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Journal articles on the topic "G 60 UL 2009 G518"
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Piccin, Andrea, Michael Steurer, Manfred Mitterer, Elisabeth Blöchl, Luigi Marcheselli, Irene Pusceddu, Alessandra Marabese, et al. "Blood Cells Dynamic and Thrombo-Haemorragic Events in Low Risk Essential Thrombocytosis Patients. A North Italian and Austrian Study." Blood 120, no. 21 (November 16, 2012): 2839. http://dx.doi.org/10.1182/blood.v120.21.2839.2839.
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Abstract Abstract 2839 Patients affected by low-risk essenthial thrombocythosis (ET) may develope thrombotic/haemorragic events at a lower rate compared to high-risk ET patients. So far, it has not be possible to identify useful markers to predict which of these patients are more likely to have an event. Previous authors [Carobbio A et al, Blood 2007] have shown that leukocytosis at diagnosis is associated with a high hazard risk (HR) of developing a thrombotic event, while high platelets count is not. Subsequently other authors [Gangant N et al, Cancer 2009] have contradicted this findings and instead shown that in low-risk ET, the increase in leukocyte count over time correlates with thrombotic events [Passamonti F et al ISTH 2009]. For these reasons we decided to evaluate risk parameters in a dynamic manner with the aim of identifying those patients who are more likely to have an event and might benefit from preventive treatment. We performed a large multicentre retrospective study that included several North Italian Haemathology centres and a large Austrian university hospital. Patient data was analysed using random effect linear regression model and a dedicated Cox model with dynamic proportional risk. We studied 136 patients with low risk ET. Out of those, 45 had a thrombotic/haemorragic event and 91 never had an event (events included: stroke, TIA, IMA, PE, PAD, epystaxis and gastrointestinal bleeding). Overall, the median age was 42 years (IQR 20; range 18–60), the median Hb was 14.0 g/dL (IQR 2.3; range 4.4–18), the median WBC was 8.1 ×103/Â μL (IQR 3.3; range 3.3–23.8), the median PLT was 701 ×103/ÂL (IQR 404; range 206–1806). Gender was M 33% (n=45), F 67% (n=91); smokers were 24% (n=18/N=74); hypercholesterolemia was 18% (n=17/N=92). The FBCs of both groups were recorded from the date of diagnosis (entry time) and up to 3 years of follow up or to the development of a thrombotic/haemorragic event (exit time). A total number of 1294 FBCs were provided by the group with event and compared to a total of 4487 FBCs from the group without event. The follow-up Hb values showed a decreasing linear pattern linear from baseline values. The PLT-count showed a trend similar to Hb over the period of follow-up in both the group without events and in the group with events. The WBC showed a decrease during follow-up in the group with events and an increase in the group without events. Surprisingly, the risk of developing an adverse event after 60 months of follow-up was reduced by 20% for each increase of 1 g/dL Hb (p =0.007), was increased by 8% for each WBC increase of 1 103/uL (p =0.026) and was decreased by 6% for each PLT increase of 100 × 103 /uL (p =0.434). No differences were seen between venous or arterious thrombotic events (Log rank test, p=0.842). In conclusion, this study confirms that baseline FBCs values are not predictive of events within the ET low risk group. The emerging new finding is that the risk of developing an event is higher when Hb is reduced. This strongly suggests a protective role of Hb in the low-risk ET group. Previous studies have shown that red cells might store and generate nitric oxide (NO), a key endothelial modulator [Kim-Shapiro DB et al 2006]. The presence of NO would keep PLT in resting state, would reduce endothelial cell adhesion and in turn reduce thrombosis rate. However this needs to be confirmed. Disclosures: Steurer: Amgen: Consultancy, Honoraria. Pizzolo:Hoffmann-La Roche: Consultancy, Honoraria.
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Dumitriu, Bogdan, Danielle M. Townsley, Christina Chen, Rodrigo T. Calado, Phillip Scheinberg, and Neal S. Young. "Telomere Elongation and Hematologic Improvement in Humans Treated with Androgens: A Prospective Clinical Trial of Danazol in Telomeropathies." Blood 124, no. 21 (December 6, 2014): 258. http://dx.doi.org/10.1182/blood.v124.21.258.258.
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Abstract Telomeres, the terminal complex of hexameric repeats and shelterin protein of linear chromosomes, shorten with every mitosis. Telomere attrition is accelerated in patients with mutations in telomerase complex genes (Calado and Young, NEJM 2009) and with replicative stress, as in chronic bone marrow failure. Historically, male hormones were effective in some patients with aplastic anemia (AA), and case reports and retrospective observations have suggested hematologic improvement in patients with telomeropathies treated with male hormones. Exposure of normal lymphocytes and CD34+ cells to androgens increased telomerase activity in vitro, and in cells from individuals carrying loss-of-function TERT mutations to normal levels (Calado et al. Blood 2009). We have conducted a phase I/II single-center trial (www.clinicaltrials.gov NCT01441037) assessing the safety and the effect of male hormones on telomere attrition in patients with telomere disease. Entry criteria included age-adjusted mean telomere content ≤1%ile, ± identified mutations in telomerase complex genes, and low blood counts (hemoglobin <9.5g/dL, platelets <30,000/uL, or neutrophils <1,000/uL) and/or pulmonary fibrosis. Danazol, 800 mg/day, was administered for 2 years. Primary protocol objectives were safety and activity of danazol in slowing telomere attrition. Secondary endpoints were hematologic response at 3 and 6 months (increase in hemoglobin >1.5 g/dL or platelets >20,000/uL or neutrophils >500/uL). Twenty seven patients were enrolled, accrual commencing August 2011. Most patients had moderate (n=20) or severe (n=4) AA, one had myelodysplasia, and two pulmonary fibrosis. Median age was 41 years (range 17-66); 15 patients were females. There was only one severe adverse event possibly related to drug. Frequent reported symptoms were muscle cramping with dehydration and exacerbation of headaches. Changes in serum lipid profiles were observed in all patients, with increased serum LDL and decreased HDL. Severe elevation in liver enzymes was not observed. One death occurred on study, not treatment related (pneumonia in a pulmonary fibrosis case). Mean telomere content of leukocytes at enrollment was compared with mean telomere content at 6, 12, and 24 months on drug as well as available samples before starting danazol. Telomere attrition prior to protocol entry, determined by q-pcr, was