130 results on '"Cazzola M"'
Search Results
2. A moderate transfusion regimen may reduce iron loading in beta-thalassemia major without producing excessive expansion of erythropoiesis.
- Author
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Cazzola M, Borgna-Pignatti C, Locatelli F, Ponchio L, Beguin Y, De Stefano P, Cazzola, M, Borgna-Pignatti, C, Locatelli, F, Ponchio, L, Beguin, Y, and De Stefano, P
- Published
- 1997
3. Dual bronchodilatory and pulmonary anti-inflammatory activity of RO5024118, a novel agonist at vasoactive intestinal peptide VPAC2 receptors.
- Author
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Tannu, SA, Renzetti, LM, Tare, N, Ventre, JD, Lavelle, D, Lin, TA, Morschauser, A, Paciorek, J, Bolin, DR, Michel, H, Singer, L, Hargaden, M, Knowles, ID, Gardiner, P, Cazzola, M, Calzetta, L, Matera, MG, Hicks, A., Tannu, S A, and Renzetti, L M
- Subjects
ANTI-inflammatory agents ,BRONCHODILATOR agents ,VASOACTIVE intestinal peptide ,GENE expression ,RESPIRATORY organs ,SMOOTH muscle ,LEUCOCYTE elastase ,AMINO acids ,ANIMAL experimentation ,CELL receptors ,DOCUMENTATION ,GUINEA pigs ,LUNGS ,MICE ,NONSTEROIDAL anti-inflammatory agents ,RATS ,BRONCHOCONSTRICTION ,IN vitro studies ,PHARMACODYNAMICS - Abstract
Background and Purpose: Vasoactive intestinal peptide is expressed in the respiratory tract and induces its effects via its receptors, VPAC(1) and VPAC(2). RO5024118 is a selective VPAC(2) receptor agonist derived via chemical modification of an earlier VPAC(2) agonist, RO0251553. In the present studies, we characterized the pharmacological activity of RO5024118.Experimental Approach: Stability of RO5024118 to human neutrophil elastase was assessed. Bronchodilatory activity of RO5024118 was investigated in guinea pig and human isolated airway smooth muscle preparations and in a guinea pig bronchoconstriction model. Pulmonary anti-inflammatory activity of RO5024118 was investigated in a lipopolysaccharide mouse model and in a porcine pancreatic elastase (PPE) rat model.Key Results: RO5024118 demonstrated increased stability to neutrophil elastase compared with RO0251553. In human and guinea pig isolated airway preparations, RO5024118 induced bronchodilatory effects comparable with RO0251553 and the long-acting β-agonist salmeterol and was significantly more potent than native vasoactive intestinal peptide and the short-acting β-agonist salbutamol. In 5-HT-induced bronchoconstriction in guinea pigs, RO5024118 exhibited inhibitory activity with similar efficacy as, and longer duration than, RO0251553. In a lipopolysaccharide-mouse model, RO5024118 inhibited neutrophil and CD8(+) cells and myeloperoxidase levels. In rats, intratracheal instillation of PPE induced airway neutrophilia that was resistant to dexamethasone. Pretreatment with RO5024118 significantly inhibited PPE-induced neutrophil accumulation.Conclusions and Implications: These results demonstrate that RO5024118 induces dual bronchodilatory and pulmonary anti-inflammatory activity and may be beneficial in treating airway obstructive and inflammatory diseases.Linked Articles: This article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2010.161.issue-6. [ABSTRACT FROM AUTHOR]- Published
- 2010
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4. Blood p50 evaluation enhances diagnostic definition of isolated erythrocytosis.
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Rumi, E., Passamonti, F., Pagano, L., Ammirabile, M., Arcaini, L., Elena, C., Flagiello, A., Tedesco, R., Vercellati, C., Marcello, A. P., Pietra, D., Moratti, R., Cazzola, M., and Lazzarino, M.
- Subjects
ERYTHROPOIETIN ,POLYCYTHEMIA ,PHENOTYPES ,BLOOD cell count ,UNIVERSITY hospitals ,PATIENTS - Abstract
Background. High oxygen-affinity haemoglobin variants and 2,3-diphosphoglycerate (2,3-DPG) deficiency are inherited diseases generating low tissue oxygen tension and erythropoietin-driven erythrocytosis, that characterizes the clinical phenotype of patients. Level of blood p50 (the oxygen tension at which haemoglobin is 50% saturated) is used to recognize these conditions. Objectives. To define the clinical utility of blood p50 measurement in the diagnosis of isolated erythrocytosis. Subjects and design. Venous blood p50 measurement was included in the diagnostic work-up of 102 consecutive patients with isolated erythrocytosis besides blood cell count, arterial oxygen saturation, serum erythropoietin measurement and screening for JAK2 mutations. Setting. Haematological Outpatient Section at University Hospital. Results. Seven patients had relative erythrocytosis. Among 95 patients with absolute erythrocytosis, 4 (4.2%) had decreased p50 level. The extended study of family members revealed a familial inheritance. Two families had haemoglobin variants already described as Haemoglobin Malmö and Haemoglobin San Diego. In one family, the proband had a new high oxygen-affinity haemoglobin variant (Haemoglobin Safi) resulting from the transversion C→A at codon 81 of the α2-globin gene. In the last family, a deficiency of 2,3-DPG was found. Within the 91 patients with normal p50 values, 46 (51%) had secondary erythrocytosis, 13 (14%) polycythemia vera and 32 (35%) idiopathic erythrocytosis. Conclusions. This study suggests that the investigation of blood p50 level may be useful to define diagnosis in patients with isolated erythrocytosis. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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5. Novel long-acting bronchodilators for COPD and asthma.
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Cazzola, M. and Matera, M. G.
- Subjects
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OBSTRUCTIVE lung diseases , *PHARMACOLOGY , *RESPIRATORY therapy equipment , *BRONCHODILATOR agents , *ASTHMA - Abstract
An important step in simplifying asthma and chronic obstructive pulmonary disease (COPD) management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Therefore, the incorporation of once-daily dose administration is an important strategy to improve adherence and is a regimen preferred by most patients, which may also lead to enhancement of compliance, and may have advantages leading to improved overall clinical outcomes. Once-daily beta2-agonists or ultra long-acting beta2-agonists (LABAs) such as carmoterol, indacaterol, GSK-159797, GSK-597901, GSK-159802, GSK-642444 and GSK-678007 are under development for the treatment of asthma and COPD. Also some new long-acting antimuscarinic agents (LAMAs) such as aclidinium, LAS-35201, GSK656398, GSK233705, NVA-237 (glycopyrrolate) and OrM3 are under development. In any case, the current opinion is that it will be advantageous to develop inhalers containing combination of several classes of long-acting bronchodilator drugs in an attempt to simplify treatment regimens as much as possible. Consequently, several options for once-daily dual-action ultra LABA+LAMA combination products are currently being evaluated. A different approach is to have a dimer molecule in which both pharmacologies are present (these molecules are known as M3 antagonist-beta2 agonist (MABA) bronchodilators). The advent of a successful MABA product will revolutionize the field and open the door for a new range of combination products. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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6. Avoidance of allergens and air pollutants in respiratory allergy.
- Author
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Liccardi, G., Custovic, A., Cazzola, M., Russo, M., D'Amato, M., and D'Amato, G.
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ALLERGENS ,AIR pollution ,RESPIRATORY allergy ,ASTHMA ,ALLERGY desensitization - Abstract
Offers suggestions on how to avoid allergens and air pollutants in respiratory allergy like asthma. Relationship between allergen sensitization or exposure and development of respiratory allergy; Impact of exposure to air contaminants to the development of respiratory allergy; Prevention strategies.
- Published
- 2001
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7. Cell cycle distribution of cord blood-derived haematopoietic progenitor cells and their recruitment into the S-phase of the cell cycle.
- Author
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Lucotti, C., Malabarba, L., Bergamaschi, G., Danova, M., Invernizzi, R., Pecci, A., Cazzola, M., Ramajoli, I., Rosti, V., Perotti, C., Torretta, L., Salvaneschi, L., and De Amici, M.
