41 results on '"Baglin, A."'
Search Results
2. Design and characterization of an APC-specific serpin for the treatment of hemophilia
- Author
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Polderdijk, Stéphanie G.I., Adams, Ty E., Ivanciu, Lacramioara, Camire, Rodney M., Baglin, Trevor P., and Huntington, James A.
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- 2017
- Full Text
- View/download PDF
3. Serpinpc in Persons with Severe Hemophilia (PwH): Updated Results from a Multi-Center, Multi-Part, First-in-Human Study
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Baglin, Trevor, primary, Koch, Annelize, additional, Mocanu, Irina, additional, Makhaldiani, Levani, additional, and Huntington, James A., additional
- Published
- 2022
- Full Text
- View/download PDF
4. Serpinpc in Persons with Severe Hemophilia (PwH): Updated Results from a Multi-Center, Multi-Part, First-in-Human Study
- Author
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Trevor Baglin, Annelize Koch, Irina Mocanu, Levani Makhaldiani, and James A. Huntington
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
5. Serpin-PC in Persons with Severe Hemophilia (PwH): Updated Results from a Multicenter Multi-Part, First-in-Human Study
- Author
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Baglin, Trevor, Huntington, James A., Koch, Annelize, Mocanu, Irina, and Makhaldiani, Levani
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- 2023
- Full Text
- View/download PDF
6. Design and characterization of an APC-specific serpin for the treatment of hemophilia
- Author
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Ty E. Adams, Stéphanie G. I. Polderdijk, Trevor Baglin, Rodney M. Camire, Lacramioara Ivanciu, and James A. Huntington
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0301 basic medicine ,Protein C inhibitor ,Immunology ,030204 cardiovascular system & hematology ,Serpin ,Hemophilia A ,Hemophilia B ,Biochemistry ,Fibrin ,Thrombosis and Hemostasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Thrombin ,In vivo ,Hemarthrosis ,Factor V Leiden ,medicine ,Animals ,Humans ,Serpins ,Protein C Inhibitor ,biology ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Drug Design ,Hemostasis ,biology.protein ,Cancer research ,Electrophoresis, Polyacrylamide Gel ,business ,Protein C ,medicine.drug - Abstract
Hemophilia is a bleeding disorder caused by deficiency in factors VIII or IX, the two components of the intrinsic Xase complex. Treatment with replacement factor can lead to the development of inhibitory antibodies, requiring the use of bypassing agents such as factor VIIa and factor concentrates. An alternative approach to bypass the Xase complex is to inhibit endogenous anticoagulant activities. Activated protein C (APC) breaks down the complex that produces thrombin by proteolytically inactivating factor Va. Defects in this mechanism (eg, factor V Leiden) are associated with thrombosis but result in less severe bleeding when co-inherited with hemophilia. Selective inhibition of APC might therefore be effective for the treatment of hemophilia. The endogenous inhibitors of APC are members of the serpin family: protein C inhibitor (PCI) and α1-antitrypsin (α1AT); however, both exhibit poor reactivity and selectivity for APC. We mutated residues in and around the scissile P1-P1' bond in PCI and α1AT, resulting in serpins with the desired specificity profile. The lead candidate was shown to promote thrombin generation in vitro and to restore fibrin and platelet deposition in an intravital laser injury model in hemophilia B mice. The power of targeting APC was further demonstrated by the complete normalization of bleeding after a severe tail clip injury in these mice. These results demonstrate that the protein C anticoagulant system can be successfully targeted by engineered serpins and that administration of such agents is effective at restoring hemostasis in vivo.
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- 2017
7. Antiphospholipid antibodies and recurrent thrombosis after a first unprovoked venous thromboembolism
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Steven R. Lentz, Luciana Spadafora, Trevor Baglin, Vinai Bhagirath, Scott Kaatz, Jim A. Julian, Frederick A. Spencer, Patricia C. Liaw, Stephan Moll, Sam Schulman, Clive Kearon, Jean M. Connors, Sameer Parpia, Jeffrey I. Weitz, Jeffrey S. Ginsberg, Craig M. Kessler, James D. Douketis, Kenneth A. Bauer, and Scott M. Stevens
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,education ,Immunology ,030204 cardiovascular system & hematology ,Biochemistry ,Fibrin Fibrinogen Degradation Products ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Risk Factors ,Internal medicine ,mental disorders ,medicine ,Humans ,Young adult ,Prospective cohort study ,Blood Coagulation ,Blood coagulation test ,Aged ,Autoantibodies ,Lupus anticoagulant ,biology ,business.industry ,Hazard ratio ,Autoantibody ,Cell Biology ,Hematology ,Venous Thromboembolism ,Middle Aged ,medicine.disease ,Confidence interval ,Immunoglobulin M ,Immunoglobulin G ,biology.protein ,Antibodies, Antiphospholipid ,Female ,Blood Coagulation Tests ,Antibody ,business ,psychological phenomena and processes ,030215 immunology - Abstract
It is uncertain whether antiphospholipid antibodies (APAs) increase the risk of recurrence after a first unprovoked venous thromboembolism (VTE). We tested for anticardiolipin antibodies, anti-β2 glycoprotein 1 antibodies, and lupus anticoagulant on 2 occasions ∼6 months apart in 307 patients with a first unprovoked VTE who were part of a prospective cohort study. We then determined if APAs were associated with recurrent thrombosis in the 290 patients who stopped anticoagulant therapy in response to negative D-dimer results. Compared with those without an APA, the hazard ratios for recurrent VTE were 1.8 (95% confidence interval [CI], 0.9-3.7; P = .09) in the 25.9% of patients with an APA on ≥1 occasions, 2.7 (95% CI, 1.1-.7; P = .03) in the 9.0% of patients with the same APA on 2 occasions, and 4.5 (95% CI, 1.5-13.0; P = .006) in the 3.8% of patients with 2 or 3 different APA types on either the same or different occasions. There was no association between having an APA and D-dimer levels. We conclude that having the same type of APA on 2 occasions or having >1 type of APA on the same or different occasions is associated with recurrent thrombosis in patients with a first unprovoked VTE who stop anticoagulant therapy in response to negative D-dimer tests. APA and D-dimer levels seem to be independent predictors of recurrence in patients with an unprovoked VTE. This trial was registered at www.clinicaltrials.gov as #NCT00720915.
- Published
- 2017
8. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment
- Author
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Taube, Janis, Halsall, David, and Baglin, Trevor
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- 2000
- Full Text
- View/download PDF
9. Activated Protein C Resistance: Effect of Platelet Activation, Platelet-Derived Microparticles, and Atherogenic Lipoproteins
- Author
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Taube, Janis, McWilliam, Nicola, Luddington, Roger, Byrne, Christopher D., and Baglin, Trevor
- Published
- 1999
- Full Text
- View/download PDF
10. Factor V Cambridge: A New Mutation (Arg306→Thr) Associated With Resistance to Activated Protein C
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Trevor Baglin, Karen T. Brown, Roger Luddington, Caroline Baglin, and David Williamson
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medicine.medical_specialty ,biology ,business.industry ,Immunology ,Haplotype ,Factor V ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Thrombosis ,Molecular biology ,Venous thrombosis ,Endocrinology ,Prothrombinase ,Internal medicine ,medicine ,biology.protein ,Coagulopathy ,Factor V Leiden ,business ,Protein C ,medicine.drug - Abstract
A new factor V mutation associated with resistance to activated protein C and thrombosis (factor V Cambridge, Arg306→Thr) was found in one patient from a carefully selected group of 17 patients with venous thrombosis and confirmed APC resistance in the absence of the common Gln506 mutation. The Arg306 mutation was also present in a first degree relative who also had APC resistance. Other potential causes of APC resistance, such as a mutation at the Arg679 site and the factor V HR2 haplotype, were excluded. Subsequent screening of 585 patients with venous thromboembolism and 226 blood donors did not show any other individual with this mutation. Factor VThr306 is the first description of a mutation affecting the Arg306 APC cleavage site and is the only mutation, other than factor V Leiden (Arg506→Gln), that has been found in association with APC resistance. This finding confirms the physiologic importance of the Arg306 APC-cleavage site in the regulation of the prothrombinase complex. It also supports the concept that APC resistance and venous thrombosis can result from a variety of genetic mutations affecting critical sites in the factor V cofactor.