estimated at loss of 227 bp/year (95% CI, 58-368bp; p=0.009). Androgen administration appeared to elongate telomeres: the average increase in telomere length at 6 months was 205 bp (95% CI, 82-329 bp; p=0.002), at 12 months 441 bp (95% CI, 263-620 bp; p=0.0001), and at 24 months 347 bp (95% CI, 87-607 bp; p=0.01). A similar trend of increase in mean telomere content with danazol was confirmed in flow-sorted lymphocytes. Hematologic response rate, as defined by protocol, was 67% at 3 months and 60% at 6 months. Nine of eleven patients who required RBCs became transfusion-independent; two of them also became platelet transfusion independent. Liver cirrhosis was present in 6 patients at enrollment; worsening of liver disease in one occurred with continued alcohol abuse. To date 8 patients have completed two years of danazol, all of them responders; 10 patients remain on danazol, and 9 patients stopped drug prior to 2 years. Blood counts in all patients have been stable with drug discontinuation, with median follow up of 258 days (range 31-335). In conclusion, male hormones are safe and efficacious in patients with inherited bone marrow failure associated with telomeropathies, producing clinically meaningful hematologic improvement. Increased mean telomere content in patients, suggests that in vitro demonstration of up-regulation by sex hormones of TERT and of telomerase enzymatic activity is the mechanism of action of androgens in vivo. To our knowledge, this is the first successful prospective effort to favorably modulate telomere length by pharmacologic intervention in humans. Sex hormones may be useful in other conditions of accelerated telomere attrition, as for example after chemotherapy, and other drugs and small molecules may be usefully screened for their effects on telomerase in vitro. Disclosures Off Label Use: we want to determine if treatment with male hormone danazol is safe and improves hematologic response as first-line treatment in patients with AA and telomere disease(www.clinicaltrials.gov NCT01441037)..
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Logan, Aaron C., Robert Su, Tracy I. George, Holbrook E. Kohrt, Bruno C. Medeiros, and Ash A. Alizadeh. "High Risk of Early Mortality in Adult Patients with Acquired Hemophagocytic Lymphohistiocytosis." Blood 114, no. 22 (November 20, 2009): 1359. http://dx.doi.org/10.1182/blood.v114.22.1359.1359.
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Abstract Abstract 1359 Poster Board I-381 Background Hemophagocytic lymphohistiocytosis (HLH) is a rare condition in which dysregulation of innate immune effectors including natural killer (NK) cells and macrophages leads to destruction of hematopoietic elements. HLH is most frequently reported in association with malignancies or viral infections, with heritable deficiencies in cytotoxicity pathways predisposing children (and rarely adults) to HLH. Criteria for diagnosing HLH include: histological evidence of hemophagocytosis, two or more cytopenias, hyperferritinemia, hypofibrinogenemia or hypertriglyceridemia, elevated soluble IL-2R, decreased in vitro NK cell function, fever, and splenomegaly. Patients meeting >=5 of these criteria are diagnosed with HLH. Source: We identified 19 consecutive adult patients (53% male; median age 43y, range 16-83) admitted to Stanford Hospital with clinical suspicion for HLH and histological evidence of hemophagocytosis between 1997 and 2009; 2 patients were excluded from analysis due to incomplete data. Of the remaining 17 patients, 11 (65%) met criteria for a diagnosis of HLH. Results At presentation, all patients were anemic with a median Hgb concentration of 8.6 g/dL. Leukopenia was present in 8/11 (73%) with a median WBC count of 2 K/uL. Thrombocytopenia was present in 10/11 (91%) patients with a median Plt count of 30 K/uL. In 6 patients not meeting HLH criteria, median hematologic findings were Hgb 8.6 g/dL, WBC 2.6 K/uL, and Plts 126 K/uL. All patients demonstrated marked elevations of ferritin, median 3915 ng/dL (range 1039 – 29,700). Triglycerides were elevated in 7/10 (70%) for whom data were available, median 296 mg/dL (range 204 – 1,506). Fibrinogen was decreased in 3/13 (23%). Soluble IL-2 receptor level was above normal limits in all patients in whom it was measured (range 796 – 17,378 U/mL), but met the >2,400 U/mL criteria in only 3/6 (50%). In vitro NK function was diminished in 2/5 (40%) patients tested. Fever and splenomegaly were found in 94% and 59% of patients, respectively. Of 11 patients meeting HLH criteria, 5 had associated malignancies (DLBCL, NK cell leukemia, T cell lymphoma, AML, and Kaposi sarcoma) and 4 had concomitant viral infections (2 EBV, 1 EBV/B19, and 1 HIV-1/HHV-8). Three patients had isolated viral infections (all EBV), while 3 had idiopathic HLH. Amongst 6 patients not meeting HLH diagnostic criteria, 2 (33%) had an associated malignancy (SLL and NK cell lymphoma), 1 had an isolated EBV infection, and 3 had idiopathic disease. At a median follow-up of 16 months for surviving patients, the case fatality rate amongst those with established HLH diagnoses was 55%, with all deaths occurring within 2 months from diagnosis. Five patients were treated according the HLH-94/04 protocol combining dexamethasone, cyclosporine and etoposide. Two patients died within 2 months of initiating treatment, and 3 remain alive (survival to date ranges 4-31 months). The longest surviving patient underwent allogeneic HCT. A patient who presented with AML-associated HLH underwent induction chemotherapy then proceeded to allogeneic HCT and remains alive 9 months after diagnosis. Amongst 6 patients not meeting HLH criteria, the case fatality rate was 67% with a median survival of 2.3 months. None of these patients were treated with the HLH-94/04 protocol; however, 2 were treated with cyclosporine and remain alive 16 and 24 months after diagnosis. Conclusions Of the HLH diagnostic criteria, multiple cytopenias, hyperferritinemia, and hypertriglyceridemia were sensitive measures, whereas hypofibrinogenemia, markedly elevated sIL-2R, and decreased in vitro NK cell function were found in fewer than half of patients. At our institution, EBV-associated HLH predominates (7/17 cases, 41%). Most of the malignancy-associated HLH we have seen also occurred in the context of EBV infection. The case fatality rate amongst all patients with histologic evidence of hemophagocytosis, including those not meeting HLH criteria, is high. In most patients, treatment according to HLH-94/04 may be appropriate and likely improves survival. In our experience with the HLH-94/04 protocol, 60% of patients remain alive. Until sufficient evidence emerges that this treatment strategy leads to durable remissions in the majority of patients, allogeneic HCT should remain a consideration for most patients. Disclosures No relevant conflicts of interest to declare.
