Elisabetta Calore

Azienda Ospedaliera Universitaria Integrata Verona, Verona, Veneto, Italy

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Publications (31)92.18 Total impact

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    ABSTRACT: TCR Α/Β and B-cell depleted hematopoietic SCT in pediatric SAA and aspergillosis Bone Marrow Transplantation (2014) 49, 847–849; doi:10.1038/ bmt.2014.58; published online 7 April 2014 Children with acquired SAA (ASAA) are at high risk of life-threatening infections without prompt therapy. 1 The gold standard treatment is hematopoietic SCT (HSCT) from a matched sibling donor, available in only 25% of cases, with a survival rate of 90%. 2 The remaining patients are eligible for immunosuppressive treatment (IST) with a response rate of 60–80%. 3 In cases of IST failure and absence of suitable donor, haploidentical HSCT (HHSCT) could be considered. To date, limited reports of the use of purified CD34 + cells are available. 2,4,5 In this setting, graft rejection (GR) and opportunistic infection due to delayed immune reconstitution are major causes of transplant failure. 4 A 4-year-old African girl was admitted to the Pediatric Hematology Oncology of Padova with fever, bruises, severe pancytopenia and reticulocytopenia. The diagnosis of ASAA was made through BM aspirate (aplasia without myelodysplasia) and trephine biopsy (o 10% of cellularity without myelofibrosis). 1 As an HLA-identical sibling donor was not available, one course of IST was administered (steroids, rabbit antilymphocyte globulin (rALG), CsA and G-CSF) 2 and was complicated by fever and progressive respiratory failure requiring intensive care. Computed tomography (CT) scan showed bilateral multiple areas of parenchymal consolidation and a peribroncheal lesion. Galacto-mannan antigen (GM) on serum and bronchoalveolar lavage samples became positive (index > 0.50). In the presence of 'probable' lung aspergillosis, voriconazole was started. The patient worsened in spite of IST there was no improvement in the blood count with concomitant clinical deterioration. Because of the lack of a suitable unrelated donor owing to the rarity of the patient's HLA, an urgent HHSCT was scheduled. Three months after diagnosis, the patient received HHCST from her mother's G-CSF-mobilized PBSCs. PBSCs were processed for T-cell receptor alpha beta (TCRαβ) and CD19 + depletion by CliniMACS System (Miltenyi, Cologne, Germany). 6 Conditioning regimen consisted of thiothepa (TT; 10 mg/kg), Cy (200 mg/kg) and rATG (Fresenius, Bad Homburg, Germany) (80 mg/kg). No prophylaxis for GVHD was performed. Rapid neutrophil and platelet engraftment was achieved (Table 1) with full donor chimerism. After initial engraftment, the patient developed secondary graft rejection (GR) on day +20, confirmed by chimerism study (100% of the recipient's cells). Because of worsening of lung aspergillosis in addition to CMV and EBV reactivation, a second HHSCT from her father was done on day +38. Conditioning regimen included TT (10 mg/kg), Cy (200 mg/kg), total lymphoid irradiation (TLI) (7.5 Gy) and rATG (Genzyme, Modena, Italia) (15 mg/kg). Prophylaxis of GVHD consisted of CsA (3 mg/kg i.v.), continued even after PBSC infusion (residual TCRαβ cells in the graft > 25 000/kg) (Table 1). Rapid neutrophil and platelet engraftment occurred (Table 1) and full donor chimerism was achieved. No progression of the lung infection was observed in the post-conditioning aplasia period. One month after the second transplant, the peripheral nodules disappeared, the peribroncheal lesion was reduced and GM on serum decreased until negativization. Two and four months after second HHSCT, the patient experienced CMV reactivation with prompt response to preemptive foscarnet. Five months later, despite continuous oral voriconazole, fever recurred. CT scan showed excavation aspects of the known lesion, at risk of endobronchial rupture with GM repositivization in the blood. Surgical lobectomy was successfully performed and the histology confirmed diagnosis of aspergillosis. Thereafter, complete resolu-tion and continuous GM negativity were seen. CsA was stopped 9 months after HSCT. T-, B-and NK-cell reconstitution data are depicted in Figure 1. Neither acute nor chronic GVHD occurred. The regimens were well tolerated without significant toxicity. The patient is currently healthy at 25 months after the second HHSCT, with full donor chimerism and transfusion independency. HHSCT using αβ-TCR/CD19 + depletion was considered a valid option for our patient in consideration of: (1) IST failure; (2) lack of a suitable donor; and (3) worsening of clinical condition.
