastric metastasis from a granulocyte colony-stimulating factor (G-CSF)-producing carcinoma of the esophagus. A 63-year-old Japanese man presented with an aggressive esophageal and gastric tumor and concomitant severe leukocytosis (21,700/mm3) with pyrexia. The serum level of G-CSF was markedly elevated to 253 pg/ml (normal < 9.8 pg/ml). Histological examination of the surgical specimen showed a moderately differentiated squamous cell carcinoma (SCC) of the esophagus and stomach, with tumor cells immunohistochemically positive for G-CSF. The leukocyte count and G-CSF concentration decreased after surgery. The patient was diagnosed with G-CSF-producing esophageal SCC with gastric metastasis. This is the first case of G-CSF-producing esophageal SCC with gastric metastasis.

Uropathogenic Escherichia coli superinfection enhances the severity of mouse bladder infection.

Urinary tract infections (UTIs) afflict over 9 million women in America every year, often necessitating long-term prophylactic antibiotics. One risk factor for UTI is frequent sexual intercourse, which dramatically increases the risk of UTI. The mechanism behind this increased risk is unknown; however, bacteriuria increases immediately after sexual intercourse episodes, suggesting that physical manipulation introduces periurethral flora into the urinary tract. In this paper, we investigated whether superinfection (repeat introduction of bacteria) resulted in increased risk of severe UTI, manifesting as persistent bacteriuria, high titer bladder bacterial burdens and chronic inflammation, an outcome referred to as chronic cystitis. Chronic cystitis represents unchecked luminal bacterial replication and is defined histologically by urothelial hyperplasia and submucosal lymphoid aggregates, a histological pattern similar to that seen in humans suffering chronic UTI. C57BL/6J mice are resistant to chronic cystitis after a single infection; however, they developed persistent bacteriuria and chronic cystitis when superinfected 24 hours apart. Elevated levels of interleukin-6 (IL-6), keratinocyte cytokine (KC/CXCL1), and granulocyte colony-stimulating factor (G-CSF) in the serum of C57BL/6J mice prior to the second infection predicted the development of chronic cystitis. These same cytokines have been found to precede chronic cystitis in singly infected C3H/HeN mice. Furthermore, inoculating C3H/HeN mice twice within a six-hour period doubled the proportion of mice that developed chronic cystitis. Intracellular bacterial replication, regulated hemolysin (HlyA) expression, and caspase 1/11 activation were essential for this increase. Microarrays conducted at four weeks post inoculation in both mouse strains revealed upregulation of IL-1 and antimicrobial peptides during chronic cystitis. These data suggest a mechanism by which caspase-1/11 activation and IL-1 secretion could predispose certain women to recurrent UTI after frequent intercourse, a predisposition predictable by several serum biomarkers in two murine models.

Serum cytokine modulation after Staphylococcus hyicus infection in BALB/c mice.

Staphylococcal infection is a severe bacterial infection. Finding satisfactory predictable biological markers is essential for the treatment of this condition. In this study, we applied a 32-marker sandwich ELISA-based antibody array to evaluate cytokine changes in Staphylococcus hyicus-inoculated BALB/c mice at 24 and 48 h post infection. Among the cytokines detected, the expression levels of granulocyte colony stimulating factor (G-CSF), interleukin 6 (IL-6), macrophage inflammatory protein 2, and keratinocyte chemoattractant (KC) were increased to levels more than twice higher than those in the control group 24 h after infection, while the expression of interleukin 12p40p70 (IL-12p40p70) was decreased to less than half the level measured in the controls. The expression of G-CSF, IL-6, monocyte chemoattractant protei-5, chemokine ligand 11, and KC was upregulated 48 h post infection, whereas IL-12p40p70 expression was still significantly lower (P < 0.05). Among the detected cytokines, the expression levels of G-CSF, IL-6, and KC were constantly upregulated, while IL-12p40p70 was downregulated. This result was then validated by an ELISA assay analysis, which confirmed that G-CSF, IL-6, KC, and IL- 12p40p70 expression levels were specifically modulated after an S. hyicus bacterial infection, while granulocyte monocyte colony stimulation factor, IL-12, and IFNγ levels were significantly increased after a viral infection. Our study indicated the potential of cytokines G-CSF, IL-6, KC, and IL- 12p40p70 as markers for detecting S. hyicus infection. The results of this study may provide useful data for the appropriate use of medication following S. hyicus infection.

Low-dose cyclophosphamide improves survival in a murine treatment model of sepsis.