- Abstract
The objective of this study was to evaluate the cycling status of cord blood (CB)-derived colony-forming cells (CFC) and long-term culture-initiating cells (LTC-IC), and their recruitment into the S-phase of the cell cycle. By using the cytosine arabinoside (Ara-C) suicide approach, we found that only small proportions of both CFC and LTC-IC were in the S-phase of the cell cycle. These estimates were confirmed by flow cytometric DNA analysis, which showed that 96 ± 2% of CB-derived CD34+ cells were in G[sub 0]/G[sub 1] and only 1.6 ± 0.4% in the S-phase. Staining of CD34+ cells with an antistatin monoclonal antibody, a marker of the G[sub 0] phase, indicated that among CD34+ cells with a flow cytometric DNA content typical of the G[sub 0]/G[sub 1] phase 68 ± 7% of cells were in the G[sub 0] phase of the cell cycle. Incubation (24 h) with interleukin 3 (IL-3), recombinant human stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) significantly increased the proportion of cells in the S-phase for both CFC and LTC-IC without inducing any loss in numbers. Flow cytometric DNA analysis also showed an increase in CD34+ cells in the S-phase upon continuous exposure to these cytokines. Our findings indicate that: (i) very few CB-derived CFC or LTC-IC were in the S-phase of the cell cycle; (ii) a substantial amount of CD34+ cells with a flow cytometric DNA content typical of the G[sub 0]/G[sub 1] fraction was cycling, as found in the G[sub 1] phase of the cell cycle; and (iii) 24-h incubation with IL-3, SCF and G-CSF could drive a proportion of progenitor cells into the S-phase without reducing their number. These data might be useful for gene transfer protocols and the ex vivo expansion of CB-derived progenitor cells. [ABSTRACT FROM AUTHOR]
- Published
- 2000
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8. Evidence for a polyclonal nature of the cell infiltrate in sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease).
- Author
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Paulli, M., Bergamaschi, G., Tonon, L., Viglio, A., Rosso, R., Facchetti, F., Geerts, M. L., Magrini, U., and Cazzola, M.
- Published
- 1995
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9. Effects of serotonin on airways: recent developments.
- Author
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Cazzola, M., Matera, M. G., G. D'Amato, and Rossi, F.
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SEROTONIN ,TRYPTAMINE ,NEUROTRANSMITTERS ,CARDIOPULMONARY system ,ASTHMA ,BOMBESIN ,SENSORY neurons - Abstract
The article presents information on the effects of serotonin on airways. Serotonin is an endogenous autacoid that can modulate activity in visceral sensory nerves. It produces complex physiologic cardiopulmonary system by interacting with both vascular and airway smooth-muscle 5-HT receptors. Although the effects of 5-HT on airways are today better defined, major. points, remain to be clarified to define the role of 5-HT, if any, in asthma in this regard, the relationships. between 5-HT and other inflammatory mediators, such as platelet-activating factor and adenosine, or substance P and bombesin should be investigated.
- Published
- 1995
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10. Classification of anaemia on the basis of ferrokinetic parameters.
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Barosi, G., Cazzola, M., Berzuini, C., Quaglini, S., and Stefanelli, M.
- Published
- 1985
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11. Quantitative evaluation of erythropoietic activity in dysmyelopoietic syndromes.
- Author
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Cazzola, M., Barosi, G., Berzuini, C., Dacco, M., Orlandi, Ester, Stefanelli, M., and Ascari, E.
- Published
- 1982
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12. Erythropoiesis in Myelofibrosis with Myeloid Metaplasia: Recognition of Different Classes of Patients by Erythrokinetics.
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Barosi, G., Cazzola, M., Frassoni, F., Orlandi, E., and Stefanelli, M.
- Published
- 1981
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13. Quantitative Assessment of Erythropoiesis in Haemolytic Disease.
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Stefanelli, M., Barosi, G., Cazzola, M., and Orlandi, Ester
- Published
- 1980
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14. Studies of Ineffective Erythropoiesis and Peripheral Haemolysis in Congenital Dyserythropoietic Anaemia Type II.
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Barosi, G., Cazzola, M., Stefanelli, M., and Ascari, E.
- Published
- 1979
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15. Estimation of Ferrokinetic Parameters by a Mathematical Model in Patients with Primary Acquired Sideroblastic Anaemia.
- Author
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Barosi, G., Cazzola, M., Morandi, S., Stefanelli, M., and Perugini, S.
- Published
- 1978
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16. An atypical myeloproliferative disorder with high thrombotic risk and slow disease progression.
- Author
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Barosi, Giovanni, Buratti, Alberto, Costa, Attilia, Liberato, Lucio N., Balduini, Carlo, Cazzola, Mario, Rosti, Vittorio, Magrini, Umberto, Ascari, Edoardo, Barosi, G, Buratti, A, Costa, A, Liberato, L N, Balduini, C, Cazzola, M, Rosti, V, Magrini, U, and Ascari, E
- Published
- 1991
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17. Red cell aplasia in myelofibrosis with myeloid metaplasia. A distinct functional and clinical entity.
- Author
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Barosi, Giovanni, Baraldi, Anna, Cazzola, Mario, Spriano, Paolo, Magrini, Umberto, Barosi, G, Baraldi, A, Cazzola, M, Spriano, P, and Magrini, U
- Published
- 1983
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18. Immunotherapy with Alpare® in patients with respiratory allergy to Parietaria pollen: a two year double-blind placebo-controlled study.
- Author
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D'Amato, G., Kordash, T. R., Liccardi, G., Lobefalo, G., Cazzola, M., and Freshwater, L. L.
- Subjects
IMMUNOLOGIC diseases ,RHINITIS ,PLACEBOS ,ALLERGIES ,PALYNOLOGY ,RESPIRATORY allergy - Abstract
Allergy to Parietaria judaica pollen causes significant morbidity in many areas of the world. In addition to rhinitis, patients who are allergic to this pollen have a high incidence of asthma. The pollinating season is long, making this particular allergy challenging for clinicians to treat. This study was designed to determine if immunotherapy with an alum adsorbed partially purified Parietaria extract (Alpare Parietaria) containing a targeted maintenance dose of 12 500 BUs was effective in decreasing rhinitis symptoms in patients allergic to Parietaria. Using a double-blind placebo-controlled technique 36 patients received placebo or active extract for 2 years. Twenty (11 placebo and nine active) completed the 2 year study. Efficacy of treatment was evaluated by determining changes in skin reactivity, visual analog scores, diary symptom scores and end of study assessments. Reactions were monitored as well. Skin-test suppression was marginally significant in the actively treated group after 1 year and showed even more significant suppression after the second year. Nasal block, rhinorrhoea and sneezing all were significantly decreased in the active group. The nasal provocation test did not show a significant change after 1 year, in either group, but after 2 years of treatment the active group did show significant improvement. Although almost all patients in the actively treated group experienced local reactions, the incidence of systemic reactions was not different between the two groups. In conclusion, immunotherapy with this extract at this dose was effective in ameliorated rhinitis symptoms in patients allergic to Parietaria judaica. [ABSTRACT FROM AUTHOR]
- Published
- 1995
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- View/download PDF
19. A double-blind, placebo-controlled trial of local nasal immunotherapy in allergic rhinitis to Parietaria pollen.
- Author
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D'Amato, G., Lobefalo, G., Liccardi, G., and Cazzola, M.
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ALLERGIC rhinitis ,PALYNOLOGY ,BLOOD plasma ,THERAPEUTICS ,IMMUNOGLOBULIN G ,PLACEBOS - Abstract
We assessed the efficacy and safety of local nasal immunotherapy (LNIT) using an extract in macronized powder form of Parietaria pollen, a very important allergenic plant in the Mediterranean and other parts of the world. Twenty-six patients aged 13-37 years, with seasonal allergic rhinitis to this pollen, were enrolled in a double-blind placebo-controlled trial, carried out from autumn 1991 to the end of June 1992. They were selected on the basis of a positive skin-prick test, radioallergosorbent test (RAST) and intranasal challenge to Parietaria antigen. Patients were randomly divided into two groups of 13; the first group was given Parietaria antigen, and the second placebo. We recorded mean weekly symptom scores and drug consumption for 17 weeks during the pollen season in the year 1992., and specific serum-IgE and IgG levels. Three patients in the active group withdrew from the study because of bronchial symptoms. A significant difference was observed in mean weekly nasal symptom scores, in drug consumption and in specific nasal threshold to Parietaria allergenic extract in the treated and control groups. No difference was observed in serum IgE and IgG levels. Serum IgE levels rose significantly only in the control group after the pollen season. This study indicates that LNIT may be a useful alternative to traditional subcutaneous immunotherapy in patients with allergic rhinitis. [ABSTRACT FROM AUTHOR]
- Published
- 1995
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20. Effect of ketanserin, a new blocking agent of the 5-HT2 receptor, on airway responsiveness in asthma.