- Published
- 1998
11. Expression of the granzyme B inhibitor PI9 predicts outcome in nasal NK/T-cell lymphoma: results of a Western series of 48 patients treated with first-line polychemotherapy within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials
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Nadine Martin-Garcia, Philippe Gaulard, Karim Belhadj, Nicolas Mounier, Stéphane Cheze, Jean Alain Kummer, Felix Reyes, Vincent Ribrag, Françoise Berger, Céline Bossard, Josette Brière, Anne-Catherine Baglin, Jacques Bosq, and Christian Gisselbrecht
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Adult ,Male ,medicine.medical_specialty ,Pathology ,T-Lymphocytes ,Immunology ,Nose ,Lymphoma, T-Cell ,Biochemistry ,Gastroenterology ,Granzymes ,International Prognostic Index ,Internal medicine ,medicine ,Humans ,T-cell lymphoma ,Serpins ,Aged ,Univariate analysis ,Hematology ,business.industry ,Cell Biology ,Middle Aged ,Prognosis ,Natural killer T cell ,medicine.disease ,Lymphoma ,Killer Cells, Natural ,Survival Rate ,Granzyme B ,Phenotype ,Treatment Outcome ,Drug Therapy, Combination ,Female ,business ,Chemoradiotherapy - Abstract
Nasal NK/T-cell lymphoma is a rare disease entity with a poor outcome. Expression of antiapoptotic proteins has not been extensively investigated in this entity. Forty-eight patients with nasal T/NK-cell lymphoma who received first-line polychemotherapy (n = 44) or chemoradiotherapy (n = 4) were analyzed for expression of active caspase-3 (aC3), granzyme B protease inhibitor 9 (PI9), and Bcl-2 proteins. Lymphomas were CD3+/CD5−/granzyme B+ and EBV-associated. Median age was 46 years. Stage I/II disease was present in 75% of the cases and an International Prognostic Index (IPI) score less than 1 in 65%. With a median follow-up of 6.3 years, 5-year event-free survival (EFS) and overall survival (OS) rates were 39% and 49%, respectively. Apoptotic index was scored as high in 32% of cases and PI9 expression as positive in 68%, whereas 35% disclosed a high number of aC3+ tumor cells. Univariate analysis showed that absence of PI9 and low apoptotic index were associated with poor outcome, but not aC3 expression nor IPI score. By multivariate analysis, both parameters affected independently EFS (P = .02 and .08, respectively) and OS (P = .009 and .04). In view of its constitutive expression by normal NK cells, it is suggested that loss of PI9 expression in tumor cells may reflect some mechanism associated with progression.
- Published
- 2006
12. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation
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Ri Liesner, Charles R. M. Hay, Simon A. Brown, Trevor Baglin, John Hanley, Michael Makris, Gerard Dolan, Sybil Hirsch, Peter William Collins, and David Keeling
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Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Time Factors ,Adolescent ,Referral ,Immunology ,Hemorrhage ,Hemophilia A ,Haemophilia ,Biochemistry ,Hemophilias ,Coagulopathy ,medicine ,Humans ,Child ,Survival rate ,Societies, Medical ,Aged ,Cause of death ,Aged, 80 and over ,business.industry ,Incidence (epidemiology) ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,United Kingdom ,Survival Rate ,Treatment Outcome ,Child, Preschool ,Population Surveillance ,Cohort ,Female ,business ,Immunosuppressive Agents - Abstract
Acquired hemophilia A is a severe bleeding disorder caused by an autoantibody to factor VIII. Previous reports have focused on referral center patients and it is unclear whether these findings are generally applicable. To improve understanding of the disease, a 2-year observational study was established to identify and characterize the presenting features and outcome of all patients with acquired hemophilia A in the United Kingdom. This allowed a consecutive cohort of patients, unbiased by referral or reporting practice, to be studied. A total of 172 patients with a median age of 78 years were identified, an incidence of 1.48/million/y. The cohort was significantly older than previously reported series, but bleeding manifestations and underlying diseases were similar. Bleeding was the cause of death in 9% of the cohort and remained a risk until the inhibitor had been eradicated. There was no difference in inhibitor eradication or mortality between patients treated with steroids alone and a combination of steroids and cytotoxic agents. Relapse of the inhibitor was observed in 20% of the patients who had attained first complete remission. The data provide the most complete description of acquired hemophilia A available and are applicable to patients presenting to all centers.
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- 2006
13. A hereditary bleeding disorder resulting from a premature stop codon in thrombomodulin (p.Cys537Stop)
- Author
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Jonathan Langdown, James A. Huntington, Roger Luddington, and Trevor Baglin
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Adult ,Male ,medicine.medical_specialty ,Thrombomodulin ,Immunology ,DNA Mutational Analysis ,Biology ,medicine.disease_cause ,Biochemistry ,Thrombosis and Hemostasis ,Thrombin ,Blood Coagulation Disorders, Inherited ,Internal medicine ,Blood plasma ,medicine ,Humans ,Blood coagulation test ,Mutation ,Cell Biology ,Hematology ,Kidney Transplantation ,Blood Coagulation Factors ,Protein Structure, Tertiary ,Transmembrane domain ,Endocrinology ,Coagulation ,Codon, Nonsense ,Female ,Mutant Proteins ,Blood Coagulation Tests ,Pancreas Transplantation ,Protein C ,medicine.drug - Abstract
In this study, we describe a novel thrombomodulin (TM) mutation (c.1611C>A) that codes for a change from cysteine 537 to a premature stop codon (p.Cys537Stop). Three members of a family with a history of posttraumatic bleeding were identified to be heterozygous for this TM mutation. All coagulation screening tests, coagulation factor assays, and platelet function test results were within normal limits. However, the endogenous thrombin potential was markedly reduced at low-tissue factor concentration, and failure to correct with normal plasma indicated the presence of a coagulation inhibitor. Plasma TM levels were highly elevated (433-845 ng/ml, normal range 2-8 ng/ml, equating to 5 to 10 nM), and the addition of exogenous protein C further decreased thrombin generation. The mutation, p.Cys537Stop, results in a truncation within the carboxyl-terminal transmembrane helix. We predict that as a consequence of the truncation, the variant TM is shed from the endothelial surface into the blood plasma. This would promote systemic protein C activation and early cessation of thrombin generation within a developing hemostatic clot, thereby explaining the phenotype of posttraumatic bleeding observed within this family.
- Published
- 2014
14. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment
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Janis M. Taube, Trevor Baglin, and David Halsall
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medicine.medical_specialty ,Time Factors ,Genotype ,medicine.drug_class ,Statistics as Topic ,Immunology ,Biology ,Biochemistry ,Gastroenterology ,Cohort Studies ,Cytochrome P-450 Enzyme System ,Risk Factors ,Internal medicine ,medicine ,Humans ,International Normalized Ratio ,Blood Coagulation ,CYP2C9 ,Alleles ,Cytochrome P-450 CYP2C9 ,Polymorphism, Genetic ,Dose-Response Relationship, Drug ,Maintenance dose ,Anticoagulant ,Warfarin ,Anticoagulants ,Cell Biology ,Hematology ,Odds ratio ,CYP2C9*3 ,Vitamin-K-epoxide reductase (warfarin-sensitive) ,Endocrinology ,Steroid 16-alpha-Hydroxylase ,Steroid Hydroxylases ,biology.protein ,Aryl Hydrocarbon Hydroxylases ,medicine.drug - Abstract
Cytochrome P-450 2C9 is the principle enzyme that terminates the anticoagulant effect of warfarin. Genetic polymorphisms inCYP2C9 producing variants with altered catalytic properties have been identified. Patients (n = 561) with a target international normalized ratio (INR) of 2.5 who had been treated with warfarin for more than 2 months were anonymously genotyped for the wild-typeCYP2C9*1 allele and the 2C9*2 and2C9*3 variants. The mean maintenance dose of warfarin in patients who were wild-type for both alleles was 5.01 mg. The maintenance dose of warfarin was significantly related to genotype (Kruskall-Wallis, χ2 = 17.985, P = .001) with mean maintenance doses in patients with variant alleles between 61% and 86% of that in wild-type patients. The odds ratio for the2C9*2 allele in patients with a maintenance dose of 1.5 mg or less was 5.42 (95% CI 1.68-17.4). The odds ratio for one or more variant alleles in patients developing an INR of 8.0 or greater was 1.52 (95% CI 0.64-3.58). The SD of the mean INR, percentage of high INRs, and person-time spent in range were determined as parameters of stability. There was no difference between patients grouped according to genotype for any parameter of stability. This study confirmed an association between CYP2C9 genotype and warfarin sensitivity. However, the possession of a variant allele does not increase the likelihood of severe over-anticoagulation or stability of anticoagulation during long-term therapy.