    Bone Marrow Transplantation 06/2014; · 3.54 Impact Factor
  • Bone marrow transplantation 04/2014; · 3.00 Impact Factor
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    ABSTRACT: To assess the non-inferiority of pegfilgrastim versus filgrastim in speeding the recovery of polymorphonuclear cells (PMN) in pediatric patients who underwent autologous peripheral blood stem cell transplant (PBSCT). The sample size of this randomized, multicenter, phase III study, was calculated assuming that a single dose of pegfilgrastim of 100 ug/kg was not inferior to 9 doses of filgrastim of 5 ug/kg/day. Randomization was performed by a computer-generated list and stored by sequentially numbered sealed envelopes. Sixty-one patients, with a median age of 11.5 years, were recruited: 29 in the filgrastim arm and 32 in the pegfilgrastim arm. Twenty percent were affected by lymphoma/leukaemia and eighty percent by solid tumors. The mean time to PMN engraftment was 10.48 days (standard deviation [SD] 1.57) and 10.44 days (SD 2.44) in the filgrastim and pegfilgrastim arms, respectively. Having fixed a non-inferiority margin Delta of 3, the primary endpoint of non-inferiority was reached. No differences were observed for other secondary endpoints: platelet engraftment, mean time to platelet recovery (28 days vs. 33 days), fever of unknown origin (79% vs. 78%), proven infection (34% vs. 28%), mucositis (76% vs. 59%). After a median follow-up of 2.3 years (95% C.I.: 1.5, 3.3), 20 deaths were observed due to disease progression. We conclude that pegfilgrastim was not inferior to daily filgrastim in pediatric patients who underwent PBSCT. EU CLINICAL TRIAL REGISTER NUMBER: 2007-001430-14.
    PLoS ONE 01/2013; 8(1):e53252. · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: Peripheral blood stem cells (PBSCs) are the preferred source in autologous transplantation. We assessed prospectively the efficacy of mobilization in pediatric patients and risk factors associated with its failure. STUDY DESIGN AND METHODS: Patients, aged 0 to 17 years, needing a first collection of PBSCs for autologous stem cell transplantation were eligible. The study period was from July 2008 to September 2010. A blood peak of fewer than 20 × 10(6) CD34+ cells/L was used as the cutoff to define a poor mobilizer. RESULTS: A total of 145 patients, 57% male (82) and 43% female (63), with a median age of 7 years, affected by solid tumor, 79% (114), and acute leukemia or lymphoma, 21% (31), were enrolled. Granulocyte-colony-stimulating factor used was filgrastim in 69%, lenograstim in 26%, and pegfilgrastim in 5% of patients. A total of 83% (121) of patients mobilized successfully, the median CD34+ count being 120 × 10(6) /L (range, 23 × 10(6) -1840 × 10(6) /L). A single leukapheresis procedure was sufficient to achieve the target CD34+ cell dose in 82% (99/121) of patients. Among 24 poor mobilizer patients, 15 underwent a second mobilizing course and nine required a marrow harvest. Factors associated with poor mobilization were metastatic disease and relapse. Among 99 patients who underwent autologous stem cell transplantation, the median times to neutrophil and platelet engraftment and of hospitalization were longer by 2, 12, and 6 days in poor versus good mobilizer group. CONCLUSIONS: In pediatric patients undergoing a first mobilization, the incidence of poor mobilization was 17%. Failure of mobilization resulted in an increase in health costs and a longer hospitalization for those who underwent autologous stem cell transplantation.