- Author
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Cazzola, M., Assogna, G., Lucchetti, O., Cicchitto, G., and D'Amato, G.
- Subjects
ANTIHYPERTENSIVE agents ,DRUG side effects ,ASTHMA ,KETANSERIN ,OBSTRUCTIVE lung diseases ,QUINAZOLINE - Abstract
Most of the antihypertensive drugs have a liability for adverse effects in asthma. Since there are few available data on the effect of ketanserin, a new antihypertensive drug which is a type-2 serotonin receptor antagonist, on human respiratory function, we have tested whether this drug can modify bronchial hyperresponsiveness to methacholine in asthmatic patients. The protective effect of intravenous ketanserin (0.14 mg/kg) was small, but significant. [ABSTRACT FROM AUTHOR]
- Published
- 1990
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21. Eosinophilic pneumonia in an asthmatic patient treated with omalizumab therapy: forme-fruste of Churg-Strauss syndrome?
- Author
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Cazzola, M., Mura, M., Segreti, A., Mattei, M. A., and Rogliani, P.
- Subjects
- *
CASE studies , *ASTHMA , *CHURG-Strauss syndrome , *ASTHMATICS , *DYSPNEA - Abstract
The article presents a case study of a 25-year-old male asthmatic patient who was diagnosed with a forme-fruste of Churg-Strauss syndrome (CSS) after he was treated with omalizumab therapy. It describes how an improvement in dyspnoea and cough symptoms was observed when omalizumab was stopped and the patient was treated with methylprednisolone. It discusses whether omalizumab may facilitate the development of CSS and, if not, whether omalizumab can be considered as a therapy for CSS.
- Published
- 2009
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22. THE TRIPLICATED ALPHA-GENE LOCUS AND HETEROZYGOUS BETA THALASSAEMIA: A CASE OF THALASSAEMIA INTERMEDIA.
- Author
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Sampietro, M., Cazzola, M., Cappellini, M. D., and Fiorelli, G.
- Published
- 1983
- Full Text
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23. ERYTHROPOIESIS AND IRON KINETICS.
- Author
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Barosi, G., Cazzola, M., Stefanelli, M., and Perugini, S.
- Published
- 1978
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24. Circulating thrombopoietin in reactive conditions behaves like an acute phase reactant.
- Author
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Cerutti, A., Custodi, P., Cazzola, M., and Balduini, C. L.
- Subjects
- *
THROMBOPOIETIN , *BLOOD platelet disorders - Abstract
In a recent study we found elevated thrombopoietin (TPO) levels along with a trend toward correlation between serum TPO and some acute phase reactants (APR) in patients with reactive thrombocytosis. In order to further clarify the behaviour of TPO in reactive conditions and to highlight the eventual drawbacks of serum TPO (sTPO) against plasma TPO (pTPO) measurements, serial measurements were made of sTPO, pTPO, interleukin (IL)-6, C-reactive protein (CRP), fibrinogen (FBG), and erythrocyte sedimentation rate (ESR) in 12 patients before and at the 3rd, 7th, 14th, 45th day after hip replacement surgery. Platelet count, sTPO and pTPO were also measured in 30 healthy donors. As expected sTPO were significantly higher than pTPO levels (approximately 30% on average) both in controls (P < 0.00001) and in patients (P < 0.00001). Overall a very good correlation (r = 0.975, P < 0.00001) was found between serum and plasma TPO, whereas no correlation was found between platelet count and the sTPO/pTPO ratio indicating that the difference between sTPO and pTPO is independent from platelet count. So both serum and plasma seem to be suitable samples for TPO measurement if it is taken into account that sTPO are about 30% higher than pTPO. All the parameters we measured in our patients increased during the post-surgery period and returned to the basal value at the 45th day. pTPO levels peaked at the 3rd day, preceding by 11 days the peak in platelet count. A significant correlation was found between pTPO and ESR (P = 0.012), pTPO and FBG (P = 0.044), pTPO and CRP (P = 0.033), and a nearly significant correlation between pTPO and IL-6 (P = 0.054). These results indicate that, in the course of reactive conditions, an early rise in TPO precedes and probably induces a later increase in platelet count. Moreover, the significant correlations along with the similarity in the chronological variations between TPO and some APRs suggest that TPO behave like an APR. [ABSTRACT FROM AUTHOR]
- Published
- 1999
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25. International Consensus Classification for myeloid neoplasms at-a-glance.
- Author
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Orazi A, Hasserjian RP, Cazzola M, Döhner H, Tefferi A, and Arber DA
- Subjects
- Humans, Consensus, Myeloproliferative Disorders diagnosis, Hematologic Neoplasms
- Published
- 2023
- Full Text
- View/download PDF
26. Dual bronchodilation for the treatment of COPD: From bench to bedside.
- Author
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Cazzola M, Page C, Rogliani P, Calzetta L, and Matera MG
- Subjects
- Administration, Inhalation, Bronchodilator Agents, Drug Combinations, Dyspnea chemically induced, Humans, Treatment Outcome, Adrenergic beta-2 Receptor Agonists therapeutic use, Muscarinic Antagonists therapeutic use, Pulmonary Disease, Chronic Obstructive drug therapy
- Abstract
Because there is a solid pharmacological rationale based on positive interactions between long-acting muscarinic receptor antagonists (LAMAs) and long-acting β-agonists (LABAs) for their ability to relax human airway smooth muscle in vitro alongside several randomised controlled trials (RCTs) and real-world observational studies that support the use of LAMA/LABA fixed-dose combinations (FDCs) for the treatment of patients with chronic obstructive pulmonary disease (COPD), in this narrative review we discuss the preclinical and clinical proofs supporting the use of LAMA + LABA therapy in COPD and why this therapeutic approach optimises bronchodilation. Robust evidence indicates that all LAMA/LABA FDCs are consistently more effective than LAMA or LABA administered alone in improving lung function, dyspnoea, quality of life and exercise capacity in patients with COPD. However, the ability of dual bronchodilation with FDCs of LAMA/LABA to prevent or reduce the risk of COPD exacerbations remains unclear due to conflicting data from large RCTs, despite several mechanisms explaining why such combinations should be of value in decreasing the frequency of COPD exacerbations. Both LABAs and LAMAs mechanistically can affect the cardiovascular system, but from clinical studies to date, LAMA/LABA FDCs have an acceptable cardiovascular safety profile, at least in the COPD population enrolled in RCTs. Indirect evidence suggests that some FDCs may even exert a protective role against serious cardiovascular adverse events compared to monotherapies. Consequently, several LAMA/LABA FDCs have been developed and approved for clinical use as treatments for patients with COPD. However, to date, there are unfortunately very few head-to-head studies comparing the safety and efficacy of different LAMA/LABA FDCs, making it difficult to choose the most appropriate combination, although the use of meta-analyses has provided some information in this regard. Endurance time Exercise time until exhaustion measured by a standard endurance test. Inspiratory capacity The maximum volume of air that can be inspired after reaching the end of a normal, quiet expiration. It is the sum of the tidal volume and the inspiratory reserve volume. St George's Respiratory Questionnaire (SGRQ) A tool to measure health status in patients with respiratory disease. It has three domains: symptoms, activity and impacts. A total score is also calculated. A minimal important difference (range) of ∼4 (2.4-5.6) units in the SGRQ total score is supported by published studies. Surface under the cumulative ranking curve analysis (SUCRA) A numerical representation of the overall rating that displays a single value for each treatment. SUCRA levels vary from 0% to 100%. The higher the SUCRA value and the closer it is to 100%, the more likely therapy is in the top rank or one of the top rankings; the lower the SUCRA value and the closer it is to 0%, the more likely therapy is in the bottom rank or one of the bottom ranks. Transition dyspnoea index (TDI) Widely used in clinical studies of COPD to measure shortness of breath, indicating change in response to an intervention. The total score ranges from -9 to 9; the negative value indicates deterioration, whereas a positive value indicates improvement. There is sufficient evidence to suggest that the minimal important difference for the TDI score is 1 unit. Trough FEV
1 The mean volume of air that can be forced out in 1 second approximately 12 (with a twice-daily agent) or 24 (with a once-daily agent) hours after the last administration of bronchodilator., (© 2022 British Pharmacological Society.)- Published
- 2022
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27. Classification of myeloid neoplasms/acute leukemia: Global perspectives and the international consensus classification approach.
