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ABSTRACT: The development of a de novo lymphoma in patients affected by chronic myelogenous leukemia (CML) is a rare event. The introduction of new molecular cytogenetic techniques, such as fluorescence in situ hybridization (FISH), allows a correct differential diagnosis between lymphoid blastic crisis and a blastoid variant of mantle cell lymphoma (MCL), which shows an aggressive behavior and some molecular characteristics detectable by cytogenetics and immunohistochemistry. We report a case of a blastoid variant of MCL that developed in a patient with CML who achieved complete cytogenetic and molecular response to imatinib mesylate treatment.
Laboratory Hematology 02/2007; 13(1):30-3.
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ABSTRACT: We evaluated the methylation status of p15 gene in a series of 65 patients with newly diagnosed acute promyelocytic leukemia (APL) receiving homogeneous treatment. Moreover, in 32 of them, the methylation status of p15 gene was correlated to the p15 m-RNA expression. In total, 31 patients had no p15 methylation (U group). An abnormal methylation pattern was found in 34 patients: in seven of these patients only methylated DNA was detected (M group), while in the remaining 27 patients (M/U group), both methylated and unmethylated DNA were amplified. Patients from M group showed a higher incidence of relapses and a lower disease-free survival (DSF) with respect to patients from U and M/U groups (29, 64 and 79% at 5 years for M, U/M and U patients, respectively, P=0.03), while p15 methylation had no impact on overall survival. The p15 expression was detectable in all patients with unmethylated DNA, in none of patients with fully methylated DNA and in 60% of patients with partially methylated DNA. The DFS estimate at 5 years for p15-negative patients was significantly lower than that of p15-positive patients (P=0.03). These data confirm that the presence of p15 methylation negatively influences the prognosis of APL, mainly when it represses the p15 gene transcription.
Leukemia 06/2003; 17(5):919-24. · 9.56 Impact Factor
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ABSTRACT: In recent years knowledge about thrombophilia and the mechanisms underlying the pathogenesis of thrombosis has increased greatly. Nevertheless the role of leukocytes and red cells in thrombogenesis is not well established and is probably underestimated.
The contribution of leukocytes and red cells to thrombogenesis has been reviewed. Moreover, the prevalence of thrombosis as a complication of hematologic diseases has been examined. The authors are involved in the investigation and management of acute and chronic hematologic diseases as well as in investigation of thrombophilia. Pub-Med was employed as a source of information.
Thrombosis is a major problem in myeloproliferative disorders such as polycythemia vera and essential thrombocythemia. A clonal involvement of megakaryocytopoiesis resulting in elevated levels of platelet-specific proteins, increased thromboxane generation, and expression of activation-dependent epitopes on the platelet surface is regarded as the main origin of thromboembolism; nevertheless, activation of leukocytes and the consequent release of elastase and alkaline phosphatase could play an important role, determining endothelial damage. Thrombosis is a relevant problem in some hemolytic anemias such as paroxysmal nocturnal hemoglobinuria and drepanocytosis. Thrombotic events in hemolytic anemias with membrane defects have been attributed, at least in part, to hypercoagulability related to the exposure of phosphatidylserine of red cell membrane activating plasma prothrombinase and supplying a procoagulant phospholipid anionic surface. A moderate but well-established risk for thrombosis occurs in acute promyelocytic leukemia and acute lymphoblastic leukemia; this risk could be increased by antiblastic drugs affecting the procoagulant activity of cells and the production of coagulation inhibitors from the liver.
Thrombotic complications during hematologic diseases other than thrombophilia due to plasma alteration could be decreased not only by anticoagulant and antiaggregating agents but also by drugs inhibiting activation of leukocytes and red cells and their interaction with platelets.