- Published
- 2000
15. Atherogenic Lipoproteins Support Assembly of the Prothrombinase Complex and Thrombin Generation: Modulation by Oxidation and Vitamin E
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Trevor Baglin, Christopher D. Byrne, Simin Rota, and Nicola A. McWilliam
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medicine.medical_specialty ,Very low-density lipoprotein ,Apolipoprotein B ,biology ,Chemistry ,Vitamin E ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Endocrinology ,Thrombin ,Prothrombinase ,Internal medicine ,medicine ,biology.protein ,Platelet ,lipids (amino acids, peptides, and proteins) ,Lipoprotein oxidation ,Lipoprotein ,medicine.drug - Abstract
The importance of lipoproteins in the etiology of atherosclerosis is well established. Evidence is now accumulating to implicate thrombin in the pathogenesis of atherosclerosis. We have investigated whether atherogenic lipoproteins can support thrombin generation. In the absence of platelets or endothelial cells, both very low-density lipoprotein (VLDL) and oxidized low-density lipoprotein (LDL) support assembly of the prothrombinase complex and generation of thrombin. Thrombin generation (per μg of apolipoprotein) supported by VLDL was 19.4-fold greater than that supported by high-density lipoprotein (HDL), P
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- 1998
16. Factor V Cambridge: a new mutation (Arg306--Thr) associated with resistance to activated protein C
- Author
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D, Williamson, K, Brown, R, Luddington, C, Baglin, and T, Baglin
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Mutation ,Drug Resistance ,Factor V ,Humans ,Thrombosis ,Arginine ,Protein C - Abstract
A new factor V mutation associated with resistance to activated protein C and thrombosis (factor V Cambridge, Arg306--Thr) was found in one patient from a carefully selected group of 17 patients with venous thrombosis and confirmed APC resistance in the absence of the common Gln506 mutation. The Arg306 mutation was also present in a first degree relative who also had APC resistance. Other potential causes of APC resistance, such as a mutation at the Arg679 site and the factor V HR2 haplotype, were excluded. Subsequent screening of 585 patients with venous thromboembolism and 226 blood donors did not show any other individual with this mutation. Factor VThr306 is the first description of a mutation affecting the Arg306 APC cleavage site and is the only mutation, other than factor V Leiden (Arg506--Gln), that has been found in association with APC resistance. This finding confirms the physiologic importance of the Arg306 APC-cleavage site in the regulation of the prothrombinase complex. It also supports the concept that APC resistance and venous thrombosis can result from a variety of genetic mutations affecting critical sites in the factor V cofactor.
- Published
- 1998
17. A hereditary bleeding disorder resulting from a premature stop codon in thrombomodulin (p.Cys537Stop)
- Author
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Langdown, Jonathan, primary, Luddington, Roger J., additional, Huntington, James A., additional, and Baglin, Trevor P., additional
- Published
- 2014
- Full Text
- View/download PDF
18. Activated protein C resistance: effect of platelet activation, platelet-derived microparticles, and atherogenic lipoproteins
- Author
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Nicola A. McWilliam, Roger Luddington, Janis M. Taube, Christopher D. Byrne, and Trevor Baglin
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Chemistry ,Fibrinogen receptor ,Lipoproteins ,Immunology ,Cell Biology ,Hematology ,Pharmacology ,Gene mutation ,Platelet membrane glycoprotein ,medicine.disease ,Cytoplasmic Granules ,Platelet Activation ,Biochemistry ,Platelet-rich plasma ,medicine ,Humans ,Platelet ,Platelet activation ,Activated protein C resistance ,Protein C ,medicine.drug ,Activated Protein C Resistance - Abstract
Plasma and platelet factor Va represent different substrates for activated protein C (APC). In this study, we have measured platelet-dependent APC resistance and the effect of aspirin and a platelet glycoprotein IIbIIIa antagonist (GR144053F) on this phenomenon. In platelet rich plasma (PRP), progressive APC resistance was observed with increasing platelet activation. APC sensitivity ratios of 1.8, 1.7, and 1.4 were observed after platelet activation with thrombin receptor activating peptide (TRAP), collagen, and A23187, respectively. Ultracentrifugation at 77,000g for 1 hour abolished APC resistance indicating that the phenotype is associated exclusively with the platelet membrane. APC resistance was not observed in the presence of phosphatidylcholine-phosphatidylserine (PCPS) vesicles or purified human plasma lipoproteins. APC resistance was observed in the presence of platelet-derived microparticles, but to a lesser degree than that in the presence of activated platelets. The platelet-dependent APC resistance phenotype was also observed when endogenous APC was generated by Protac (American Diagnostica, Inc, Greenwich, CT). In vitro inhibition of platelet activation with aspirin had no effect, but the fibrinogen receptor antagonist, GR144053F, inhibited platelet-dependent APC resistance. These results indicate that platelet activation results in an APC-resistant phenotype comparable to that observed in the plasma of patients with factor V gene mutations affecting critical APC cleavage sites. This suggests that platelet activation at the site of endothelial damage downregulates a critical natural anticoagulant mechanism. The antithrombotic effect of aspirin may be due to an indirect effect on platelet-dependent APC resistance with reduced platelet retention within a developing thrombus. The more potent antithrombotic effect of glycoprotein IIbIIIa antagonists may in addition be the result of reduced platelet factor Va expression and modulation of the platelet-dependent APC resistance phenotype.
- Published
- 1999
19. International Good Clinical Practices Guidelines (GCPG) for Antithrombotics in CANCER Patients
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Dominique, Farge, primary, Philippe, Debourdeau, additional, Marielle, Beckers, additional, Baglin, Caroline, additional, Bauersachs, Rupert, additional, Brenner, Benjamin, additional, Brilhante, Dialina, additional, Falanga, Anna, additional, Gerotziafas, Grigoris T, additional, Haim, Nissim, additional, Kakkar, Ajay, additional, Khorana, Alok A., additional, Lecumberri, Ramon, additional, Mandala, Mario, additional, Marthy, Michel, additional, Monreal, Manuel, additional, Mousa, Shaker S, additional, Noble, Simon, additional, Pabinger, Ingrid, additional, Prandoni, Paolo, additional, Prins, Martin, additional, Qari, Mohammed H., additional, Streiff, Michael B., additional, Syrigos, Konstantin, additional, Bounameaux, Henri, additional, and Buller, Harry Roger, additional
- Published
- 2012
- Full Text
- View/download PDF
20. International Clinical Practice Guidelines for the Treatment and Prophylaxis of Thrombosis Associated with Central Venous Catheters in Patients with Cancer
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Philippe, Debourdeau, primary, Dominique, Farge, additional, Marielle, Beckers, additional, Baglin, Caroline, additional, Bauersachs, Rupert, additional, Brenner, Benjamin, additional, Brilhante, Dialina, additional, Falanga, Anna, additional, Gerotziafas, Grigoris T, additional, Haim, Nissim, additional, Kakkar, Ajay, additional, Khorana, Alok A., additional, Lecumberri, Ramon, additional, Mandala, Mario, additional, Marty, Michel, additional, Monreal, Manuel, additional, Mousa, Shaker S, additional, Noble, Simon, additional, Pabinger, Ingrid, additional, Prandoni, Paolo, additional, Prins, Martin, additional, Qari, Mohammed H., additional, Streiff, Michael B., additional, Syrigos, Konstantin, additional, Buller, Harry Roger, additional, and Bounameaux, Henri, additional
- Published
- 2012
- Full Text
- View/download PDF
21. International Clinical Practice Guidelines for the Treatment and Prophylaxis of Thrombosis Associated with Central Venous Catheters in Patients with Cancer
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Rupert Bauersachs, Dialina Brilhante, G T Gerotzafias, Mario Mandalà, Simon Noble, Henri Bounameaux, Ramón Lecumberri, Anna Falanga, H. R. Büller, Michael B. Streiff, C. Baglin, Nissim Haim, Manuel Monreal, Alok A. Khorana, Michel Marty, Dominique Farge, Mohammed H. Qari, Shaker A. Mousa, Philippe Debourdeau, M Beckers, Ingrid Pabinger, Barry M. Brenner, Paolo Prandoni, Ajay K. Kakkar, Martin H. Prins, Konstantinos N. Syrigos, Epidemiologie, MUMC+: KIO Kemta (9), RS: CAPHRI School for Public Health and Primary Care, ACS - Amsterdam Cardiovascular Sciences, and Vascular Medicine
