Publications by authors named "Federico Mosna"

27 Publications

  • Page 1 of 1

Nelarabine as salvage therapy and bridge to allogeneic stem cell transplant in 118 adult patients with relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma. A CAMPUS ALL study.

Am J Hematol 2020 12 31;95(12):1466-1472. Epub 2020 Aug 31.

Ematologia, Dipartimento di Medicina Traslazionale e di Precisione, "Sapienza" Università di Roma, Rome, Italy.

The outcome of relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) in adults is poor, with less than 20% of patients surviving at 5 years. Nelarabine is the only drug specifically approved for R/R T-ALL/T-LBL, but the information to support its use is based on limited available data. The aim of this observational phase four study was to provide recent additional data on the efficacy and safety of nelarabine in adults with R/R T-ALL/T-LBL and to evaluate the feasibility and outcome of allogeneic hematopoietic stem cell transplant (SCT) after salvage with nelarabine therapy. The primary endpoints were overall response rate (ORR) and overall survival (OS). Additional endpoints were safety, SCT rate and post-SCT OS. Between May 2007 and November 2018, 118 patients received nelarabine salvage therapy at 27 Italian hematology sites. The median age was 37 years (range 18-74 years), 73% were male, 77 had a diagnosis of T-ALL and 41 of T-LBL, and 65/118 (55%) had received more than two lines of therapy. The median number of nelarabine cycles was two (range 1-4); 43/118 (36%) patients had complete remission (CR), 16 had partial remission (14%) and 59 (50%) were refractory, with an ORR of 50%. The probability of OS, from the first dose of nelarabine, was 37% at 1 year with a median survival of 8 months. The OS at 1 year was significantly better for the 47 patients (40%) who underwent SCT after nelarabine salvage therapy (58% vs 22%, log-rank P < .001). The probability of OS at 2 and 5 years from SCT was 46% and 38%, respectively. Seventy-five patients (64%) experienced one or more drug-related adverse events (AE). Grade III-IV neurologic toxicities were observed in 9/118 (8%) of cases and thrombocytopenia or/and neutropenia (grade III-IV) were reported in 41% and 43% of cases, respectively. In conclusion, this is one of the largest cohorts of adult patients with R/R T-ALL/T-LBL treated in real life with nelarabine. Taking into account the poor prognosis of this patient population, nelarabine represents an effective option with an ORR of 50% and a CR rate of 36%. In addition, 40% of cases following nelarabine salvage therapy could undergo SCT with an expected OS at 2 and 5 years of 46% and 38%, respectively. The safety profile of nelarabine was acceptable with only 8% of cases showing grade III-IV neurological AE.
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http://dx.doi.org/10.1002/ajh.25957DOI Listing
December 2020

A Comparison of the Conditioning Regimens BEAM and FEAM for Autologous Hematopoietic Stem Cell Transplantation in Lymphoma: An Observational Study on 1038 Patients From Fondazione Italiana Linfomi.

Biol Blood Marrow Transplant 2018 09 29;24(9):1814-1822. Epub 2018 May 29.

Oncologia Medica 1, Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy.