Sepsis is a complex medical condition characterized by a systemic inflammatory response in the setting of infection. We hypothesized that combining antibiotics plus an immunosuppressant would protect against the morbidity and mortality of polymicrobial sepsis in mice better than would antibiotics alone. We used a murine cecal-ligation-and-puncture model in which mice were treated either with imipenem plus cyclophosphamide or imipenem alone. Titration to a low cyclophosphamide dose revealed that combination therapy increased survival by 20% compared with imipenem alone (56% vs. 36%, P < 0.001). To investigate the mechanism by which combination therapy did this, we reviewed quantitative and qualitative markers of the systemic immune response, end-organ damage, and the local immune response at the site of injury. Cyclophosphamide treatment was not associated with depletion of peripheral leukocytes or differences in pulmonary damage. However, mice that received combination therapy had higher plasma granulocyte colony-stimulating factor levels than did those treated with antibiotics alone. In addition, mice treated with cyclophosphamide had higher levels of bacterial colonization in intestinal Peyer's patch lymph nodes at 72 h after the septic insult. Intraperitoneal macrophage phenotypes and phagocytosis activity did not differ between groups. We conclude that the inflammatory response plays a significant role in the mortality of polymicrobial sepsis and that the regulation of this element is both feasible and beneficial in this disease model.

Comparison of serum granulocyte colony-stimulating factor levels between preterm and term births.

Preterm birth (PTB) is the major obstetric problem in developed countries, accounting for the majority of neonatal mortality and morbidity. Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic cytokine that mediates the increase in leukocytes in pregnancy and may play a role in placentation. We aimed to investigate the differences of serum G-CSF levels between subsequent spontaneous PTB and term-delivered healthy pregnant women. Serum samples, collected from total of 600 singleton otherwise healthy pregnants at 24-28 weeks of gestation during a routine antenatal visit, were used to assess G-CSF levels; 40 of the total pregnants who delivered their infants spontaneously after preterm labor before 37 weeks of gestation were selected as the study group. Also, 120 pregnants were selected as a control group using a 1/3 ratio. Student's t-test, chi-square test, Mann-Whitney U-tests, and ROC curve analysis for prediction of PTB were used for the comparison of groups. P<0.05 was accepted as statistically significant. There was no significant difference in maternal serum G-CSF levels between the study and control groups (p=0.28) but maternal white blood cell (WBC) count was significantly different between them (p=0.00). In addition, G-CSF was insufficient in the prediction of PTB (AUC=0.419). In the preterm and term groups, no correlation was found between WBC and G-CSF (p=0.165 vs. p=0.703). There were no differences in serum levels of G-CSF between term- and preterm-delivered pregnants. There was no predictive role for serum G-CSF in PTB.

Abstract 1103: MDSC targeting therapy for uterine cervical cancer displaying TRL

Abstract Objectives: The aim of this study was to investigate the clinical implications and underlying mechanism of tumor-related-leukocytosis (TRL) in cervical cancer. Methods: The clinical data of cervical cancer patients who were treated with definitive radiotherapy were analyzed to investigate the association between TRL and treatment outcome in retrospective and prospective settings. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were employed to examine the mechanisms responsible for TRL in cervical cancer, focusing on the myeloid-derived suppressor cell (MDSC) and tumor-derived granulocyte colony-stimulating factor(G-CSF). Results: TRL was significantly associated with shorter survival. The TRL-positive patients displayed upregulated tumor G-CSF expression and elevated serum G-CSF levels and increased MDSC frequencies in the blood compared with the TRL-negative patients. In vitro and in vivo investigations revealed that tumor-derived G-CSF is involved in the underlying causative mechanism of TRL and that the increase in the number of MDSC induced by tumor-derived G-CSF is responsible for the rapidly progressive nature of TRL-positive cervical cancer. The administration of anti-Gr-1 antibody or the depletion of MDSC by splenectomy significantly inhibited tumor growth in TRL-positive cervical cancer. Conclusion: TRL is an indicator of a poor prognosis in cervical cancer patients treated with definitive radiotherapy. MDSC induced by tumor-derived G-CSF is responsible for the rapidly progressive nature of TRL-positive cervical cancer. MDSC-targeting treatments might have therapeutic potential in TRL-positive cervical cancer. Note: This abstract was not presented at the meeting. Citation Format: Yuri Matsumoto, Mahiru Kawano, Tomoyuki Sasano, Seiji Mabuchi. MDSC targeting therapy for uterine cervical cancer displaying TRL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1103. doi:10.1158/1538-7445.AM2014-1103

Progenitor cell mobilization after exercise is related to systemic levels of G-CSF and muscle damage.