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Schanz, Julie, Heinz Tüchler, Francesc Sole, Mar Mallo, Barbara Hildebrandt, Christian Steidl, Christa Fonatsch, et al. "Prognostic Impact of Monosomy 7 as a Single Anomaly In Primary MDS – Reclassification From Poor to Intermediate Prognosis." Blood 116, no. 21 (November 19, 2010): 1861. http://dx.doi.org/10.1182/blood.v116.21.1861.1861.
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Abstract Abstract 1861 Introduction: Total or partial Monosomy 7 (-7/del(7q)) is one of the most frequent cytogenetic abnormalities in MDS, occurring in about 11% of abnormal cases in patients (pts) with primary MDS. The cytogenetic module of the IPSS defines any abnormality of chromosome 7 as unfavourable and classifies them, combined with complex abnormalities, into the poor risk cytogenetic subgroup. However, in previous publications from other groups, the prognosis of isolated -7/del(7q) was described as intermediate. The aim of the present study was to re-analyze the prognostic impact of -7/del(7q) as a single anomaly based on a large, international MDS database which was previously presented at the 2009 ASH-meeting (Schanz et al. abstract #2772). Materials and Method: Patients with -7/del(7q), derived from the international MDS database were examined. The large international data collection contains 2901 patients with MDS, originating from the German-Austrian (GA)-, the International MDS Risk Analysis Workshop (IMRAW)- and the Spanish Cytogenetic Working group (GCECGH) and the International Cytogenetics Working Group of the MDS Foundation (ICWG). Inclusion criteria for the study were defined as follows: Primary MDS, age >=16, and bone marrow blasts <=30%. Regarding therapy, patients with primary MDS who received supportive care, short courses of oral chemotherapy or hemopoietic growth factors were included. Univariate and multivariate analysis were performed for overall survival (OS) and risk of AML-transformation (AML-t). In multivariate analysis, site, age, gender, bone marrow blast count, date of first diagnosis and number of peripheral cytopenias were defined as co-variables. Results: In total, 60 patients (2.1% of all pts/4.4% of abnormal cases) with an isolated -7/del(7q) were detected. The median age of these pts was 66.1 years, which is significantly lower compared to pts without monosomy 7 (70.0 years; p<0.01; t-test, 2-sided). Regarding peripheral blood count, the mean hemoglobin in -7/del(7q) pts (9.2 g/dl) as well as ANC (1.7*103/ul) did not differ significantly as compared to pts without -7/del(7q) whereas the platelet count in pts with -7/del(7q) was significantly lower (82*103/ul vs. 125*103/ul; p<0.01). The median overall survival in -7/del(7q) pts was 16.0 (95% CI 14.0–21.4) months and the Hazard ratio (HR; as compared to a normal karyotype with a median survival of 47.4 (44.0-53.4) months as the reference category) was 1.6 (1.1-2.3; <0.01). Regarding the risk of AML-transformation, the median time to AML was 42.2 (14.4-not reached) months and the HR 1.7 (0.9-3.2; p<0.01). In comparison, this differed significantly from the median survival- (p<0.0001) and time to AML-transformation (p=0.027) for complex abnormalities, which are included with -7/del(7q) in the poor risk IPSS cytogenetic subgroup and were 5.7 (4.7-6.8) and 8.2 (6.4-14.0) months, respectively. The HR for complex abnormalities was 4.3 (3.4-5.4; p<0.01) for OS and 5.2 (3.8-7.5; p<0.01) for AML-transformation. Conclusions: The re-analysis of -7/del(7q), based on the largest MDS patient cohort yet published, confirms that the prognostic impact of an isolated total or partial monosomy 7 for overall survival as well as the risk of AML-transformation is intermediate, rather than poor. This finding is anticipated to be considered in the upcoming revision of the IPSS. Acknowledgments: The authors like to thank the MDS-Foundation for its support. Disclosures: Valent: Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Bennett:Johnson & Johnson: Consultancy.
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Amaru, Ricardo, Ariel Amaru, Hortensia Miguez, Gina Torres, Josue Mamani, Maria Aguilar, and Heriberto Cuevas. "Successful Treatment of HU-Refractory Polycythemia Vera with Atorvastatin and Low Dose Hydroxyurea. Results from a Pilot Study in Bolivia." Blood 126, no. 23 (December 3, 2015): 5621. http://dx.doi.org/10.1182/blood.v126.23.5621.5621.
