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T Barbui

Publications and source records attributed to T Barbui.

At least 109 records · Page 6Linked to original sources
PubMed1996

The natural history of monoclonal villous lymphocytosis: a chronic lymphoproliferative disorder of CD11c+ B cells.

The long-term outcome of three asymptomatic subjects with isolated persistent lymphocytosis of monoclonal villous B-cells (MVL) is reviewed. After 7.5 years, evolution to a splenic lymphoma variant (SLVL) was documented in only one patient, accompanied by a loss of interleukin-1beta autocrine production, confirming that MVL can be an early form of a malignant disorder. The clinical course was uneventful in the other two cases; a progressive lowering of lymphocyte count being noted in one. While the strict relationship of MVL to SLVL is confirmed, time to progression is unpredictable and the mechanisms by which it occurs still remain to be elucidated.

Aged↗
PubMed1996

Feasibility of randomised clinical trials in rare diseases: the case of polycythemia vera.

Although it has long been recognised as the only reliable instrument for producing scientific evidence on the benefit/risk profile of therapeutic interventions, the technology of randomised clinical trials (RCT) is far from being the backbone of medical knowledge. Randomised clinical trials in polycythemia vera have been carried out when their methodology was being built up and, therefore, was rather unsatisfactory. Now we have aggressive cytoreductive treatments with chemotherapeutic agents loaded with doubts on long-term safety, while phlebotomy and preventive antiplatelet therapy are left to personal preferences because of debatable results of old, low-power clinical trials. A complex profile of uncertainties requires a simple, but articulated strategy of care and research to allow at the same time a reasonable transfer of the best available validated knowledge and a timely investigation of the most relevant questions. Without doubts, multi-country, collaborative RCTs is the key (not isolated or abstract) element of the current scenario. The declared background hypothesis is the willingness of a medical caring community of being, at the same time and with the same patients, a research community. The trial design comes in as the simplest technical way to deal with uncertainty. Data to be collected, criteria, contents, intensity of follow-up, and documentation of the events are exactly the same as those which are planned and adopted in routine care. One of the greatest achievements of the multicenter trials with this orientation has been to produce a "core" of data and practices, on which the main analyses will be made, but which at the same time reflect an optimal level of assistance to the majority of patients. The purpose of this paper is therefore twofold: a) to provide a brief methodological review of the controlled evidence available for the direction of therapeutic practice for PV: b) to outline and discuss the opportunity, general design, and feasibility of research strategies where a comparative large-scale trial between therapeutic alternatives could play a central role.

Cohort Studies↗
PubMed1996

Treatment strategies in essential thrombocythemia. A critical appraisal of various experiences in different centers.

The therapeutic strategy in patients with Essential Thrombocythemia (ET) is a difficult balance between the prevention of bleeding and thrombotic complications and the risks of drug side effects and toxicity. Major bleeding is rare and seem to be related to higher platelet counts: therefore, a platelet count over 1500 x 10(9)/L is generally regarded as an indication for cytoreduction. Thrombotic complications include microvascular occlusive symptoms, which are reversible with low-dose aspirin, and large vessels thrombosis. The risk of major thrombosis is higher in ET patients aged more than 60 ys. and with previous occlusive event. In this high-risk group, the non-alkylating agent hydroxyurea (HU) significantly reduces the rate of vascular complications and has emerged as the treatment of choice. However, the long-term risk/benefit of HU remains disputed because its leukemogenic potential has not been ruled out. This holds also for other myelosuppressive agents, such as busulphan and pipobroman. Other drugs of particular interest for young patients include recombinant alpha-interferon (IFN) and Anagrelide. Both of them are effective in lowering platelet count, but their efficacy in reducing clinical complications remains to be demonstrated. However, both IFN and Anagrelide have shown to have frequent and clinically important side effects. Thus, further clinical studies are required to establish their role in the strategy of ET patient treatment.

Adult↗
PubMed1996

Molecular diagnosis and clinical relevance of t(9;22), t(4;11) and t(1 ;19) chromosome abnormalities in a consecutive group of 141 adult patients with acute lymphoblastic leukemia.

