M Falda

Ospedale San Giovanni Battista, ACISMOM, Torino, Piedmont, Italy

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Publications (79)410.91 Total impact

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    ABSTRACT: About one third of patients with myelodysplastic syndrome (MDS) receiving allogeneic hematopoietic stem cell transplantation (HSCT) are cured by this treatment. Treatment failure may be due to transplant complications or relapse. In order to identify predictive factors for transplantation outcome, we studied 519 patients with MDS or oligoblastic acute myeloid leukemia (AML, <30% marrow blasts) who received allogeneic an HSCT and were reported to the GITMO registry between 2000 and 2011. Univariate and multivariate survival analyses were performed using Cox proportional hazards regression. High-risk category, as defined by the IPSS-R, and monosomal karyotype were independently associated with relapse and lower overall survival after transplantation. On the other hand, older recipient age and high hematopoietic cell transplantation-comorbidity index (HCT-CI) were independent predictors of non-relapse mortality. Accounting for various combinations of patient's age, IPSS-R category, monosomal karyotype, and HCT-CI, the 5-year probability of survival after allogeneic HSCT ranged from 0 to 94%. This study indicates that IPSS-R risk category and monosomal karyotype are important factors predicting transplantation failure both in MDS and oligoblastic AML. In addition, it reinforces the concept that allogeneic HSCT offers optimal eradication of myelodysplastic hematopoiesis when the procedure is performed before MDS patients progress to advanced disease stages.
    Blood 02/2014; 123(15). DOI:10.1182/blood-2013-12-542720 · 10.43 Impact Factor
  • Journal of chemotherapy (Florence, Italy) 09/2013; 26(5). DOI:10.1179/1973947813Y.0000000142 · 1.07 Impact Factor
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    ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Registry studies have shown that advanced disease stage at transplantation is associated with inferior overall survival. To define the optimal timing of allogeneic HSCT, we carried out a decision analysis by studying 660 patients who received best supportive care and 449 subjects who underwent transplantation. Risk assessment was based on both the International Prognostic Scoring System (IPSS) and the World Health Organization classification-based Prognostic Scoring System (WPSS). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of allogeneic HSCT on survival. This model estimated life expectancy from diagnosis according to treatment policy at different risk stages. Relative to supportive care, estimated life expectancy increased when transplantation was delayed from the initial stages until progression to intermediate-1 IPSS-risk or to intermediate WPSS-risk stage, and then decreased for higher risks. Modeling decision analysis on WPSS versus IPSS allowed better estimation of the optimal timing of transplantation. These observations indicate that allogeneic HSCT offers optimal survival benefits when the procedure is performed before MDS patients progress to advanced disease stages. Am. J. Hematol. 88:581–588, 2013. © 2013 Wiley Periodicals, Inc.
    American Journal of Hematology 07/2013; 88(7). DOI:10.1002/ajh.23458 · 3.48 Impact Factor
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    ABSTRACT: ABSTRACT Aim of present study was to investigate the outcome of 94 adult patients with myelodysplasia (MDS) who received an allogeneic stem cell transplantation between January 1995 and September 2010 in two Italian hematological centers. At the time of transplant, 53 patients (56%) had relapsed/refractory disease. The cumulative incidence of grades II-IV acute graft-versus-host disease (GVHD) and chronic GVHD were 33% (21%-45%, 95% CI) and 78% (66%-90%, 95% CI) respectively. The cumulative incidence of transplant-related mortality (TRM) at 100 days was 13% (5%-21%, 95% CI). The 2-year progression free survival (PFS) and overall survival (OS) were 41% (31%-51%, 95% CI) and 49% (38%-59%, 95% CI) respectively. On multivariate analysis, advanced disease stage at transplantation was the major independent variable associated with an inferior 2-year PFS (HR 3.58, 1.93-6.64, 95% CI, p<0.001) and OS (HR 3.6, 1.90-6.83 95% CI). The use of an alternative donor was the independent variable associated with TRM (HR 3.50, 1.38-8.88, 95% CI, p 0.04). In conclusion, our data suggest that disease status at the time of transplant is the major predictor for improved PFS and OS, and treatments required to reach this goal may have value in leading to improved outcome.