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Abstract Background Polycythemia Vera (PV) is a clonal myeloproliferative neoplasm, characterized by the JAK2V617F mutation. The main goal of current therapies for PV is to prevent thrombotic events and delay transformation to Myelofibrosis (MF) or Acute Myeloid Leukemia (AML).Treatment for PV to keep an hematocrit (Hct) level <45 %, has been associated with a reduction in cardiovascular deaths and thrombotic events (Marchioli, R et al. NEJM 2013). Currently, low-risk PV patients (<60 years and no previous thrombotic events) are treated with aspirin and phlebotomy while high-risk patients require additional cytoreductive therapy, usually with Hydroxyurea (HU). Resistance to HU is associated with an increased risk of transformation and reduced survival. This is why for HU-refractory patients, second line treatments with interferon alpha, anagrelide or even ruxolitinib are recommended. In Latin America, because of high cost and drugs availability, this last group reflects difficulties to be treated. Because statins have been reported to modulate the erythroid clonogenic activity of normal BM erythroid colonies we performed a pilot study to investigate in vitro and in vivo the biologic and clinical activity of atorvastatin in PV patients Patients and Methods Ten high risk PV patients with a median age of 64.3 years (range 58-73) entered into this study. The diagnosis of PV was done according to the 2008 World Health Organization diagnostic criteria and patients were stratified according to an algorithm proposal provided by Griesshammer et al. (Ann Hematol, 2015). The definition of HU resistance (Barosi, G et al.: BJH 2009) was applicable to five patients (median age 63.9 years) failing to achieve a satisfactory hematologic response upon treatment with more than 2 g of HU, 100 mg of Aspirin and phlebotomies. The assessment of the JAK2V617F mutation was performed as previously described (Guerini et al.: Leukemia 2009). Colony assay, proliferation and apoptosis tests were performed with or without Simvastatin (3.5 uM), as previously described (Amaru, A, Experimental Hematology 2012), on cell lines (UKE1 and K562) and bone marrow mononuclear cells obtained from PV patients and healthy donors. Patients with HU refractory PV (n=5) and high risk PV with hypercholesterolemia (n=5) were eligible to receive Atorvastatin (20 mg/day) added on the top of the ongoing treatment with phlebotomies, Aspirin (100 mg/day) and cytoreductive HU therapy (500 mg/day). All treated patients were high altitude residents (> 3.600 m.a.s.l.) of La Paz (Bolivia) where the normal Hct level of healthy subjects is 48-57% for men and 44-54% for women. This pilot study was approved by the Review Board of the Hospital and the University of San Andres, La Paz. Results In a preliminary set of in vitro proliferation cell assays, simvastatin (3.5 uM), added for 5 days, induced a 33% inhibition of cell proliferation of UKE-1 (JAK2V617F mutated) as compared to 5 % of K562 (BCR/ABL positive). A comparable result was obtained in a 7-day clonogenic cell assay where the colony inhibition was 50 % for UKE-1 and 10 % for K562. On the basis of these results similar experiments were also performed using BM mononuclear cells derived from PV patients and healthy donors. In these experiments performed with the addition of simvastatin, it induced a 41% of inhibition in BFU-E colonies of PV patients and a 25% of inhibition in healthy donors. Furthermore, BFU-E colonies inhibited by simvastatin presented a decrease in hemoglobinization and the size of colonies. HU refractory PV patients and High-risk PV patients with hypercholesterolemia treated with the addition of Atorvastatin, Aspirin, cytoreductive HU and phlebotomies; after a follow-up of 2.6 years (1-7 years), induced a decrease of WBC from 16.500 to 9.270/ul, Hct 61.1 to 52.3% and PLT 457.900,000 to 324.7000/ul. The number of required phlebotomies is reduced in comparison to the required at starting treatment. None of the patients presented thrombotic or cardiopulmonary event. One patient died within two years of starting treatment, due to complications of diabetes mellitus. Conclusions In vitro and in vivo, statins showed some evidence of inhibitory activity of the hematopoiesis of PV patients. These preliminary results might indicate the opportunity to further investigate the potential clinical value of these molecules in the treatment of PV. Disclosures Off Label Use: Atorvastatin was used for its antiproliferative activity on myeloid progenitor cells shown by in vitro experiments.
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Dimicoli, Sophie, Elias Jabbour, Gautam Borthakur, Tapan Kadia, Zeev Estrov, Hui Yang, Mary A. Kelly, Sherry Pierce, Hagop M. Kantarjian, and Guillermo Garcia-Manero. "Phase II Study of the Histone Deacetylase Inhibitor Panabinostat (LBH589) in Patients with Low or Intermediate-1 Risk Myelodysplastic syndrome." Blood 118, no. 21 (November 18, 2011): 1731. http://dx.doi.org/10.1182/blood.v118.21.1731.1731.
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Abstract Abstract 1731 Panabinostat is a very potent panhistone deacetylase inhibitor (HDACi) with activity in acute myelogenous leukemia (CCR 2006;12: 4628). We hypothesized that single agent panabinostat could be active in patients with low and intermediate-1 risk MDS. Oral route of administration and safety profile further increased interest in this approach. To test this concept we designed a phase II study of panabinostat for patients above 18 years of age with lower risk disease. Patients could have received prior therapy or be treatment naïve. Appropriate renal, hepatic and cardiac functions were required. Patients were excluded if they had previous HDACi treatment. Patients with history of cardiac pathology such as rhythm alterations were excluded from the study. Use of drugs that could induce QT prolongation and CYP3A4 inhibitors were not allowed. Panabinostat was used at dose of 20 mg orally three times a week for consecutive 3 weeks with cycles repeated every 4 weeks. The primary objective of the study was overall response rate defined by IWG. A maximum of 40 patients could be enrolled. The study was to stop early if the expected response rate was less than 15%. Stopping rules were as follows: Stop if the number of patients with hematologic improvement/the number of patients evaluated was 0/15 or 1/32. The study also contained a stopping rule for non-hematological toxicity. Thirteen patients were enrolled between August 2009 and December 2010. Median age was 70 years (range 47 to 84, 84% of patients older than 60), 70% were transfusion dependent, 70% had intermediate-1 risk MDS, most patients were diploid but one patient with del(5q), one with trisomy 8, one with complex cytogenetics and 2 with deletion of 20q were included. Median percent of marrow blasts was 1% (range 1 to 6%). At start of therapy, median hemoglobin was 9.5 (range 7.5–11.2 G/dL), median platelet count was 56 (range 6–431 k/uL) and median white blood cell count was 4.6 (range 0.8–20.3 k/uL). Approximately 40% had previous therapy for MDS including hypomethylating agents, lenalidomide and investigational agent. Median number of prior therapies for treated patients was 2 (range 1 to 4). Median duration of disease at time of enrollment was 10 months (range 1–50). Patients received a median of 4 cycles of panabinostat (range 1–9). Of 13 patients, 1(8%) achieved a hematological improvement including both an erythroid and platelet response that lasted for 3 months. No complete remissions or partial responses were documented. Six patients (46%) had stable disease for a median duration of 6 months (range 2–13.6). Median overall survival was 15 months (1–31 months). Two patients died because progression to AML. Therapy was well tolerated: no major adverse events were documented except for one patient that developed significant QTc prolongation. Adverse events included mild fatigue and gastrointestinal toxicity. As a biomarker of molecular activity, histone H3 acetylation was measured in 5 patients with variable results. Induction of acetylation was documented in 2. Despite the fact that the stopping rule for activity was not officially met, because of the very modest clinical activity observed, the study was closed to new patient entry. In conclusion, panabinostat given as a single agent orally at a dose of 20 mg thee times a week for 3 weeks followed by one week of rest has limited clinical activity in patients with lower risk MDS. Disclosures: No relevant conflicts of interest to declare.