BEAM (carmustine [bis-chloroethylnitrosourea (BCNU)]-etoposide-cytarabine-melphalan) chemotherapy is the standard conditioning regimen for autologous stem cell transplantation (ASCT) in lymphomas. Owing to BCNU shortages, many centers switched to fotemustine-substituted BEAM (FEAM), lacking proof of equivalence. We conducted a retrospective cohort study in 18 Italian centers to compare the safety and efficacy of BEAM and FEAM regimens for ASCT in lymphomas performed from 2008 to 2015. We enrolled 1038 patients (BEAM = 607, FEAM = 431), of which 27% had Hodgkin lymphoma (HL), 14% indolent non-Hodgkin lymphoma (NHL), and 59% aggressive NHL. Baseline characteristics including age, sex, stage, B-symptoms, extranodal involvement, previous treatments, response before ASCT, and overall conditioning intensity were well balanced between BEAM and FEAM; notable exceptions were median ASCT year (BEAM = 2011 versus FEAM = 2013, P < .001), Sorror score ≥3 (BEAM = 15% versus FEAM = 10%, P = .017), and radiotherapy use (BEAM = 18% versus FEAM = 10%, P < .001). FEAM conditioning resulted in higher rates of gastrointestinal and infectious toxicities, including severe oral mucositis grade ≥3 (BEAM = 31% versus FEAM = 44%, P < .001), and sepsis from Gram-negative bacteria (mean isolates/patient: BEAM = .1 versus FEAM = .19, P < .001). Response status at day 100 post-ASCT (overall response: BEAM = 91% versus FEAM = 88%, P = .42), 2-year overall survival (83.9%; 95% confidence interval [CI], 81.5% to 86.1%) and progression-free survival (70.3%; 95% CI, 67.4% to 73.1%) were not different in the two groups. Mortality from infection was higher in the FEAM group (subhazard ratio, 1.99; 95% CI, 1.02 to 3.88; P = .04). BEAM and FEAM do not appear different in terms of survival and disease control. However, due to concerns of higher toxicity, fotemustine substitution in BEAM does not seem justified, if not for easier supply.
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http://dx.doi.org/10.1016/j.bbmt.2018.05.018DOI Listing
September 2018

Endothelin-1 receptor blockade as new possible therapeutic approach in multiple myeloma.

Br J Haematol 2017 09 9;178(5):781-793. Epub 2017 Jun 9.

Haematology and Bone-Marrow Transplant Unit, Department of Medicine, Verona University, Verona, Italy.

New effective treatments are needed to improve outcomes for multiple myeloma (MM) patients. Receptors with restricted expression on plasma cells (PCs) represent attractive new therapeutic targets. The endothelin-1 (EDN1) axis, consisting of EDN1 acting through EDN-receptor A (EDNRA) and B (EDNRB), was previously shown to be overexpressed in several tumours, including MM. However, there is incomplete understanding of how EDN1 axis regulates MM growth and response to therapy. Besides EDNRA, the majority of MM cell lines and primary malignant PCs express high levels of EDNRB and release EDN1. Similarly, bone-marrow microenvironment cells also secrete EDN1. Investigating the extent of epigenetic dysregulation of EDNRB gene in MM, we found that hypermethylation of EDNRB promoter and subsequent down-regulation of EDNRB gene was observed in PCs or B lymphocytes from healthy donors compared to EDNRB-expressing malignant PCs. Pharmacological blockade with the dual EDN1 receptor antagonist bosentan decreased cell viability and MAPK activation of U266 and RPMI-8226 cells. Interestingly, the combination of bosentan and the proteasome inhibitor bortezomib, currently approved for MM treatment, resulted in synergistic cytotoxic effects. Overall, our data has uncovered EDN1-mediated autocrine and paracrine mechanisms that regulate malignant PCs growth and drug response, and support EDN1 receptors as new therapeutic targets in MM.
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http://dx.doi.org/10.1111/bjh.14771DOI Listing
September 2017

Minimal Residual Disease in Acute Myeloid Leukemia: Still a Work in Progress?

J Clin Med 2017 Jun 3;6(6). Epub 2017 Jun 3.

Hematology, Ospedale "Ca' Foncello", AULSS 2, 31100 Treviso, Italy.

Minimal residual disease evaluation refers to a series of molecular and immunophenotypical techniques aimed at detecting submicroscopic disease after therapy. As such, its application in acute myeloid leukemia has greatly increased our ability to quantify treatment response, and to determine the chemosensitivity of the disease, as the final product of the drug schedule, dose intensity, biodistribution, and the pharmakogenetic profile of the patient. There is now consistent evidence for the prognostic power of minimal residual disease evaluation in acute myeloid leukemia, which is complementary to the baseline prognostic assessment of the disease. The focus for its use is therefore shifting to individualize treatment based on a deeper evaluation of chemosensitivity and residual tumor burden. In this review, we will summarize the results of the major clinical studies evaluating minimal residual disease in acute myeloid leukemia in adults in recent years and address the technical and practical issues still hampering the spread of these techniques outside controlled clinical trials. We will also briefly speculate on future developments and offer our point of view, and a word of caution, on the present use of minimal residual disease measurements in "real-life" practice. Still, as final standardization and diffusion of the methods are sorted out, we believe that minimal residual disease will soon become the new standard for evaluating response in the treatment of acute myeloid leukemia.
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http://dx.doi.org/10.3390/jcm6060057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483867PMC
June 2017

Clinical outcome of myeloid sarcoma in adult patients and effect of allogeneic stem cell transplantation. Results from a multicenter survey.