    Leukemia & lymphoma 06/2013; 55(4). DOI:10.3109/10428194.2013.816422 · 2.89 Impact Factor
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    ABSTRACT: To evaluate trends in allografting from unrelated donors we conducted a study on 196 consecutive myeloma patients transplanted between 2000 and 2009 in Italy. Twenty-eight %, 37% and 35%, respectively, received a myeloablative, a reduced-intensity and a non-myeloablative conditioning. In these 3 cohorts, one-year and five-year transplant-related mortality were 28.8% and 37.0%; 20.3% and 31.3%; 25.0% and 30.3% respectively (p=0.745); whereas median overall (OS) and event-free survivals (EFS) from transplant were 29 and 10, 11 and 6, 32 and 13 months (p=0.039 and p=0.049). Overall cumulative incidences of acute and chronic graft-versus-host-disease (GVHD) were 46.1% and 51.1%. By Cox multivariate analyses, chronic GVHD was significantly associated with longer OS (HR 0.51; p=0.009), whereas the use of peripheral blood stem cells was borderline significant (HR 0.55; p=0.051). Better response post-transplant was associated with longer EFS (HR 2.13-4.25; p<0.001). Acute GVHD was associated with poorer OS (HR 2.53; p=0.001). This analysis showed a strong association of acute and chronic GVHD, and depth of response post-transplant with clinical outcomes. Long-term disease control remains challenging regardless of the conditioning. In the light of these results, prospective trials may be designed to better define the role of allografting from unrelated donors in myeloma.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2013; 19(6). DOI:10.1016/j.bbmt.2013.03.012 · 3.35 Impact Factor
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    ABSTRACT: An unrelated donor (UD) search was submitted to the Italian Bone Marrow Donor Registry between February 2002 and December 2004, for 326 consecutive patients with hematological malignancies, eligible for a reduced intensity conditioning (RIC) UD transplant. Only two regimens were allowed: melphalan, alemtuzumab, fludarabine and total body irradiation of 200 cGy (regimen A) and thiotepa, cyclophosphamide, anti-thymocyte globulin (regimen B). The outcome of patients receiving an UD transplant (n=121) was compared with patients who did not find a donor (n=205), in a time dependent analysis, correcting for time to transplant. The median follow up from activation of donor search was 6.1 years. UD transplant was associated with a significantly better survival in patients with acute leukemia and non-Hodgkin's lymphoma (NHL) whereas only a favorable trend was documented for Hodgkin's disease. No survival benefit was registered for chronic leukemias. The outcome of the two different conditioning regimens was comparable, in terms of survival, transplant-related mortality and graft versus host disease. In conclusion, finding an UD and undergoing a RIC transplant significantly improves survival of patients with acute leukemia and NHL. The advantage is less clear for HD and chronic leukemias. The role of different conditioning regimens remains to be elucidated by prospective clinical trials.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2012; 26(8):1779-85. DOI:10.1038/leu.2012.55 · 9.38 Impact Factor
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    ABSTRACT: Patients who relapse after an autologous hematopoietic stem cell transplantation (SCT) have a very poor prognosis. We have retrospectively analyzed diffuse large B cell lymphoma patients who underwent an allo-SCT after an auto-SCT relapse reported in the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) database. From 1995 to 2008, 3449 autologous transplants were reported in the GITMO database. Eight hundred eighty-four patients relapsed or progressed after transplant; 165 patients, 19% of the relapsed patients, were treated with allo-transplant. The stem cell donor was related to the patient in 108 cases. A reduced intensity conditioning regimen was used in 116. After allo-SCT, 72 patients (43%) obtained a complete response and 9 obtained a partial response with an overall response rate of 49%; 84 patients (51%) experienced rapid progression of disease. Ninety-one patients died, 45 due to disease and 46 due to treatment-related mortality. Acute graft-versus-host disease was recorded in 57 patients and a chronic GvHD in 38 patients. With a median follow-up of 24 months (2-144) after allo, overall survival (OS) was 39%, and after a median of 21 months (2-138) after allo, progression-free survival (PFS) was 32%. Multivariate analysis indicated that the only factors affecting OS were status at allo-SCT, and those affecting PFS were status at allo-SCT and stem cell donor. This retrospective analysis shows that about one-fifth of patients with diffuse large B cell lymphoma who experience relapse after autologous transplantation may be treated with allogeneic transplantation. Moreover, the only parameter affecting either OS or PFS was the response status at the time of allo-SCT.