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Mushtaq, Muhammad Umair, Sibgha Gull Chaudhary, Laura C. Michaelis, Karen-Sue B. Carlson, Sameem Abedin, Lyndsey Runass, Michael J. Fallon, et al. "Comparison of Salvage Chemotherapy Regimens in Relapsed/Refractory Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 2708. http://dx.doi.org/10.1182/blood-2018-99-113764.
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Abstract Background Induction therapy for acute myeloid leukemia (AML) with a cytarabine-anthracycline regimen (7+3) is well-established; however, there is no standard salvage therapy for patients with relapsed/refractory AML (RR-AML). There is a paucity of data regarding outcomes with salvage regimens in RR-AML that include cladribine, cytarabine, and filgrastim with mitoxantrone (CLAG-M) or without mitoxantrone (CLAG), and mitoxantrone, etoposide, and cytarabine (MEC). We compared outcomes of patients receiving CLAG-M, CLAG or MEC as salvage therapy for RR-AML. Methods A multi-center retrospective study was conducted, including 146 adult RR-AML patients who underwent salvage therapy at the University of Wisconsin and Medical College of Wisconsin from 2009 to 2018. Demographic, clinical and pathologic factors were ascertained at the time of RR-AML diagnosis. The Center for International Blood and Marrow Transplant Research (CIBMTR) response criteria were used. Refractory AML was defined as failure to achieve remission after one or more courses of induction chemotherapy. Minimal residual disease (MRD)-negative was defined by the absence of leukemic cells by morphology and flow cytometry (<0.01%). Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using chi-square and t-test, and logistic regression analyses were performed for baseline characteristics and response to salvage chemotherapy. Kaplan-Meier analyses, using the log-rank test, were conducted. Cox regression analyses were used to correlate factors with OS. Hazard ratios (HR) with 95% CI were obtained. Statistical significance was considered at P<0.05. Results The study included 146 patients with relapsed (57.5%, n=84) or refractory (42.5%, n=62) AML who received CLAG-M (51%, n=74), MEC (39%, n=57) or CLAG (10%, n=15) salvage chemotherapy. Baseline characteristics were similar between the three groups (all P>0.1). Median age was 60 years (range 22-77 years) and 59% patients were male. AML was classified according to WHO 2016 guidelines as AML with recurrent genetic abnormalities (23%), myelodysplasia (MDS)-related AML (25%), therapy-related AML (8%) and AML not otherwise specified (44%). Cytogenetics were good (5%), intermediate (60%) and poor (36%) with normal (41%), complex (25%), trisomy (8%) and monosomy 5 or 7 (5.5%) being common karyotypes. Among those who had molecular testing (n=119), NPM1 and FLT3-ITD were reported in 21% and 20% patients respectively. AML risk status was good (16%), intermediate (32%) and poor (52%), based on cytogenetic and molecular abnormalities as per ELN 2017 and NCCN 2018 guidelines. Extramedullary disease was present in 13% patients. Prior hematopoietic stem cell transplant (HSCT) was performed in 13% patients. Median lab values prior to salvage regimen were: hemoglobin 9.1 g/dL, platelets 49 K/uL, leukocytes 2.5 K/uL, LDH 231 U/L and bone marrow myeloblasts 28%. Overall response rate was 49% (CLAG-M 55%, n=41/74; MEC 44%, n=25/57, CLAG 40%, n=6/15) with complete remission (CR) rate of 46% (CLAG-M 54%, MEC 37%, CLAG 40%) [P=0.140]. Three percent patients (n=5; CLAG-M=1, MEC=4) had CR with incomplete hematologic recovery (CRi). MRD analysis was available for 83 patients and a trend was seen in MRD-negative CR rates favoring CLAG-M (44%) over MEC (25%) or CLAG (17%) [P=0.128]. Sixty-six patients (45%) received subsequent HSCT (CLAG-M 50%, n=37/74; MEC 44%, 25/57; CLAG 27%, n=4/15) [P=0.245]. At last follow-up, 34% patients were in CR (CLAG-M 42%, MEC 28%, CLAG 20%) [P=0.120]. Fifty (34%) patients were alive at last follow-up (CLAG-M 46%, MEC 23%, CLAG 20%) [P=0.010]. Median OS was 9.7 months (95% CI 6.8-12.6) that was significantly better with CLAG-M (13.3 months, 95% CI 2.4-24.3) compared to MEC (6.9 months, 95% CI 2.9-10.9) or CLAG (6.2 months, 95% CI 2.4-12.6) [P=0.025] Figure 1. In multivariate model adjusted for age, gender and refractory vs relapsed AML, MEC (HR 1.75, 95% CI 1.13-2.71, P=0.013) and CLAG (HR 1.97, 95% CI 1.02-3.79, P=0.043) regimens had worse OS compared to CLAG-M. After adjusting for age, gender, refractory vs relapsed AML and HSCT, CLAG-M remained independent predictor of better OS (HR 0.64, 95% CI 0.42-0.97, P=0.037). Conclusion CLAG-M compared to MEC or CLAG is associated with significantly better OS in RR-AML regardless of age, refractory vs relapsed AML and HSCT. Our findings support the use of CLAG-M as a preferred salvage regimen for RR-AML. Figure 1. Figure 1. Disclosures Atallah: Novartis: Consultancy; BMS: Consultancy; Jazz: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy.