    Transfusion 10/2012; · 3.53 Impact Factor
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    ABSTRACT: Several studies proved that virus-specific T-cells play a pivotal role in controlling cytomegalovirus (CMV) infection in adult allogeneic hematopoietic stem-cell transplant (HSCT) patients. Fewer data are available in pediatric HSCT settings, when immature and inexperienced immune system may affect antiviral immune reconstitution. We analyzed prospectively the CMV-specific T-cell reconstitution in a cohort of 31 pediatric allogeneic HSCT recipients at 30, 60, 90, 120, 180, and 360 days after HSCT. Depending on donor-recipient CMV serostatus, we observed distinct patterns and kinetics of CMV-specific T-cell immune reconstitution: during the early time-points, patients displayed a severe reduction in CMV-specific T-cell recovery in both CMV seropositive donor (D+) group and CMV seronegative donor (D-) on CMV seropositive recipients (R+). From day 90 onward, statistical significant differences in the profile of T-cell immune reconstitution emerged between D+ and D-. The pattern of immune reconstitution was characterized by heterogeneous kinetics and efficiencies: we report cases of: (1) spontaneous antiviral T-cell recovery with no previous viremia, (2) immune T-cell recovery anticipated by CMV viremia, and (3) no T-cell immune reconstitution despite previous viremia episodes. Given the heterogeneous scenarios of antiviral T-cell immune recovery in pediatric allogeneic HSCT, we conclude that the evaluation of the antiviral immune reconstitution is a promising and appealing system for identifying patients at higher risk of CMV infection. The use of interferon-γ ELISPOT test is a valid tool for immunological monitoring and predicting CMV viremia in pediatric HSCT.
    Transplantation 03/2012; 93(5):536-42. · 3.78 Impact Factor
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    ABSTRACT: A number of apoptotic stimuli produce a different response by CD4(+) regulatory and effector lymphocytes. So far, little is known concerning the sensitivity of CD4(+) regulatory T cells (Treg) to genotoxic agents. Observations from a mouse model suggest that Treg are more resistant to DNA damage compared to CD4(+) T effector cells (Teff). By flow cytometry we analysed the apoptotic response to genotoxic stimuli in culture, comparing Treg and Teff. CD4(+) regulatory lymphocytes appeared to be more resistant than CD4(+) effector lymphocytes. Results of costaining experiments for CD45RA suggest that this dissimilarity is not related to the differentiation to a CD45RA negative phenotype. Further, neither the antiapoptotic protein Bcl-2 nor Bcl-xL were found to be expressed in greater amounts by Treg compared to Teff. The differential sensitivity of Treg and Teff to DNA-damage inducing agents may be of clinical relevance in cancer therapy. © 2011 International Society for Advancement of Cytometry.
    Cytometry Part A 11/2011; 79(11):903-11. · 3.71 Impact Factor
  • Digestive and Liver Disease 10/2011; 43. · 3.16 Impact Factor
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    ABSTRACT: An 8-year old boy, affected by severe aplastic anemia, developed a probable pulmonary invasive aspergillosis (IA) early after a second unrelated allogeneic hematopoietic stem cell transplant (HSCT). He was treated promptly with the combination of liposomal amphotericin B and caspofungin. Despite the initial stabilization, the patient deteriorated and the antifungal therapy was switched to voriconazole and caspofungin. The patient gradually improved and was discharged home on day +29 post-HSCT on oral voriconazole. On day +119, a sudden episode of hemoptysis occurred and a right superior lobectomy was decided to remove the residual aspergilloma. The patient is now alive and well more than 24 months from HSCT. This case demonstrated that antifungal combination therapy and surgery are valid options to cure pulmonary IA even in patients at high-risk and severely immunosuppressed.
    Pediatric reports 06/2011; 3(2):e18.