- Author
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Arber DA, Hasserjian RP, Orazi A, Mathews V, Roberts AW, Schiffer CA, Roug AS, Cazzola M, Döhner H, and Tefferi A
- Subjects
- Consensus, Humans, Leukemia, Myeloid, Acute, Myeloproliferative Disorders
- Published
- 2022
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- View/download PDF
28. PD-L1 overexpression correlates with JAK2-V617F mutational burden and is associated with 9p uniparental disomy in myeloproliferative neoplasms.
- Author
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Milosevic Feenstra JD, Jäger R, Schischlik F, Ivanov D, Eisenwort G, Rumi E, Schuster M, Gisslinger B, Machherndl-Spandl S, Bettelheim P, Krauth MT, Keil F, Bock C, Cazzola M, Gisslinger H, Kralovics R, and Valent P
- Subjects
- Cell Cycle Proteins genetics, Humans, Janus Kinase 2 genetics, Mutation, Nuclear Proteins genetics, Transcription Factors, B7-H1 Antigen genetics, Myeloproliferative Disorders genetics, Polycythemia Vera genetics, Uniparental Disomy genetics
- Abstract
Myeloproliferative neoplasms (MPN) are chronic stem cell disorders characterized by enhanced proliferation of myeloid cells, immune deregulation, and drug resistance. JAK2 somatic mutations drive the disease in 50-60% and CALR mutations in 25-30% of cases. Published data suggest that JAK2-V617F-mutated MPN cells express the resistance-related checkpoint PD-L1. By applying RNA-sequencing on granulocytes of 113 MPN patients, we demonstrate that PD-L1 expression is highest among polycythemia vera patients and that PD-L1 expression correlates with JAK2-V617F mutational burden (R = 0.52; p < .0001). Single nucleotide polymorphism (SNP) arrays showed that chromosome 9p uniparental disomy (UPD) covers both PD-L1 and JAK2 in all MPN patients examined. MPN cells in JAK2-V617F-positive patients expressed higher levels of PD-L1 if 9p UPD was present compared to when it was absent (p < .0001). Moreover, haplotype-based association analyses provided evidence for germline genetic factors at PD-L1 locus contributing to MPN susceptibility independently of the previously described GGCC risk haplotype. We also found that PD-L1 is highly expressed on putative CD34
+ CD38- disease-initiating neoplastic stem cells (NSC) in both JAK2 and CALR-mutated MPN. PD-L1 overexpression decreased upon exposure to JAK2 blockers and BRD4-targeting agents, suggesting a role for JAK2-STAT5-signaling and BRD4 in PD-L1 expression. Whether targeting of PD-L1 can overcome NSC resistance in MPN remains to be elucidated in forthcoming studies., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)- Published
- 2022
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29. Long-acting muscarinic antagonists and small airways in asthma: Which link?
- Author
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Cazzola M, Calzetta L, and Matera MG
- Subjects
- Adrenal Cortex Hormones, Humans, Lung, Receptors, Muscarinic, Asthma drug therapy, Muscarinic Antagonists
- Abstract
Involvement of small airways, those of <2 mm in internal diameter, is present in all stages of asthma and contributes substantially to its pathophysiologic expression. Therefore, small airways are a potential target to achieve optimal asthma control. Airway tone, which is increased in asthma, is mainly controlled by the vagus nerve that releases acetylcholine (ACh) and activates muscarinic ACh receptors (mAChRs) post-synaptically on airway smooth muscle (ASM). In small airways, M
3 mAChRs are expressed, but there is no vagal innervation. Non-neuronal ACh released from the epithelial cells that may express choline acetyltransferase in response to inflammatory stimuli, as well as from other structural cells in the airways, including fibroblasts and mast cells, can activate mAChRs. By antagonizing M3 mAChR, the contraction of the ASM is prevented and, potentially, local inflammation can be reduced and the progression of remodeling may be averted. In fact, ACh also contributes to inflammation and remodeling of the airways and regulates the growth of ASM. Several experimental studies have demonstrated the potential benefit derived from the use of mAChR antagonists, mainly long-acting mAChR antagonists (LAMAs), on small airways in asthma. However, there are several confounding factors that may cause a wrong estimation of the relationship between LAMAs and small airways in asthma. Further studies are needed to differentiate broncholytic and anti-inflammatory effects of LAMAs and to better understand the interaction between LAMAs and corticosteroids, also in the context of a triple therapy that includes a β2 -AR agonist, at different levels of the bronchial tree., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)- Published
- 2021
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30. Impaired virus-specific T cell responses in patients with myeloproliferative neoplasms treated with ruxolitinib.
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Rumi E, Sant'Antonio E, Cavalloni C, Comolli G, Ferretti VV, Cassaniti I, Pietra D, Trotti C, Ciboddo M, Furione M, Vanni D, Casetti IC, Favaron C, Baldanti F, Arcaini L, and Cazzola M
- Subjects
- Adult, Aged, Aged, 80 and over, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes virology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes virology, Cytomegalovirus drug effects, Cytomegalovirus immunology, Cytomegalovirus Infections drug therapy, Cytomegalovirus Infections virology, Epstein-Barr Virus Infections drug therapy, Epstein-Barr Virus Infections virology, Female, Follow-Up Studies, Herpesvirus 4, Human drug effects, Herpesvirus 4, Human immunology, Humans, Interferon-gamma metabolism, Male, Middle Aged, Myeloproliferative Disorders drug therapy, Myeloproliferative Disorders virology, Nitriles, Prognosis, Pyrimidines, Survival Rate, Viral Load, Virus Activation drug effects, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cytomegalovirus Infections immunology, Epstein-Barr Virus Infections immunology, Myeloproliferative Disorders immunology, Pyrazoles pharmacology, Virus Activation immunology
- Abstract
Ruxolitinib is effective in myeloproliferative neoplasms (MPN) but can cause reactivation of silent infections. We aimed at evaluating viral load and T-cell responses to human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) in a cohort of 25 MPN patients treated with ruxolitinib. EBV-DNA and HCMV-DNA were quantified monthly using real-time polimerase chain reaction (PCR) on peripheral blood samples, and T-cell subsets were analyzed by flowcytometry. HCMV and EBV-directed T-cell responses were evaluated using the IFN-γ ELISPOT assay. Most patients had CD4+ and/or CD8+ T-cells below the normal range; these reductions were related to the duration of ruxolitinib treatment. In fact, reduced T-lymphocytes' subsets were found in 93% of patients treated for ≥5 years and in 45% of those treated for <5 years (P = .021). The former also had lower median numbers of CD4+ and CD8+ cells. Subclinical reactivation of EBV and HCMV occurred in 76% and 8% of patients. We observed a trend to an inverse relationship between EBV and CMV-specific CD4+ and CD8+ T-cell responses and viral load, and a trend to an inverse correlation with ruxolitinib dose. Therefore, our data suggest that the ruxolitinib treatment may interfere with immunosurveillance against EBV and HCMV., (© 2020 John Wiley & Sons Ltd.)
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- 2020
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31. Splanchnic vein thromboses associated with myeloproliferative neoplasms: An international, retrospective study on 518 cases.
