Combination therapy with sorafenib and S-1 for renal cell carcinoma producing granulocyte colony-stimulating factor.

We present the first case report of the use of sorafenib and S-1 for the treatment of renal cell carcinoma (RCC) producing granulocyte colony-stimulating factor (G-CSF). This entity is clinically rare and has a poor outcome. A 78-year-old Japanese man presented with macrohematuria, left flank pain, and a palpable mass. Laboratory data showed marked leukocytosis with increased serum and urinary G-CSF. The histopathological diagnosis was unclassified RCC. New combination therapy with sorafenib and S-1 exerted a therapeutic effect and apparently decreased serum and urinary G-CSF levels, although the patient died of gastrointestinal perforation. The use of combined sorafenib and S-1 may be worthy of consideration in the treatment of RCC producing G-CSF.

Extent and magnitude of catecholamine surge in pediatric burned patients.

Increased catecholamine (CA) levels after severe burn are associated with stress, inflammation, hypermetabolism, and impaired immune function. The CA secretion profiles in burned patients are not well described. Mechanisms, duration, and extent of CA surge are unknown. The purpose of this large unicenter study was to evaluate the extent and magnitude of CA surge after severe burn in pediatric patients. Patients admitted between 1996 and 2008 were enrolled in this study. Twenty-four-hour urine collections were performed during acute hospitalization and up to 2 years postburn. Results from the samples collected from 12 normal, healthy volunteers were compared with the data from the burned patients. Relevant demographic and clinical information was obtained from medical records. Student t-test and one-way ANOVA were used to analyze the data where appropriate. Significance was accepted at P < 0.05. Four hundred thirteen patients were enrolled in this study; 17 patients died during acute hospitalization. Burn caused a marked stress and inflammatory response, indicated by massive tachycardia and elevated proinflammatory cytokines. In burned patients, CA levels are consistently and significantly modulated after burn when compared with the levels in normal, healthy volunteers. Catecholamine levels were significantly higher in boys compared with girls, correlated with burn size in burns greater than 40%, and were increased in older children. There were differences over time in survivors versus nonsurvivors, with CA levels significantly higher in nonsurvivors at two time points. Inflammatory cytokines show a similar profile during the study period. Our study gives clinicians a useful insight into the extent and magnitude of CA elevation to better design treatment strategies.

[Refolding and purification of recombinant human granulocyte colony-stimulating factor from Escherichia coli by using protein folding liquid chromatography].

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) in the form of inclusion bodies expressed in Escherichia coli (E. coli) was simultaneously refolded and purified using protein folding liquid chromatography (PFLC). Cu2+ -iminodiacetic acid (IDA) Sepharose was selected as the stationary phase for immobilized metal ion affinity chromatography. rhG-CSF was purified and the aggregates were diminished under a linear gradient elution of imidazole in the presence of a suitable concentration of urea. Using only one PFLC run, the refolded rhG-CSF had a specific bioactivity of 1.8 x 10(8) IU/mg and a purity of 97%, with the mass recovery of 32%.

Granulocyte colony-stimulating factor serum and urine concentrations in neutropenic neonates before and after intravenous administration of recombinant granulocyte colony-stimulating factor.

BACKGROUND: Recombinant granulocyte colony-stimulating factor (rG-CSF) has been suggested as a treatment for certain varieties of neonatal neutropenia, but little is known about the pharmacologic disposition of rG-CSF in that population. METHODS: Ten neutropenic neonates were treated with rG-CSF, 10 micrograms/kg intravenously once daily for 3 to 5 days. Serum and urine samples were obtained before rG-CSF dosing and at intervals thereafter for G-CSF quantification by enzyme-linked immunosorbent assay. RESULTS: Five of the neutropenic neonates (termed group 1) were not infected but likely had hyporegenerative neutropenia (4 were born after pregnancy-induced hypertension/intrauterine growth restriction, and 1 had Rh hemolytic disease). Five other infants (group 2) had neutropenia accompanying bacterial sepsis and shock. Before receiving the first dose of rG-CSF, endogenous G-CSF serum and urine concentrations were relatively low in group 1, averaging 130 pg/mL (range: 48-209) in serum and 53 pg/mL (range: 15-141) in urine. Serum concentrations immediately before the final dose were much higher (range: 81-24 835 pg/mL), whereas urine concentrations were unchanged (range: <7 pg/mL-126 pg/mL). In group 2 patients, before receiving the first-dose of rG-CSF, endogenous concentrations were very high, averaging 59 575 pg/mL (range: 20 028-98 280) in serum and 3189 pg/mL (range: 23-4770) in urine. Predose serum concentrations before the final dose (range: 427-14 460 pg/mL) were lower than before the first dose. The area under the concentration curve after the first dose of rG-CSF administration in group 1 was significantly lower than after the first dose in group 2, but no difference in area under the concentration curve was observed between groups 1 and 2 after the last dose of rG-CSF. SPECULATION: The principal means of clearing G-CSF from the serum is by saturable binding to specific G-CSF receptors (G-CSF-Rs). Therefore, the very high G-CSF serum and urine concentrations of group 2 patients before the first rG-CSF dose implies that their G-CSF-Rs were saturated before the dose was given. We speculate that if G-CSF-Rs are saturated with endogenous G-CSF, treatment with rG-CSF will add little or nothing to the granulocytopoietic effort. On this basis, we judge that neonates with septic shock and neutropenia are unlikely to derive benefit from rG-CSF administration.