Haematologica 01/2002; 86(12):1236-44. · 6.42 Impact Factor
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ABSTRACT: In myelodysplastic syndrome (MDS), the expression of the cyclin-dependent kinase inhibitor p15(ink4B) (p15) is frequently decreased because of the aberrant methylation of the gene promoter; p15 is normally up-regulated during megakaryocytic differentiation. It was hypothesized that p15 methylation and deregulation of gene expression contribute to defective megakaryocytopoiesis in patients with MDS. Here it is shown that the increasing autocrine production of TGF-beta1 stimulates megakaryocytic differentiation in normal CD34(+) cells and that p15 mediates, at least in part, this effect. This TGF-beta1-dependent pathway is altered in MDS CD34(+) progenitors because of p15 methylation. The demethylating agent 2-deoxyAZAcytidin can restore the normal demethylated state of the p15 gene and increase its expression. Nevertheless, MDS CD34(+) cells only poorly differentiate to the megakaryocytic lineage. These findings suggest that p15 methylation occurs in a neoplastic clone with a profound defect of cell proliferation, survival, and differentiation that cannot be overcome by using a demethylating drug.
Blood 08/2001; 98(2):495-7. · 9.90 Impact Factor
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Blood 06/2001; 97(10):3314-5. · 9.90 Impact Factor
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L Teofili,
A L Di Febo,
F Pierconti,
N Maggiano,
M Bendandi,
S Rutella,
A Cingolani,
N Di Renzo,
P Musto,
S Pileri,
G Leone,
L M Larocca
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ABSTRACT: The receptor for hepatocyte growth factor (HGF) is a transmembrane tyrosine kinase that is encoded by the proto-oncogene c-met. Recently, c-MET was detected in Reed-Sternberg (RS) cells from Epstein-Barr virus-positive (EBV(+)) Hodgkin disease (HD). The c-MET, EBER-1, and LMP-1 expression in 45 lymph node biopsies and 12 bone marrow biopsies obtained from patients with HD was analyzed. In addition, HGF levels in serum samples from 80 healthy individuals and 135 HD patients in different phases of disease. In all 45 lymph node and 12 bone marrow samples examined, RS cells expressed c-MET but not HGF(+). These results were independent of the EBV infection. Interestingly, several HGF(+) dendritic-reticulum cells were found scattered around c-MET(+) RS cells. The mean +/- SEM serum HGF levels in HD patients at diagnosis and at the time of relapse were 1403 +/- 91 (95% confidence interval [CI], 1221-1585) and 1497 +/- 242 pg/mL (95% CI, 977-2017), respectively. HGF values were significantly higher than those of healthy individuals (665 +/- 28 pg/mL; 95% CI, 600-721; and P <.001 for both groups of patients) and of HD patients in remission (616 +/- 49 pg/mL; 95% CI, 517-714; and P <.001 for both groups of patients). A significant correlation was found between serum HGF levels and B symptoms at diagnosis (P =.014). In conclusion, this study indicates that HGF and c-MET constitute an additional signaling pathway between RS cells and the reactive cellular background, thereby affecting adhesion, proliferation, and survival of RS cells. Furthermore, the serum concentration of HGF in HD patients may be a useful tool in monitoring the status of disease.
Blood 02/2001; 97(4):1063-9. · 9.90 Impact Factor
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Haematologica 10/2000; 85(9):986-7. · 6.42 Impact Factor
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E O La Barbera,
P Chiusolo,
L Laurenti,
G Menichella,
A L Di Febo,
N Piccirillo,
E Sorà,
R Marra, L Teofili,
G Leone,
S Sica
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ABSTRACT: We determined the response rate to MiCMA (mitoxantrone, carboplatinum, methylprednisolone and aracytin) in a group of 29 patients with Hodgkin's disease (HD) and poor prognostic factors either resistant to first line or relapsing after conventional chemotherapy and subsequently evaluated the role of autologous stem-cell transplantation (ASCT) in these patients after MiCMA.
The treatment was intended as a brief tumor debulking program before ASCT. Twenty-nine patients with primary refractory HD or relapsed HD were submitted to two courses of MiCMA (mitoxantrone 10 mg/m2 day 1; carboplatinum 100 mg/m2 days 1-4; aracytin 2 g/m2 day 5; methylprednisolone 500 mg/m2 days 1-5) and subsequently evaluated for response. Those with responding or stable disease, received one or two other courses of MiCMA followed by ASCT.
