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Eradication of Chronic Myeloid Leukemia Stem Cells: A Novel Mathematical Model Predicts No Therapeutic Benefit of Adding G-CSF to Imatinib  [PDF]
Jasmine Foo,Mark W. Drummond,Bayard Clarkson,Tessa Holyoake,Franziska Michor
PLOS Computational Biology , 2009, DOI: 10.1371/journal.pcbi.1000503
Abstract: Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggested as a mechanism conferring insensitivity to imatinib, and exposure to the Granulocyte-Colony Stimulating Factor (G-CSF), together with imatinib, has led to a significant reduction in leukemic stem cells in vitro. In this paper, we design a novel mathematical model of stem cell quiescence to investigate the treatment response to imatinib and G-CSF. We find that the addition of G-CSF to an imatinib treatment protocol leads to observable effects only if the majority of leukemic stem cells are quiescent; otherwise it does not modulate the leukemic cell burden. The latter scenario is in agreement with clinical findings in a pilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the production of cycling leukemic stem cells. Although the pilot study did not include enough patients to draw any conclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib. Our results suggest that the additional use of G-CSF may be detrimental to patients in the clinic.
A mathematical model of granulopoiesis incorporating the negative feedback dynamics and kinetics of G-CSF/neutrophil binding and internalisation  [PDF]
Morgan Craig,Antony R Humphries,Michael C Mackey
Quantitative Biology , 2015,
Abstract: We develop a physiological model of granulopoiesis which includes explicit modelling of the kinetics of the cytokine granulocyte colony-stimulating factor (G-CSF) incorporating both the freely circulating concentration and the concentration of the cytokine bound to mature neutrophils. G-CSF concentrations are used to directly regulate neutrophil production, with the rate of differentiation of stem cells to neutrophil precursors, the effective proliferation rate in mitosis, the maturation time, and the release rate from the mature marrow reservoir into circulation all dependent on the level of G-CSF in the system. The dependence of the maturation time on the cytokine concentration introduces a state-dependent delay into our differential equation model, and we show how this is derived from an age-structured partial differential equation model of the mitosis and maturation, and also detail the derivation of the rest of our model. The model and its estimated parameters are shown to successfully predict the neutrophil and G-CSF responses to a variety of treatment scenarios, including the combined administration of chemotherapy and exogenous G-CSF. This concomitant treatment was reproduced without any additional fitting to characterise drug-drug interactions.
G-CSF in Peg-IFN induced neutropenia in liver transplanted patients with HCV recurrence  [cached]
Francesca Lodato, Francesco Azzaroli, Maria Rosa Tamè, Maria Di Girolamo, Federica Buonfiglioli, Natalia Mazzella, Paolo Cecinato, Enrico Roda, Giuseppe Mazzella
World Journal of Gastroenterology , 2009,
Abstract: AIM: To evaluate the efficacy of granulocyte colony stimulating factors (G-CSF) in liver transplanted patients with hepatitis C (HCV) recurrence and Pegylated-IFN α-2b induced neutropenia, and to evaluate the impact of G-CSF administration on virological response.METHODS: Sixty-eight patients undergoing antiviral treatment for post-liver transplantation (OLT) HCV recurrence were enrolled. All patients developing neutropenia received G-CSF.RESULTS: Twenty three (34%) received G-CSF. Mean neutrophil count at the onset of neutropenia was 700/mmc (range 400-750/mmc); after 1 mo of G-CSF it increased to 1210/mmc (range 300-5590/mmc) (P < 0.0001). Three patients did not respond to G-CSF. Treatment duration was similar in neutropenic and non-neutropenic patients. No differences in the rate of discontinuation, infections or virological response were observed between the two groups. G-CSF was protective for the onset of de novo autoimmune hepatitis (P < 0.003).CONCLUSION: G-CSF administration is effective in the case of Peg-IFN induced neutropenia increasing neutrophil count, prolonging treatment and leading to sustained virological response (SVR) rates comparable to non-neutropenic patients. It prevents the occurrence of de novo autoimmune hepatitis.
Nivestim (filgrastim): a new, convenient, daily G-CSF is effective for the prevention of febrile neutropenia
EJHP Author
European Journal of Oncology Pharmacy , 2010,
Abstract: Clinical research has shown that Nivestim can reduce the duration of chemotherapy-induced neutropenia (CIN) and prevent febrile neutropenia (FN) in patients with cancer.
Utilidad del factor estimulador de colonias de granulocitos (G-CSF) en episodios de neutropenia febril de alto riesgo en ni os con cáncer Usefulness of G-CSF in pediatric high risk cancer patients with fever and neutropenia  [cached]
NATALIE RODRíGUEZ Z.,JUAN TORDECILLA C.,MYRIAM CAMPBELL B.,PILAR JOANNON S.