Leuk Res 2017 02 20;53:74-81. Epub 2016 Dec 20.

Division of Hematology and Bone Marrow Transplantation, Azienda Sanitaria-Universitaria Integrata, University of Udine, Italy.

Introduction: Myeloid Sarcoma (MS) is a rare hematologic myeloid neoplasm that can involve any site of the body. It can occur as an exclusively extramedullary form or it can be associated with an acute myeloid leukemia (AML), a chronic myeloproliferative neoplasm (MPN) or a myelodysplastic syndrome (MDS) at onset or at relapse. The rarity of MS does not enable prospective clinical trials and therefore a specific multicenter register can be useful for the clinical and biological studies of this rare disease.

Patients And Results: we report the clinical characteristics and outcome of 48 histologically confirmed MS, diagnosed and treated in 9 Italian Hematological Centers in the last 10 years. The patient's median age was 46 years. There were 9/48 de novo extramedullary MS, 24/48 de novo AML-related MS and 15/48 were secondary AML-related MS. The most common extramedullary anatomic sites of disease were: skin, lymph nodes and soft tissues. Forty-three patients (90%) underwent a program of intensive chemotherapy including FLAI, HDAC-IDA, HyperCVAD and MEC schemes, with a DDI of 5% and a CR Rate of 45%. Twenty-two (46%) patients underwent Allogeneic SCT, 13 from a MUD, 8 from an HLA-identical sibling donor and 1 from an haploidentical donor. The median OS of the whole population (48 pts) was 16.7 months. The OS probability at 1, 2 and 5 years was 64%, 39% and 33%, respectively. The OS was better in patients that underwent an intensive therapeutic program (median OS: 18 months vs 5 months). Among the intensively treated patients, in univariate analysis, the OS was better in young patients (P=0,008), in patients that underwent Allo-SCT (P=0,009) and in patients that achieved a CR during treatment (P=0,001), and was worse in pts with secondary AML-related MS (P=0,007). Age, response to intensive chemotherapy and Allo-SCT were the only three variables that significantly influenced DFS (P=0,02, P=0,01 and P=0,04, respectively). In multivariable analysis, Allo-SCT and response to intensive chemotherapy remained significant in predicting a better OS (P=0,04 and P=0,001, respectively), and response to intensive chemotherapy was the only significant variable in predicting DFS (P=0,01). After Allo-SCT we observe a survival advantage in patients who achieved a pre-transplant CR (P=0,008) and in those who developed a chronic GvHD (P=0,05).

Conclusions: Patients with MS, both with de novo and secondary forms, still have a very unfavorable outcome and require an intensive therapeutic program, that includes Allo-SCT whenever possible. The outcome after Allo-SCT is positively influenced by the development of chronic GvHD suggesting a Graft versus MS effect.
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http://dx.doi.org/10.1016/j.leukres.2016.12.003DOI Listing
February 2017

Stem Cell Modeling of Core Binding Factor Acute Myeloid Leukemia.

Stem Cells Int 2016 13;2016:7625827. Epub 2016 Jan 13.

Hematology, Department of Specialty Medicine, Ospedale Santa Maria di Ca' Foncello, Piazza Ospedale 1, 31100 Treviso, Italy.

Even though clonally originated from a single cell, acute leukemia loses its homogeneity soon and presents at clinical diagnosis as a hierarchy of cells endowed with different functions, of which only a minority possesses the ability to recapitulate the disease. Due to their analogy to hematopoietic stem cells, these cells have been named "leukemia stem cells," and are thought to be chiefly responsible for disease relapse and ultimate survival after chemotherapy. Core Binding Factor (CBF) Acute Myeloid Leukemia (AML) is cytogenetically characterized by either the t(8;21) or the inv(16)/t(16;16) chromosomal abnormalities, which, although being pathognomonic, are not sufficient per se to induce overt leukemia but rather determine a preclinical phase of disease when preleukemic subclones compete until the acquisition of clonal dominance by one of them. In this review we summarize the concepts regarding the application of the "leukemia stem cell" theory to the development of CBF AML; we will analyze the studies investigating the leukemogenetic role of t(8;21) and inv(16)/t(16;16), the proposed theories of its clonal evolution, and the role played by the hematopoietic niches in preserving the disease. Finally, we will discuss the clinical implications of stem cell modeling of CBF AML for the therapy of the disease.
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http://dx.doi.org/10.1155/2016/7625827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737463PMC
February 2016