There were 10 complete responses (34% CR), 15 partial responses (52% PR) and 4 treatment failures with disease progression (14% PD). In total there were 25 evaluable responses out of 29 patients (86% CR + PR). Myelosuppression was the main toxicity of this treatment. At this time 20 patients (69%) are alive with a median follow-up of 26.5 months (7-100), 13 patients in CR (45%), 8 patients died, 7 of them from disease progression and one due to multi-organ failure, one patient is lost to follow-up. All but one of the patients who achieved CR after MiCMA are alive. Only the number of extranodal sites was found to predict a poor response to MiCMA.
A short pre-transplantation treatment with MiCMA is an effective tumor debulking approach in patients with refractory or relapsed HD.
Annals of Oncology 08/2000; 11(7):867-71. · 6.43 Impact Factor
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ABSTRACT: In this paper we describe a case of a 65-year old man with a lymphoid blastic crisis of a chronic granulocytic leukemia occurring seven years after a palatine tonsillar non-Hodgkin's lymphoma treated with chemotherapy and radiation therapy. Bone marrow cytogenetic study demonstrated the presence of the typical t(9;22)(q34;q11) and the molecular biology study showed the p210 rearrangement (b2a2). The patient died within a few months, unresponsive to any treatment. This is the first case, described in literature, of a secondary chronic granulocytic leukemia onset with a lymphoid blastic crisis. The authors report the case and a literature review.
Haematologica 06/2000; 85(5):544-8. · 6.42 Impact Factor
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ABSTRACT: Expression of the cyclin-dependent kinase inhibitor p15(INK4B) frequently is altered in myeloid malignancies. We previously demonstrated that p15(INK4B) is expressed in normal myeloid cells. The aim of this study was to investigate whether p15(INK4B) expression is restricted to the granulomonocytic lineage and to evaluate its modulation during normal and leukemic myeloid differentiation.
Normal CD34(+) cells were cultured in serum-free media to obtain granulomonocytic, erythroid, or megakaryocytic unilineage differentiation. NB4 promyelocytic cell line and fresh leukemic blasts from seven patients with acute promyelocytic leukemia were cultured with all-trans retinoic acid. At different times of culture, cell samples were collected to evaluate p15(INK4B) by semiquantitative reverse transcriptase polymerase chain reaction.
p15(INK4B) mRNA was found during granulomonocytic and megakaryocytic, but not erythroid, differentiation. In the granulomonocytic lineage, p15(INK4B) was detectable when the majority of cells were at the promyelocytic stage and increased progressively in more mature elements. In the megakaryocytic lineage, p15(INK4B) was expressed in the early phase of differentiation, before megakaryoblasts had appeared, and was mantained throughout the time of culture. NB4 cell line and five of seven leukemic samples displayed undetectable or very low level of p15(INK4B) that rapidly increased during retinoic acid-induced differentiation. Two leukemic samples (both collected from two patients developing all-trans retinoic acid syndrome) showed high basal levels of p15(INK4B), which was not modified by retinoic acid treatment.
p15(INK4B) upregulation occurs specifically during normal granulomonocytic and megakaryocytic commitment. In acute promyelocytic leukemic blasts, p15(INK4B), which is detectable at a very low level, is promptly increased by retinoic acid. In contrast, two acute promyelocytic leukemia samples obtained from patients who developed all-trans retinoic acid syndrome showed high basal levels of p15(INK4B) that did not increase further during all-trans retinoic acid-induced differentiation.
Experimental Hematology 06/2000; 28(5):519-26. · 2.90 Impact Factor
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Thrombosis and Haemostasis 07/1999; 81(6):991-2. · 5.04 Impact Factor
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Annals of Oncology 02/1999; 10(1):124-5. · 6.43 Impact Factor
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Haematologica 02/1999; 84(E-letters):E01. · 6.42 Impact Factor
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ABSTRACT: The cyclin-dependent kinase inhibitor (CDKI) p15INK4B (p15) induces cell cycle arrest in G0/G1 phase. Several studies report deletion or transcriptional loss of the p15 gene in myeloid and lymphoid hematological malignancies, and a possible role as a tumor suppressor gene has been proposed for this CDKI. In this study we evaluated the expression of p15 by cytofluorometric, immunohistochemical, and reverse transcriptase-polymerase chain reaction (RT-PCR) methods in CD34+ progenitors (both during steady state and after chemotherapy and/or granulocyte-colony stimulating factor [G-CSF] administration) and in cells belonging to different hematopoietic differentiative lineages. We found that p15 is not expressed in normal G0/G1-arrested peripheral blood (PB)- or bone marrow (BM)-CD34+ cells. Moreover, p15 is expressed in G0/G1-blocked CD34+ cells mobilized by chemotherapy and G-CSF but not in CD34+ cells mobilized by G-CSF alone. To clarify the role of p15 in normal hematopoiesis, we used flow cytometry to investigate its expression in normal differentiating BM and PB cells. We found that p15 was expressed in cells belonging to the granulocyte-monocyte lineage and in B and T lymphocytes, whereas erythroid and megakaryocytic cells were p15 negative. These findings, which were confirmed both by immunohistochemical and RT-PCR analysis, definitely establish a linkage between p15 expression and granulocyte-monocyte differentiation.
