Publications (25)158.38 Total impact
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Article: Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: results from the Interfant-99 Study.
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ABSTRACT: To define a role for hematopoietic stem cell transplantation (HSCT) in infants with acute lymphoblastic leukemia and rearrangements of the mixed-lineage-leukemia gene (MLL(+)), we compared the outcome of MLL(+) patients from trial Interfant-99 who either received chemotherapy only or HSCT. Of 376 patients with a known MLL status in the trial, 297 (79%) were MLL(+). Among the 277 of 297 MLL(+) patients (93%) in first remission (CR), there appeared to be a significant difference in disease-free survival (adjusted by waiting time to HSCT) between the 37 (13%) who received HSCT and the 240 (87%) who received chemotherapy only (P = .03). However, the advantage was restricted to a subgroup with 2 additional unfavorable prognostic features: age less than 6 months and either poor response to steroids at day 8 or leukocytes more than or equal to 300 g/L. Ninety-seven of 297 MLL(+) patients (33%) had such high-risk criteria, with 87 achieving CR. In this group, HSCT was associated with a 64% reduction in the risk of failure resulting from relapse or death in CR (hazard ratio = 0.36, 95% confidence interval, 0.15-0.86). In the remaining patients, there was no advantage for HSCT over chemotherapy only. In summary, HSCT seems to be a valuable option for a subgroup of infant MLL(+) acute lymphoblastic leukemia carrying further poor prognostic factors. The trial was registered at www.clinicaltrials.gov as #NCT00015873 and at www.controlled-trials.com as #ISRCTN24251487.Blood 10/2010; 116(15):2644-50. · 9.90 Impact Factor -
Article: Molecular characterization of paediatric idiopathic hypereosinophilia.
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ABSTRACT: The hypereosinophilic syndromes (HES) include a group of heterogeneous diseases characterized by the persistent increase of the number of eosinophils in blood and bone marrow. Few cases of paediatric hypereosinophilia (pHES) have been described in the literature. Early identification of pHES that may evolve towards a lymphomyeloproliferative disease is relevant in light of prognostic and therapeutic implications. Molecular features of 10 pHES patients were analysed at presentation and during their clinical course, including analysis of BCR-ABL1 and FIP1L1/PDGFRA fusion genes, quantitation of WT1 gene copy number and clonality of T-cell receptor (TCR) and immunoglobulin heavy chain (IGH). All patients had normal karyotype and germline TCR configuration. Five children showed IGH clonality at presentation: of these, two developed a B non-Hodgkin lymphoma and a B-lineage acute lymphocytic leukaemia at six and 12 months respectively, two spontaneously reverted to a polyclonal IGH profile during the follow-up, and the last one persisted with pHES without B-clonal evolution after 19 months. One patient had a PDGFRA/FIP1L1 fusion and achieved hematologic and molecular remission after imatinib therapy. IGH rearrangement was observed to be a frequent molecular feature of pHES and may precede B-cell clonal expansion and evolution into B-cell malignancies in children.British Journal of Haematology 10/2010; 151(5):440-6. · 4.94 Impact Factor -
Article: Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study.
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ABSTRACT: The Associazione Italiana di Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster Acute Lymphoblastic Leukemia (AIEOP-BFM ALL 2000) study has for the first time introduced standardized quantitative assessment of minimal residual disease (MRD) based on immunoglobulin and T-cell receptor gene rearrangements as polymerase chain reaction targets (PCR-MRD), at 2 time points (TPs), to stratify patients in a large prospective study. Patients with precursor B (pB) ALL (n = 3184) were considered MRD standard risk (MRD-SR) if MRD was already negative at day 33 (analyzed by 2 markers, with a sensitivity of at least 10(-4)); MRD high risk (MRD-HR) if 10(-3) or more at day 78 and MRD intermediate risk (MRD-IR): others. MRD-SR patients were 42% (1348): 5-year event-free survival (EFS, standard error) is 92.3% (0.9). Fifty-two percent (1647) were MRD-IR: EFS 77.6% (1.3). Six percent of patients (189) were MRD-HR: EFS 50.1% (4.1; P < .001). PCR-MRD discriminated prognosis even on top of white blood cell count, age, early response to prednisone, and genotype. MRD response detected by sensitive quantitative PCR at 2 predefined TPs is highly predictive for relapse in childhood pB-ALL. The study is registered at http://clinicaltrials.gov: NCT00430118 for BFM and NCT00613457 for AIEOP.Blood 02/2010; 115(16):3206-14. · 9.90 Impact Factor -
Article: Pharmacokinetics of daunorubicin and daunorubicinol in infants with leukemia treated in the interfant 99 protocol.