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Time Factors ,International Cooperation ,medicine.medical_treatment ,CENTRAL VEIN CATHETER ,Biochemistry ,HEMATOLOGIC MALIGNANCIES ,law.invention ,UPPER EXTREMITY ,DOUBLE-BLIND ,Randomized controlled trial ,Risk Factors ,law ,Jugular vein ,Neoplasms ,Upper Extremity Deep Vein Thrombosis ,Central Venous Catheters ,Medicine ,Thrombolytic Therapy ,LOW-DOSE WARFARIN ,ADULT PATIENTS ,Cooperative Behavior ,Prospective cohort study ,ddc:616 ,Evidence-Based Medicine ,Anticoagulant ,Equipment Design ,catheter ,MOLECULAR-WEIGHT HEPARIN ,Hematology ,Dialysis catheter ,Thrombosis ,Pulmonary embolism ,Benchmarking ,Catheter ,Treatment Outcome ,ACCESS DEVICES ,clinical practice guidelines ,Central venous catheter ,Catheterization, Central Venous ,GRADE system ,medicine.medical_specialty ,Consensus ,medicine.drug_class ,Immunology ,Low molecular weight heparin ,Antineoplastic Agents ,Hemorrhage ,Risk Assessment ,LONG-TERM USE ,Fibrinolytic Agents ,Internal medicine ,Humans ,cancer ,Intensive care medicine ,Device Removal ,thrombosis ,business.industry ,Patient Selection ,anticoagulant ,Retrospective cohort study ,Cell Biology ,Guideline ,medicine.disease ,equipment and supplies ,RANDOMIZED-TRIAL ,Surgery ,business - Abstract
Abstract 4357 Background Use of long term indwelling central venous catheter (CVC) is associated with symptomatic (Σ) events in up to 30% of cancer patients (pts), which may lead to pulmonary embolism (PE) and loss of the CVC. Lack of consensus on management of CVC related thrombosis (CVCT) and heterogeneity in clinical practices worldwide led us to establish international Good Clinical Practices Guidelines (GCPG) for the management of CRT in cancer pts. Methods The international working group (WG) met 4 times and worked 2 years with the methodological support and quality control of the French institute of Cancer (INCa). All studies on cancer, venous thromboembolism (VTE, including pulmonary embolism PE), and anticoagulant drugs (AC) published from 1996 to 2011 weree searched using MEDLINE®database. Meta-analyses, systematic reviews, randomized or non-randomized prospective or retrospective studies in the absence of randomized clinical trials, and abstracts only if a full paper had been accepted in a peer-reviewed medical journal were included in the analysis. The included studies concerned the prophylaxis and treatment of CVC in cancer pts. Studies in non-cancer pts, pts with a peripheral or dialysis catheter, or with a history of cancer in remission for more than 5 years were not considered. The main study outcomes were rates of proven catheter related thrombosis (CRT), extension of CRT, PE associated with CRT, major and minor bleeding, thrombocytopenia, and death. Quality of the studies was evaluated in a double-blind manner by the methodologists using the GRADE appraisal grids. Extracted data were entered in evidence tables, subsequently validated by all the WG. The level of evidence (High A, Moderate B, Low C, Very low D) depended on study design, limitations, inconsistency, indirectness, imprecision and publication bias. For each question, results analysis were summarized and discussed by the WG. Overall conclusions and recommendations were classified as Strong (Grade 1 Guideline) or Weak (Grade 2 Guideline) based on evidence levels, the balance between desirable/undesirable effects, values and preferencesand costs. In the absence of scientific evidence, judgment based on consensus within the WG was defined as Best Clinical Practice (BCP). The GCP were reviewed and evaluated using a specific grid in February 2012 by 45 independent experts in managing cancer pts worldwide and 3 pt representatives. Results 1. For the treatment of established CVC in cancer pts, we found no prospective randomized study, only 2 non-randomized prospective studies and 1 retrospective study examining the efficacy and safety of LMWH+VKA. One retrospective study evaluated the benefit of CVC removal and 2 retrospective studies, with few patients assessing the thrombolytic drugs values. We recommend A) For the treatment of Σ CRT in cancer pts, AC is recommended for a minimum of months; in this setting, LMWH are suggested. Oral VKA can be used [BCP]. B) The CVC can be kept in place if it is functional, well-positioned, non-infected and shows good evolution under close surveillance; whether the CVC is kept or removed, no standard approach in term of duration of anticoagulation is established [BCP]. 2. For the prophylaxis of CVCRT in cancer pts, 6 randomized studies investigated the efficacy and safety of VKA vs. placebo or no treatment, 1 the efficacy and safety of UFH, 6 the value of LMWH and one double-blind randomized study the thrombolytic drugs in the prevention of CVC-RT. Six meta-analyses of AC and CVC thromboprophylaxis have been performed. The type of catheter (open-ended, such as the Hickman® catheter, versus closed-ended catheter with a valve, such as the Groshong®catheter), its position (above, below or at the junction of the superior vena cava and the right atrium), and the method of placement may influence the onset of CVCT on the basis of 6 retrospective, 4 prospective non-randomized trials, 3 randomized trials and 1 meta-analysis. In light of these data, A. Use of AC for routine prophylaxis of CRT is not recommended [1A]; B. CVC should be inserted on the right side, in the jugular vein, and distal extremity of the central catheter should be located at the junction of the superior vena cava and the right atrium [1A]. Conclusion Dissemination and implementation of these international GCPG on the prevention and treatment of CRT in cancer ptsat each national level is a major public health priority, necssitating world wide collaboration. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2012
22. International Good Clinical Practices Guidelines (GCPG) for Antithrombotics in CANCER Patients
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Debourdeau Philippe, Nissim Haim, Shaker S Mousa, Michel Marthy, C. Baglin, Beckers Marielle, Konstantin Syrigos, Martin H. Prins, Harry R. Büller, Mohammed H. Qari, Mario Mandalà, Ajay K. Kakkar, Manuel Monreal, Paolo Prandoni, Benjamin Brenner, Grigoris T. Gerotziafas, Ingrid Pabinger, Farge Dominique, Simon Noble, Michael B. Streiff, Anna Falanga, Alok A. Khorana, Ramón Lecumberri, Henri Bounameaux, Dialina Brilhante, and Rupert Bauersachs
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medicine.medical_specialty ,Aspirin ,business.industry ,medicine.drug_class ,Immunology ,Anticoagulant ,Low molecular weight heparin ,Cell Biology ,Hematology ,Vitamin K antagonist ,medicine.disease ,Fondaparinux ,Biochemistry ,Pulmonary embolism ,Surgery ,Internal medicine ,medicine ,business ,Contraindication ,Fibrinolytic agent ,medicine.drug - Abstract
Abstract 1161 Background Heterogeneity in clinical practices worldwide for Venous Thromboembolism (VTE) is a major challengs. This concern led us to establish international good clinical practices guidelines (GCPG) for the management VTE in cancer patients (pts). Methods Twenty-four international experts (WG) worked with the methodological support of the French Cancer institute (INCa). All studies on cancer, venous thromboembolism (VTE, pulmonary embolism PE), and anticoagulant drugs (AC) published from 1996 to 2011 were searched using MEDLINE®database. Studies quality was evaluated double-blind manner by the methodologists using the GRADE appraisal grids. Main study outcomes were rates of VTE, major and minor bleeding, thrombocytopenia and death. Extracted data were entered in evidence tables and validated by the WG. High A, Moderate B, Low C, Very low D levels of evidence depended on study design, limitations, inconsistency, indirectness, imprecision and publication bias. Guidelines were classified as Strong (Grade 1) or Weak (Grade 2) based on GRADE. If absence of scientific evidence, the WG consensus judgement was defined as Best Clinical Practice (BCP). The GCP were then evaluated by 45 independent experts worldwide and 3 pt representatives using a specific grid. Results in cancer pts A) For initial treatment of established VTE: low molecular weight heparin (LMWH) is recommended [1B], Fondaparinux and unfractionated heparin (UFH) can be also used [2D]. Thrombolysis may be considered on a case-by-case basis, with attention to contraindication (bleeding risk) [BCP], Vena Cava Filters (VCF) may be considered if contraindication to AC of PE recurrence under optimal AC with periodic reassessment of contraindications