    Annals of Hematology 01/2012; 91(6):931-9. DOI:10.1007/s00277-011-1395-9 · 2.40 Impact Factor
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    ABSTRACT: Because information on management and outcome of AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC) is scarce, a retrospective registry study was performed by the Acute Leukemia Working Party of EBMT. Among 2815 RIC transplants performed for AML in complete remission (CR) between 1999 and 2008, cumulative incidence of relapse was 32% ± 1%. Relapsed patients (263) were included into a detailed analysis of risk factors for overall survival (OS) and building of a prognostic score. CR was reinduced in 32%; remission duration after transplantation was the only prognostic factor for response (P = .003). Estimated 2-year OS from relapse was 14%, thereby resembling results of AML relapse after standard conditioning. Among variables available at the time of relapse, remission after HSCT > 5 months (hazard ratio [HR] = 0.50, 95% confidence interval [CI], 0.37-0.67, P < .001), bone marrow blasts less than 27% (HR = 0.53, 95% CI, 0.40-0.72, P < .001), and absence of acute GVHD after HSCT (HR = 0.67, 95% CI, 0.49-0.93, P = .017) were associated with better OS. Based on these factors, 3 prognostic groups could be discriminated, showing OS of 32% ± 7%, 19% ± 4%, and 4% ± 2% at 2 years (P < .0001). Long-term survival was achieved almost exclusively after successful induction of CR by cytoreductive therapy, followed either by donor lymphocyte infusion or second HSCT for consolidation.
    Blood 12/2011; 119(6):1599-606. DOI:10.1182/blood-2011-08-375840 · 10.43 Impact Factor
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    ABSTRACT: Zygomycosis is an emerging fungal infection that is associated with high mortality in hematological patients and stem cell transplantation (SCT) recipients. Radiology--computed tomography (CT) imaging in particular--facilitates the detection of lung involvement at an early stage of the infection. The reversed halo sign (RHS) has previously been reported in cryptogenetic organizing pneumonia and, more recently, as a manifestation of pulmonary zygomycosis. Here we describe a case of histologically proven zygomycosis due to Rhizopus microsporus in a SCT recipient. A chest CT scan performed on day +6 due to persistent fever unresponsive to antibiotics revealed the presence of the RHS, i.e., a focal ground-glass opacity mass surrounded by a solid ring of consolidation. The patient was treated with a combination of liposomal amphotericin B, caspofungin, and deferasirox, but subsequently developed a large pneumothorax and died on day +49 due to progressive infection. This case supports earlier observations that RHS may be an early radiological sign of zygomycosis, facilitating an aggressive diagnostic strategy.
    Infection 07/2011; 40(1):77-80. DOI:10.1007/s15010-011-0156-y · 2.86 Impact Factor
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    ABSTRACT: A. Busca, I. Cavecchia, F. Locatelli, S. D' Ardia, F.G. De Rosa, F. Marmont, G. Ciccone, I. Baldi, R. Serra, E. Gaido, M. Falda. Blood stream infections after allogeneic stem cell transplantation: a single-center experience with the use of levofloxacin prophylaxis. Transpl Infect Dis 2011. All rights reserved Abstract: Blood stream infections (BSIs) remain one of the major causes of morbidity and mortality for patients receiving an allogeneic hematopoietic stem cell transplantation (HSCT). In the present study, we evaluated the incidence and characteristics of BSI within 1 year after allogeneic HSCT in 269 consecutive adult patients who received antibacterial prophylaxis with levofloxacin. Cumulative incidence of BSI was 12% (95% confidence interval, 8–16%). Bacteria were responsible for 30 out of the 32 BSI, while fungi were responsible for 2 episodes of BSI. The median onset of BSI was day 8 (range 1–328 days) post transplant, and 66% of BSI occurred before neutrophil recovery. Gram-positive organisms accounted for 60% (n=18) of bacteremia, and gram-negative isolates for 40% (n=12) of the cases. Coagulase-negative staphylococci were the most commonly isolated gram-positive pathogens (53% of the cases), while Escherichia coli was the most commonly isolated gram-negative bacteria (58% of the cases). Candida albicans and Candida guillermondii were isolated from patients with candidemia. Resistance to fluoroquinolones (FQ) was common with 13% of gram-positive isolates being susceptible to FQ, while 50% of the gram-negative rods were susceptible to FQ. Crude mortality and mortality attributable to BSI were both 3% (1 of 32). In conclusion, our data suggest that despite the emergence of antibiotic resistance, FQ prophylaxis may be considered an appealing approach in allogeneic HSCT recipients and is also worth evaluating in randomized studies.