Over a time period of five years leukemic blast samples from 141 consecutive patients with adult ALL were referred to our laboratory, for molecular evaluation of chromosome abnormalities. The t(9;22), t(4;11) and t(1;19) which are most commonly found in adult ALL with a B-precursor phenotype were molecularly analyzed by similar RT-PCR based protocols. BCR-ABL transcripts generated by the t(9;22) translocation were demonstrated in 36 patients (25%) and were restricted to the 109 patients with B precursor ALL (33% of this group). Of 83 patients showing a, common phenotype (CD10+), 34 were BCR-ABL positive (41%) whereas only 2 out of 26 with Null ALL (HLADr+, CD19+, CD10) were positive. Interestingly, the percent of BCR-ABL positive CD1O+ ALL increases significantly with age being 20% in patients less than 30 years old and more than 50% in older patients. None of the T-ALL (24 patients) and B-ALL (8 patients) were positive. The majority of cases (67%) showed the p190 gene subtype. The cytogenetic diagnosis of Philadelphia chromosome was always confirmed by the molecular analysis and this approach allowed for the detection of the presence of the BCR-ABL rearrangement in 26 patients when a negative result or no metaphases were obtained. The complete remission rate was similar among BCR-ABL positive and negative patients but a shorter remission duration was observed in those showing molecular evidence of t(9;22) and this finding was significantly evident in CD1O+ ALL patients. By means of comparison, in most of the same adult ALL patients, we analyzed the yet unrecognized prevalence of the t(4;11) and t(1;19) translocations by the molecular analysis of their chromosomal breakpoints. Rearrangements of the ALL-1 gene on 11q23 band and ALL- l1AF.4 fusion transcripts specific for the t(4;11) were demonstrated in 7 out of the 21 Null ALL investigated, with no additional positive cases found among the other ALL subgroups. Overall the clinical behavior of t(4; 11) positive patients was dismal with a very short CR duration. Chimeric E2A-PBX1 transcripts generated by the t(1;19) were found in only two of the 87 B-precursor ALL analyzed. The presented results provide further evidence for the utility of RT-PCR based methods for the molecular diagnosis of chromosome translocations in ALL. The identification of such abnormalities can significantly contribute to the identification of more appropriate therapeutic options for standard and high risk ALL patients

Adolescent↗
PubMed1996

The role of anthracyclines in adult acute lymphoblastic leukaemia.

The role of anthracyclines (ANT) in the treatment of adult acute lymphoblastic leukaemia (ALL) is poorly defined as regards drug dosage, schedule, preferable compound, and indications for use in specific treatment phases or disease subset. We therefore reviewed ANT treatment results in adult ALL. Altogether, an early and intensive use of ANT would improve both initial response rate and long-term disease-free survival; idarubicin (IDR) exhibits a considerable antileukaemic activity deserving further evaluation as possible reference drug; and the prognosis of CD10+ t(9;22)/BCR-ABL- ALL can be particularly good following an early dose-intensive ANT consolidation program.

Adolescent↗
PubMed1996

G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation of resistant or relapsing acute leukemias.

Peripheral blood progenitor cells (PBPC) were mobilized by G-CSF in normal HLA identical siblings and used for allogeneic transplantation in eight patients with refractory or relapsed acute leukemias. G-CSF administration was well tolerated and no significant side-effects were registered. The number of circulating WBC peaked at day 5 after G-CSF (range: 22.6-74.6 x 10(9)/l) with a median of 65 CD34+ cells/microl (38-155). As a consequence of leukaphereses, platelets progressively decreased, reaching the nadir after the last procedure (84-205 x 10(9)/l). A mean of two aphereses (1-3) were performed between day +4 and +7 during which 10 liters of blood were processed each time by a cell separator. Conditioning regimens were: fractionated total body irradiation (FTBI) plus either HDAra-C (2 g/m2 x 2/day for 6 days) (n=5) or melphalan (110 mg/m2) (n= 1) and busulfan (4 mg/kg/day for 4 days) and melphalan (110 mg/m2) in two patients relapsed after a previous FTBI-based allogeneic or autologous BMT. At transplantation, a median of 6.9 x 10(6) CD34+ cells/kg (4.2-16.5) and 279 x 10(6) CD3+ cells/kg (161-786) were infused. Engraftment of both neutrophils (> or v=1.5 x 10(9)/l) and platelets (> or v=20 x 10(9)/l) was observed in all patients after a median time of 18 days (range: 11-20 and 10-26, respectively). The evaluation of engraftment after transplantation was accomplished by PCR analysis of four hypervariable genomic regions (VNTR) (ApoB, ApoC2, YNZ-22, and MCT 118) which allowed to demonstrate the condition of donor chimaera in all patients after transplantation. As far as the clinical outcome, two patients died of interstitial pneumonitis at day +243 and +69 and two patients died at day +62 and +152 of pulmonary aspergillosis. Four patients remain alive in remission between day +88 and +287 with grade 0-l GVHD. Allogeneic PBPC transplantation is associated with a complete hematologic recovery and despite the infusion of a large amount of mature CD3+ lymphocytes, apparently acute GVHD is not worse than expected after transplantation of bone marrow progenitors.