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    ABSTRACT: Veno-occlusive disease (VOD) is a major complication following hematopoietic stem cell transplantation (HSCT). Its diagnosis is based on clinical criteria, which have a limited sensitivity. Increased plasminogen activator inhibitor-1 (PAI-1) levels have been suggested as a marker of VOD. We aimed to prospectively evaluate how the fibrinolytic parameters behaved to discriminate VOD from other liver disorders occurring after HSCT in a pediatric population. A total of 195 HSCT were performed on 161 children and VOD complicated 11 cases (6.8%). Alanine aminotransferase, total bilirubin, PAI-1 antigen (PAI-1:Ag) and activity, t-PA antigen, D-dimer, prothrombin time, activated partial thromboplastin time, antithrombin, fibrinogen, and platelet counts were measured in 105 HSCT before and then weekly for 1 month after HSCT. An early, significant increase in the fibrinolytic parameters was seen in patients who developed VOD, even before VOD was diagnosed clinically, by comparison with patients without complications or those with non-VOD liver disorders. The combined increase in bilirubin, D-dimer, and PAI-1:Ag levels beyond the normal range distinguished VOD cases from other liver complications with a high sensitivity and specificity. Our study demonstrates that fibrinolytic tests can help diagnose VOD after HSCT in the pediatric population.
    Pediatric Blood & Cancer 06/2011; 58(5):791-7. · 2.35 Impact Factor
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    ABSTRACT: In HSCT setting, KIR-driven alloreactivity might be better predicted if the donor KIR genotype is considered in addition to the recipient HLA genotype. The prediction of NK cell alloreactivity relies on the missing ligand in the recipient, a scenario that can be found in HLA-identical and non-identical allotransplants. The aim of this study was to investigate at genetic level the prognostic impact of recipient HLA-I lacking for donor KIR on allotransplanted patients outcome. We analysed donors KIR genotype and HLA genotype of 60 paediatric patients who received related (n=15) or unrelated (n=45) transplantation. When patients were grouped based on the KIR gene type involved in the KIR/HLA-I mismatch, we did not observe any relapse in the group of patients characterized by mismatches involving only inhibitory KIR. On the contrary, all relapses were observed in patients showing at least one activating gene involved in the mismatch (p<0.05). Although the biological mechanism accounting for this putative genetic rule is still to be clarified, we suggest that a careful survey of KIR/HLA-I mismatching should be taken into account in the selection of donor in related and unrelated HSCT.
    Pediatric Transplantation 03/2011; 15(2):198-204. · 1.50 Impact Factor
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    ABSTRACT: Posttransplant lymphoproliferative disease caused by Epstein-Barr virus (EBV-PTLD) is a severe complication after allogeneic hematopoietic stem-cell transplantation (HSCT). We evaluated whether the modulation of immunosuppression (IS) guided by quantitative polymerase chain reaction for EBV (EBV-PCR) was effective as a first-line therapeutic approach for EBV reactivation. Eighty-nine pediatric patients who received an HSCT from an unrelated donor were prospectively assessed by quantitative EBV-PCR. The EBV-PCR threshold to modulate IS was set to more than 300 genomic copies (gc)/10 peripheral blood mononuclear cells. EBV-PCR positivity was observed in 56 (63%) of 89 patients at a median time of 44 days after HSCT. The variables associated with EBV-PCR positivity were bone marrow stem cells (P=0.047) and a lower total dose of nuclear cells reinfused (P=0.03). Thirty-one patients (35%) had more than or equal to 300 gc. IS was withdrawn or reduced in 18 (58%) and 13 (42%) of the 31 patients, respectively. EBV viral load (EBV-VL) less than 300 gc was achieved in 30 of these 31 patients at a median of 25 days. Only 1 (1%) of the 89 patients progressed to EBV-PTLD. The patients with EBV-VL more than 300 gc had a lower incidence of acute graft versus host disease III-IV than patients with EBV-VL less than 300 gc: 13% vs. 36%, P=0.02. No differences in terms of chronic graft versus host disease, overall survival, event-free survival and transplant-related mortality were observed between the two groups. We conclude that PCR-guided modulation of IS may play a role in early intervention for EBV-PTLD and a prospective, randomized study is needed.
    Transplantation 06/2010; 89(12):1533-40. · 3.78 Impact Factor
  • Thrombosis Research - THROMB RES. 01/2010; 125.