to AC.VCF are not recommended for primary VTE prophylaxis [BCP]. For early maintenance (10 days-3 mths) and long-term treatment (>3 mths) of established VTE: LMWH are preferred over vitamin K antagonist (VKA) [1A]; LMWH should be used at least 3 mths After 3–6 mths, continuation of LMWH or VKA should be based on individual benefit-risk ratio [BCP]. If VTE recurrence, 3 options: switch from VKA to LMWH; increase in LMWH dose in pts treated with LMWH; VCF insertion [BCP]. B) To prevent postoperative VTE: LMWH once a day or low dose UFH 3 times a day are recommended; AC prophylaxis should start 12 to 2 hrs preoperatively and continued at least 7 to 10 days [ 1A]. No evidence support fondaparinux as an alternative to LMWH [2C]. The highest prophylactic dose of LMWH is recommended [ 1A]. Extended prophylaxis (4 weeks) after major laparotomy may be indicated if high VTE and low bleeding risks [2B]. For laparoscopic surgery, LMWH may be recommended as for laparotomy [BCP]. External compressions devices (ECD) are not recommended as monotherapy except if AC is contraindicated [ 2C]. C) In hospitalized medical cancer pts with reduced mobility, prophylaxis with LMWH UFH or fondaparinux [1B] is recommended. For ALL children and adults treated with L-asparaginase, depending on local policy and each pt prophylaxis may be considered [BCP]. In pts receiving chemotherapy, prophylaxis is not recommended routinely [1B]. Primary VTE prophylaxis VTE may be indicated for locally advanced or metastatic pancreatic [1B] or lung [2B] cancer pts treated with chemotherapy and having low bleeding risk. In pts treated by IMiDs with steroids and/or anthracycline, VTE prophylaxis is recommended: low or therapeutic VKA doses, LMWH at prophylactic doses and low-dose aspirin have shown similar effects [2C]. D) A brain tumor per se is not a contraindication to AC for established VTE [2C], for which we prefer LMWH [BCP]. LMWH or UFH are recommended postoperatively to prevent VTE in neurosurgery cancer pts [1A]. If creatinine clearance 50 G/L and no bleeding, full doses AC can be used for established VTE; if platelet < 50 G/L, treatment and dose depend on a case-by-case basis [BCP ]; if platelet >80 G/L, AC prophylaxis may be used and if < 80 G/L, only on a case-by-case basis [BCP]. In pregnant cancer pts, standard treatment for established VTE and prophylaxis should be implemented [BCP]. Conclusion Dissemination and implementation of international GCPG for the management of VTE, the second cause of death in cancer pts, is a major public health priority. Disclosures: No relevant conflicts of interest to declare.
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- 2012
23. Factor V Cambridge: A New Mutation (Arg306→Thr) Associated With Resistance to Activated Protein C
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Williamson, David, primary, Brown, Karen, additional, Luddington, Roger, additional, Baglin, Caroline, additional, and Baglin, Trevor, additional
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- 1998
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24. Predicting Disease Recurrence in Patients with Previous Unprovoked Venous Thromboembolism: The DASH Prediction Score
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Tosetto, Alberto, primary, Iorio, Alfonso, additional, Marcucci, Maura, additional, Baglin, Trevor, additional, Cushman, Mary, additional, Eichinger, Sabine, additional, Palareti, Gualtiero, additional, Poli, Daniela, additional, Tait, Campbell R, additional, and Douketis, James D., additional
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- 2011
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25. Predicting Disease Recurrence in Patients with Previous Unprovoked Venous Thromboembolism: The DASH Prediction Score
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Alberto Tosetto, Gualtiero Palareti, Daniela Poli, Maura Marcucci, Sabine Eichinger, Mary Cushman, Alfonso Iorio, Campbell Tait, Trevor Baglin, and James D. Douketis
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First episode ,Pediatrics ,medicine.medical_specialty ,Pregnancy ,medicine.drug_class ,Proportional hazards model ,business.industry ,Immunology ,Cancer ,Cell Biology ,Hematology ,Disease ,Vitamin K antagonist ,medicine.disease ,Biochemistry ,Dash ,medicine ,business ,Prospective cohort study - Abstract
Abstract 544 Background. In patients with unprovoked venous thromboembolism (VTE) occurring in the absence of major provoking factors, the optimal duration of anticoagulation is anchored on estimating the risk for disease recurrence in the individual patient. Evidence from several studies suggests that, at least in selected patient subgroups, the risk for recurrence may approximates the annual risk for anticoagulant-related major hemorrhage, which is estimated at 1–3%, and a recent ISTH consensus considers an annual risk of recurrence below 5% as acceptable to justify stopping anticoagulant therapy. Aim. To develop a clinical prediction guide that stratifies patients according to recurrence risk and, thereby, facilitate decisions about whether to continue or stop anticoagulation. Methods. Individual patient data meta-analysis of 7 prospective studies enrolling patients with a first episode of objectively diagnosed VTE. Eligible VTE cases were those which occurred in the absence of surgery, trauma, active cancer, immobility, or pregnancy and the puerperium. Follow-up started when anticoagulant therapy was stopped and ended when one of the following occurred: symptomatic, objectively documented, recurrent VTE; death from another cause; resumption of anticoagulant therapy for another reason; or the study ended. Predictors were identified using stratified Cox regression, and the weight of predictors was obtained after model shrinkage to correct for over-optimism. The discriminative ability of the prediction rule was estimated using time-dependent c-statistics, and was internally validated by bootstrap analysis. Results. 1818 consecutively referred cases with unprovoked VTE treated for at least three months with a vitamin K antagonist were eligible for analysis. Abnormal D-dimer after stopping anticoagulation, age < 50 years, male sex and VTE not associated with hormonal therapy (in women) were the main predictors of recurrence. Optimism-corrected regression coefficients were used to derive a prognostic recurrence score (DASH, D-dimer, Age, Sex, Hormonal therapy), that showed a good predicting capability (ROC area=0.71). The DASH score attributes the following points: +2 for positive (abnormal) post-anticoagulation D-dimer, +1 for age ≤ 50 years, +1 for male sex, −2 for hormone use at time of initial VTE (in women only). The annualized recurrence risk was 3.1% (95% confidence interval [CI] 2.3 – 3.9) in patients with a DASH score ≤ 1, 6.4% (95% CI 4.8–7.9) in patients with a DASH score 2, and 12.3% (95% CI, 9.9–14.7) in patients with a DASH score ≥ 3, as reported by the Kaplan-Meier recurrence-free survival plot. By considering at low recurrence risk those patients with a DASH score ≤ 1, life-long anticoagulation might be avoided in 51.6% of patients with unprovoked VTE. Conclusions. The DASH score appears to reliably predict recurrence risk in patients with a first unprovoked VTE and may be used to decide whether anticoagulant therapy should be continued indefinitely or stopped after an initial treatment period of at last three months. Patients with a DASH score ≤ 1 appear to have an annual risk for recurrence (3.1%) that may be sufficiently low to justify stopping anticoagulation in an average patient after 3–6 months of anticoagulation, whereas a DASH score ≥ 2 appears to confer a risk of recurrent VTE that may warrant indefinite anticoagulation. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2011
26. Peripheral T-Cell Lymphomas with Follicular Growth Patterns Are Derived from Follicular Helper T Cells (TFH): A Link with Angioimmunoblastic T-Cell Lymphomas?.
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Huang, Yenlin, primary, Moreau, Anne, additional, Dupuis, Jehan, additional, Streubel, Berthold, additional, Petit, Barbara, additional, Legouill, S., additional, Martin-Garcia, Nadine, additional, Copie-Bergman, Christiane, additional, Gaillard, Fanny, additional, Baglin, Anne-Catherine, additional, Briere, Josette, additional, Roncador, Giovanna, additional, Haioun, Corinne, additional, Delfau-Larue, Marie-Helene, additional, Chott, Andreas, additional, and Gaulard, Philippe, additional
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- 2007
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27. Further Evidence for an Anti-Thrombotic Role for Tumor Necrosis Factor alpha.