    Transplant Infectious Disease 05/2011; 14(1):40-8. DOI:10.1111/j.1399-3062.2011.00650.x · 1.98 Impact Factor
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    ABSTRACT: Graft versus host disease (GVHD) represents one of the major limiting factors to the successful applicability of hematopoietic stem cells transplantation (HSCT). In particular, allogeneic HSCT from alternative donors with unmanipulated graft results in an increased risk of both acute and chronic GVHD compared with matched sibling donor transplants [1]. At the present, none of the GVHD prophylactic strategies currently in use, including calcineurin inhibitors [2], T-lymphocyte depletion, and monoclonal antibodies [3,4], have been proven to be of superior efficacy over another.
    American Journal of Hematology 02/2011; 86(2):214-7. DOI:10.1002/ajh.21907 · 3.48 Impact Factor
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    ABSTRACT: Although chemotherapy and transplantation improve outcome of patients with hematological malignancy, complications of these therapies are responsible for a 20-50% mortality rate that increases when respiratory symptoms evolve into acute lung injury (ALI). The aim of this study is to determine the effectiveness of early continuous positive airway pressure (CPAP) delivered in the ward to prevent occurrence of ALI requiring intensive care unit (ICU) admission for mechanical ventilation. Patients with hematological malignancy presenting in the hematological ward with early changes in respiratory variables were randomized to receive oxygen (N = 20) or oxygen plus CPAP (N = 20). Primary outcome variables were need of mechanical ventilation requiring ICU admission, and intubation rate among those patients who required ICU admission. At randomization, arterial-to-inspiratory O(2) ratio in control and CPAP group was 282 ± 41 and 256 ± 52, respectively. Patients who received CPAP had less need of ICU admission for mechanical ventilation (4 versus 16 patients; P = 0.0002). CPAP reduced the relative risk for developing need of ventilatory support to 0.25 (95% confidence interval: 0.10-0.62). Among patients admitted to ICU, intubation rate was lower in the CPAP than in the control group (2 versus 14 patients; P = 0.0001). CPAP reduced the relative risk for intubation to 0.46 (95% confidence interval: 0.27-0.78). This study suggests that early use of CPAP on the hematological ward in patients with early changes in respiratory variables prevents evolution to acute lung injury requiring mechanical ventilation and ICU admission.
    Intensive Care Medicine 10/2010; 36(10):1666-74. DOI:10.1007/s00134-010-1934-1 · 7.21 Impact Factor
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    ABSTRACT: Hodgkin lymphoma relapsing after autologous transplantation (autoSCT) has a dismal outcome. Allogeneic transplantation (alloSCT) using reduced intensity conditioning (RIC) is a salvage option, but its effectiveness is still unclear. To evaluate the role of RIC alloSCT, we designed a retrospective study based on the commitment of attending physicians to perform a salvage alloSCT; thus, only Hodgkin lymphoma patients having human leukocyte antigen-typing immediately after the failed autoSCT were included. Of 185 patients, 122 found an identical sibling (55%), a matched unrelated (32%) or a haploidentical sibling (13%) donor; 63 patients did not find any donor. Clinical features of both groups did not differ. Two-year progression-free (PFS) and overall survival (OS) were better in the donor group (39.3% vs 14.2%, and 66% vs 42%, respectively, P < .001) with a median follow-up of 48 months. In multivariable analysis, having a donor was significant for better PFS and OS (P < .001). Patients allografted in complete remission showed a better PFS and OS. This is the largest study comparing RIC alloSCT versus conventional treatment after a failed autoSCT, indicating a survival benefit for patients having a donor.