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Sant'Antonio E, Guglielmelli P, Pieri L, Primignani M, Randi ML, Santarossa C, Rumi E, Cervantes F, Delaini F, Carobbio A, Betti S, Rossi E, Lavi N, Harrison CN, Curto-Garcia N, Gisslinger H, Gisslinger B, Specchia G, Ricco A, Vianelli N, Polverelli N, Koren-Michowitz M, Ruggeri M, Girodon F, Ellis M, Iurlo A, Mannelli F, Mannelli L, Sordi B, Loscocco GG, Cazzola M, De Stefano V, Barbui T, Tefferi A, and Vannucchi AM
- Subjects
- Adolescent, Adult, Age Factors, Aged, Anticoagulants adverse effects, Female, Gastrointestinal Hemorrhage chemically induced, Gastrointestinal Hemorrhage epidemiology, Humans, Male, Middle Aged, Myeloproliferative Disorders drug therapy, Myeloproliferative Disorders epidemiology, Prevalence, Risk Factors, Anticoagulants administration & dosage, Hematologic Neoplasms drug therapy, Hematologic Neoplasms epidemiology, Venous Thrombosis drug therapy, Venous Thrombosis epidemiology, Venous Thrombosis etiology
- Abstract
Myeloproliferative Neoplasms (MPN) course can be complicated by thrombosis involving unusual sites as the splanchnic veins (SVT). Their management is challenging, given their composite vascular risk. We performed a retrospective, cohort study in the framework of the International Working Group for MPN Research and Treatment (IWG-MRT), and AIRC-Gruppo Italiano Malattie Mieloproliferative (AGIMM). A total of 518 MPN-SVT cases were collected and compared with 1628 unselected, control MPN population, matched for disease subtype. Those with MPN-SVT were younger (median 44 years) and enriched in females compared to controls; PV (37.1%) and ET (34.4%) were the most frequent diagnoses. JAK2V617F mutation was highly prevalent (90.2%), and 38.6% of cases had an additional hypercoagulable disorder. SVT recurrence rate was 1.6 per 100 patient-years. Vitamin K-antagonists (VKA) halved the incidence of recurrence (OR 0.48), unlike cytoreduction (OR 0.96), and were not associated with overall or gastrointestinal bleeding in multivariable analysis. Esophageal varices were the only independent predictor for major bleeding (OR 17.4). Among MPN-SVT, risk of subsequent vascular events was skewed towards venous thromboses compared to controls. However, MPN-SVT clinical course was overall benign: SVT were enriched in PMF with lower IPSS, resulting in significantly longer survival than controls; survival was not affected in PV and slightly reduced in ET. MPN-U with SVT (n = 55) showed a particularly indolent phenotype, with no signs of disease evolution. In the to-date largest, contemporary cohort of MPN-SVT, VKA were confirmed effective in preventing recurrence, unlike cytoreduction, and safe; the major risk factor for bleeding was esophageal varices that therefore represent a major therapeutic target., (© 2019 Wiley Periodicals, Inc.)
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- 2020
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32. Distinct and convergent consequences of splice factor mutations in myelodysplastic syndromes.
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Madan V, Li J, Zhou S, Teoh WW, Han L, Meggendorfer M, Malcovati L, Cazzola M, Ogawa S, Haferlach T, Yang H, and Koeffler HP
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Mutation, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes metabolism, Myelodysplastic Syndromes pathology, RNA Splicing, RNA Splicing Factors genetics, RNA Splicing Factors metabolism
- Abstract
Myelodysplastic syndromes (MDS) are characterized by recurrent somatic alterations often affecting components of RNA splicing machinery. Mutations of splice factors SF3B1, SRSF2, ZRSR2 and U2AF1 occur in >50% of MDS. To assess the impact of spliceosome mutations on splicing and to identify common pathways/genes affected by distinct mutations, we performed RNA-sequencing of MDS bone marrow samples harboring spliceosome mutations (including hotspot alterations of SF3B1, SRSF2 and U2AF1; small deletions of SRSF2 and truncating mutations of ZRSR2), and devoid of other common co-occurring mutations. We uncover the landscape of splicing alterations in each splice factor mutant MDS and demonstrate that small deletions in SRSF2 cause highest number of splicing alterations compared with other spliceosome mutations. Although the mis-spliced events observed in different splice factor mutations were largely non-overlapping, a subset of genes, including EZH2, were aberrantly spliced in multiple mutant groups. We also verified aberrant splicing of key genes USP9X, USP24 (deubiquitinating enzymes), LUC7L2 (splice factor) and EED (PRC2 component) in MDS harboring small deletions of SRSF2. Pathway analysis revealed that mis-spliced genes in different mutant groups were enriched in RNA splicing and transport as well as several signaling cascades, suggesting converging biological consequences downstream of distinct spliceosome mutations. Our study reveals splicing signatures of each splice factor mutation and identifies shared and distinct sets of mis-spliced genes and affected biological processes in different spliceosome mutant MDS., (© 2019 Wiley Periodicals, Inc.)
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- 2020
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33. Impact of bone marrow fibrosis grade in post-polycythemia vera and post-essential thrombocythemia myelofibrosis: A study of the MYSEC group.
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Mora B, Guglielmelli P, Rumi E, Maffioli M, Barraco D, Rambaldi A, Caramella M, Komrokji RS, Kiladjian JJ, Gotlib J, Iurlo A, Cervantes F, Devos T, Palandri F, De Stefano V, Ruggeri M, Silver RT, Albano F, Benevolo G, Cavalloni C, Uccella S, Accetta R, Siracusa C, Agnoli S, Merli M, Barbui T, Bertù L, Cazzola M, Vannucchi AM, and Passamonti F
- Subjects
- Female, Humans, Male, Middle Aged, Polycythemia Vera, Primary Myelofibrosis pathology, Thrombocythemia, Essential
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- 2020
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34. Ruxolitinib treatment and risk of B-cell lymphomas in myeloproliferative neoplasms.
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Rumi E, Zibellini S, Boveri E, Cavalloni C, Riboni R, Casetti IC, Ciboddo M, Trotti C, Favaron C, Pietra D, Candido C, Ferretti VV, Cazzola M, and Arcaini L
- Subjects
- Female, Follow-Up Studies, Humans, Male, Nitriles, Pyrimidines, Risk Factors, Lymphoma, B-Cell drug therapy, Lymphoma, B-Cell mortality, Myeloproliferative Disorders drug therapy, Myeloproliferative Disorders mortality, Pyrazoles administration & dosage
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- 2019
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35. Pregnancy outcome and management of 25 pregnancies in women with polycythemia vera.
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Bertozzi I, Rumi E, Cavalloni C, Cazzola M, Fabris F, and Randi ML
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- Adolescent, Adult, Child, Female, Fibrinolytic Agents therapeutic use, Humans, Italy, Janus Kinase 2 genetics, Mutation, Pregnancy, Retrospective Studies, Young Adult, Abortion, Spontaneous etiology, Polycythemia Vera drug therapy, Pregnancy Complications, Hematologic drug therapy, Pregnancy Outcome
- Published
- 2018
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36. Advances in understanding the pathogenesis of familial myeloproliferative neoplasms.
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Rumi E and Cazzola M
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- Genetic Predisposition to Disease, Germ-Line Mutation, Hematologic Neoplasms genetics, Humans, Pedigree, Phenotype, Polymorphism, Single Nucleotide, Myeloproliferative Disorders genetics
- Abstract
Myeloproliferative neoplasms (MPNs) are generally acquired as a result of a somatic stem cell mutation leading to clonal expansion of myeloid precursors. In addition to sporadic cases, familial MPN occurs when one or several MPN affect different relatives of the same family. MPN driver mutations (JAK2, CALR, MPL) are somatically acquired also in familial cases, so a genetic predisposition to acquire one of the MPN driver mutations would be inherited, even though the causative germline mutations underlying familial MPN remain largely unknown. Recently some germline variants [ATG2B and GSKIP duplication, RBBP6 mutations, SH2B3 (LNK) mutations], which can cause familial MPN, have been reported but these mutations are rare and do not explain most familial cases. Patients with familial MPN show the same clinical features and suffer the same complications as those with sporadic disease. This review aims to offer up-to-date information regarding the genetics of familial MPN., (© 2017 John Wiley & Sons Ltd.)
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- 2017
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37. Independent prognostic impact of tumour-infiltrating macrophages in early-stage Hodgkin's lymphoma.