Revista chilena de infectología , 2005,
Abstract: La neutropenia febril (NF) secundaria a quimioterapia es causa importante de morbilidad y mortalidad en los pacientes oncológicos pediátricos. El uso de factor estimulante de colonias de granulocitos (G-CSF) después de ciclos de quimioterapia intensa ha disminuido la frecuencia de complicaciones infecciosas asociadas, pero su utilización durante el episodio de NF es controvertida. Se analizaron 35 episodios de NF de alto riesgo. En forma randomizada 18 pacientes recibieron G-CSF asociado al tratamiento antimicrobiano habitual (grupo A) y 17 no lo recibieron (grupo B). Ambos grupos tenía parámetros biomédicos y clínicos similares. No se encontró diferencias significativas con respecto a la duración de la hospitalización (promedio grupo A 8 días vs grupo B 7 días) ni del tratamiento antimicrobiano (promedio 8 vs 7 días), de la fiebre (promedio 2 vs 3 días) y del período de neutropenia (promedio 3 vs 4 días). Considerando la revisión de la literatura y la experiencia local creemos que el uso de G-CSF no estaría recomendado en el manejo de pacientes oncológicos con episodios de NF Chemotherapy associated febrile neutropenia is an important cause of morbidity and mortality in pediatric patients with cancer. The use of granulocyte_colony stimulating factor (G-CSF) post chemotherapy decreases the risk of infectious complications but its efficacy during the febrile neutropenic episode remains controversial. Thirty five episodes of high-risk febrile neutropenia were randomized into two treatment arms, 18 received antibiotics and G-CSF (group A) and 17 received antibiotics only upon admission (group B). Both groups were comparable in terms of demographic and clinical characteristics. No significant differences between groups were found in duration of hospitalization (mean group A 7 vs group B 8 days), antibiotic treatment (mean 7 vs 8 days), fever (3 vs 2 days), nor of neutropenia (4 vs 3 days). One patient in group A died after RSV infection. Considering these results and a literature review, we propose that G-CSF should not be recommended in children during the course of their febrile neutropenic episode
Utilidad del factor estimulador de colonias de granulocitos (G-CSF) en episodios de neutropenia febril de alto riesgo en ni?os con cáncer
RODRíGUEZ Z.,NATALIE; TORDECILLA C.,JUAN; CAMPBELL B.,MYRIAM; JOANNON S.,PILAR; RIZZARDINI L.,CARLOS; SOTO A.,VERóNICA; VERDUGO L.,PATRICIA;
Revista chilena de infectología , 2005, DOI: 10.4067/S0716-10182005000300001
Abstract: chemotherapy associated febrile neutropenia is an important cause of morbidity and mortality in pediatric patients with cancer. the use of granulocyte_colony stimulating factor (g-csf) post chemotherapy decreases the risk of infectious complications but its efficacy during the febrile neutropenic episode remains controversial. thirty five episodes of high-risk febrile neutropenia were randomized into two treatment arms, 18 received antibiotics and g-csf (group a) and 17 received antibiotics only upon admission (group b). both groups were comparable in terms of demographic and clinical characteristics. no significant differences between groups were found in duration of hospitalization (mean group a 7 vs group b 8 days), antibiotic treatment (mean 7 vs 8 days), fever (3 vs 2 days), nor of neutropenia (4 vs 3 days). one patient in group a died after rsv infection. considering these results and a literature review, we propose that g-csf should not be recommended in children during the course of their febrile neutropenic episode
Efficacy and safety of ior? LeukoCIM (G-CSF) in patients with neutropenia after chemotherapy
Pérez Ruiz,Leslie; Ramos Cede?o,Ana María; Fernández águila,Julio Dámaso; Guerra Alfaro,Tamara; Cabrera Zamora,Maritza; Pascau Illas,Luciano Julián;
Revista Cubana de Farmacia , 2011,
Abstract: neutropenia and infections are the most restrictive side effects during chemotherapy application. the granulocytic colonies stimulating factor activates the neutrophils, shortens the neutropenic period and can be effective against the potential risk of infection. the purpose of this study was to evaluate the efficacy and safety of leukocim? (cimab, havana). a retrospective observational study was carried out with data from the patients with neutropenic episodes enrolled in the open-label, non-randomized, multicenter, phase iv clinical trial. these patients were from gustavo aldereguía lima hospital. they had been evaluated for one year. demographic information, clinical data and side effects were analyzed. as prophylaxis indication leukocim? was administrated 24-72 h after the last chemotherapy dose and as treatment when neutropenia was diagnosed. in both cases, a daily single 300 μg dose was administrated subcutaneously. the application of the next chemotherapy cycle on time was the main variable of response and the product safety was assessed by measuring the side effects. forty seven patients with 95 neutropenic episodes were enrolled. the 82.1 % of episodes received their next chemotherapy cycle on time. the most frequent side effects were: bone pain and fever (11.2 % respectively), hyperuricemia (9.2 %), leukocytosis and neutrophilia (7.1 %) and increased ldh (6.1 %). leukocim? was effective in patients receiving chemotherapy, because it accelerated neutrophil recovery, decreased the incidence of febrile neutropenia and improved delivery of protocol doses of chemotherapy on time. additionally, this product was considered safe for the studied patients since just known adverse events were reported.