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Roos, Jonathan C., primary, Baglin, Trevor P., additional, and Ostor, Andrew J., additional
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- 2006
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28. Expression of the granzyme B inhibitor PI9 predicts outcome in nasal NK/T-cell lymphoma: results of a Western series of 48 patients treated with first-line polychemotherapy within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials
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Bossard, Céline, primary, Belhadj, Karim, additional, Reyes, Felix, additional, Martin-Garcia, Nadine, additional, Berger, Françoise, additional, Kummer, Jean Alain, additional, Brière, Josette, additional, Baglin, Anne-Catherine, additional, Cheze, Stéphane, additional, Bosq, Jacques, additional, Ribrag, Vincent, additional, Gisselbrecht, Christian, additional, Mounier, Nicolas, additional, and Gaulard, Philippe, additional
- Published
- 2006
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29. Peripheral T-Cell Lymphomas with Follicular Growth Patterns Are Derived from Follicular Helper T Cells (TFH): A Link with Angioimmunoblastic T-Cell Lymphomas?
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Marie-Hélène Delfau-Larue, Jehan Dupuis, Fanny Gaillard, Corinne Haioun, Christiane Copie-Bergman, Josette Brière, Barbara Petit, Steven Legouill, Nadine Martin-Garcia, Yenlin Huang, Giovanna Roncador, Anne Moreau, Berthold Streubel, Philippe Gaulard, Anne-Catherine Baglin, and Andreas Chott
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CD20 ,education.field_of_study ,Pathology ,medicine.medical_specialty ,T cell ,Immunology ,Population ,Cell Biology ,Hematology ,Biology ,medicine.disease ,BCL6 ,Biochemistry ,Immunophenotyping ,medicine.anatomical_structure ,B symptoms ,medicine ,biology.protein ,T-cell lymphoma ,CD5 ,medicine.symptom ,education - Abstract
Nodal peripheral T-cell lymphomas represent a heterogeneous category, composed of three entities: anaplastic large cell lymphomas, peripheral T-cell lymphomas unspecified (PTCLu) and angioimmunoblastic T-cell lymphomas (AITL). The later entity has been recently recognized to derive from follicular helper T cells (TFH). Among PTCLu - which represents an ill-defined entity - a peculiar form with follicular growth pattern (PTCL-F) has been recently reported, and one article stated their association with t(5 ;9)(q33 ;q22) involving ITK and SYK (Leukemia2006; 20: 313–318). However, the origin of tumor cells and clinical aspects of this group of PTCL-F are still unknown. The aim of this study was to analyse a series of PTCL-F to describe their clinical and histopathological aspects, to identify their cell of origin, and their relationship with AITL. Fourty-two patients from 32 to 85 years of age with 51 biopsies were selected from three Departments of Pathology (Creteil, n=24, Nantes n=13, Vienna n=14). All patients showed histopathologic features of PTCL-F in at least one biopsy. Biopsies were classified into three categories according to predominant morphological features at low power magnification: follicular lymphoma-like (n=7), progressive transformation of germinal center-like (n=22), and AITL-like features with follicular colonization (n=19). Several cases have combinations of patterns. The neoplastic population is characterized by medium-sized cells with clear cytoplasm surrounded by IgD+ B-cells. Tumor cells are of helper T-cell immunophenotype [CD2+ (33/33 = 100%), CD3+ (45/48 = 93%), CD4+ (35/42 = 83%), CD5+ (39/39 = 100%), CD7+ (7/37 = 19%)], with frequent expression of CD10 (29/43 = 67%) and of TFH markers [PDCD-1 (32/36 = 88%), CXCL13+ (33/38 = 87%), BCL6+ (15/25 = 60%), CD57+ (9/16 = 56%)]. Scattered CD20+ B-immunoblasts (27/28 = 96%) and EBV+ cells (18/30 = 60%) are also frequently observed. Seven out of 31 patients (22%) in the 3 morphological patterns have t(5 ;9)(q33 ;q22) detected by fluorescent in situ hybridization. At prentation and/or at relapse, most patients had multiple lymphadenopathies (19/23 = 83%) and disseminated disease (stages III–IV, 22/28 = 79%). Skin lesions and B symptoms were present in 7/19 (37%) and 6/22 (27%) patients, respectively. In addition, 2 patients with sequential biopsies disclosed typical clinical & histopathological features of AITL in one episode. Our results show that this rare form of PTCL has an immunophenotype indicative of TFH origin, is associated with t(5 ;9) in a proportion of cases, shows some similarities in morphology and immunophenotype with AITL, suggesting a relationship, and generates diagnostic pitfalls, especially with atypical reactive lymphoid lesions and some B-cell lymphomas. The use of immunohistochemistry with TFH markers and molecular studies can help to make a correct diagnosis.
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- 2007
30. The Heparin Binding Properties of Heparin Cofactor II Suggest an Antithrombin -Like Activation Mechanism.
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Okeeffe, Denis J., primary, Baglin, Trevor P., additional, Gallagher, John T., additional, Olson, Steve T., additional, and Huntington, James A., additional
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- 2004
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31. Further Evidence for an Anti-Thrombotic Role for Tumor Necrosis Factor alpha
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Andrew J. K. Östör, Jonathan C. P. Roos, and Trevor Baglin
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medicine.medical_specialty ,business.industry ,Immunology ,Warfarin ,Cell Biology ,Hematology ,Thrombophilia ,medicine.disease ,Biochemistry ,Gastroenterology ,Thrombosis ,Infliximab ,Etanercept ,Venous thrombosis ,Embolism ,Internal medicine ,medicine ,Adalimumab ,business ,medicine.drug - Abstract
Experiments in mice have suggested that TNFα can reduce thrombosis in vivo. Cambien et al., (2003) found that administration of TNFα decreased platelet aggregation, expression of P-selectin and binding of fibrinogen. This correlated with an increased bleeding time which was not seen in mice lacking inducible nitric oxide synthase or TNF receptor 1 and 2. That TNFα may act to reduce thrombus formation in humans has been suggested by isolated case reports where patients, following treatment with infliximab (Remicade, Centocor) to lower TNFα levels, developed a pro-thrombotic state. Complications include pulmonary thrombo-embolism, Budd-Chiari syndrome, deep venous thrombosis, retinal vein thrombosis and cerebral thrombophlebitis. These reports hint at a role for TNFα as an anti-thrombotic agent in humans but are confounded by the murine component of infliximab which may potentially trigger severe infusion reactions and could hence conceivably account for the thrombosis. We report two patients who developed pulmonary emboli following treatment with the alternative anti-TNFα therapies: etancercept (Enbrel, Wyeth) and adalimumab (Humira, Abbott). Both males were in their early sixties with long-established seropositive erosive rheumatoid arthritis and developed pulmonary embolus 4 months after introduction of etanercept 25 mg twice weekly (patient 1) and 6 months after commencing adalimumab 40mg fortnightly (patient 2). They presented to our regional hospital with signs and symptoms suggestive of pulmonary embolus secondary to deep vein thrombosis. Investigations including appropriate imaging studies and blood tests confirmed the diagnosis and the men were commenced on warfarin. Hypercoaguablility screening, including activated partial thromboplastin time, dilute Russell viper venom time, silica clotting time, antithrombin, protein C & S, cardiolipin IgG & IgM and factor II were all normal. Neither patient had antinuclear antibodies though both were positive for rheumatoid factor. Patient 2 alone was heterozygous for the Factor V Leiden mutation but had no previous personal or family history of thrombosis. Both patients continued on their respective anti-TNFα therapies and Patient 1 had a further serious thrombotic episode 6 weeks after completing a 6-month course of warfarin, indicating persistent thrombotic tendency on treatment. A causal link between thrombosis and anti-TNFα treatment is suggested by the absence of predisposing sources and the timing of the emboli which occurred shortly after introduction of therapy in patients with long disease histories and no prior evidence of hypercoagulability. Unlike infliximab, etanercept and adalimumab do not contain murine components. Etanercept is a soluble TNFα receptor whilst adalimumab is a fully humanized monoclonal antibody, thus ruling out immune reactions to foreign components as a cause of thrombosis. A review of the collected reports of adverse effects of medication maintained by the UK Medicines and Healthcare Regulatory Agency indicates that by June 2006 pulmonary embolus has been reported 16, 8 and 6 times in patients receiving infliximab, etanercept and adalimumab respectively. This data and our case reports suggest that TNFα acts to inhibit thrombosis in humans in vivo and raises the question of whether patients treated with agents designed to lower TNFα levels should be offered prophylaxis to reduce risk of thrombosis.