Different types of exercise are characterized by the ability to induce specific physiological stimuli that might be able to induce the mobilization of progenitor cells. The aim of the current study was to investigate the mobilization of hematopoietic progenitor cells (HPCs) and endothelial progenitor cells (EPCs) in response to endurance, resistance, and eccentric endurance exercise and their relation to markers of muscle damage and inflammation. Healthy male subjects performed acute bouts of either endurance exercise, resistance exercise, or eccentric endurance exercise. Numbers of progenitor cells and several markers of muscle damage and inflammation were determined. Although the endurance exercise was followed by an immediate and short increase of both HPCs and EPCs, the eccentric exercise evoked a long lasting increase up to 24 h for HPCs and 48 h for EPCs (P < 0.05). After resistance exercise, an increase of HPCs was only found 3 h after exercise (P < 0.05). A correlation was found between mobilized progenitor cells and systemic levels of granulocyte colony-stimulating factor (G-CSF) levels (r = 0.54 and r = 0.51, P < 0.05) as well as for HPCs and creatine kinase levels (r = 0.57, P < 0.05). These results suggest that mobilization of progenitor cells is related to the type of exercise and possibly mediated by G-CSF and muscle damage.

200: Regulation of G-CSF and its receptor in skeletal muscle in response to exercise-induced damage in vivo and LPS stimulation in vitro

The cytokine granulocyte-colony stimulating factor (G-CSF) binds to its receptor (G-CSFR) to stimulate haematopoietic stem cell mobilization, myelopoiesis and the production and activation of neutrophils. G-CSF is increased in the circulation in response to exercise-induced muscle damage and the G-CSF receptor (G-CSFR) has recently been identified in skeletal muscle and muscle cells [1] . While G-CSF/G-CSFR activation mediates pro- and anti-inflammatory responses, our understanding of their role and regulation in skeletal muscle is limited. The aim of this study was to investigate in vitro and in vivo the role and regulation of G-CSF and the G-CSFR in skeletal muscle under conditions of muscle inflammation and damage. Firstly, C2C12 myotubes were treated with G-CSF to determine if it modulates the inflammatory response induced by lipopolysaccharide (LPS). Secondly, we measured the regulation of G-CSF and its receptor following eccentric exercise-induced muscle damage and investigated if their expression levels were redox-dependent by administering the antioxidant N-AcetylCysteine. LPS stimulation of C2C12 myotubes resulted in G-CSF production. The addition of G-CSF following LPS stimulation of C2C12 myotubes increased IL-6 mRNA and cytokine release into the media. Following eccentric exercise-induced muscle damage in humans G-CSF levels were either marginally increased in circulation or remain unaltered in skeletal muscle. Similarly, G-CSFR levels remained unchanged in response to damaging exercise while the G-CSF/G-CSFR response was not redox sensitive. Collectively, these findings suggest that G-CSF may cooperate with IL-6 and potentially promote muscle regeneration in vitro, whereas in vivo aseptic inflammation induced by exercise did not change G-CSF and G-CSFR responses. These observations suggest that different models of inflammation produce a different G-CSF responses.

Granulocyte colony-stimulating factor: is it predictive for in-vitro fertilization outcome in patients with polycytic ovary syndrome?

To evaluate the effect of serum and follicular fluid (FF) granulocyte colony-stimulating factor (G-CSF) levels on clinical and laboratory in-vitro fertilization (IVF) outcome in patients with polycystic ovary syndrome (PCOS).

Enteral Granulocyte-Colony Stimulating Factor and Erythropoietin Early in Life Improves Feeding Tolerance in Preterm Infants: A Randomized Controlled Trial