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Gotti M, Nicola M, Lucioni M, Fiaccadori V, Ferretti V, Sciarra R, Costanza M, Bono E, Molo S, Maffi A, Croci GA, Varettoni M, Frigeni M, Pascutto C, Arcaini L, Bonfichi M, Paulli M, and Cazzola M
- Subjects
- Adult, Aged, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Biomarkers, Biopsy, Cell Count, Female, Hodgkin Disease therapy, Humans, Immunohistochemistry, Macrophages metabolism, Male, Middle Aged, Neoplasm Staging, Prognosis, Proportional Hazards Models, Retrospective Studies, Survival Analysis, Hodgkin Disease mortality, Hodgkin Disease pathology, Macrophages pathology
- Abstract
Although patients with early-stage Hodgkin's lymphoma have a high rate of cure, a portion of these are resistant to or relapse after standard treatment. Current prognostic criteria based on clinical and laboratory parameters at diagnosis do not allow to accurately identify the subset of patients with less favourable clinical outcome. An increased number of tumour-infiltrating macrophages was found to be associated with shortened survival in patients with classic Hodgkin's Lymphoma. The aim of this study was to assess the clinical significance of the proportion of CD68-positive infiltrating macrophages in patients with early-stage classic Hodgkin's lymphoma. By using immunohistochemistry technique, we evaluated for CD68 expression diagnostic biopsies of 106 patients affected by supradiaphragmatic early-stage classic Hodgkin's lymphoma treated at our institution since 2000 to 2010. All patients were treated with adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy followed by radiotherapy in the majority. The 2-year overall survival and progression-free survival (PFS) in the entire cohort were 97% and 83% respectively. The 2-year PFS was statistically different between patients with favourable and those with unfavourable prognosis according to the European Organisation for Research and Treatment of Cancer (EORTC) risk criteria (96% vs 79%, p = 0.039) and between patients having less than 25% of CD68-positive infiltrating macrophages and those with more than 25% (85% vs 67%, p = 0.012). All patients with favourable EORTC criteria had CD68 expression lower than 25%. Within those with unfavourable EORTC criteria, patients with a CD68+ count greater than 25% had a worse 2-year PFS than patients having values lower than 25% (64% vs 82%, p = 0.03). Moreover, in multivariate analysis, after adjusting for CD68+ macrophages count and EORTC score, only CD68+ macrophages count higher than 25% retained a prognostic effect on PFS (hazard ratio = 2.8, 95%CI: 1.1-7.6, p = 0.038). Our data show that a proportion of tumour-infiltrating macrophages greater than 25% is associated with unfavourable clinical outcome in patients with early-stage Hodgkin's lymphoma Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)
- Published
- 2017
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38. Safety and efficacy of ruxolitinib in splanchnic vein thrombosis associated with myeloproliferative neoplasms.
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Pieri L, Paoli C, Arena U, Marra F, Mori F, Zucchini M, Colagrande S, Castellani A, Masciulli A, Rosti V, De Stefano V, Betti S, Finazzi G, Ferrari ML, Rumi E, Ruggeri M, Nichele I, Guglielmelli P, Fjerza R, Mannarelli C, Fanelli T, Merli L, Corbizi Fattori G, Massa M, Cimino G, Rambaldi A, Barosi G, Cazzola M, Barbui T, and Vannucchi AM
- Subjects
- Adult, Aged, Drug Administration Schedule, Female, Humans, Janus Kinases genetics, Male, Middle Aged, Myeloproliferative Disorders blood, Myeloproliferative Disorders complications, Nitriles, Platelet Count, Pyrazoles administration & dosage, Pyrimidines, Splenomegaly prevention & control, Treatment Outcome, Venous Thrombosis blood, Venous Thrombosis etiology, Janus Kinases antagonists & inhibitors, Myeloproliferative Disorders drug therapy, Pyrazoles adverse effects, Pyrazoles therapeutic use, Splanchnic Circulation drug effects, Venous Thrombosis prevention & control
- Abstract
Splanchnic vein thrombosis (SVT) is one of the vascular complications of myeloproliferative neoplasms (MPN). We designed a phase 2 clinical trial to evaluate safety and efficacy of ruxolitinib in reducing splenomegaly and improving disease-related symptoms in patients with MPN-associated SVT. Patients diagnosed with myelofibrosis (12 cases), polycythemia vera (5 cases) and essential thrombocythemia (4 cases) received ruxolitinib for 24 weeks in the core study period. Spleen volume was assessed by magnetic resonance imaging (MRI) and splanchnic vein circulation by echo-Doppler analysis. Nineteen patients carried JAK2V617F, one had MPLW515L, and one CALRL367fs*46 mutation. Eighteen patients had spleno-portal-mesenteric thrombosis, two had Budd-Chiari syndrome, and one had both sites involved; 16 patients had esophageal varices. Ruxolitinib was well tolerated with hematological toxicities consistent with those of patients without SVT and no hemorrhagic adverse events were recorded. After 24 weeks of treatment, spleen volume reduction ≥35% by MRI was achieved by 6/21 (29%) patients, and a ≥50% spleen length reduction by palpation at any time up to week 24 was obtained by 13/21 (62%) patients. At week 72, 8 of the 13 (62%) patients maintained the spleen response by palpation. No significant effect of treatment on esophageal varices or in splanchnic circulation was observed. MPN-related symptoms, evaluated by MPN-symptom assessment form (SAF) TSS questionnaire, improved significantly during the first 4 weeks and remained stable up to week 24. In conclusion, this trial shows that ruxolitinib is safe in patients with MPN-associated SVT, and effective in reducing spleen size and disease-related symptoms., (© 2016 Wiley Periodicals, Inc.)
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- 2017
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39. The effect of arterial hypertension on thrombosis in low-risk polycythemia vera.
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Barbui T, Vannucchi AM, Carobbio A, Rumi E, Finazzi G, Gisslinger H, Ruggeri M, Randi ML, Cazzola M, Rambaldi A, Gisslinger B, Pieri L, Thiele J, Pardanani A, and Tefferi A
- Subjects
- Female, Humans, Hypertension etiology, Hypertension prevention & control, Male, Middle Aged, Polycythemia Vera complications, Polycythemia Vera therapy, Thrombosis etiology, Thrombosis prevention & control, Hypertension epidemiology, Polycythemia Vera epidemiology, Thrombosis epidemiology
- Published
- 2017
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40. Recent advances in the understanding of myelodysplastic syndromes with ring sideroblasts.
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Malcovati L and Cazzola M
- Subjects
- Anemia, Sideroblastic etiology, Anemia, Sideroblastic metabolism, Anemia, Sideroblastic pathology, Bone Marrow metabolism, Bone Marrow pathology, Erythroid Precursor Cells metabolism, Humans, Iron metabolism, Mitochondria metabolism, Mutation, Myelodysplastic Syndromes mortality, Myelodysplastic Syndromes therapy, Myeloproliferative Disorders diagnosis, Myeloproliferative Disorders etiology, Phenotype, Phosphoproteins genetics, Prognosis, RNA Splicing, RNA Splicing Factors genetics, Erythroid Precursor Cells pathology, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes etiology
- Abstract
Myeloid neoplasms with ring sideroblasts are currently categorized within the myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in the World Health Organization classification. Recent findings have identified that the presence of ring sideroblasts in these disorders has a unique molecular basis, i.e., the somatic mutation of SF3B1, a gene encoding a splicing factor. Mutations of SF3B1 occur in up to 90% of patients with refractory anaemia with unilineage dysplasia (RARS) and 70% of those with refractory cytopenia with multilineage dysplasia and ring sideroblasts or RARS associated with marked thrombocytosis. Experimental evidence has shown that mutant SF3B1 results in the abnormal splicing of several genes, primarily due to misrecognition of 3' splice sites. The resulting aberrant mRNAs undergo nonsense-mediated mRNA decay (NMD), resulting in haploinsufficiency of canonical transcripts and protein expression. In addition, it is also possible that NMD-insensitive aberrant transcripts are translated into proteins with altered function. Patients with MDS carrying the SF3B1 mutation show a homogeneous disease phenotype characterized by isolated erythroid dysplasia and mild dysplasia in granulocytic or megakaryocytic lineages, supporting the notion that the SF3B1 mutation identifies a distinct entity within MDS. The available evidence suggests that these findings may have relevant impact on the diagnosis, classification and management of patients with these neoplasms., (© 2016 John Wiley & Sons Ltd.)
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- 2016
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41. Prognostic impact of bone marrow fibrosis in primary myelofibrosis. A study of the AGIMM group on 490 patients.