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- 2006
32. UKHCDO Acquired Haemophilia Study: A Complete National Cohort
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Peter William Collins, S. A. Brown, Raina Liesner, Trevor Baglin, C. R. M. Hay, Michael Makris, Gerry Dolan, John Hanley, and David Keeling
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medicine.medical_specialty ,Hematology ,Cyclophosphamide ,business.industry ,Mortality rate ,medicine.medical_treatment ,Incidence (epidemiology) ,Immunology ,Immunosuppression ,Cell Biology ,Malignancy ,medicine.disease ,Biochemistry ,Surgery ,Internal medicine ,Cohort ,Toxicity ,medicine ,business ,medicine.drug - Abstract
The literature on acquired haemophilia A (AH) predominantly consists of tertiary referral centre patients. This may have introduced referral and reporting bias with younger and more severely affected patients over-represented. This study reports all patients with AH presenting between May 2001 and April 2003 from 255 out of the 256 haematology departments in the UK. A total of 173 patients were reported, incidence 1.5/million/year. Age related incidences for the 0–15, 16–64, 65–89 and >89 year age groups were 0.04, 0.28, 7.0 and 10.3/million/year Compared to previous cohorts, patients were older, more likely to have malignancy (15% of patients) and less likely to be post partum (1.7% of patients, 1:350 000 UK births). The bleeding phenotype was variable, 33% required no haemostatic treatment and 8% had fatal bleeds. Fatal bleeds occurred between 1 and 146 days. Early fatal bleeds were gastrointestinal and lung haemorrhage (days 1–4) and later fatal bleeds were intracranial and retroperitoneal. Immunosuppression was at the discretion of the local clinician. Treatment groups were similar in age and sex and presenting FVIII levels and inhibitor titres. Complete remission (CR) (defined as FVIII normal, inhibitor undetectable and off immunosuppression) was achieved in 77% of steroid treated patients (n=41) after a median of 53 days, 76% of steroid and cyclophosphamide treated patients (n=88) (median 46 days) and 33% of cyclophosphamide treated patients (n=9) (median 210 days). Remission was not related to age or presenting FVIII level or inhibitor titre. Death occurred in 50% of steroid treated patients after a median of 79 days, 41% of steroid and cyclophosphamide treated patients (median 78 days) and 33% of cyclophosphamide treated patients (median 232 days). Survival was not related to presenting FVIII level or inhibitor titre but was higher in younger patients. Intravenous immunoglobulin (IVIG) was ineffective. CR was attained in 73% of patients treated with IVIG (n=48) compared with 78% not treated with IVIG (n=78). Relapse occurred in 22% of patients treated with steroids and 24% of patients treated with steroids and cyclophosphamide between 1 week and 3 years (median 3 months) after stopping immunosuppression. Second CR was induced in 63% of patients with a further 19% requiring maintenance immunosuppression to sustain remission. These data, which are unbiased with regard to referral and reporting practice, from the largest and most representative cohort of AH patients so far collected, do not support the commonly held views that steroids and cyclophosphamide lead to better outcomes than steroids alone, that IVIG is a useful adjunct therapy or that the FVIII or inhibitor levels at diagnosis should guide therapeutic decisions. The high relapse rate and variable bleeding phenotype, ranging from fatal to requiring no haemostatic therapy, are highlighted. Treatment guidelines based on data from referral centre patients may not be applicable to patients with AH presenting at other centres who are likely to be older, less able to tolerate immunosuppression and to have milder bleeding. The death rate in AH is high but not due to bleeding in most cases. Studies should investigate both the efficacy and toxicity of treatment regimens.
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- 2005
33. Primary Nasal NK/T Cell Lymphoma: Cytology and Level of the Antiapoptotic PI9 Protein Have Prognostic Relevance
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Anne-Catherine Baglin, Karim Belhadj, Françoise Berger, Felix Reyes, Nadine Martin-Garcia, Céline Bossard, Josette Brière, Alain Kümmer, Odile Casiraghi, Eric Lepage, and Philippe Gaulard
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biology ,T cell ,Immunology ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Inhibitor of apoptosis ,Biochemistry ,Lymphoma ,medicine.anatomical_structure ,Granzyme ,Cytology ,medicine ,Cancer research ,biology.protein ,T-cell lymphoma ,Chemoradiotherapy - Abstract
Nasal NK/T cell lymphoma is a rare disease entity characterized by a nasopharyngeal presentation, a common origin from NK cells, an association with EBV and a predilection for Asians and South Americans contrasting with its rarity in Western countries. Several studies (Chim C.S. et al., Blood 2004; Li C.C. et al., Cancer 2004) indicate that the disease has a poor outcome following conventional combined chemoradiotherapy treatments, which might be related to resistance to therapy-induced apoptosis. It has been shown (Hermine O. et al., Blood 1996; Ten Berge R. et al., Blood 2002) that high level of expression of antiapoptotic proteins by lymphoma cells is associated with poor outcome in a variety of lymphomas. In a retrospective analysis of 37 patients treated with first-line chemotherapy (n=34) or chemoradiotherapy (n=3) according to the LNH87, LNH93 and LNH98 trials of the GELA, we have analyzed by immunohistochemistry the expression of the granzyme B-protease inhibitor 9 (PI9) regarded as an inhibitor of apoptosis, and of the active form of caspase-3 (aC-3), an effector of apoptosis. The diagnosis was based on biopsies of the upper respiratory tract showing a proliferation of neoplastic cells with a CD3+/CD5− (100%), CD56+ (90%), TIA1/GrB+ (100%) phenotype and EBV association (100%). Among the 37 patients, 73% were < 60y, 68% were male. 76% had stage I, 5% Stage II, 19% stage IV and 68% had an IPI score of 0–1. With a median follow-up of 6.3 y, 5y-event-free and overall survivals were 38% and 47%, respectively. According to cytology, tumors were subclassified into predominatly small cell (52%) and predominatly large cell (48%) categories. PI9 was scored as positive (>10% of tumor cells) in 68% of the cases, whereas 35% were assigned a high number (>10 per field at high magnification) of aC-3 positive tumor cells. Univariate analysis showed that small cell cytology and absence of PI9 expression were associated with poor outcome, but not the level of aC-3 expression nor IPI score. By multivariate analysis, cytology and PI9 downregulation were shown to independently affect event-free (P=0.01 and 0.05, respectively) and overall survival (P=0.009 and 0.006). We conclude that nasal NK/T cell lymphomas disclose cytological heterogeneity which has prognostic relevance. We also found that lack of expression of PI9 is associated with poor outcome, an unexpected finding in view of the known antiapoptotic function of this protein. Since PI9 is constitutively expressed by normal NK cells, it might be postulated that its impaired expression in tumor cells reflects a yet unknown mechanism associated with progression.
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- 2004
34. The Heparin Binding Properties of Heparin Cofactor II Suggest an Antithrombin -Like Activation Mechanism
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John T. Gallagher, Trevor Baglin, Denis O'Keeffe, James A. Huntington, and Steve T. Olson
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Heparin cofactor II ,Conformational change ,Chemistry ,Immunology ,Antithrombin ,Allosteric regulation ,Cell Biology ,Hematology ,Heparin ,Serpin ,Biochemistry ,Thrombin ,medicine ,Binding selectivity ,medicine.drug - Abstract
Heparin cofactor II(HCII) is a serpin which specifically inhibits thrombin. Like antithrombin(AT) it requires glycosaminoglycan(GAG) binding before full activation. However unlike antithrombin no specific activators have been identified. What currently prevents selective therapeutic activation of HCII is the lack of knowledge of the determinants of GAG binding specificity. We have investigated the heparin binding properties of HCII using size fractionated heparins. The affinity of heparins for HCII, ranging in size from 8 to 26 saccharide units, were determined by following change in fluorescence of the extrinsic probe TNS. The effect of heparin concentration(from 1 to 100nM) on the rate of thrombin inhibition was determined for the same heparins under psuedo first-order conditions. Based on these studies we can conclude that binding is non specific with a minimal heparin length of 13 monosaccaride units required. The observed dependence of catalytic activity on heparin length is caused entirely by the size dependence of heparin affinity for HCII. By studying affinity at different ionic strengths it is clear that binding is critically dependent on ionic strength with a very weak non-ionic contribution to binding. Rapid binding experiments were conducted under psuedo first-order conditions in heparin using a stopped-flow fluorometer. These studies of heparin binding indicate an induced- fit mechanism which involves a conformational change in HCII. The low affinity of HCII can now be understood as a failure of interactions to reduce the rate of the reverse conformational, in a manner analogous to the interaction of AT with low affinity heparin. HCII is activated by a fully allosteric mechanism which produces a 2000 fold increase in activation on heparin binding. We conclude that the heparin binding mechanism of HCII is closely analogous to that of AT, and that the design or discovery of high affinity, HCII-specific GAGs is thus feasible.