Pharmacokinetics of glycosylated recombinant human granulocyte colony-stimulating factor (lenograstim) in healthy male volunteers.

AIMS: The aim of this open, randomised, crossover, parallel-group study was to compare the pharmacokinetics and neutrophil responses of lenograstim when administered subcutaneously (s.c.) and intravenously (i.v.). METHODS: A total of 27 healthy male volunteers was recruited. Lenograstim doses (0.5, 2, 5, or 10 microg kg(-1)) were administered s.c. or i.v. once-daily for 5 days, and then, after a 10-day washout period, vice versa for a further 5 days. Lenograstim concentrations and absolute neutrophil counts (ANCs) were measured predosing and postdosing on days 1 and 5. RESULTS: Maximum serum concentrations of lenograstim were higher following i.v. dosing (mean 5.2-185.5 vs 0.7-30.0 ng ml(-1) after s.c. dosing on day 1) and attained sooner (median 0.5-0.8 vs 4.7-8.7 h on day 1). However, apparent elimination half-lives of lenograstim were longer following s.c. dosing (mean 2.3-3.3 vs 0.8-1.2 h after i.v. dosing on days 1 and 5). ANCs increased in a dose-dependent manner with both routes of lenograstim, but more prolonged rises and higher ANC peaks were attained following s.c. doses. ANCs peaked on day 6 following 5 microg kg(-1) s.c. doses (mean peak=26.3x10(9) cells l(-1)), but on day 2 after 5 microg kg(-1) i.v. doses (mean peak = 12.4 x 10(9) cells l(-1)). Irrespective of route, the most common adverse events were headaches and back/spine pain; at doses of up to 5 microg kg(-1) these were mild and generally well tolerated. CONCLUSIONS: While supporting the use of both s.c. and i.v. administered lenograstim to treat neutropenia, these results demonstrate that neutrophil responses are more sustained and prolonged with the s.c. route.

Soluble interleukin-6 receptor, interleukin-10 and granulocyte colony-stimulating factor in acute pyelonephritis: relationship to markers of bacterial virulence and renal function.

BACKGROUND: Cytokines and cytokine receptors are involved in the systemic and local inflammatory response in patients with urinary tract infections. METHODS: We examined urine and serum concentrations of soluble IL-6 receptor (sIL-6R), IL-10 and granulocyte colony-stimulating factor (G-CSF) in 29 women with acute pyelonephritis caused by Escherichia coli 2 weeks after the infection, during the subsequent episode of cystitis or asymptomatic bacteriuria and also later when the same patients were free from bacteriuria. Concentrations of sIL-6R, IL-10 and G-CSF were related to the expression of five virulence markers of E. coli and to glomerular filtration rate (GFR) after pyelonephritis. RESULTS: On admission because of acute pyelonephritis the serum concentration of sIL-6R was similar to that of 12 healthy controls. Two weeks after the infection when all patients had received antibiotic treatment, the serum concentration of sIL-6R was significantly higher compared to that on admission (p < 0.001) and also higher compared to healthy controls (p = 0.001). Patients with increased concentrations of sIL-6R in serum 2 weeks after infection had significantly lower GFR at follow-up (p < 0.05). Patients with acute pyelonephritis had higher concentrations of G-CSF and IL-10 in serum compared to healthy subjects (p < 0.001 and p = 0.06, respectively). G-CSF in serum was higher in patients infected by E. coli producing cytotoxic necrotizing factor (p < 0.05). Patients infected by strains producing hemolysin had lower concentrations of sIL-6R (p < 0.001). Patients with detectable levels of the anti-inflammatory cytokine IL-10 in serum had significantly higher concentrations of IL-6 and the soluble tumor necrosis factor receptors I and II in serum as compared to patients in whom IL-10 was not detectable (p < 0.001, p = 0.001 and p < 0.05, respectively. CONCLUSION: These investigations, together with our previous findings summarized in this paper, contribute to an increased understanding of the local and systemic inflammatory response arising in response to acute pyelonephritis.

Bladder carcinoma producing granulocyte colony-stimulating factor.

A patient presented with grade 3 transitional cell carcinoma of the bladder showing a marked increase in granulocyte colony-stimulating factor (G-CSF). G-CSF was identified in the carcinoma by immunohistochemical procedures. The serum and urinary levels of G-CSF were persistently elevated during his clinical course. These results suggest that the carcinoma produced G-CSF and was responsible for its high levels in serum and urine.