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Guglielmelli P, Rotunno G, Pacilli A, Rumi E, Rosti V, Delaini F, Maffioli M, Fanelli T, Pancrazzi A, Pieri L, Fjerza R, Pietra D, Cilloni D, Sant'Antonio E, Salmoiraghi S, Passamonti F, Rambaldi A, Barosi G, Barbui T, Cazzola M, and Vannucchi AM
- Subjects
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Anemia etiology, Blood Cell Count, Female, Hemoglobins analysis, Humans, Male, Middle Aged, Mutation, Primary Myelofibrosis complications, Primary Myelofibrosis genetics, Primary Myelofibrosis mortality, Prognosis, Splenomegaly etiology, Thrombocytopenia etiology, Young Adult, Primary Myelofibrosis diagnosis
- Abstract
The prognostic significance of bone marrow (BM) fibrosis grade in patients with primary myelofibrosis (PMF) is still debated. A fibrosis grade greater than 1 was shown to associate with higher risk of death, and addition of fibrosis grade to IPSS score resulted in a more accurate prediction of survival. The aim of this study was to analyze the prognostic impact of BM fibrosis in 490 patients with PMF, evaluated at diagnosis, molecularly annotated and with extensive follow-up information. We found that fibrosis grade 2 and greater on a 0-3 scale was associated with clinical characteristics indicative of a more advanced disease, such as anemia, leukopenia, thrombocytopenia, constitutional symptoms, larger splenomegaly and a higher IPSS risk category. Patients with higher grade of fibrosis were also more likely to have additional somatic mutations in ASXL1 and EZH2, that are prognostically adverse. Median survival was significantly reduced in patients with grade 2 and 3 fibrosis as compared with grade 1; this effect was maintained when analysis was restricted to younger patients. In multivariate analysis, fibrosis grade independently predicted for survival regardless of IPSS variables and mutational status; the adverse impact of fibrosis was noticeable especially in lower IPSS risk categories. Overall, results indicate that higher grades of fibrosis correlate with unique clinical and molecular aspects and represent an independent adverse variable in patients with PMF; these observations deserve confirmation in prospectively designed series of patients. Am. J. Hematol. 91:918-922, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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42. Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group.
- Author
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Rotunno G, Pacilli A, Artusi V, Rumi E, Maffioli M, Delaini F, Brogi G, Fanelli T, Pancrazzi A, Pietra D, Bernardis I, Belotti C, Pieri L, Sant'Antonio E, Salmoiraghi S, Cilloni D, Rambaldi A, Passamonti F, Barbui T, Manfredini R, Cazzola M, Tagliafico E, Vannucchi AM, and Guglielmelli P
- Subjects
- Adult, Aged, Aged, 80 and over, Disease Progression, Female, Genotype, Humans, Male, Middle Aged, Myeloproliferative Disorders epidemiology, Myeloproliferative Disorders mortality, Myeloproliferative Disorders pathology, Polycythemia Vera genetics, Polycythemia Vera mortality, Polycythemia Vera pathology, Primary Myelofibrosis epidemiology, Primary Myelofibrosis etiology, Primary Myelofibrosis genetics, Primary Myelofibrosis mortality, Prognosis, Retrospective Studies, Survival Rate, Thrombocythemia, Essential genetics, Thrombocythemia, Essential mortality, Thrombocythemia, Essential pathology, Mutation, Myeloproliferative Disorders genetics
- Abstract
Transformation to secondary myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PPV-MF) and essential thrombocythemia (PET-MF). Although primary (PMF) and secondary MF are considered similar diseases and managed similarly, there are few studies specifically focused on the latter. The aim of this study was to characterize the mutation landscape, and describe the main clinical correlates and prognostic implications of mutations, in a series of 359 patients with PPV-MF and PET-MF. Compared with PV and ET, the JAK2V617F and CALR mutated allele burden was significantly higher in PPV-MF and/or PET-MF, indicating a role for accumulation of mutated alleles in the process of transformation to MF. However, neither the allele burden nor the type of driver mutation influenced overall survival (OS), while absence of any driver mutation (triple negativity) was associated with significant reduction of OS in PET-MF, similar to PMF. Of the five interrogated subclonal mutations (ASXL1, EZH2, SRSF2, IDH1, and IDH2), that comprise a prognostically detrimental high molecular risk (HMR) category in PMF, only SRSF2 mutations were associated with reduced survival in PET-MF, and no additional mutation profile with prognostic relevance was highlighted. Overall, these data indicate that the molecular landscape of secondary forms of MF is different from PMF, suggesting that unknown mutational events might contribute to the progression from chronic phase disease to myelofibrosis. These findings also support more extended genotyping approaches aimed at identifying novel molecular abnormalities with prognostic relevance for patients with PPV-MF and PET-MF. Am. J. Hematol. 91:681-686, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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43. Successful treatment with Rituximab and Bendamustine in a patient with newly diagnosed Waldenström's Macroglobulinemia complicated by Bing-Neel syndrome.
- Author
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Varettoni M, Marchioni E, Bonfichi M, Picchiecchio A, Arcaini L, Arbasino C, Gotti M, Da Vià M, Delmonte M, Sciarra R, and Cazzola M
- Subjects
- Bendamustine Hydrochloride, Bone Marrow drug effects, Bone Marrow metabolism, Bone Marrow pathology, Central Nervous System Neoplasms complications, Central Nervous System Neoplasms metabolism, Central Nervous System Neoplasms pathology, Humans, Male, Middle Aged, Remission Induction, Rituximab, Treatment Outcome, Waldenstrom Macroglobulinemia complications, Waldenstrom Macroglobulinemia metabolism, Waldenstrom Macroglobulinemia pathology, Antibodies, Monoclonal, Murine-Derived therapeutic use, Antineoplastic Agents therapeutic use, Central Nervous System Neoplasms drug therapy, Immunologic Factors therapeutic use, Nitrogen Mustard Compounds therapeutic use, Waldenstrom Macroglobulinemia drug therapy
- Published
- 2015
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44. Bone marrow assessment in asymptomatic immunoglobulin M monoclonal gammopathies.
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Varettoni M, Arcaini L, Rattotti S, Ferretti V, and Cazzola M
- Subjects
- Humans, Waldenstrom Macroglobulinemia diagnosis, Waldenstrom Macroglobulinemia therapy
- Published
- 2015
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45. Common germline variation at the TERT locus contributes to familial clustering of myeloproliferative neoplasms.
- Author
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Jäger R, Harutyunyan AS, Rumi E, Pietra D, Berg T, Olcaydu D, Houlston RS, Cazzola M, and Kralovics R
- Subjects
- Adult, Cohort Studies, Genetic Loci, Haplotypes, Hematologic Neoplasms diagnosis, Hematologic Neoplasms pathology, Humans, Italy, Male, Middle Aged, Multigene Family, Myeloproliferative Disorders diagnosis, Myeloproliferative Disorders pathology, Pedigree, Penetrance, Risk, Genetic Predisposition to Disease, Germ-Line Mutation, Hematologic Neoplasms genetics, Janus Kinase 2 genetics, Myeloproliferative Disorders genetics, Telomerase genetics
- Abstract
The C allele of the rs2736100 single nucleotide polymorphism located in the second intron of the TERT gene has recently been identified as a susceptibility factor for myeloproliferative neoplasms (MPN) in the Icelandic population. Here, we evaluate the role of TERT rs2736100_C in sporadic and familial MPN in the context of the previously identified JAK2 GGCC predisposition haplotype. We have confirmed the TERT rs2736100_C association in a large cohort of Italian sporadic MPN patients. The risk conferred by TERT rs2736100_C is present in all molecular and diagnostic MPN subtypes. TERT rs2736100_C and JAK2 GGCC are independently predisposing to MPN and have an additive effect on disease risk, together explaining a large fraction of the population attributable fraction (PAF = 73.06%). We found TERT rs2736100_C significantly enriched (P = 0.0090) in familial MPN compared to sporadic MPN, suggesting that low-penetrance variants may be responsible for a substantial part of familial clustering in MPN., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2014
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46. A lower intensity of treatment may underlie the increased risk of thrombosis in young patients with masked polycythaemia vera.