Multicentre survey to explore current survival of patients with acute myeloid leukaemia who failed induction chemotherapy.

Eur J Haematol 2016 Jun 17;96(6):586-92. Epub 2015 Aug 17.

Division of Hematology and SCT, University Hospital of Udine, Udine, Italy.

Background: Acute myeloid leukaemia not responsive to first induction chemotherapy (PIF-AML) still remains a challenge, and there are only few recent epidemiological data regarding the outcome of these patients. In this multicentre survey, we evaluate the prognosis and outcome of patients with PIF-AML, who were diagnosed and treated in the last 5 yrs in four Italian institutions.

Results: One hundred PIF-AML were recorded, 57 males and 43 females, with a median age of 63 yrs (19-79), 42% were younger than 60 yrs; 42% had a secondary AML and 40% had an adverse karyotype. According to cytogenetic/molecular risk stratification at diagnosis, 33% of patients were classified as favourable/intermediate-1 risk and 56% as intermediate-2/adverse risk. After a median follow-up of 11 months (1-49), 77% of patients died, while 23% were alive (with 12/23 in cCR). Thirty-six patients underwent allogeneic SCT, and of these, 11 of 36 (31%) were alive at last follow-up. The 12- and 24-month OS probability of the whole population was 45% and 21%, respectively. In multivariate analysis, the probability of OS of the whole population was significantly improved by Allo-SCT procedure (12-month OS probability 60% vs. 35%; P < 0.0001) and was better in patients with favourable/intermediate-1 risk at diagnosis (12-month OS probability 58% vs. 40%; P = 0.028). In transplanted cases, a pretransplant responsive disease was the only significant factor to predict a favourable outcome after Allo-SCT (P = 0.006).

Conclusion: Treatment options of PIF-AML still are limited and the prognosis, even recently, remains extremely poor. This survey shows that PIF-AML is still rarely cured without Allo-SCT and confirms the importance of initiating an urgent unrelated donor search in cases without a matched sibling donor. Moreover, the outcome of Allo-SCT is better in patients who achieve a good AML debulking before transplant. To reach this goal, new predictive scores and new protocols of salvage therapy (with target drugs or combinations) need to be explored urgently in PIF-AML.
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http://dx.doi.org/10.1111/ejh.12635DOI Listing
June 2016

Complex karyotype, older age, and reduced first-line dose intensity determine poor survival in core binding factor acute myeloid leukemia patients with long-term follow-up.

Am J Hematol 2015 Jun 1;90(6):515-23. Epub 2015 Apr 1.

Department of Hematology, General Hospital, Treviso, Italy.

Approximately 40% of patients affected by core binding factor (CBF) acute myeloid leukemia (AML) ultimately die from the disease. Few prognostic markers have been identified. We reviewed 192 patients with CBF AML, treated with curative intent (age, 15-79 years) in 11 Italian institutions. Overall, 10-year overall survival (OS), disease-free survival (DFS), and event-free survival were 63.9%, 54.8%, and 49.9%, respectively; patients with the t(8;21) and inv(16) chromosomal rearrangements exhibited significant differences at diagnosis. Despite similar high complete remission (CR) rate, patients with inv(16) experienced superior DFS and a high chance of achieving a second CR, often leading to prolonged OS also after relapse. We found that a complex karyotype (i.e., ≥4 cytogenetic anomalies) affected survival, even if only in univariate analysis; the KIT D816 mutation predicted worse prognosis, but only in patients with the t(8;21) rearrangement, whereas FLT3 mutations had no prognostic impact. We then observed increasingly better survival with more intense first-line therapy, in some high-risk patients including autologous or allogeneic hematopoietic stem cell transplantation. In multivariate analysis, age, severe thrombocytopenia, elevated lactate dehydrogenase levels, and failure to achieve CR after induction independently predicted longer OS, whereas complex karyotype predicted shorter OS only in univariate analysis. The achievement of minimal residual disease negativity predicted better OS and DFS. Long-term survival was observed also in a minority of elderly patients who received intensive consolidation. All considered, we identified among CBF AML patients a subgroup with poorer prognosis who might benefit from more intense first-line treatment.
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http://dx.doi.org/10.1002/ajh.24000DOI Listing
June 2015