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Grosso, Dolores, Onder Alpdogan, Matthew Carabasi, Joanne Filicko-O'Hara, Margaret Kasner, Ubaldo Martinez, William O'Hara, John L. Wagner, Mark Weiss, and Neal Flomenberg. "A 2 Step Approach To Myeloablative Haploidentical Hematopoietic Stem Cell Transplantation (HSCT): Low Non-Relapse Related Mortality (NRM) and High Overall Survival (OS) Rates Confirmed In Second Generation Trial." Blood 122, no. 21 (November 15, 2013): 3360. http://dx.doi.org/10.1182/blood.v122.21.3360.3360.
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Abstract Over 7 years ago, we developed a 2 step myeloablative approach to haploidentical HSCT in which patients, after conditioning with 12 Gy of total body irradiation (TBI days -9 to -6), receive a fixed dose of 2 x 108/kg of donor T cells (DLI-step 1 of HSCT) immediately after the last fraction of TBI. This large dose of haploidentical lymphocytes results in high fever, and in some cases, diarrhea and rash, developing on days-5 and -4. Cyclophosphamide (CY) 60 mg/kg, given on days -3 and -2 for T cell tolerization, results in complete resolution of this “alloreaction.” Tacrolimus and MMF are begun on day-1, followed by a CD 34 selected donor product infused on day 0 (Step 2 of HSCT). The separation of the lymphoid and myeloid portions of the graft (1) avoids the exposure of allogeneic stem cells to CY, (2) avoids the polarization of T cells to a TH2 phenotype because the donor T cells are collected prior to the initiation of G-CSF, (3) allows the administration of a fixed dose of T cells establishing a consistent platform from which to compare outcomes, and (4) provides a method to deliver higher doses of T cells. Recent data suggests that T cell doses > 1.1 x108/kg are associated with superior GVT effects as compared to lower T cell doses (Guo et al. JCO, 2012;30:4084 and Colvin et al. BBMT, 2009;15:421). To date, over 180 patients have undergone 2 step haploidentical myeloablative and reduced intensity HSCT at our institution. In the initial myeloablative haploidentical trial (2006-2009), twenty-seven patients underwent treatment using this approach. Immune reconstitution was brisk with median CD3/4 and CD3/8 counts at day +28 of 33.6 and 28.7 cells/ul respectively Cumulative incidences of grades III-IV graft versus host disease (GVHD), NRM, and relapse-related mortality were 7.4%, 22.2%, and 29.8% respectively. OS for the 12 patients without disease at HSCT was 75% and 48% for the whole cohort with 51-79 (median 63) months of follow-up. A 2nd generation myeloablative 2 step trial specific to patients without morphologic evidence of disease at the time of their haploidentical HSCT completed accrual in 2013. Twenty-eight patients with AML (15), ph+ ALL (4), B cell ALL (4), T cell ALL (2), MDS (1), mantle cell NHL (1), and hepatosplenic NHL (1), were treated and are 3-32 (median 14) months post HSCT. All patients engrafted and no patients died of GVHD or infection. Median CD3/4 and CD3/8 counts at 28 days were 74 and 47 cells/ul respectively. The only death related to treatment occurred in a patient who suffered a subdural hematoma after an LP performed for fever. Four patients have relapsed (14%), 3 of whom have died of their disease. The probability of OS of the patients treated on the current trial is 85% at 15 months. The combination of the most recently treated 28 patients with the 12 patients treated on the initial trial who were in morphologic CR at the time of HSCT, has resulted in a probable OS rate of 78% with 3 to 79 (median 18 months of follow-up). For patients without morphologic evidence of their disease at the time of HSCT, the 2 step myeloablative approach to haploidentical HSCT has been associated with robust immune reconstitution resulting in low rates of infectious death. There have been no deaths from GVHD, and very low rates of treatment-related mortality. OS rates of the good risk patients treated on this approach are very high due to this low degree of NRM. The results of this 2nd generation trial have confirmed that the 2 step myeloablative approach to haploidentical HSCT is safe and efficacious and produces outcomes that are comparable to those reported by CIBMTR (2000-2010) for recipients of matched related or other alternative donor grafts. This approach has become our alternative HSCT strategy of choice allowing virtually every patient to be treated with HSCT rapidly at our institution. Disclosures: Kasner: Roche: Research Funding.
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Grosso, Dolores, Matthew Carabasi, Janet Brunner, Beth Colombe, Joanne Filicko-O'Hara, Eileen C. Finnegan, Phyllis Flomenberg, et al. "A Two Step Myeloablative Approach to Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Hematological Malignancies From HLA Partially-Matched (Haploidentical) Related Donors." Blood 114, no. 22 (November 20, 2009): 2292. http://dx.doi.org/10.1182/blood.v114.22.2292.2292.