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    ABSTRACT: Osteonecrosis (ON) is a critical complication in the treatment of childhood leukemia and lymphoma. It particularly affects survivors of acute lymphoblastic leukemia and non-Hodgkin lymphoma reflecting the cumulative exposure to glucocorticosteroid therapy. ON is often multiarticular and bilateral, specially affecting weight-bearing joints. A conventional approach suggests a surgical intervention even if pharmacological options have also recently been investigated. We reported two cases of long time steroid-treated patients who underwent Bone Marrow Transplantation (BMT) for hematological disease. Both patients developed femoral head osteonecrosis (ON) that was diagnosed by magnetic resonance imaging (MRI) and the ON was also accompanied with pain and a limp. Despite of the conventional strategies of therapy, we successfully started a short-term treatment with bisphosphonates in order to decrease the pain and the risk of fracture.
    Case Reports in Medicine 01/2010; 2010:206132.
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    ABSTRACT: We describe two episodes of CMV retinitis in a pediatric patient who underwent a CD34+ selected graft from his haploidentical father. Both recipient and donor were cytomegalovirus (CMV) seropositive. Both episodes occurred late post-grafting during a phase of complete immunological recovery with sufficient numbers of circulating CMV-specific clones. Antiviral treatment with foscarnet and ganciclovir was successful but prolonged treatment was required to prevent relapses. We hypothesize that this complication was more related to an immune reconstitution process than to an immune-deficient state post-grafting. We conclude that CMV retinitis is a late complication of HSCT that can occur despite satisfactory immune reconstitution. Usually, it is responsive to antiviral therapy. Dilated fundoscopic examination is essential both for examining patients with reduced visual acuity and for screening asymptomatic patients.
    International Journal of Hematology 08/2008; 88(2):145-8. · 1.68 Impact Factor
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    ABSTRACT: Acute GVHD (aGVHD) is a major cause of morbidity and mortality after unrelated BMT (UBMT). Our purpose was to analyze the role of extracorporeal photochemotherapy (ECP) in controlling grade II-IV aGVHD in children given UBMT. Of 41 consecutive children, 31 developed grade II-IV aGVHD after UBMT: 16 had a good response to steroids (GR group), whereas 15 underwent ECP (ECP group) within 100 days of UBMT. Eligibility criteria for starting ECP were steroid resistance, dependence or viral reactivations. Criteria for judging response to aGVHD treatment were that the resolution of all signs were considered a complete response (CR), at least a 50% improvement was classified as a partial response (PR) and stable or progressive disease was judged as no response (NR). On completing ECP, the CR rate was 73%, whereas the GR group had a CR rate of 56% by day 100. The 2-year overall survival and progression-free survival rates were 57 and 67% in the GR group vs 85 and 87% in the ECP group. Our data seem to suggest that ECP may improve outcome in patients after UBMT. These findings need to be confirmed in a larger population.
    Bone marrow transplantation 07/2008; 42(6):421-5. · 3.00 Impact Factor
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    ABSTRACT: GvHD remains a source of significant morbidity and mortality in the setting of allogeneic haematopoietic SCT. Improving outcomes in stem cell transplant recipients requires additional therapeutic modalities for GvHD, especially for patients who fail to respond to initial therapy with steroids. Moreover, while the absence of acute GvHD (aGvHD) is associated with a higher risk of relapse of the underlying malignant disease, severe aGvHD usually induces the occurrence of life-threatening complications such as severe infections. This article summarizes the current state of aGvHD prophylaxis and treatment.
    Bone Marrow Transplantation 06/2008; 41 Suppl 2:S65-70. · 3.54 Impact Factor
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    ABSTRACT: A reliable diagnosis of invasive aspergillosis (IA) is hampered by the difficulty in obtaining suitable tissue samples. To evaluate the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the LightCycler PCR for the diagnosis of IA, 536 blood samples were collected over a 22-month period from 62 paediatric patients (median age 10 years, range 1-18) considered at risk of IA. The galactomannan antigen (GM) and fungal DNA were assessed on serial blood samples. IA was diagnosed in eight of 62 patients (13%): proven, five, probable, three. Sensitivity, specificity, PPV and NPV of LightCycler PCR varied according to the number of positive samples used to define positivity: 88%; 37%; 17% and 95% for single sample positivity; and 63%, 81%, 33% and 94% for serial sample positivity respectively. The concordance between positivity of LightCycler PCR assay and the diagnosis of IA was 79%. The single positivity of LightCycler PCR assay showed a good sensitivity for the diagnosis of IA in paediatric patients. The high NPV makes LightCycler PCR a promising tool in addition to GM testing to design a strategy of pre-emptive antifungal therapy, although further validation studies are needed.