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ABSTRACT: There is an extreme paucity of pharmacokinetic data for anticancer agents in infants. Therefore, we aimed at characterizing the pharmacokinetics for daunorubicin in infants and examined their relationship to age, body weight, and body surface area. Leukemia patients treated according to the Interfant 99 protocol received 30 mg/m(2) daunorubicin, with dose reduction to 3/4 for patients 6-12 months old and 2/3 for patients <6 months, respectively. Plasma samples from 21 patients (aged 0.05-1.88 years) were collected and analyzed for daunorubicin and daunorubicinol. Samples from 12 children (age 1.6-18.8 years), who received daunorubicin in an earlier investigation, were used for pharmacokinetic model building using the software NONMEM. Plasma concentration time profiles could be described using a two compartment model. Daunorubicin clearance was 43.9 L hr(-1) m(-2) +/- 65% and central volume of distribution 16.4 L m(-2) +/- 46%, whereas apparent clearance of daunorubicinol was 19.1 L hr(-1) m(-2) +/- 32% and apparent volume of distribution 228 L m(-2) +/- 80% (mean +/- interindividual variability). No age-dependency in any of the BSA-normalized pharmacokinetic parameters was observed. Consequently, due to the empirical dose reduction in infants the overall exposure to daunorubicinol in infants was smaller than would be expected from older children. Patients aged <6 months experienced more infections in the induction phase than the group aged 6-12 months at diagnosis. Other toxicities were similar in both groups. We observed no indication of an age-dependency in the pharmacokinetics of daunorubicin. Pediatr Blood Cancer 2010;54:355-360.Pediatric Blood & Cancer 09/2009; 54(3):355-60. · 1.89 Impact Factor -
Article: Rearrangements of the RAR‐α gene in acute promyelocytic leukaemia:
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ABSTRACT: Summary We have used genomic probes which specifically recognize DNA rearrangements of the RAR- locus on chromosome 17q21 in patients with acute promyelocytic leukaemia (APL) and acute myeloid leukaemia (AML) subtypes. Molecular data were examined in comparison with morphological and immunophenotypic characterization at diagnosis in 20 hypergranular FAB M3 cases, five microgranular APL (M3v), 51 non-M3 AML and 12 myeloid CML blast crises.Rearrangements of the RAR- locus were only detected in 23/25 APL cases and in none of the other FAB subtypes analysed. Surface marker characterization showed a consistent immunophenotypic profile—HLADR negative. CD9 and CD13/33 positive—in all M3 and M3v cases. Neither HLADR negativity nor CD9 positivity were associated with RAR- rearrangements in non M3 AML.Our data indicate that RAR- gene rearrangements are relevant diagnostic features of both M3 and M3v, and may prove useful molecular marker for follow-up analysis in APL patients.British Journal of Haematology 03/2008; 78(4):494 - 499. · 4.94 Impact Factor -
Article: A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial.