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Abstract Abstract 2292 Poster Board II-269 Lack of a matched donor remains a major obstacle to the application of allogeneic HSCT in all appropriate patients. We developed a haploidentical 2 step myeloablative transplant regimen that used Cyclophosphamide (CY) tolerization to avoid severe GVHD while still allowing rapid post-HSCT immune reconstitution. We refer to this as a two step approach because the patients receive the lymphoid and stem cell portions of the graft at different times during the transplant regimen rather than as a single transplant inoculum. Between 2006 and 2009 twenty-seven patients, median age of 52 years (range 19-67), with high risk hematological malignancies were transplanted from haploidentical donors that were mismatched for HLA-A, B, C, and DR in the GVHD direction at 4 antigens (13), 3 antigens (11), and 2 antigens (2). One patient had no mismatches in the GVHD direction but was a 3 antigen mismatch in the rejection direction. The patients were given a conditioning regimen consisting of eight fractions (total dose 12 Gy) of total body irradiation (TBI) followed immediately thereafter by a donor lymphocyte infusion (DLI) of 2 ×10e8 CD3+ donor T cells, the first step of the transplant process. Within 24 hours, this dose of T cells consistently produced an in-vivo allogeneic reaction characterized by fever (median temperature 103.8f) and in many cases rash and diarrhea. Skin biopsies performed on 2 of the patients with rash were consistent with GVHD. After a median time of 63 hours (range 60-66 hours) following the DLI, CY (60 mg/kg/day) was given for 2 days to eliminate alloactivated donor and host T cells. The symptoms caused by the DLI typically disappeared 24 hours after completion of CY. The second step of the transplant occurred when a CD34 selected HSC product from the same donor was infused 24 hours after the end of the infusion of CY. GM-CSF was used post HSCT to accelerate white cell recovery and to promote a TH1 type immune response. Tacrolimus and mycophenylate mofetil were used for GVHD prophylaxis. Donor apheresis was performed over 2 days for lymphocyte collection followed by administration of G-CSF for 5 days and an additional 2 aphereses for HPC collection on days 4 and 5 of G-CSF administration. Fifteen of 27 patients (56%) are alive without evidence of their disease 3 to 32 months past HSCT. One additional patient is alive but with relapsed disease. Kaplan-Meier estimates of survival are 70% in patients without disease at the time of HSCT and 43% in patients not in remission at HSCT. Eleven patients (41%) died, 5 from relapsed disease, 3 from toxicity, and 3 from infection. Of the 6 relapses, 5 occurred in mothers who received transplants from their children. There were no deaths attributable to GVHD and only 1 brief occurrence of severe (grade III gut) GVHD. Fifteen patients (55%) developed grade 1-2 GVHD, mostly of the skin and easily controlled with steroids in 11 or with steroids plus photopheresis in 4 patients. Three patients developed limited chronic GVHD, one of whom is off immunosuppressive therapy. Immune reconstitution was brisk. Patients typically reached CD3+CD4+ counts of >100 cells/ul within a few months of discontinuation of immunosuppressive therapy. Two multiparous females with pre-existing anti-donor antibodies experienced humorally mediated rejections. Both died of toxicities related to a second HSCT. The other toxic death occurred in the patient with no mismatches in the GVHD direction who experienced a flare of his Crohn's disease shortly before conditioning. Three infectious deaths occurred, one due to progression of preexisting aspergillus lung disease and bacteremia, 1 due to RSV pneumonia, and 1 due to brain abscess. This 2 step technique; 1) allows for the administration of a prescribed amount of tolerized lymphocytes in an effort to promote consistent immunologic outcomes post transplant, 2) prevents exposure of the donor HSC to CY, 3) prevents exposure of the donor lymphocytes to G-CSF thus avoiding skewing to a TH2 T cell phenotype, and 4) allows for a greater separation between TBI and CY in the conditioning regimen which may help decrease regimen related toxicity. The high overall survival rate in patients in remission at the time of transplant illustrates the importance of early identification of patients for haploidentical HSCT who are without well matched donors. These encouraging clinical outcomes suggest that this novel 2 step approach to HSCT should be further explored. Disclosures: Off Label Use: Off Label Use of CD34 selection Device.
Dissertations / Theses on the topic "G 60 UL 2009 G518"
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Girard, Thomas Marilou. "Morphostratigraphie et évolution géomorphologique holocène du secteur sud du détroit de Nastapoka, est de la baie d'Hudson." Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/26533/26533.pdf.
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Gravel, Marie-Andrée. "L'accidentologie au Québec : évolution et différenciation selon le sexe, entre 1990-1992 et 2007-2009." Thesis, Université Laval, 2013. http://www.theses.ulaval.ca/2013/30196/30196.pdf.
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Au Québec, l’implication féminine dans les accidents routiers avec blessés évolue et les raisons associées à ces changements doivent être mises en lumière afin de mieux cibler les interventions gouvernementales en matière de sécurité routière. Ce mémoire présente un portrait évolutif différencié selon le sexe de l’accidentologie québécoise pour deux périodes d’étude, 1990-1992 et 2007-2009. Les données proviennent du ministère des Transports (MTQ) et de la Société d’assurance automobile du Québec (SAAQ). Les résultats présentent, principalement par l’évolution du nombre de titulaires de permis de conduire, une augmentation de la présence féminine sur les routes du Québec et dans le bilan routier. On dénote également une diminution globale de l’implication des conducteurs québécois dans les accidents corporels, cette diminution étant plus faible chez les femmes. L’analyse des relations entre le sexe et les caractéristiques des accidents et les modèles de régression démontrent que le sexe demeure un déterminant en accidentologie. Mots-clés : Accidents; Conducteurs; Sexe; Femmes; Implication accidentelle; Sécurité routière; VictimesThe growing presence of women on the roads of Quebec is important and needs to be explored. Women's crash involvement is changing and the reasons associated must be highlighted in order to better target government road safety interventions. This analysis is an evolving portrait differentiated according to gender of the Quebec accidentology for two periods, 1990-1992 and 2007-2009. Data used in this study come from the Ministère des transports (MTQ) and the Société d'assurance automobile du Québec (SAAQ). The results present, mainly by the growth in the number of licence holders, an increase in the women’s presence in road safety records. Also, it reflects an overall decrease of the driver’s involvement in crash with injuries, this decrease being lower among women. Analysis of the relationship between sex and the accident characteristics and regression models demonstrate that sex remains a determinant in accidentology. Keywords : Crashes; Drivers; Sex; Women; Crash involvement; Road safety; Victims
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Dupré, Sophie. "La navigation dans les eaux arctiques canadiennes : du concept de risque à la géopolitique." Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/26043/26043.pdf.