    Mycoses 04/2008; 51(6):497-504. · 1.28 Impact Factor
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    ABSTRACT: We investigated the incidence, risk factors and outcome of haemorrhagic cystitis (HC) in paediatric patients undergoing HSCT and the predictive value of BK viruria and viraemia for developing HC. Over a period of 54 months, 74 patients were recruited. The cumulative incidence of HC was 22%. Among 15 patients prospectively monitored for BK viruria and viraemia, four patients developed HC of grade > or =II. This group, which had two consecutive BK positive samples, showed a sensitivity of 100%, a specificity of 82%, a positive predictive value of 67%, and negative predictive value of 100% for developing HC. Analysed by a receiver-operator characteristic curve (ROC), a urine BK load >9 x 10(6) genomic copies/ml had a sensitivity of 95% and specificity of 90%; while a blood BK load >1 x 10(3) genomic copies/ml had a sensitivity of 40% and a specificity of 93% for HC, respectively. In univariate analysis, BK positivity was the only factor significantly associated with HC. After a median follow-up of 1.8 years, patients with HC showed a lower overall survival, 40 vs 65%, P 0.01, and a lower event-free survival, 42 vs 62%, P 0.03, compared to patients without HC. We conclude that BK detection in urine and/or plasma is a specific predictor for developing HC.
    Bone Marrow Transplantation 02/2008; 41(4):363-70. · 3.54 Impact Factor
  • International Journal of Infectious Diseases - INT J INFECT DIS. 01/2006; 10.
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    ABSTRACT: Veno-occlusive disease (VOD) is one of the most frequent complications after stem cell transplantation. We conducted a prospective survey of 244 hematopoietic stem cell transplants in children to determine the incidence of VOD, its main risk factors, treatment and effect on the transplant. Two hundred and forty-four hematopoietic stem cell transplants (HSCT) performed in 220 pediatric patients from 1993 to 2003 were evaluated. The series included 127 males and 93 females with a median age of 6.7 years at the time of transplantation. VOD was diagnosed following 26 of the 244 transplants (cumulative incidence 11%), but a higher incidence was found in patients with at least one known risk factor for VOD (cumulative incidence 20%). In multivariate analysis, risk factors for VOD were age < 6.7 years; type of VOD prophylaxis, and busulphan-containing conditioning regimens. Routine treatment of VOD was based on supportive care and, starting from 1999, defibrotide was used. All patients were monitored with daily Doppler ultrasound-(US) for early diagnosis of inversion of portal blood flow. Twelve patients developed inversion of portal flow (9 had severe VOD; 3 had moderate VOD) and were promptly started on fibrinolytic and anticoagulant therapy with heparin and recombinant tissue plasminogen activator (rt-PA). Hepatic flow reverted to normal in all 12 patients; only 4 patients ultimately developed multiorgan failure and died. The transplant-related-mortality (TRM) rate in patients with or without inversion of portal flow was 33% vs 7%, (p=0.1). The TRM in patients with or without VOD was 19% vs 8% (p=0.001). This study showed that younger age, type of VOD prophylaxis, and busulphan-based conditioning regimens are independent risk factors for VOD. Inversion of portal flow was found in 9 of 10 patients with severe VOD. Doppler US monitoring may be helpful in early identification of the patients with VOD-induced inversion of portal flow who might benefit from therapy with heparin and rt-PA.
    Haematologica 10/2005; 90(10):1396-404. · 5.94 Impact Factor

Publication Stats

447 Citations
92.18 Total Impact Points

Institutions

  • 2012–2013
    • Azienda Ospedaliera Universitaria Integrata Verona
      • Division of Paediatric Oncohematology
      Verona, Veneto, Italy
  • 2010
    • University-Hospital of Padova
      Padua, Veneto, Italy
  • 1999–2010
    • University of Padova
      • • Department of Pediatrics
      • • Department of Women’s and Children’s Health - SDB
      Padova, Veneto, Italy