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ABSTRACT: Acute lymphoblastic leukaemia in infants younger than 1 year is rare, and infants with the disease have worse outcomes than do older children. We initiated an international study to investigate the effects of a new hybrid treatment protocol with elements designed to treat both acute lymphoblastic leukaemia and acute myeloid leukaemia, and to identify any prognostic factors for outcome in infants. We also did a randomised trial to establish the value of a late intensification course. Patients aged 0-12 months were enrolled by 17 study groups in 22 countries between 1999 and 2005. Eligible patients were stratified for risk according to their peripheral blood response to a 7-day prednisone prophase, and then given a hybrid regimen based on the standard protocol for acute lymphoblastic leukaemia, with some elements designed for treatment of acute myeloid leukaemia. Before the maintenance phase, a subset of patients in complete remission were randomly assigned to receive either standard treatment or a more intensive chemotherapy course with high-dose cytarabine and methotrexate. The primary outcomes were event-free survival (EFS) for the initial cohort of patients and disease-free survival (DFS) for the patients randomly assigned to a treatment group. Data were analysed on an intention-to-treat basis. This trial was registered with ClinicalTrials.gov, number NCT 00015873, and at controlled-trials.com, number ISRCTN24251487. In the 482 enrolled patients who underwent hybrid treatment, 260 (58%) were in complete remission at a median follow-up of 38 (range 1-78) months, and EFS at 4 years was 47.0% (SE 2.6, 95% CI 41.9-52.1). Of 445 patients in complete remission after 5 weeks of induction treatment, 191 were randomised: 95 patients to receive a late intensification course, and 96 to a control group. At a median follow-up of 42 (range 1-73) months, 60 patients in the treatment group and 57 controls were disease-free. DFS at 4 years did not differ between the two groups (60.9% [SE 5.2] for treatment group vs 57.0% [5.5] for controls; p=0.81). During the intensification phase, of 71 patients randomly assigned to the treatment group, and for whom toxicity data were available, 35 (49%) had infections, 21 (30%) patients had mucositis, 22 (31%) patients had toxic effects on the liver, and 2 (3%) had neurotoxicity. All types of rearrangements in the (mixed lineage leukaemia) MLL gene, very high white blood cell count, age of younger than 6 months, and a poor response to the prednisone prophase were independently associated with inferior outcomes. Patients treated with our hybrid protocol, and especially those who responded poorly to prednisone, had higher EFS than most reported outcomes for treatment of infant ALL. Delayed intensification of chemotherapy did not benefit patients.The Lancet 08/2007; 370(9583):240-50. · 38.28 Impact Factor -
Article: Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience.
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ABSTRACT: In idiopathic thrombocytopenic purpura (ITP), corticosteroids have been widely recognized as the most appropriate first-line treatment, even if the best therapeutic approach is still a matter of debate. Recently, a single high-dose dexamethasone (HD-DXM) course was administered as first-line therapy in adult patients with ITP. In this paper we show the results of 2 prospective pilot studies (monocentric and multicentric, respectively) concerning the use of repeated pulses of HD-DXM in untreated ITP patients. In the monocenter study, 37 patients with severe ITP, age at least 20 years and no more than 65 years, were enrolled. HD-DXM was given in 4-day pulses every 28 days, for 6 cycles. Response rate was 89.2%; relapse-free survival (RFS) was 90% at 15 months; long-term responses, lasting for a median time of 26 months (range 6-77 months) were 25 of 37 (67.6%). In the multicenter study, 95 patients with severe ITP, age at least 2 years and no more than 70 years, were enrolled. HD-DXM was given in 4-day pulses every 14 days, for 4 cycles; 90 patients completed 4 cycles. Response rate (85.6%) was similar in patients classified by age (<18 years, 36 of 42=85.7%; >or=18 years, 41 of 48=85.4%, P=not significant), with a statistically significant difference between the second and third cycle (75.8% vs 89%, P=.018). RFS at 15 months 81%; long-term responses, lasting for a median time of 8 months (range 4-24 months) were 67 of 90 (74.4%). In both studies, therapy was well tolerated. A schedule of 3 cycles of HD-DXM pulses will be compared with standard prednisone therapy (eg, 1 mg/kg per day) in the next randomized Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) trial.Blood 02/2007; 109(4):1401-7. · 9.90 Impact Factor -
Article: Idiopathic thrombocytopenic purpura (ITP) in children.