Intracoronary delivery of autologous cardiac stem cells improves cardiac function in a porcine model of chronic ischemic cardiomyopathy.

Circulation 2013 Jul 11;128(2):122-31. Epub 2013 Jun 11.

Division of Cardiovascular Medicine and Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40202, USA.

Background: Relevant preclinical models are necessary for further mechanistic and translational studies of c-kit+ cardiac stem cells (CSCs). The present study was undertaken to determine whether intracoronary CSCs are beneficial in a porcine model of chronic ischemic cardiomyopathy.

Methods And Results: Pigs underwent a 90-minute coronary occlusion followed by reperfusion. Three months later, autologous CSCs (n=11) or vehicle (n=10) were infused into the infarct-related artery. At this time, all indices of left ventricular (LV) function were similar in control and CSC-treated pigs, indicating that the damage inflicted by the infarct in the 2 groups was similar; 1 month later, however, CSC-treated pigs exhibited significantly greater LV ejection fraction (echocardiography) (51.7±2.0% versus 42.9±2.3%, P<0.01), systolic thickening fraction in the infarcted LV wall, and maximum LV dP/dt, as well as lower LV end-diastolic pressure. Confocal microscopy showed clusters of small α-sarcomeric actin-positive cells expressing Ki67 in the scar of treated pigs, consistent with cardiac regeneration. The origin of these cycling myocytes from the injected cells was confirmed in 4 pigs that received enhanced green fluorescent protein -labeled CSCs, which were positive for the cardiac markers troponin I, troponin T, myosin heavy chain, and connexin-43. Some engrafted CSCs also formed vascular structures and expressed α-smooth muscle actin.

Conclusions: Intracoronary infusion of autologous CSCs improves regional and global LV function and promotes cardiac and vascular regeneration in pigs with old myocardial infarction (scar). The results mimic those recently reported in humans (Stem Cell Infusion in Patients with Ischemic CardiOmyopathy [SCIPIO] trial) and establish this porcine model of ischemic cardiomyopathy as a useful and clinically relevant model for studying CSCs.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.112.001075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807652PMC
July 2013

The National Institutes of Health criteria for classification and scoring of chronic graft versus host disease: long-term follow-up of a single center series.

Leuk Lymphoma 2013 May 19;54(5):1020-7. Epub 2013 Feb 19.

Section of Hematology and Bone Marrow Transplant Unit, Department of Medicine, University of Verona , Verona , Italy.

We assessed the retrospective applicability and prognostic value of the National Institutes of Health (NIH) classification of chronic graft versus host disease (cGVHD) in 159 consecutive patients after allogeneic hematopoietic stem cell transplant (HSCT). Seventy-four patients (46.5%) were affected by late-acute GVHD (n = 19; 25.7%), classic cGVHD (n = 44; 59.4%) and overlap syndrome (n = 11; 14.9%). Overall, patients with NIH-defined cGVHD (i.e. classic cGVHD and overlap syndrome) had better 10-year overall survival (OS) as compared to patients without GVHD (76.9% vs. 47.4%, p = 0.0002) or with late-acute GVHD (47.4%, p = 0.001). Relapse mortality (RM) was lower in patients with NIH-defined cGVHD than in patients without GVHD (14.5% vs. 38.7%, p = 0.001), but comparable to that of late-acute type (19.4%, p = 0.31). Non-relapse mortality (NRM) was lower in patients with NIH-defined cGVHD as compared to late-acute GVHD (10.0% vs. 41.1%, p = 0.0005), as well as patients without GVHD (22.2%, p = 0.045). At multivariate analysis, NIH-defined cGVHD remained independently predictive for lower RM, but not for NRM. Thus, the new NIH classification identifies two subtypes of GVHD (late-acute and chronic) with different long-term outcomes and impact on RM and NRM.
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http://dx.doi.org/10.3109/10428194.2012.733877DOI Listing
May 2013

Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow-derived mesenchymal stromal cells.