    Blood 03/2010; 115(18):3671-7. DOI:10.1182/blood-2009-12-253856 · 10.43 Impact Factor
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    ABSTRACT: This study was performed to examine the characteristics of transplant activity for patients with myelodysplastic syndromes (MDS) older than 50 years within the European Group for Blood and Marrow Transplantation, and to evaluate the factors predicting outcome within this group of patients. We performed a retrospective multicenter analysis of 1,333 MDS patients age 50 years or older who received transplantation within the EBMT since 1998. The median recipient age was 56 years, with 884 patients (66%) age 50 to 60 years and 449 (34%) patients older than 60 years. There were 811 HLA-matched sibling (61%) and 522 (39%) unrelated donor transplants. Five hundred patients (38%) received standard myeloablative conditioning (SMC), and 833 (62%) received reduced intensity conditioning (RIC). The 4-year estimate for overall survival of the whole cohort was 31%. On multivariate analysis, use of RIC (hazard ratio [HR], 1.44; 95% CI, 1.13 to 1.84; P < .01) and advanced disease stage at transplantation (HR, 1.51; 95% CI, 1.18 to 1.93; P < .01) were associated with an increased relapse rate. In contrast, advanced disease stage at transplantation (HR, 1.43; 95% CI, 1.13 to 1.79; P = .01), use of an unrelated donor (P = .03), and RIC (HR, 0.79; 95% CI, 0.65 to 0.97; P = .03) were independent variables associated with nonrelapse mortality. Advanced disease stage at transplantation (HR, 1.55; 95% CI, 1.32 to 1.83; P < .01) was the major independent variable associated with an inferior 4-year overall survival. Allogeneic hematopoietic stem-cell transplantation remains a potential curative therapeutic option for many older patients with MDS. In this analysis, disease stage at time of transplantation, but not recipient age or the intensity of the conditioning regimens, was the most important factor influencing outcomes.
    Journal of Clinical Oncology 12/2009; 28(3):405-11. DOI:10.1200/JCO.2009.21.8073 · 18.43 Impact Factor
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    ABSTRACT: Transfusion-dependency affects the natural history of myelodysplastic syndromes. Secondary iron overload may concur to this effect. The relative impact of these factors on the outcome of patients with myelodysplastic syndrome receiving allogeneic stem-cell transplantation remains to be clarified. We retrospectively evaluated the prognostic effect of transfusion history and iron overload on the post-transplantation outcome of 357 patients with myelodysplastic syndrome reported to the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) registry between 1997 and 2007. Transfusion-dependency was independently associated with reduced overall survival (hazard ratio=1.48, P=0.017) and increased non-relapse mortality (hazard ratio=1.68, P=0.024). The impact of transfusion-dependency was noted only in patients receiving myeloablative conditioning (overall survival: hazard ratio=1.76, P=0.003; non-relapse mortality: hazard ratio=1.70, P=0.02). There was an inverse relationship between transfusion burden and overall survival after transplantation (P=0.022); the outcome was significantly worse in subjects receiving more than 20 red cell units. In multivariate analysis, transfusion-dependency was found to be a risk factor for acute graft-versus-host disease (P=0.04). Among transfusion-dependent patients undergoing myeloablative allogeneic stem cell transplantation, pre-transplantation serum ferritin level had a significant effect on overall survival (P=0.01) and non-relapse mortality (P=0.03). This effect was maintained after adjusting for transfusion burden and duration, suggesting that the negative effect of transfusion history on outcome might be determined at least in part by iron overload. Pre-transplantation transfusion history and serum ferritin have significant prognostic value in patients with myelodysplastic syndrome undergoing myeloablative allogeneic stem cell transplantation, inducing a significant increase of non-relapse mortality. These results indicate that transfusion history should be considered in transplantation decision-making in patients with myelodysplastic syndrome.