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ABSTRACT: Idiopathic thrombocytopenic purpura in children remits spontaneously in the majority of cases but most children require treatment. Between 1995 and 2005, 265 children (0-15 years old) have been consecutively observed and treated: 28 children with high doses of methylprednisolone (HDMP) (15 mg/kgx4 days), 63 with HDMP (7.5 mg/kgx4 days), 37 with HD dexamethasone (DXM) pulses, 29 with low doses of MP, and 51 with different doses of intravenous immunoglobulins (IVIG) (0.4 or 0.8 g/kg). Fifty-seven children have not been treated because of a platelet count>or=10x10(9)/L and no significant bleeding. Two hundred forty-four (92.1%) children reached a persistent CR, 237 (89.4%) after a first-line treatment or the wait and see strategy. No statistically significant differences in CR related to different treatments have been observed. IVIG and HDMP (7.5 mg/kg for 4 days) are the best treatments to reach quickly safe platelet levels>or=30x10(9)/L (3-6 days) and CR (7-11 days). Among non-responding (NR) patients, seven have been splenectomized and three reached stable CR. These results emphasize differences with adult ITP.Pediatric Blood & Cancer 11/2006; 47(5 Suppl):665-7. · 1.89 Impact Factor -
Article: Osteogenesis induced by autologous bone marrow cells transplant in the pediatric skull.
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ABSTRACT: The ability of cranial bone to repair defects of continuity is limited and it is mostly dependent on the age of the patient. In infancy and in early pediatric age, the scarce thickness of the calvarial bones and the need for a harmonic development of the child's skull limit the application of most of the surgical procedures usually utilized in older patients. We tested the ability of mononucleated cells, derived from the patient's bone marrow and transplanted on the site of the cranial bone defect, to increase the rate of mineralization of the autologous osteogenesis to obtain the complete restoration of the skull continuity. Four children, aged 26, 28, 37, and 79 months, respectively, affected by a stabilized and persistent cranial bone defect of posttraumatic or postsurgical origin, were treated. A sandwich-shaped shell, made of extrused absorbable polylactic copolymers material, was used to hold in place a freeze-dried mineralized collagen matrix associated with a nonceramic hydroxyapatite scaffold, where autologous bone marrow mononucleated cells were inseminated. In all patients, a rapid autologous bone osteogenesis was observed with a clear dimensional reduction of the bone defect few months after the autologous bone marrow cells seeding. The preliminary results of this research suggest the use of autologous bone marrow cells to increase the autologous osteogenesis in early pediatric age in cases in which correction of skull bone defects is best realized with autologous bone.Child s Nervous System 10/2006; 22(9):1158-66. · 1.54 Impact Factor -
Article: Rapid T-cell receptor CD4+ repertoire reconstitution and immune recovery in unrelated umbilical cord blood transplanted pediatric leukemia patients.
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ABSTRACT: Umbilical cord blood transplantation has been successfully employed for treatment of many immune and hematologic disorders. The aim of this study was to evaluate the quality of immune reconstitution after umbilical cord blood transplantation in 6 leukemia children. T-cell receptor Vbeta third complementary region spectratyping was used for monitoring the contribution of the thymic pathway in patients' immune reconstitution. Absolute numbers of lymphocyte subsets (T, B, and natural killer), and lymphoproliferative in vitro response to mitogens, recovered within 12 months after transplantation. Furthermore, an overall diversification of T-cell receptor complexity in the repopulating T cells, with a polyclonal Gaussian profiles in most (74%) of total families was observed. Noteworthy, we showed a wider and more rapid reconstitution of T-cell receptor CD4+ T cell families compared with T-cell receptor CD8+ T ones still exhibiting some perturbations at 24 months. These data show that umbilical cord blood transplantation allows immune reconstitution already within 12 months with generation of newly diversified CD4+ T lymphocyte subsets.Journal of Pediatric Hematology/Oncology 08/2006; 28(7):403-11. · 1.16 Impact Factor -
Article: Infant leukaemia: clinical, biological and therapeutic advances.