To evaluate the efficacy and safety of enteral recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human erythropoietin (rhEPO) in preventing feeding intolerance. An interventional randomized control trial was conducted in 90 preterm infants born at ≤33 weeks gestational age. The neonates were assigned to 4 groups; 20 received rhG-CSF, 20 received rhEPO, 20 received both, and 30 received distilled water (placebo control). The test solution was given at the beginning of enteral feeding and was discontinued when enteral intake reached 100 mL/kg/day or after a maximum of 7 days, whichever came first. Feeding tolerance and adverse effects of treatment were assessed. Serum granulocyte colony-stimulating factor and erythropoietin levels were measured on days 0 and 7 of treatment. All neonates tolerated the treatment without side effects. Neonates who received rhG-CSF and/or rhEPO had better feeding tolerance, as reflected by earlier achievement of 75 mL/kg/day, 100 mL/kg/day, and full enteral feeding of 150 mL/kg/day with earlier weight gain and a shorter hospital stay (P < .05). The risk of necrotizing enterocolitis was reduced from 10% to 0% in all treatment groups (P < .05). There was a shorter duration of withholding of feeding secondary to feeding intolerance among neonates receiving both rhG-CSF and rhEPO compared with those receiving placebo (P < .05). Serum levels of granulocyte colony-stimulating factor and erythropoietin at 0 and 7 days did not differ across the treatment groups. Enteral administration of rhG-CSF and/or rhEPO improves feeding outcome and decreases the risk of necrotizing enterocolitis in preterm neonates. The mechanism may involve the prevention of villous atrophy.

Effective prevention of postoperative recurrence of a granulocyte colony-stimulating factor-producing fallopian tube carcinoma by using concurrent chemoradiotherapy

Granulocyte colony-stimulating factor (G-CSF)-producing tumors are very rare in the field of gynecology and generally tend to have poor prognoses. We report a case of platinum-refractory G-CSF-producing fallopian tube cancer that was successfully treated with concurrent chemotherapy and TomoTherapy®. A 76-year-old woman with an abnormally high white blood cell (WBC) count was referred to our hospital by a local clinic. Comprehensive laboratory testing excluded a possible hematological disorder; however, on the basis of imaging findings, surgery was scheduled for a suspected fallopian tube cancer. The results of blood tests performed after the patient arrived at our hospital revealed a WBC count of 67000 cells/µL and a maximum neutrophil percentage of 96.6 %. Total hysterectomy and bilateral salpingo-oophorectomy were performed, and the histopathological analysis revealed a poorly differentiated serous adenocarcinoma of the fallopian tube. However, the postoperative blood tests revealed a G-CSF level of 183 pg/mL (normal range is <39 pg/mL). Because the preoperative WBC count and neutrophil percentage were high and the pathological specimens stained positive for G-CSF on immunohistochemical analysis, a diagnosis of a G-CSF-producing tumor was made. The tumor enlarged even though combination chemotherapy of paclitaxel and carboplatin was administered and concurrent chemoradiotherapy (CCRT) with TomoTherapy® and nedaplatin was administered. The G-CSF level increased to 852 pg/mL, after which the tumor subsequently reduced in size and the G-CSF level normalized; currently, a complete response has been maintained for 1.5 years post-surgery. This case suggests that primary TomoTherapy®-based CCRT might be effective for the treatment of G-CSF-producing tumors.

Early propranolol administration to severely injured patients can improve bone marrow dysfunction.

Bone marrow (BM) dysfunction is common in severely injured trauma patients, resulting from elevated catecholamines and plasma granulocyte colony-stimulating factor (G-CSF) as well as prolonged mobilization of hematopoietic progenitor cells (HPCs). We have previously shown that propranolol (β-blocker [BB]) reduces HPC mobilization in a rodent model of injury and hemorrhagic shock. We hypothesize that BB would prevent BM dysfunction in humans following severe injury. Forty-five severely injured trauma patients were studied in a prospective, randomized pilot trial. Twenty-five patients received BB, and 20 served as untreated controls. The dose of propranolol was adjusted to decrease the heart rate by 10% to 20% from baseline. Blood was analyzed for the presence of HPC (blast-forming unit erythroid cells [BFU-E] and colony-forming unit erythroid cells) and G-CSF. Demographic data, Injury Severity Score (ISS), hemoglobin, reticulocyte number, and outcome data were obtained. The mean age of the study population was 33 years; 87% were male, with a mean ISS of 29. There is a significant increase in BFU-E in peripheral blood immediately following traumatic injury, and this mobilization persists for 30 days. The use of BB significantly decreases BFU-E and colony-forming unit erythroid cells at all time points. G-CSF is significantly elevated in both groups on admission; the use of BB decreases G-CSF levels by 51% as compared with 37% for controls. The average hemoglobin is nearly 1 g higher on the day of discharge with propranolol treatment (BB, 9.9 ± 0.4 g/dL vs. no BB, 9.1 ± 0.6 g/dL). Following severe trauma, early treatment with propranolol following resuscitation is safe. The use of propranolol blunts early tachycardia, reduces HPC mobilization, and results in a faster return to baseline of the G-CSF peak seen after injury. There is also a trend toward faster recovery and resolution of anemia. Propranolol may be the first therapeutic agent to show improved BM function after severe injury. Therapeutic study, level III.