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- 2004
35. Atherogenic Lipoproteins Support Assembly of the Prothrombinase Complex and Thrombin Generation: Modulation by Oxidation and Vitamin E
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Rota, Simin, primary, McWilliam, Nicola A., additional, Baglin, Trevor P., additional, and Byrne, Christopher D., additional
- Published
- 1998
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36. Thrombin Generation by Apoptotic Vascular Smooth Muscle Cells
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Flynn, Paul D., primary, Byrne, Christopher D., additional, Baglin, Trevor P., additional, Weissberg, Peter L., additional, and Bennett, Martin R., additional
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- 1997
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37. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation
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Collins, Peter W., Hirsch, Sybil, Baglin, Trevor P., Dolan, Gerard, Hanley, John, Makris, Michael, Keeling, David M., Liesner, Ri, Brown, Simon A., and Hay, Charles R. M.
- Abstract
Acquired hemophilia A is a severe bleeding disorder caused by an autoantibody to factor VIII. Previous reports have focused on referral center patients and it is unclear whether these findings are generally applicable. To improve understanding of the disease, a 2-year observational study was established to identify and characterize the presenting features and outcome of all patients with acquired hemophilia A in the United Kingdom. This allowed a consecutive cohort of patients, unbiased by referral or reporting practice, to be studied. A total of 172 patients with a median age of 78 years were identified, an incidence of 1.48/million/y. The cohort was significantly older than previously reported series, but bleeding manifestations and underlying diseases were similar. Bleeding was the cause of death in 9% of the cohort and remained a risk until the inhibitor had been eradicated. There was no difference in inhibitor eradication or mortality between patients treated with steroids alone and a combination of steroids and cytotoxic agents. Relapse of the inhibitor was observed in 20% of the patients who had attained first complete remission. The data provide the most complete description of acquired hemophilia A available and are applicable to patients presenting to all centers.
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- 2007
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38. Expression of the granzyme B inhibitor PI9 predicts outcome in nasal NK/T-cell lymphoma: results of a Western series of 48 patients treated with first-line polychemotherapy within the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials
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Bossard, Céline, Belhadj, Karim, Reyes, Felix, Martin-Garcia, Nadine, Berger, Françoise, Kummer, Jean Alain, Brière, Josette, Baglin, Anne-Catherine, Cheze, Stéphane, Bosq, Jacques, Ribrag, Vincent, Gisselbrecht, Christian, Mounier, Nicolas, and Gaulard, Philippe
- Abstract
Nasal NK/T-cell lymphoma is a rare disease entity with a poor outcome. Expression of antiapoptotic proteins has not been extensively investigated in this entity. Forty-eight patients with nasal T/NK-cell lymphoma who received first-line polychemotherapy (n = 44) or chemoradiotherapy (n = 4) were analyzed for expression of active caspase-3 (aC3), granzyme B protease inhibitor 9 (PI9), and Bcl-2 proteins. Lymphomas were CD3+/CD5−/granzyme B+ and EBV-associated. Median age was 46 years. Stage I/II disease was present in 75% of the cases and an International Prognostic Index (IPI) score less than 1 in 65%. With a median follow-up of 6.3 years, 5-year event-free survival (EFS) and overall survival (OS) rates were 39% and 49%, respectively. Apoptotic index was scored as high in 32% of cases and PI9 expression as positive in 68%, whereas 35% disclosed a high number of aC3+ tumor cells. Univariate analysis showed that absence of PI9 and low apoptotic index were associated with poor outcome, but not aC3 expression nor IPI score. By multivariate analysis, both parameters affected independently EFS (P = .02 and .08, respectively) and OS (P = .009 and .04). In view of its constitutive expression by normal NK cells, it is suggested that loss of PI9 expression in tumor cells may reflect some mechanism associated with progression.
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- 2007
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39. UKHCDO Acquired Haemophilia Study: A Complete National Cohort.
- Author
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Collins, P., Baglin, T., Brown, S., Dolan, G., Hanley, J., Keeling, D., Liesner, R., Makris, M., and Hay, C.
- Published
- 2005
- Full Text
- View/download PDF
40. C282Y Hemochromatosis Mutation Does Not Contribute to Hypercoagulability in a Factor V Leiden Population Referred for Venous Thrombosis: Response
- Author
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Taylor, S.A.M., Lillicrap, D., and Baglin, T.P.
- Published
- 1999
41. Primary Nasal NK/T Cell Lymphoma: Cytology and Level of the Antiapoptotic PI9 Protein Have Prognostic Relevance.
- Author
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Bossard, Céline, Belhadj, Karim, Reyes, Felix, Martin-Garcia, Nadine, Kümmer, Alain, Berger, Françoise, Brière, Josette, Baglin, Anne-Catherine, Casiraghi, Odile, Lepage, Eric, and Gaulard, Philippe
- Abstract
Nasal NK/T cell lymphoma is a rare disease entity characterized by a nasopharyngeal presentation, a common origin from NK cells, an association with EBV and a predilection for Asians and South Americans contrasting with its rarity in Western countries. Several studies (Chim C.S. et al., Blood 2004; Li C.C. et al., Cancer 2004) indicate that the disease has a poor outcome following conventional combined chemoradiotherapy treatments, which might be related to resistance to therapy-induced apoptosis. It has been shown (Hermine O. et al., Blood 1996; Ten Berge R. et al., Blood 2002) that high level of expression of antiapoptotic proteins by lymphoma cells is associated with poor outcome in a variety of lymphomas. In a retrospective analysis of 37 patients treated with first-line chemotherapy (n=34) or chemoradiotherapy (n=3) according to the LNH87, LNH93 and LNH98 trials of the GELA, we have analyzed by immunohistochemistry the expression of the granzyme B-protease inhibitor 9 (PI9) regarded as an inhibitor of apoptosis, and of the active form of caspase-3 (aC-3), an effector of apoptosis. The diagnosis was based on biopsies of the upper respiratory tract showing a proliferation of neoplastic cells with a CD3+/CD5− (100%), CD56+ (90%), TIA1/GrB+ (100%) phenotype and EBV association (100%). Among the 37 patients, 73% were < 60y, 68% were male. 76% had stage I, 5% Stage II, 19% stage IV and 68% had an IPI score of 0–1. With a median follow-up of 6.3 y, 5y-event-free and overall survivals were 38% and 47%, respectively. According to cytology, tumors were subclassified into predominatly small cell (52%) and predominatly large cell (48%) categories. PI9 was scored as positive (>10% of tumor cells) in 68% of the cases, whereas 35% were assigned a high number (>10 per field at high magnification) of aC-3 positive tumor cells. Univariate analysis showed that small cell cytology and absence of PI9 expression were associated with poor outcome, but not the level of aC-3 expression nor IPI score. By multivariate analysis, cytology and PI9 downregulation were shown to independently affect event-free (P=0.01 and 0.05, respectively) and overall survival (P=0.009 and 0.006). We conclude that nasal NK/T cell lymphomas disclose cytological heterogeneity which has prognostic relevance. We also found that lack of expression of PI9 is associated with poor outcome, an unexpected finding in view of the known antiapoptotic function of this protein. Since PI9 is constitutively expressed by normal NK cells, it might be postulated that its impaired expression in tumor cells reflects a yet unknown mechanism associated with progression.
- Published
- 2004
- Full Text
- View/download PDF
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