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ABSTRACT: Infant acute lymphoid leukaemia (IALL) represents a distinct subset with an extremely poor response to therapy, despite major progress in the treatment of childhood leukaemia. However, several studies have shown that, even in this generally considered homogeneous group, a distinction could be made with regard to prognosis. The outcome of IALL patients with ALL-1/MLL rearrangements at the 11q23 cytogenetic band, early pre-B immunophenotype, high WBC count and age below 6 mo is significantly worse than in patients without these characteristics, and current therapies appear inadequate in a significant number of cases. Therefore, an international protocol (Interfant 99) was recently started, using a more aggressive approach, which included lymphoid- and myeloid-specific drugs, and indications for stem-cell transplantation. We reviewed the clinical characteristics of the disease, the results of several recent international clinical trials, and our experience with 16 infants with acute lymphoid leukaemia diagnosed and treated at our institution. CONCLUSION: It is extremely important to stratify patients for prognosis, taking into account clinical and biological variables with independent prognostic value. The aim is to select more adequate, risk-adapted, therapeutic strategies which also consider related or unrelated bone marrow transplant consolidation for patients with very poor prognosis.Acta paediatrica (Oslo, Norway: 1992). Supplement 08/2006; 95(452):47-51. -
Article: Role of treatment intensification in infants with acute lymphoblastic leukemia: results of two consecutive AIEOP studies.
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ABSTRACT: Fifty-two infants with acute lymphoblastic leukemia (ALL) enrolled in the AIEOP ALL-91 and ALL-95 studies were treated with the intermediate or high risk protocols according to their presenting features and early response to treatment. The 5-year event-free survival was 33.3% (95% CI 12.1-54.5), 53.5% (95% CI 35.7-71.3) and 45.0% (95% CI 31.3-58.7) in the ALL-91 and ALL-95 studies and in the overall cohort, respectively. In the ALL-95 high-risk group (BFM therapy intensified by three blocks and double protocol II) nine of 17 patients treated with chemotherapy only and three of four transplanted patients were alive and in complete remission. The corresponding figures for patients treated in the ALL-91 high-risk protocol (reduced induction and nine blocks) were one of seven patients treated with chemotherapy only and none of two who were transplanted.Haematologica 05/2006; 91(4):534-7. · 6.42 Impact Factor -
Article: Treatment reduction in highly selected standard-risk childhood acute lymphoblastic leukemia. The AIEOP ALL-9501 study.
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ABSTRACT: Treatment of childhood standard-risk (SR) acute lymphoblastic leukemia (ALL) is generally successful. However, intensive chemotherapy regimens may be associated with severe treatment sequelae. Efforts are therefore being made to identify those patients in whom less intensive treatment would be equally successful but cause fewer long-term sequelae. The aim of this study was to evaluate the efficacy of treatment reduction in a subset of children with ALL at minimal risk of failure. The population of patients with SR ALL included children aged between 1 and 6 years with less than 20,000 WBC/mm3, non-T immunophenotype, DNA index between 1.16 and 1.6, absence of t(9;22) and t(4;11) clonal translocations, no extramedullary leukemia, good response to prednisone and complete remission (CR) at the end of induction therapy. A reduced-intensity, BFM-type treatment schedule (AIEOP-ALL 9501 protocol) was used. Induction therapy was based on vincristine, prednisone, L-asparaginase and intrathecal methotrexate only; high-dose-methotrexate (2 g/m2) was given x4. The BFM Protocol II was given as reinduction therapy; thus the total dose of anthracyclines was 120 mg/m2 and no epipodophyllotoxins or cranial irradiation were employed. Between May 1995 and December 1999, 123 patients were identified as having SR-ALL (7.8% of the ALL-95 population), of whom 102 received the SR protocol. After a median follow-up of 5.9 years, 11 patients in the SR protocol had relapsed, 1 had died in remission, and 1 had developed a second malignant neoplasm. The probabilities (standard errors) of survival and event-free survival (EFS) were, respectively, 97.0% (1.7) and 86.7% (3.5) at 5 years, and 95.3% (2.4) and 86.7% (3.5) at 7 years. Although most of the relapsed patients were rescued, the long-term EFS probability in this small, highly selected group of patients remains inferior to expectation. Thus, alternative selection criteria, such as treatment response measured by minimal residual disease, should be considered to address the issue of treatment reduction.Haematologica 10/2005; 90(9):1186-91. · 6.42 Impact Factor -
Article: Idiopathic hypereosinophilic syndrome: a case evolving in B-lymphoblastic lymphoma.