- Author
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Lussana F, Carobbio A, Randi ML, Elena C, Rumi E, Finazzi G, Bertozzi I, Pieri L, Ruggeri M, Palandri F, Polverelli N, Elli E, Tieghi A, Iurlo A, Ruella M, Cazzola M, Rambaldi A, Vannucchi AM, and Barbui T
- Subjects
- Adolescent, Adult, Female, Hemoglobins genetics, Hemoglobins metabolism, Humans, Male, Risk Factors, Janus Kinase 2 genetics, Janus Kinase 2 metabolism, Mutation, Polycythemia Vera blood, Polycythemia Vera complications, Polycythemia Vera diagnosis, Polycythemia Vera epidemiology, Polycythemia Vera genetics, Polycythemia Vera therapy, Thrombosis blood, Thrombosis diagnosis, Thrombosis epidemiology, Thrombosis etiology, Thrombosis genetics
- Abstract
In patients who do not meet the World Health Organization (WHO) criteria for overt polycythaemia vera (PV), a diagnosis of masked PV (mPV) can be determined. A fraction of mPV patients may display thrombocytosis, thus mimicking essential thrombocythaemia (ET). No previous studies have examined clinical outcomes of mPV among young JAK2-mutated patients. We analysed a retrospective cohort of 538 JAK2-mutated patients younger than 40 years, after a re-assessment of the diagnosis according to the haemoglobin threshold for mPV. In this cohort of patients, 97 (18%) met the WHO criteria for PV, 66 patients (12%) were classified as mPV and 375 (70%) as JAK2-mutated ET. Surprisingly, a significant difference in the incidence of thrombosis was found when comparing mPV versus overt PV patients (P = 0·04). In multivariate analysis, the only factor accounting for the difference in the risk of thrombosis was the less frequent use of phlebotomies and cytoreduction in mPV patients compared to those with overt PV. Thus, we emphasize the need for the identification of mPV in young JAK2-mutated patients in order to optimize their treatments., (© 2014 John Wiley & Sons Ltd.)
- Published
- 2014
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47. Pregnancy complications predict thrombotic events in young women with essential thrombocythemia.
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Randi ML, Bertozzi I, Rumi E, Elena C, Finazzi G, Vianelli N, Polverelli N, Ruggeri M, Vannucchi AM, Antonioli E, Lussana F, Tieghi A, Iurlo A, Elli E, Ruella M, Fabris F, Cazzola M, and Barbui T
- Subjects
- Abortion, Spontaneous epidemiology, Adolescent, Adult, Anticoagulants therapeutic use, Comorbidity, Female, Hemorrhage epidemiology, Humans, Janus Kinase 2 genetics, Mutation, Missense, Point Mutation, Pregnancy, Pregnancy Complications epidemiology, Pregnancy Outcome, Prognosis, Retrospective Studies, Stillbirth epidemiology, Stroke etiology, Thrombocythemia, Essential genetics, Thrombophilia drug therapy, Thrombophilia etiology, Thrombosis etiology, Young Adult, Pregnancy Complications, Hematologic epidemiology, Stroke epidemiology, Thrombocythemia, Essential complications, Thrombosis epidemiology
- Abstract
Although Philadelphia-negative myeloproliferative neoplasms (MPNs) occur typically in middle to advanced age, any age group may be affected, posing a challenge for their management during pregnancy when they occur in young females. There is a high incidence of thromboembolic events and pregnancy complications in patients with myeloproliferative neoplasms, and a possible relationship between these complications is a matter of concern. The aim of this article was to correlate thrombosis and pregnancy outcome in 158 females with ET experiencing 237 pregnancies. Seven patients had a thrombotic event before their first pregnancy, one of them ended (14.3%) in a miscarriage. Among the 151 patients with no history of thrombosis before they became pregnant, 40 (26.5%) had a miscarriage (P = NS). Eighteen patients (11.4%) developed major thrombotic complications (12 splanchnic vein, 1 cerebral vein, 2 coronary syndromes, and 3 strokes) after at least one pregnancy (4 uneventful and 14 complicated). The occurrence of thrombosis was significantly more frequent (P < 0.001) in patients with a history of pregnancy complications (28%) than in those experiencing a normal pregnancy and delivery (3.7%). Pregnancy complications in women with ET are associated with a higher risk of subsequent thromboses, so pregnant women with this neoplasm who miscarry need to be carefully monitored., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2014
- Full Text
- View/download PDF
48. A novel germline JAK2 mutation in familial myeloproliferative neoplasms.
- Author
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Rumi E, Harutyunyan AS, Casetti I, Pietra D, Nivarthi H, Moriggl R, Cleary C, Bagienski K, Astori C, Bellini M, Berg T, Passamonti F, Kralovics R, and Cazzola M
- Subjects
- Adolescent, DNA Mutational Analysis, Exons, Humans, Male, Myeloproliferative Disorders diagnosis, Pedigree, Germ-Line Mutation, Janus Kinase 2 genetics, Myeloproliferative Disorders genetics
- Published
- 2014
- Full Text
- View/download PDF
49. Chronic lymphocytic leukemia with del13q14 as the sole abnormality: dynamic prognostic estimate by interphase-FISH.
- Author
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Orlandi EM, Bernasconi P, Pascutto C, Giardini I, Cavigliano PM, Boni M, Zibellini S, and Cazzola M
- Subjects
- ADP-ribosyl Cyclase 1 genetics, Adult, Aged, Aged, 80 and over, Alleles, Cell Nucleus ultrastructure, Clone Cells ultrastructure, Disease Progression, Disease-Free Survival, Female, Follow-Up Studies, Gene Deletion, Genes, Retinoblastoma, Humans, Interphase genetics, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Male, Membrane Glycoproteins genetics, Middle Aged, Neoplasm Proteins genetics, Prognosis, Proportional Hazards Models, Retinoblastoma Protein deficiency, Retinoblastoma Protein genetics, Risk, ZAP-70 Protein-Tyrosine Kinase genetics, Chromosome Deletion, Chromosomes, Human, Pair 13 genetics, In Situ Hybridization, Fluorescence methods, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
This study analyzed 140 patients with isolated del13q14 on interphase FISH (I-FISH), to identify subsets with a different progression risk and to assess the acquisition of additional chromosomal abnormalities (clonal evolution) in treatment-naïve del13q14 patients. A monoallelic deletion (del13qx1) was detected in 123 cases (88%), a biallelic deletion (del13qx2) in eight and a mosaic of monoallelic and biallelic deletions (del13qx1/del13qx2) in nine. In 33% of cases, deletion encompassed the Rb1 locus The median percentage of abnormal nuclei was 50% (15%-96%), and it was higher in patients with a biallelic/mosaic pattern in comparison with patients with monoallelic deletion. Sixty two patients (44%) have been treated; 5-year treatment free survival rate was 56% and the median treatment free survival was 65 months. The baseline percentage of deleted nuclei, as a continuous variable, was related to progression (HR: 1.02; p = 0.001). According to deletion burden, three groups were identified: 64 cases (46%) had <50% deleted nuclei, 47 (33%) had 50-69% deleted nuclei, and 29 (21%) had ≥70% deleted nuclei. The 5-year untreated rate was 70.5% , 52.6% and 28.7% (p < 0.0001), respectively. In multivariate analysis using IGHV mutational status, presence of a nullisomic clone, CD38 expression and percentage of deleted nuclei as covariates, only IGHV mutational status and the percentage of deleted nuclei were independent risk factors for treatment. In 103 patients serially monitored by I-FISH before starting any treatment, we observed a significant increase in the proportion of del13q14 cells, and this increase affected the risk of subsequent treatment requirement (HR 2.54, p = 0.001). The appearance of a new clone was detected in 16 patients (15.5%) and chromosome 13 was involved in 14 of them. I-FISH monitoring proves worthwhile for a dynamic risk stratification and for planning clinical surveillance., (Copyright © 2012 John Wiley & Sons, Ltd.)
- Published
- 2013
- Full Text
- View/download PDF
50. The ERCC2 Gln/Gln polymorphism at codon 751 is not associated with leukaemic transformation in primary myelofibrosis.
- Author
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Susini MC, Guglielmelli P, Spolverini A, Biamonte F, Mannarelli C, Barosi G, Zoi K, Reiter A, Duncombe A, Cervantes F, Cazzola M, Cross N, and Vannucchi AM
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Codon genetics, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Young Adult, Cell Transformation, Neoplastic genetics, Leukemia genetics, Polymorphism, Single Nucleotide, Primary Myelofibrosis genetics, Xeroderma Pigmentosum Group D Protein genetics
- Published
- 2013
- Full Text
- View/download PDF
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