    Haematologica 11/2009; 95(3):476-84. DOI:10.3324/haematol.2009.011429 · 5.87 Impact Factor
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    ABSTRACT: Iron overload (IO) is a known adverse prognostic factor in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) for thalassemia and appears to play a similar role in patients with other hematologic disorders. The estimation of IO is based primarily on serum ferritin level; however, many confounding factors can result in ferritin overestimation, especially in HSCT recipients. The aim of the present study was to quantify IO after HSCT using a superconducting quantum interference device (SQUID), and to evaluate the impact of IO on hepatic function and infections. In addition, the feasibility of iron depletion was investigated. A total of 102 consecutive allogeneic HSCT recipients admitted to our outpatient department between December 2005, and December 2007, were analyzed. Primary diagnosis included acute leukemia/myelodysplastic syndrome in 61% of cases. Assessment of IO after HSCT included serum ferritin; in those with hyperferritinemia (ferritin>1000 ng/mL), liver iron concentration (LIC) was evaluated by SQUID magnetic susceptometry. Iron removal therapy was offered to patients with moderate IO (LIC 1000-2000 microg Fe/g wet weight [ww]) or severe IO (LIC >2,000 microg Fe/g ww). Fifty-seven patients had a ferritin level <1000 ng/mL: the median time between HSCT and assessment of ferritin level was 1006 days (range, 93-5239 days), significantly different from the median time of 183 days (range, 78-2957 days) in the 45 patients with a ferritin level >1000 ng/mL. Out of 42 patients evaluated by SQUID, 29 had moderate to severe IO (median LIC value, 1493 microg Fe/g ww [range, 1030-3253]). In a multivariate analysis, a significant correlation was found between a ferritin level >1000 ng/mL and the presence of at least one abnormal liver function test (LFT) ORo=6.8; 95% CI=2.2-20.6). In addition, the rate of proven/probable invasive fungal disease was significantly higher in the patients with hyperferritinemia (13% vs 0%; P=.006). Nineteen of the 24 patients considered eligible for iron-depletion therapy underwent regular phlebotomy; 13 completed the program in a median of 287 days (range, 92-779 days), reaching the target of a ferritin level<500 ng/mL; LIC was significantly reduced (median, 1419 microg Fe/g ww to 625 microg Fe/g ww; P < .001) in 8 of the 9 patients who were revaluated by SQUID at the end of the iron-depletion program. In conclusion, the measurement of LIC obtained by SQUID documented the presence of moderate/severe IO in 69% of the patients with a high ferritin level. Our data showed that in HSCT recipients, high ferritin level is an independent risk factor for abnormal LFTs, and IO may be considered a potential risk factor for fungal infections. A phlebotomy program may be feasible in two-thirds of the patients who might benefit from iron depletion.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2009; 16(1):115-22. DOI:10.1016/j.bbmt.2009.09.011 · 3.35 Impact Factor
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    ABSTRACT: The importance of HLA donor-recipient matching in unrelated haematopoietic SCT (HSCT) is the subject of debate. In this retrospective study, we analyzed 805 adult patients from the Italian Registry receiving HSCT for a haematological malignancy from January 1999 to June 2006 and correlated the degree of HLA matching with transplant outcome. All patient-donor pairs had high-resolution typing at HLA-A, -B, -C, -DRB1 and -DQB1. There was a significantly higher risk of overall mortality, non-relapse mortality, graft failure and acute GVHD (aGVHD) for patients receiving HSCT from an unrelated donor with one or more low- or high-resolution mismatch/es (Mm/s). When only a single HLA Mm is present (9/10 matched pairs), mortality risk is higher than among 10/10 matched pairs in patients transplanted with acute leukaemia in the first CR ('early' patients) but not in the other patients (advanced patients): HR=1.69, 95% CI=0.94-3.02, P=0.08; HR=1.03, 95% CI=0.80-1.32, P=0.82, for early and advanced patients, respectively. These results confirm that the advantage of a 10/10 match has a greater effect in early patients, thus suggesting that a 9/10 matched donor can be chosen in patients with advanced disease lacking a rapidly available 10/10 matched one.
    Bone marrow transplantation 05/2009; 44(9):571-7. DOI:10.1038/bmt.2009.67 · 3.47 Impact Factor
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    ABSTRACT: Administration of mesenchymal stem cells (MSCs) improves the recovery from acute kidney injury (AKI). The mechanism may involve paracrine factors promoting proliferation of surviving intrinsic epithelial cells, but these factors remain unknown. In the current study, we found that microvesicles derived from human bone marrow MSCs stimulated proliferation in vitro and conferred resistance of tubular epithelial cells to apoptosis. The biologic action of microvesicles required their CD44- and beta1-integrin-dependent incorporation into tubular cells. In vivo, microvesicles accelerated the morphologic and functional recovery of glycerol-induced AKI in SCID mice by inducing proliferation of tubular cells. The effect of microvesicles on the recovery of AKI was similar to the effect of human MSCs. RNase abolished the aforementioned effects of microvesicles in vitro and in vivo, suggesting RNA-dependent biologic effects. Microarray analysis and quantitative real time PCR of microvesicle-RNA extracts indicate that microvesicles shuttle a specific subset of cellular mRNA, such as mRNAs associated with the mesenchymal phenotype and with control of transcription, proliferation, and immunoregulation. These results suggest that microvesicles derived from MSCs may activate a proliferative program in surviving tubular cells after injury via a horizontal transfer of mRNA.