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ABSTRACT: Idiopathic hypereosinophilic syndrome (HES) is a rare disease characterized by tissue involvement and organ dysfunction due to abnormal eosinophil proliferation. Evolution of HES into myeloid or T-cell malignancies has been frequently reported. Here, we describe a case of HES that preceded the occurrence of a high-grade B-lymphoblastic lymphoma in which clonal evolution has been demonstrated at the molecular level.Leukemia Research 09/2005; 29(8):975-9. · 2.92 Impact Factor -
Article: GIMEMA-AIEOPAIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children.
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ABSTRACT: The role of all-trans retinoic acid (ATRA) in pediatric acute promyelocytic leukemia (APL) is the topic of several ongoing studies. The results of the Italian pediatric experience with the multicentric Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA)-Italian Pediatric Hematology and Oncology Group (AIEOP) "AIDA" (ATRA and idarubicin) trial are presented. Of the 983 patients with APL enrolled in this protocol between January 1993 and June 2000, 124 (13%) had younger than 18 years. Treatment consisted of ATRA and idarubicin induction followed by 3 polychemotherapy consolidation courses. Molecular response by reverse transcriptase-polymerase chain reaction (RT-PCR) was assessed after consolidation and patients who were PCR- were randomized for different maintenances. One hundred and seven children were eligible and evaluable for induction: 103 (96%) achieved a hematologically complete remission. Overt ATRA syndrome was observed in 2 patients and pseudotumor cerebri was observed in 10 patients. Ninety-four patients were evaluable for RT-PCR analysis at the end of consolidation: 91 (97%) proved PCR+ and 3 PCR-. The overall survival and event-free survival (EFS) are 89% (95% confidence interval [c.i.]: 83%-95%) and 76% (c.i.: 65%-85%), respectively, at more than 10 years. A white blood cell (WBC) count at diagnosis of greater than 10 x 10(9)/L had a significant impact on EFS (59% vs 83% at 10 years). These results highlight the efficacy and feasibility of the AIDA protocol in the pediatric APL population.Blood 08/2005; 106(2):447-53. · 9.90 Impact Factor -
Article: Outcome of very late relapse in children with acute lymphoblastic leukemia.