Adolescent↗
PubMed1996

Platelet-derived microvesicles in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.

Thrombotic thrombocytopenic purpura (TTP) and the related hemolytic uremic syndrome (HUS) are disorders characterized by thrombocytopenia, microangiopathic hemolytic anemia, a variable degree of impairment of renal function and fluctuating neurological symptoms, which are thought to be due to platelet activation and subsequent formation of thrombi in the microcirculation. Since platelet activation is accompanied by the generation of microvesicles (PMPs), we determined their presence in patients with TTP and HUS by flow cytometry. The analysis was performed in whole blood, using FITC-conjugated monoclonal antibodies (CD 42b and/or CD 61a). PMPs were discriminated from platelets on the basis of size and fluorescence profiles. Their levels in 21 normal controls ranged between 2.4% and 9.4% (mean +/- SD: 5.2 +/- 1.99%). No correlations were found with platelet number. PMPs were then evaluated in 13 patients with TTP and 2 cases of HUS. In all patients they were found higher than in controls, ranging from 11.0 to 91.1% (45.0 +/- 26.0%; p = 0.0001 vs controls). PMPs were serially measured in patients with TTP: at diagnosis a correlation between PMPs and platelet number was found (R]2 = 0.669) and the time-course showed that the improvement of both microangiopathy and clinical manifestations of cerebral and renal involvement was accompanied by a progressive normalization of PMP levels and platelet count. PMP levels were measured also in patients suffering from other forms of thrombocytopenia: they were 17 patients with idiopathic thrombocytopenic purpura and 10 patients with acute leukemias and severe thrombocytopenia during the aplastic phase following chemotherapy. PMP ranges were: 2.0-79.6% (21.6 +/- 20.8%; p = 0.001 vs controls) and 4.6-12.5% (8.8 +/- 2.4%; p = 0.0001 vs controls), respectively. No correlations were found between platelet number and the absolute number of PMPs in these 2 groups of patients. These findings show that increased levels of PMPs may be found in peripheral thrombocytopenias and suggest that their presence may be clinically relevant, particularly in the microangiopathic forms.

Adolescent↗
PubMed1996

Thrombocytopenia in the antiphospholipid syndrome: pathophysiology, clinical relevance and treatment.

The antiphospholipid syndrome (APS) is characterized by the association of antiphospholipid antibodies with venous and/or arterial thrombosis, recurrent abortions and thrombocytopenia. With respect to this latter clinical manifestation, a variable degree of thrombocytopenia occurs in approximately 20-40% of the patients with APS, it is generally mild and does not modify the policy for treatment of thrombosis. Severe thrombocytopenia is relatively uncommon and seldom associated with bleeding complications. When required, its treatment is similar to that of idiopathic thrombocytopenic purpura. Finally, uncertainties still exist as to the interaction between aPL antibodies and platelets and to the role of platelets and these antibodies on the pathogenesis of the thrombotic complications of the APS.

Antiphospholipid Syndrome↗
PubMed1995

Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia administered all-trans-retinoic acid.

All-trans-retinoic acid (ATRA) induces complete remission (CR) in up to 90% of acute promyelocytic leukemia (APL) patients with rapid amelioration of the bleeding syndrome. Previous studies indicate that ATRA treatment in vitro of the APL NB4 cell line can affect their procoagulant activity (PCA). To assess whether ATRA has this effect also in vivo, we prospectively studied the PCA of bone marrow blasts from APL patients on therapy with ATRA alone or associated with chemotherapy. Samples were obtained before, during, and after ATRA. To characterize the coagulopathy, we measured a series of plasma hemostatic variables before and during the first two weeks of therapy, as follows: (1) markers of hypercoagulability; (2) natural anticoagulants; (3) fibrinolysis proteins; and (4) elastase. The results by enzymatic and immunologic methods show that both total (tissue factor-like) and factor VII-independent (cancer procoagulant-like) blast cell PCAs, present before therapy, were reduced during (69% and 65% decrement, respectively) and virtually undetectable after ATRA. The plasma hemostatic assessment of patients before treatment was elevated hypercoagulability markers, low mean protein C, normal fibrinolysis proteins, and increased elastase. After starting ATRA, hypercoagulability markers were reduced within 4 to 8 days, protein C augmented, the overall fibrinolytic balance was unmodified, and elastase remained elevated. These results were not different either with or without chemotherapy and are consistent with the clinical findings of rapid improvement of the coagulopathy.