Uterine cervical cancer displaying tumor-related leukocytosis: a distinct clinical entity with radioresistant feature.

Tumor-related leukocytosis (TRL) is occasionally found in patients with nonhematopoietic malignancies. We investigated the clinical implication of TRL and individualized treatment for TRL-positive cervical cancer, as well as the underlying biological mechanism. Clinical data from 258 cervical cancer patients treated with definitive radiotherapy were analyzed to investigate the association between TRL and treatment outcome. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were used to examine the mechanisms responsible for TRL in cervical cancer, focusing on the role of tumor-derived granulocyte colony-stimulating factor (G-CSF) and myeloid-derived suppressor cells (MDSCs). All statistical tests were two-sided. TRL was statistically significantly associated with younger age (Wilcoxon rank sum test, P = .03), larger tumor size (Wilcoxon rank sum test, P = .006), advanced clinical stage (χ(2) test, P = .01), and shorter overall survival (Cox proportional hazard modeling and Wald tests, P < .001). Among cervical cancer patients, TRL was associated with upregulated tumor G-CSF expression (χ(2) test, P < .001), elevated serum G-CSF levels (Student t test, P = .03), larger spleens (Student t test, P = .045), and increased MDSC frequencies in the blood (Student t test, P < .001) compared with the TRL-negative patients. In vitro and in vivo experiments revealed that tumor-derived G-CSF was involved in the underlying causative mechanism of TRL and MDSCs induced by tumor-derived G-CSF are responsible for the rapidly progressive and radioresistant nature of TRL-positive cervical cancer. The administration of anti-Gr-1 neutralizing antibody or the depletion of MDSCs by splenectomy (n = 6 per group) inhibited tumor growth and enhanced radiosensitivity in TRL-positive cervical cancer xenografts (Wilcoxon rank sum test, P = .008 and P = .02, respectively). TRL is associated with resistance to radiotherapy among cervical cancer patients, and MDSC-targeting treatments may have therapeutic potential in these patients.

The rate of liver impairment, character of bacteremia and serum bactericidal activity in patients with cirrhosis.

Dependence of prevalence and severity of bacteremia on the rate of liver impairment, serum bactericidal activity (SBA), and serum concentrations of C-reactive protein (CRP) and granulocyte colony-stimulating factor (G-CSF) in 80 hospitalized patients with liver cirrhosis (LC) have been studied. It was shown that risk factors associated with the development of bacteremia are high by Child-Pugh score and low SBA, CRP and G-CSF levels. Patients with LC, class A had the highest SBA, CRP and G-CSF levels. Still 14,3% of them developed less severe bacteremia associated with one type of microorganisms isolated from blood. Patients with LC, class B had intermediate SBA, CRP and G-CSF levels. They developed severe bacteremia in 52,6% of cases and less severe bacteremia – in 21,1% of cases. Patients with LC, class C had low SBA, CRP and G-CSF levels. They developed severe bacteremia in 62,5% of cases and less severe bacteremia – in 25% of cases.

Effectiveness of pazopanib for postoperative recurrence of granulocyte colony-stimulating factor-producing primary hepatic angiosarcoma

A 38-year-old Japanese woman was referred to our hospital with complaints of fever, general fatigue, and upper abdominal discomfort. Computed tomography revealed a massive tumor in the right lobe of the liver, and laboratory data demonstrated increased white blood cell (WBC) count and serum granulocyte colony-stimulating factor (G-CSF) level. An extended right hepatectomy was performed, and pathological examination revealed spindle-shape tumor cells that formed vessel-like structures that were compatible with hepatic angiosarcoma. As a rapid recurrence occurred after surgery, S-1 was administered as a first-line chemotherapy, and weekly paclitaxel was administered as the second-line chemotherapy. However, patient eventually became resistant to these therapies. Therefore, pazopanib, a multitargeted tyrosine kinase inhibitor, was administered, after which both the WBC count and G-CSF level rapidly decreased. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) revealed decreased FDG uptake. This is the first report on the administration of pazopanib as a third-line chemotherapeutic agent for treating G-CSF-producing primary hepatic angiosarcoma. The efficacy of this therapy was demonstrated with FDG-PET.