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ABSTRACT: Few data are available on the long-term outcome of children who present with a very late relapse of acute lymphoblastic leukemia, so treatment of these patients remains controversial. The present study was aimed at investigating clinical features and treatment outcome of children with very late relapse, diagnosed and treated in Italy in the last 20 years. All children diagnosed in Italian centers with a first relapse of acute lymphoblastic leukemia occurring >or= 60 months after attainment of first complete remission were included in this study. These relapses were diagnosed between 1982 and 1997. Ninety-three patients (58 males, 62.4%) had a first very late relapse occurring at a median time of 6.1 years (range 5.8 - 13.7 years) after the initial diagnosis. At a median follow-up time of 9.1 years after relapse, the overall 5-year survival (SE) and event-free-survival (SE) were 55.6% (5.2) and 39.5% (5.1), respectively. In multivariate analysis the site of relapse was the only significant predictor of duration of the second complete remission. Patients with isolated bone marrow relapse fared worse than those with combined or isolated extramedullary relapse [5-year event-free survival (SE) 24.5% (5.9), 51.3% (11.1) and 68.4% (10.7), respectively; (p=0.004)]. All 7 patients who underwent an allogeneic bone marrow transplantation from a matched related donor are alive in second complete remission. In this evaluation patients with a very late relapse isolated to the bone marrow had a poor outcome while re-treatment of extramedullary or combined relapse was associated with better cure rate. Our data suggest that patients with very late isolated bone marrow relapse should be treated intensively; bone marrow transplantation from a matched related donor may be indicated.Haematologica 04/2004; 89(4):427-34. · 6.42 Impact Factor -
Article: Osteonecrosis: An emerging complication of intensive chemotherapy for childhood acute lymphoblastic leukemia.
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ABSTRACT: Osteonecrosis (ON) is a potentially disabling complication of combination chemotherapy including high doses of steroids. The incidence and main risk factors for symptomatic ON have been investigated in a large group of children treated with high-dose steroids, prednisone and dexamethasone for childhood acute lymphoblastic leukemia (ALL). From May 1995 to December 1999, 1421 patients <18 years old, with newly diagnosed non-B ALL, were registered in the AIEOP-ALL 95 study. Their data were reviewed to identify patients who developed symptomatic ON. For those who were positively identified additional data were requested concerning ON-related symptoms, treatment and outcome. Overall, 15 of the 1421 patients developed symptomatic ON (1.1%) in a total of 29 sites. The estimated 5-year cumulative risk for clinically diagnosed ON was 1.6% (SE 0.4). The incidence was significantly higher among females (p=0.01) and older patients, with a peak rate of 7.4% (2.3) among those aged 10 to 17 years (p<0.0001). When the two factors, i.e. age and gender were combined, there was a striking increase in the risk among female patients aged 10 to 17 years. The median time between the diagnosis of ALL and that of ON was 17 months (range 8-45). The hip was the most frequently involved (19/29) site. Symptomatic ON occurred in only 1.1% of patients treated with BFM-type, intensive chemotherapy for childhood ALL. Female adolescents appear to be the subset of patients with the highest risk of ON, especially when categorized as having high risk leukemia and thus administered higher cumulative doses of dexamethasone.Haematologica 08/2003; 88(7):747-53. · 6.42 Impact Factor -
Article: A multiplex reverse transcriptase-polymerase chain reaction strategy for the diagnostic molecular screening of chimeric genes: a clinical evaluation on 170 patients with acute lymphoblastic leukemia.
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ABSTRACT: In the last few years molecular methods have allowed the identification of leukemia-associated genetic lesions, which may represent the most accurate predictors of clinical outcome. These considerations strengthen the need for rapid identification of the abnormalities. Our aim was to demonstrate whether a modified multiplex reverse transcription polymerase chain reaction (RT-PCR) system might be successfully used to screen a large number of patients with acute lymphoblastic leukemia (ALL). In this study we adapted the multiplex RT-PCR assay, previously described by Pallisgaard et al., to detect all the most frequent genetic lesions with their characteristic splicing variants occurring in acute lymphoblastic leukemia, such as the MLL/AF4, MLL/ENL, BCR/ABL p190 (e1a2) and p210 (b2a2,b3a2) isoforms, E2A/PBX1, TEL/AML1, SIL/TAL1 and the novel NUP98/RAP1GDS1 transcript, recently described in a T-ALL leukemic subtype. We used the multiplex RT-PCR assay to screen 170 ALL patients (70 children and 100 adults). PCR positivity was detected in 67 (39%) of the 170 ALL patients studied. The comparison between cytogenetic and molecular analyses showed complete correspondence between the two assays in all patients with an evaluable karyotype. Finally, the observed incidence of genetic lesions in our ALL patients was similar to the frequency usually reported both in children and in adults with ALL. These results show that, compared to single RT-PCR reactions, our multiplex RT-PCR system allows rapid, specific, simultaneous as well as a less expensive, laborious and time-consuming detection of the most frequent fusion transcripts in ALL patients. Therefore, it might be recommended for rapid diagnostic molecular screening of large numbers of patients, such as those enrolled in multicenter, co-operative studies. Furthermore, we have shown that multiplex RT-PCR is an open system that can easily be adapted to detect new leukemic genes.Haematologica 04/2003; 88(3):275-9. · 6.42 Impact Factor -
Article: Genotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis.