The Cyclical Integration Model as a Way of Managing Major Educational Change  [PDF]
Richard G. Berlach
Education Research International , 2011, DOI: 10.1155/2011/963237
Abstract: Where minds meet, there lies the change vector. With regard to change management, however, minds regularly fail to meet in the crucial change space. They either unwittingly zip past each other, deliberately avoid one another, or worse still, collide with excruciating impact. This paper examines the interrelated role of government, the public service and professionals in successfully transitioning major change initiatives. It is argued that unless these agencies operate in synchrony, change negotiation is likely to be hampered. To this end, a model of “Cyclical Integration” is presented and supported by driving questions for each of the three agencies facilitating the change process. Although it is considered that these questions are sufficiently broad to encompass change management across any number of enterprises, what is being considered in this paper is the arena of compulsory education.
Efficacy and safety of ior LeukoCIM (G-CSF) in patients with neutropenia after chemotherapy Eficacia y seguridad del ior LeukoCIM (FEC-G) en pacientes con neutropenia posquimioterapia
Leslie Pérez Ruiz,Ana María Ramos Cede?o,Julio Dámaso Fernández águila,Tamara Guerra Alfaro
Revista Cubana de Farmacia , 2011,
Abstract: Neutropenia and infections are the most restrictive side effects during chemotherapy application. The granulocytic colonies stimulating factor activates the neutrophils, shortens the neutropenic period and can be effective against the potential risk of infection. The purpose of this study was to evaluate the efficacy and safety of LeukoCIM (CIMAB, Havana). A retrospective observational study was carried out with data from the patients with neutropenic episodes enrolled in the open-label, non-randomized, multicenter, phase IV clinical trial. These patients were from Gustavo Aldereguía Lima hospital. They had been evaluated for one year. Demographic information, clinical data and side effects were analyzed. As prophylaxis indication LeukoCIM was administrated 24-72 h after the last chemotherapy dose and as treatment when neutropenia was diagnosed. In both cases, a daily single 300 μg dose was administrated subcutaneously. The application of the next chemotherapy cycle on time was the main variable of response and the product safety was assessed by measuring the side effects. Forty seven patients with 95 neutropenic episodes were enrolled. The 82.1 % of episodes received their next chemotherapy cycle on time. The most frequent side effects were: bone pain and fever (11.2 % respectively), hyperuricemia (9.2 %), leukocytosis and neutrophilia (7.1 %) and increased LDH (6.1 %). LeukoCIM was effective in patients receiving chemotherapy, because it accelerated neutrophil recovery, decreased the incidence of febrile neutropenia and improved delivery of protocol doses of chemotherapy on time. Additionally, this product was considered safe for the studied patients since just known adverse events were reported. La neutropenia y las infecciones constituyen los eventos adversos más limitantes en la aplicación de quimioterapia. Los factores estimulantes de colonias de granulocitos activan los neutrófilos, acortan el periodo neutropénico y pueden ser efectivos contra los riesgos potenciales de infección. El propósito de este estudio fue evaluar la efectividad y seguridad del LeukoCIM (CIMAB, La Habana). Se realizó un estudio retrospectivo, observacional con los datos de los pacientes incluidos en el ensayo clínico fase IV abierto, no aleatorizado y multicéntrico. Estos pacientes provenían del Hospital Gustavo Aldereguía Lima y se evaluaron durante un a o. Se analizaron los datos demográficos, clínicos y de seguridad. Como profilaxis el fármaco fue administrado de 24-72 h después de la última dosis de quimioterapia y como tratamiento cuando la neutropenia había sido
Mathematical Model of Shock Waves  [PDF]
Alexei Krouglov
Physics , 2001,
Abstract: Presented here is the mathematical model describing the phenomenon of shock waves. The underlying concept is based on the time-space model of wave propagation.
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