Adolescent↗
PubMed1995

Kaolin clotting time and dilute Russell's viper venom time distinguish between prothrombin-dependent and beta 2-glycoprotein I-dependent antiphospholipid antibodies.

Antiphospholipid (aPL) antibodies include anticardiolipin (aCL) and lupus anticoagulant (LA) antibodies. LA antibodies recognize the complex of lipid-bound (human) prothrombin, in this way inhibiting the phospholipid-dependent coagulation reactions, whereas aCL antibodies are directed towards beta 2-glycoprotein I (beta 2-GPI) bound to an anionic lipid surface. According to their behavior in coagulation reactions, we have divided aCL antibodies into two groups: aCL-type A, which inhibit the phospholipid-dependent coagulation reactions because they enhance the binding of beta 2-GPI to the procoagulant phospholipid surface; and aCL-type B antibodies, which are devoid of anticoagulant properties. We report the distinctive laboratory and clinical profiles of 25 patients with well-characterized, phospholipid-dependent inhibitor of coagulation. Fourteen patients had LA antibodies (aCL-type B were concomitantly present in 10 cases, while in the other four, aCL titer was normal), and the other 11 had aCL-type A antibodies. The laboratory evaluation of the two groups showed the dilute Russell viper venom time (dRVVT) to be the most abnormal coagulation test in the aCL-type A-positive group, whereas the kaolin clotting time (KCT) was the most abnormal assay in the LA-positive group. In fact, the ratios of the coagulation times of patient plasma over normal pooled plasma (mean +/- standard deviation) for LA versus aCL-type A antibodies were 1.48 +/- 0.27 versus 2.20 +/- 0.42, P = .0001, and 2.22 +/- 0.42 versus 1.50 +/- 0.42, P = .0003, for the dRVVT and KCT, respectively. No differences were observed either in the ratios of the activated partial thromboplastin times and the prothrombin times or the plasma levels of beta 2-GPI and prothrombin. Conversely, aCL titers were significantly higher in aCL-type A-positive patients (147 +/- 44 U) than in the LA-positive group (61 +/- 55 U; P = .0003). We ruled out the possibility that platelet contamination of plasma could account for the observed coagulation profiles, as the two patterns were reproduced in platelet-free plasma. In addition, we performed clotting tests in plasma in the presence of phospholipids and calcium after addition of factor IXa or factor Xa. The assay performed with factor Xa was more sensitive to the presence of aCL-type A antibodies, while the assay performed with factor IXa was preferentially sensitive to LA-containing plasmas, supporting the earlier findings with the dRVVT and KCT assays.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1995

All-trans retinoic acid and cyclic adenosine monophosphate cooperate in the expression of leukocyte alkaline phosphatase in acute promyelocytic leukemia cells.

Treatment of acute promyelocytic leukemia (APL) blasts with cyclic adenosine monophosphate (cAMP) analogs, in combination with all-trans retinoic acid (ATRA), results in the upregulation of the expression of leukocyte alkaline phosphatase (LAP), a marker for the differentiation of the granulocyte. The synergistic interaction between the cyclic nucleotide analogs and the retinoid is not unique to APL cells, as it is observed also in the peripheral granulocytes of chronic myelogenous leukemia (CML) patients. The molecular mechanisms underlying LAP induction were studied in NB4, an immortalized APL cell line. Induction of LAP enzymatic activity is dependent on the time of exposure and on the concentrations of dibutyryl-cAMP or 8-bromo-cAMP and ATRA, two factors that influence the kinetics of appearance of detectable levels of the enzyme. Augmentation of LAP levels by ATRA and cAMP is the result of both transcriptional and early posttranscriptional events and requires de novo protein synthesis. LAP induction correlates with augmentation in the levels of the type I catalytic subunit of cAMP-dependent protein kinase transcript and with granulocytic differentiation. The transcriptional component of the process leading to increased LAP gene expression was reproduced in its main features by transient transfection experiments performed in COS-7 cells using the normal retinoic acid receptor type alpha (RAR-alpha) or the APL-specific aberrant form (PML-RAR) and the upstream promoter of the liver/bone/kidney (L/B/K)-type alkaline phosphatase gene. The promoter is upregulated by treatment with ATRA, and this upregulation is further increased by cAMP analogs.