Experimental Hematology 12/1998; 26(12):1133-9. · 2.90 Impact Factor
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Thrombosis and Haemostasis 10/1998; 80(3):519. · 5.04 Impact Factor
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L M Larocca,
F O Ranelletti,
N Maggiano,
S Rutella,
E O La Barbera,
C Rumi,
F Serra,
M T Voso,
M Piantelli, L Teofili,
G Leone
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ABSTRACT: Autologous bone-marrow transplantation (ABMT) is widely used in the treatment of acute leukemias where a matched sibling donor is not available for allogeneic transplantation. However, a major problem in ABMT is relapse, and ex vivo purging may be very important in preventing it. We show here that quercetin enhances the growth-inhibitory effect of hyperthermia (HT) in AML (19 cases) and ALL (6 cases) leukemic blasts. Furthermore, the inhibitory effect of this combined treatment resulted in leukemic-cell apoptosis. On the contrary, normal hematopoietic progenitors were neither growth-inhibited nor induced to apoptosis by HT-plus-quercetin treatment. To explain this difference in sensitivity of leukemic and normal hematopoietic progenitors, we analyzed the effect of quercetin on heat-induced expression of heat-shock protein-70 (HSP-70), which has been shown to be important in regulating thermosensitivity. We found that quercetin inhibits heat-induced HSP-70 expression both at protein and at mRNA levels in AML and ALL blasts. In normal CD34+ progenitors, the combined treatment with HT and quercetin did not reduce HSP-70 expression and did not induce cell apoptosis. Considering the difference in heat sensitivity of normal CD34+ and leukemic progenitors in the presence of quercetin, the combined use of HT and quercetin could constitute a purging protocol for ABMT.
International Journal of Cancer 10/1997; 73(1):75-83. · 5.44 Impact Factor
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ABSTRACT: The effects of rhG-CSF on lymphocyte blastogenesis were evaluated in six healthy donors, submitted to progenitor cell mobilization for allogeneic transplantation. Neutrophil, monocyte and lymphocyte count increased 6.7-fold, 5.3-fold and 2.0-fold on day +4 of rhG-CSF as compared with baseline. The DNA stimulation index (DNA SI) of 72 h phytohemagglutinin (PHA)-treated cultures decreased from 20% (15-35.5) prior to rhG-CSF to 6.7% (1.5-11.9; P = 0.0026), 8% (4-12; P = 0.0091) and 15% (9-22; P = 0.0091) on days +2, +4 and +6; similarly, reactivity to concanavalin A decreased from 18% (12-20) to 1.8% (0.5-7; P < 0.01), 3% (2-8; P < 0.01) and 5% (2-11; P = 0.009). No changes of lymphocyte response to pokeweed mitogen were observed. DNA SI of PHA-treated cultures inversely correlated with neutrophil and monocyte count. IL-1 receptor antagonist (IL-1ra) and lactoferrin (Lf) plasma levels sharply increased and correlated with neutrophil and monocyte count. IL-10 increased five-fold on day +2, returned to pretreatment values thereafter and did not show any correlation with DNA SI, suggesting that it was not responsible for the observed phenomena. Interestingly, DNA SI of PHA-treated cultures inversely correlated with IL-1ra and Lf levels. CD3+ and CD19+ lymphocyte activation status, ie CD23, CD25, CD30 and HLA-DR coexpression, was not affected by rhG-CSF administration. Pharmacological doses of rhG-CSF in healthy donors inhibit lymphocyte blastogenesis via an increased production and/or release of immunoregulatory soluble mediators, ie IL-1ra and Lf, by primed neutrophils and monocytes.