Blood 2011 Jul 20;118(2):380-9. Epub 2011 May 20.

Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, University of Verona, Verona, Italy.

Although many literature data are available on the role of Notch signaling in T-cell acute lymphoblastic leukemia (ALL) biology, the importance of this molecular pathway in the development of B-lineage ALL (B-ALL) cells in the BM microenvironment is unknown so far. In this study, we used anti-Notch molecules neutralizing Abs and γ-secretase inhibitor (GSI) XII to investigate the role of the Notch signaling pathway in the promotion of human B-ALL cell survival in presence of stromal cell support. The treatment with combinations of anti-Notch molecule neutralizing Abs resulted in the decrease of B-ALL cell survival, either cultured alone or cocultured in presence of stromal cells from normal donors and B-ALL patients. Interestingly, the inhibition of Notch-3 and -4 or Jagged-1/-2 and DLL-1 resulted in a dramatic increase of apoptotic B-ALL cells by 3 days, similar to what is obtained by blocking all Notch signaling with the GSI XII. Our data suggest that the stromal cell-mediated antiapoptotic effect on B- ALL cells is mediated by Notch-3 and -4 or Jagged-1/-2 and DLL-1 in a synergistic manner.
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http://dx.doi.org/10.1182/blood-2010-12-326694DOI Listing
July 2011

A proliferation-inducing ligand (APRIL) serum levels predict time to first treatment in patients affected by B-cell chronic lymphocytic leukemia.

Eur J Haematol 2011 Sep 26;87(3):228-34. Epub 2011 Jul 26.

Section of Hematology, Department of Medicine, University of Verona, Piazzale L A Scuro 10, Verona, Italy.

Purpose: A proliferation-inducing ligand (APRIL), a tumor necrosis factor superfamily member involved in B-lymphocytes differentiation and survival, plays a role in protecting B-Cell Chronic lymphocytic leukemia (B-CLL) cells from apoptosis. Having observed that APRIL serum (sAPRIL) levels were higher in B-CLL patients with CLL at diagnosis as compared to healthy donors (14.61±32.65 vs. 4.19±3.42 ng/mL; P<0.001), we tested the correlation existing in these patients between sAPRIL, clinical-biological parameters and disease progression.

Experimental Design: sAPRIL levels were measured by ELISA in 130 patients with B-CLL at diagnosis and in 25 healthy donors.

Results: sAPRIL levels did not correlate with gender, age, clinical stage, blood cell counts, β2-microglobulin (β2M) levels, ZAP-70 and CD38 expression. Using median sAPRIL natural logarithm (ln) as cutoff, we distinguished two groups of patients (APRIL(LOW) and APRIL(HIGH) ) who were comparable with regard to clinical-biological parameters and overall survival, but different with regard to time to the first treatment (TTFT; P=0.035). According to univariate analysis, high lymphocyte count, high β2M, Binet stage B-C, ZAP-70 expression and ln(sAPRIL) above median were associated with earlier TTFT. Advanced clinical stage, high β2M, ZAP-70 expression and ln(sAPRIL) above median remained independently predictive of shorter TTFT at multivariate analysis. Moreover, sAPRIL increased its prognostic significance when patients were stratified according to independent favorable clinical-biological characteristics (low β2M, stage A and lack of ZAP-70 expression).

Conclusions: sAPRIL is a novel indicator of shorter TTFT in B-CLL and a predictor of progression especially in patients otherwise considered at low risk according to validated prognostic factors.
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http://dx.doi.org/10.1111/j.1600-0609.2011.01650.xDOI Listing
September 2011

Toll-like receptor-3-activated human mesenchymal stromal cells significantly prolong the survival and function of neutrophils.

Stem Cells 2011 Jun;29(6):1001-11

Section of General Pathology, Department of Pathology and Diagnostics, University of Verona, Italy.