    Journal of the American Society of Nephrology 05/2009; 20(5):1053-67. DOI:10.1681/ASN.2008070798 · 9.47 Impact Factor
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    ABSTRACT: Valganciclovir is a well established drug for the management of cytomegalovirus (CMV) infection in haematopoietic stem cell transplantation (HSCT). Data concerning its safety regarding the development of drug resistance are required. The aim of the present study was to retrospectively investigate CMV drug resistance in a group of HSCT patients experiencing relapses of CMV infection after a first-line pre-emptive antiviral therapy. Thirteen adult HSCT patients out of 26 with asymptomatic CMV infection, experiencing relapsing infections 45-155 days after either intravenous (iv) ganciclovir (2 patients) or valganciclovir (11 patients), were studied. Genotypic assays for mutations in the viral phosphotransferase (UL97) and DNA-polymerase (UL54) genes were directly applied on patient specimens. Baseline CMV sequences were compared with those at the time of relapses to identify drug-resistant strains. UL97 mutations A594V and M460V known to confer drug resistance developed in one relapsing patient who received iv ganciclovir as first-line therapy, corresponding to a rate of 7.7% of relapses due to drug-resistant strains and an overall 3.8% rate of infections due to CMV drug-resistant strains. UL54 drug resistance mutations were absent. No evidence of drug resistance was found in patients on valganciclovir either as first-line therapy or as treatment for relapses. The safety profile of valganciclovir as anti-CMV pre-emptive therapy was confirmed, as well as that monitoring CMV drug resistance with genotypic tests on sequential isolates over the time-course of therapy offers guidance to tailor antiviral treatment in a clinically relevant time frame.
    Journal of Antimicrobial Chemotherapy 02/2009; 63(3):600-8. DOI:10.1093/jac/dkn521 · 5.44 Impact Factor
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    ABSTRACT: The correlation between the bromodeoxiuridine (BrdU)-labelling index (LI) of plasma cells and a new proliferation marker, the Argyrophilic Nucleolar Organizer Regions (AgNORs), was investigated in 44 myeloma patients at diagnosis. A preliminary analysis was made to verify the reproducibility of the assessment of plasma cell infiltration (PC%) in bone marrow aspirates, used to collect cells for LI determination, and in bone marrow biopsies, used for AgNORs evaluation. Although an overall good correlation was observed between PC% in biopsies and aspirates (r=0.58, p=0.001), the ratio between PC% in biopsies and in aspirates ranged form 0.35 to 7.5. Only 17 patients (38.6%) were within the 0.5-1.5 range. A positive correlation between LI and AgNORs was observed in these patients (r=0.68, p=0.003), whereas the correlation was lost in patients with higher ratio between PC% in biopsies and in aspirates (r=0.08, p=0.69). The prognostic significance of AgNORs was confirmed by survival analysis, showing a reduced survival for patients with high (>4.4) AgNOR counts (14 months vs 35 months, p=0.004). The AgNORs analysis therefore allows the simultaneous evaluation of myeloma cell infiltration, degree of differentiation and kinetics of growth in bone marrow biopsies. AgNOR counts deserve to be included in the procedures for diagnosis and prognostic evaluation of myeloma patients.
    European Journal Of Haematology 01/2009; 56(1-2):39-44. DOI:10.1111/j.1600-0609.1996.tb00291.x · 2.41 Impact Factor

Publication Stats

3k Citations
410.91 Total Impact Points

Institutions

  • 2000–2014
    • Ospedale San Giovanni Battista, ACISMOM
      Torino, Piedmont, Italy
  • 2002–2013
    • Azienda Ospedaliera Città della Salute e della Scienza di Torino
      • Division of Hematology
      Torino, Piedmont, Italy
  • 2005–2012
    • Università degli Studi di Torino
      • Dipartimento di Scienze Mediche
      Torino, Piedmont, Italy
  • 2007
    • Ospedale Maggiore di Lodi
      Lodi, Lombardy, Italy
  • 2006
    • Hospital de la Santa Creu i Sant Pau
      • Hematology Clinic Services
      Barcino, Catalonia, Spain
    • University of Rome Tor Vergata
      Roma, Latium, Italy
  • 1996
    • Sapienza University of Rome
      • Department of Cellular Biotechnology and Hematology BCE
      Roma, Latium, Italy