Bone Marrow Transplantation 09/1997; 20(5):355-64. · 3.75 Impact Factor
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ABSTRACT: Cycling status, myeloperoxidase expression, informative surface markers, and proliferative potential of peripheral blood hemopoietic progenitors (PBHP) were evaluated by flow cytometry in 10 patients affected by resistant lymphoma, and submitted to stem cell mobilization with combination chemotherapy (MiCMA) followed by recombinant human granulocyte colony-stimulating factor (rhG-CSF, 5 micrograms/kg/day). CD34+ PBHP coexpressed myeloid-associated and activation antigens, i.e., CD33 (96%, range 85-99), CD13 (99.5%, range 99.4-99.8), HLA-DR (99%, range 96.5-99.8), and CD38 (98%, range 90-100), lacked intracytoplasmic myeloperoxidase (MPO, < 3%), and resided in the Gzero/G1 phase of the cell cycle (96.5%, range 81-99.5, compared with 70%, range 49-78 bone marrow HP; p = 0.0007), independently of surface membrane phenotype; S-phase percentages of sorted CD34+ CD33(+)/-, CD34+CD38(+)/-, CD34+HLA-DR(+)/-, CD34+CD45RA(+)/-, CD34+CD45RO(+)/-, and CD34+CD41a(+)/- subpopulations were always negligible. In colony assays, 5-week-old long-term cultures seeded with CD34+CD33- cells yielded as many colonies as did CD34+CD33+ cells. In conclusion, rhG-CSF-mobilized CD34+ PBHPs contain noncycling, highly immature progenitors in which the expression of myeloid-associated antigens, i.e., CD33 or CD13, might not be indicative of myeloid commitment.
Experimental Hematology 04/1997; 25(3):246-51. · 2.90 Impact Factor
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European journal of histochemistry: EJH 02/1997; 41 Suppl 2:43-4. · 1.69 Impact Factor
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ABSTRACT: Budd-Chiari syndrome is a severe disease characterized by occlusion of large hepatic veins leading to death if untreated. Using the classical criteria for the diagnosis of polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF), overt PV was the underlying cause in about 10% of the cases and ET or IMF in only a very few. Using spontaneous endogenous erythroid colony (EEC) formation in vitro and/or bone marrow biopsies, a primary myeloproliferative disorder (PMD) was present in 78% of the patients with apparently idiopathic Budd-Chiari syndrome and in about half of the patients with portal, splenic, and/or mesenteric vein thrombosis. The diagnoses in 40 reported cases with hepatic vein thrombosis and spontaneous EEC were overt PV in 25 and latent unclassified PMD in 15 patients. The diagnoses of 40 reported cases with splanchnic vein thrombosis and spontaneous EEC were overt PV in 12, ET in 2, IMF in 2, and latent unclassified PMD with the presence of EEC in 24 patients. Thrombocytosis as a manifestation of myeloproliferative disease was recorded in 34 of 80 (42.5%) patients with spontaneous EEC and Budd-Chiari syndrome or portal vein thrombosis. Thrombocythemia was present in 15 of 41 patients with a proven and in 19 of 39 patients with a latent myeloproliferative disorder. Patients with hepatic vein or splanchnic vein thrombosis associated with a PMD are predominantly females younger than 45. It is concluded that both spontaneous EEC and histopathology from bone marrow biopsy provide specific information as sensitive clues to the diagnosis of all variants of overt and latent myeloproliferative disorders. The association of hepatic and splanchnic vein thrombosis and PMD is not fully understood. Therapeutic options of Budd-Chiari syndrome include anticoagulation with heparin, fibrinolysis followed by oral anticoagulation, and appropriate treatment of the underlying PMD. In case of failure, invasive options include local procedures such as angioplasty or stenting, venous decompression by portal-systemic shunts, or liver transplantation.
Seminars in Thrombosis and Hemostasis 02/1997; 23(5):411-8. · 4.52 Impact Factor