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Cette recherche en géopolitique a pour ambition d’analyser la situation sociopolitique particulière de l’Arctique canadien par le biais des représentations qu’elle engendre à différentes échelles. L’engouement actuel pour la zone arctique, en lien avec le réchauffement climatique, amène à repenser certaines stratégies, notamment la réglementation des espaces maritimes. Un différend oppose déjà les États-Unis au Canada dans la manière de percevoir les eaux arctiques, dont le célèbre passage du Nord-Ouest. En effet, en matière de statut, les premiers considèrent le Passage du Nord-Ouest comme un détroit international, les seconds comme des eaux intérieures canadiennes. Dans ce contexte, le Canada -qui ces dernières années ne cesse de revendiquer sa souveraineté sur ces eaux arctiques - doit aussi y assurer une certaine sécurité de navigation, au risque de perdre toute crédibilité en cas de problème maritime.
Ainsi, mon analyse se focalise sur la navigation dans les eaux arctiques. Je renseigne d’abord celle-ci de manière tangible pour réfléchir ensuite à ses enjeux et conséquences pour le territoire arctique et sa mise en valeur. En termes d’aménagement, les acteurs interagissent avec le territoire en fonction des perceptions et représentations qu’ils ont de celui-ci et, réciproquement, le territoire se construit par le biais de ces représentations engendrées. Or, la mise en valeur du territoire arctique sous l’effet de la navigation témoigne d’un développement plutôt exogène et empreint de représentations fort diversifiées. Il convient alors de s‘interroger sur le contexte de formation des représentations grâce à une approche historique avant de traiter des risques et vulnérabilités de la navigation en tant que tels.The aim of this geopolitics research is to analyze the particular sociopolitical situation of the Canadian Arctic using the representations it generates at different scales. The increasing interest in the Arctic zone, associated with a warming climate, makes us think back certain strategies, especially the regulation of maritime spaces. There is already a conflict between the United States and Canada in how the Arctic water is perceived, including the Northwest Passage, in terms of statute: international strait versus Canadian inland waters. In this context, Canada – which, over the past years, is continually claiming sovereignty over those Arctic waters – must also guarantee a safe navigation; otherwise it will lose credibility if any maritime problem occurs. Thus, my analysis focuses on navigation in Arctic waters. First, I give information about this navigation in a tangible way. Second, I broaden the study to what are the stakes and the consequences on the Arctic territory and its development. From a management perspective, stakeholders interact with the territory according to the perceptions and the representations they have of it and, vice versa, the territory is built by the means of these generated representations. However, the enhancement of the Arctic territory under the influence of navigation expansion shows rather exogenous development and the mark of extremely diversified representations. Finally, we will enquire into the context of structuring formation by means of a historical approach before discussing risks and vulnerabilities of navigation.
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Lévesque, Anne Marie. "Salluit : analyse et reconstitution d'événements climatiques significatifs pertinents à l'aménagement du territoire et à la sécurité publique." Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/26621/26621.pdf.
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Girard-Cloutier, Anne-Marie. "Reconstitution paléobotanique et paléoclimatique en Ungava: analyse pollinique des sédiments du cratère des Pingualuit." Thesis, Université Laval, 2011. http://www.theses.ulaval.ca/2011/28016/28016.pdf.
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Lemieux, Anne-Marie. "Changements environnementaux et culturels en milieu arctique : site archéologique IbGk-3, île Drayton, Inukjuak." Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/26559/26559.pdf.
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L'Hérault, Emmanuel. "Contexte climatique critique favorable au déclenchement de ruptures de mollisol dans la vallée de Salluit, Nunavik." Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/26580/26580.pdf.
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Colpron-Tremblay, Julien. "Dynamique à long terme de la sapinière de la Forêt Montmorency à l'aide de l'analyse paléobotanique de dépôts organiques forestiers." Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/26070/26070.pdf.
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D'Amours, Christine. "Établissement et évolution des populations gaspésiennes aux XIXe et XXe siècles." Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/26635/26635.pdf.
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En raison de la topographie de la région et des activités de pêche pratiquées par sa population, les populations de la Gaspésie, composées de diverses communautés ethnoculturelles, se sont principalement réparties le long du littoral de cette péninsule. Selon la littérature, des difficultés de communication auraient engendré un isolement régional. L’étude de l’évolution démographique de la Gaspésie, les relations de sociabilité et les trajectoires migratoires des habitants d’un échantillon de localités au cours du XIXe siècle jusqu’en 1940 sont observées selon trois sous-régions distinctes : la Haute-Gaspésie, la Côte-de-Gaspé et la Baie-des-Chaleurs. Les trajectoires migratoires sont soumises aux caractéristiques du territoire, chaque localité entretenant des relations avec des régions distinctes au détriment, bien souvent, d’autres sous-régions gaspésiennes. Un éloignement entre ses sous-régions est plus présent, contribuant à expliquer la lenteur avec laquelle l’identité régionale s’est forgée.
Mots-clés : Gaspésie, migration, peuplement, isolement, mobilité, diversité ethnoculturelleBecause of the region’s topography and of its economic activities – more particularly those related to the fisheries, the distribution of the population in Gaspésie, characterized by an ethnocultural diversity, is mainly structured on the coast of the peninsula. According to existing literature, communication issues have led the Gaspesians to develop in isolation. The study of the demographic evolution of Gaspésie, the sociability relations and the migratory trajectories of the inhabitants of sampled localities from the 19th century until 1940 is observed in three sub-regions: Haute-Gaspésie, Côte-de-Gaspé and Baie-des-Chaleurs. Migratory trajectories are subjected to the peculiarities of the territory, each locality maintaining relationships with specific regions, often to the detriment of other Gaspesian sub-regions. There exists an important distance between the sub-regions, contributing to the slowness with which a regional identity was forged. Keywords: Gaspésie, migration, settlement, isolation, mobility, ethnocultural diversity
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Magnan, Gabriel. "Fréquence passée des feux et successions végétales dans les tourbières ombrotrophes près de Radisson, Québec nordique." Thesis, Université Laval, 2009. http://www.theses.ulaval.ca/2009/26080/26080.pdf.
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