Alkaline Phosphatase↗
PubMed1995

Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis.

BACKGROUND: Abnormalities in the number and function of platelets may contribute to thromboembolic complications in patients with essential thrombocythemia. We assessed whether maintaining the platelet count below 600,000 per cubic millimeter with hydroxyurea reduces the incidence of thrombosis in patients with essential thrombocythemia and a high risk of thrombosis. METHODS: A total of 114 patients with essential thrombocythemia (77 women and 37 men; median age, 68 years; range, 40 to 85) and a median platelet count of 788,000 per cubic millimeter (range, 533,000 to 1,240,000 per cubic millimeter) were randomly assigned to receive hydroxyurea (56 patients) or no myelosuppressive therapy (58 patients). Ninety-seven (85 percent) were over 60 years old, and 52 (46 percent) had had thrombosis. The two groups were matched for age, sex, and platelet count at randomization. Antiplatelet prophylaxis with aspirin or ticlopidine was not stopped. Follow-up lasted a median of 27 months in both groups. RESULTS: Two patients (3.6 percent) treated with hydroxyurea had thrombotic episodes (one stroke and one myocardial infarction), whereas 14 patients (24 percent) in the control group had thrombotic episodes (one stroke, five transient ischemic attacks, five peripheral arterial occlusions, one deep-vein thrombosis, and two cases of superficial thrombophlebitis). The difference (20.4 percentage points; 95 percent confidence interval, 8.5 to 32 percent) was statistically significant (chi-square with Yates' correction, 8.3; 1 df; P = 0.003). CONCLUSIONS: Hydroxyurea is effective in preventing thrombosis in high-risk patients with essential thrombocythemia.

Adult↗
PubMed1995

Establishment of human acute myelogenous leukemia lines secreting interleukin-1 beta in SCID mice.

A reproducible in vivo model of human acute myelogenous leukemia (AML) was established in severe combined immunodeficient (SCID) mice. The AML-CL and AML-PS lines were originated from leukemic blasts purified respectively from the peripheral blood of a 27-year-old woman with previously untreated hyperleukocytotic AML and from the bone marrow of a 61-year-old man during the third leukemic relapse. The 2 lines were maintained and serially transplanted i.p. in SCID mice. AML-PS and AML-CL produced ascitogenous gross tumors after approximately 4 and 6 weeks, respectively, and all mice died within 6-8 weeks. Microscopic evaluation of different organs at autopsy showed massive involvement of bone marrow, liver and spleen, though with differences in the tumor burdens for the 2 lines (AML-CL > AML-PS). Flow cytometric analysis documented the spread of leukemic cells to bone marrow, peripheral blood and spleen. AML-PS and AML-CL cells show an immunophenotypic profile (CD13+, CD33+) and cytogenetic findings similar to freshly isolated blasts. Interleukin-1 beta (IL-1 beta) gene expression was observed by Northern blot analysis in leukemic cells from AML-CL and AML-PS SCID mice. After 24 hr of culture both lines released IL-1 beta in culture supernatants. High levels of circulating IL-1 beta were secreted in plasma of tumor-bearing mice. This AML-SCID murine model could contribute to an understanding of the mechanisms of AML growth in vivo and the possible role of the autocrine production of IL-1 beta in promoting cell growth.

Adult↗
PubMed1995

A recombination event in the closely linked plasminogen and apolipoprotein(a) gene loci.

Genetic studies as well as in situ hybridisation data have strongly demonstrated that the genes coding for apoprotein(a) and plasminogen are linked and localised to chromosome 6 at band 6q26-27. We describe in this report the presence of a recombination event in a region of approximately 50 kb of DNA separating the two genes. The recombination was found in an Italian family, in which a mutation affecting both plasminogen plasma level and activity of plasminogen activity has been detected. Polymerase chain reaction and sequencing analysis showed the presence of a mutation different from those previously reported in two Japanese families.

Adult↗