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ABSTRACT: Autosomal-recessive osteopetrosis is a severe genetic disease caused by osteoclast failure. Approximately 50% of the patients harbor mutations of the ATP6i gene, encoding for the osteoclast-specific a3 subunit of V-ATPase. We found inactivating ATP6i mutations in four patients, and three of these were novel. Patients shared macrocephaly, growth retardation and optic nerve alteration, osteosclerotic and endobone patterns, and high alkaline phosphatase and parathyroid hormone levels. Bone biopsies revealed primary spongiosa lined with active osteoblasts and high numbers of tartrate-resistant acid phosphatase (TRAP)-positive, a3 subunit-negative, morphologically unremarkable osteoclasts, some of which located in shallow Howship lacunae. Scarce hematopoietic cells and abundant fibrous tissue containing TRAP-positive putative osteoclast precursors were noted. In vitro osteoclasts were a3-negative, morphologically normal, with prominent clear zones and actin rings, and TRAP activity more elevated than in control patients. Podosomes, alphaVbeta3 receptor, c-Src, and PYK2 were unremarkable. Consistent with the finding in the bone biopsies, these cells excavated pits faintly stained with toluidine blue, indicating inefficient bone resorption. Bone marrow transplantation was successful in all patients, and posttransplant osteoclasts showed rescue of a3 subunit immunoreactivity.American Journal Of Pathology 02/2003; 162(1):57-68. · 4.89 Impact Factor -
Article: Allogeneic bone marrow transplantation for infantile globoid-cell leukodystrophy (Krabbe's disease).
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ABSTRACT: A 4-month-old-girl affected by early expression of Krabbe's disease was treated with allogeneic bone marrow transplantation (BMT). The stem cell donor was her heterozygous HLA-identical mother. The central nervous system (CNS) involvement at diagnosis was evident, but minimal. After BMT the child presented a severe hypotonia and an acute tetraventricular hydrocephalus; she died 180 days after the BMT with progressive severe neurologic deterioration. Leukocyte galactocerebrosidase (GALC) activity was present at donor levels 20 days after BMT. Full donor chimerism was evident 18 days after BMT. This report confirms that in early onset "Krabbe's syndrome" if the diagnosis is delayed after the birth, the progression of the neurologic deterioration is not reversed by BMT. It is to be demonstrated if a very early hemopoietic stem cell transplantation during the first weeks of life, could be appropriate and efficacious.Pediatric Transplantation 11/2002; 6(5):427-31. · 1.48 Impact Factor
Top co-authors
Top Journals
- Haematologica (4)
- Blood (3)
- British Journal of Haematology (3)
- Blood (2)
- American Journal Of Pathology (1)
Institutions
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1988–2008
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Università degli Studi di Roma "La Sapienza"
- Department of Cellular Biotechnology and Hematology BCE
Roma, Latium, Italy
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2005
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University of Rome Tor Vergata
- Facoltà di Medicina e Chirurgia
Roma, Latium, Italy
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2003
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A.R.N.A.S. Ospedale Civico Palermo
Italy
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2002
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Ospedale Pediatrico Bambino Gesù
- Unità Operativa di Oncoematologia
Roma, Latium, Italy
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