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are stromal precursors endowed with extensive immunomodulative properties. In this study, we aimed to assess whether Toll-like receptor-3 (TLR3)- and TLR4-activated BM-MSC influence human neutrophil (PMN) responses under coculture conditions. We show that TLR3 triggering by polyinosinic:polycytidylic acid dramatically amplifies, in a more significant manner than TLR4 triggering by lipopolysaccharide, the antiapoptotic effects that resting BM-MSC constitutively exert on PMN under coculture conditions, preserving a significant fraction of viable and functional PMN up to 72 hours. In addition, TLR3- and TLR4-activated BM-MSC enhance respiratory burst ability and CD11b expression by PMN. The coculture in the absence of cell contact and the incubation of PMN in supernatants harvested from TLR3- and TLR4-activated BM-MSC yield comparable results in terms of increased survival and immunophenotypic changes, thus suggesting the involvement of endogenous soluble factors. Neutralizing experiments reveal that the biological effects exerted on PMN by TLR3-activated BM-MSC are mediated by the combined action of interleukin 6, interferon-β (IFN-β), and granulocyte macrophage colony-stimulating factor (GM-CSF), while those exerted by TLR4-activated BM-MSC mostly depend on GM-CSF. MSC isolated from thymus, spleen, and subcutaneous adipose tissue behaves similarly. Finally, the effects exerted by TLR3- or TLR4-stimulated BM-MSC on PMN are conserved even after the previous priming of BM-MSC with IFN-γ and tumor necrosis factor-α. Our data highlight a novel mechanism by which MSC sustain and amplify the functions of PMN in response to TLR3- and TLR4-triggering and may consequently contribute to inflammatory disorders.
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http://dx.doi.org/10.1002/stem.651DOI Listing
June 2011

Efficacy assessment of interferon-alpha-engineered mesenchymal stromal cells in a mouse plasmacytoma model.

Stem Cells Dev 2011 Apr 12;20(4):709-19. Epub 2010 Oct 12.

Department of Pathology and Diagnostics, University of Verona, Verona, Italy.

Bone marrow mesenchymal stromal cells (BM-MSCs) may survive and proliferate in the presence of cycling neoplastic cells. Exogenously administered MSCs are actively incorporated in the tumor as stromal fibroblasts, thus competing with the local mesenchymal cell precursors. For this reason, MSCs have been suggested as a suitable carrier for gene therapy strategies, as they can be genetically engineered with genes encoding for biologically active molecules that can inhibit tumor cell proliferation and enhance the antitumor immune response. We used BM-MSCs engineered with the murine interferon-alpha (IFN-α) gene (BM-MSCs/IFN-α) to assess in a mouse plasmacytoma model the efficacy of this approach toward neoplastic plasma cells. We found that IFN-α can be efficiently produced and delivered inside the tumor microenvironment. Subcutaneous multiple administration of BM-MSCs/IFN-α significantly hampered the tumor growth in vivo and prolonged the overall survival of mice. The antitumor effect was associated with enhanced apoptosis of tumor cells, reduction in microvessel density, and ischemic necrosis. By contrast, intravenous administration of BM-MSCs/IFN-α did not significantly modify the survival of mice, mainly as a consequence of an excessive entrapment of injected cells in the pulmonary vessels. In conclusion, BM-MSCs/IFN-α are effective in inhibiting neoplastic plasma cell growth; however, systemic administration of engineered MSCs needs to be improved to make this approach potentially suitable for the treatment of multiple myeloma.
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http://dx.doi.org/10.1089/scd.2010.0095DOI Listing
April 2011

Cell therapy for cardiac regeneration after myocardial infarct: which cell is the best?

Cardiovasc Hematol Agents Med Chem 2010 Oct;8(4):227-43

Stem Cell Research Laboratory, Section of Hematology, Department of Clinical and Experimental Medicine, University of Verona, Verona, Italy.

In the last decade several attempts have been made to achieve the goal of cardiac regeneration after myocardial infarction. To date, two cell types have completed phase-III clinical trials: Skeletal Myoblasts and Bone-Marrow Mononuclear Cells (BM-MNCs). In the first case, all benefits have been limited by an increased risk of arrhythmia. In the case of BM-cells, most studies showed a significant, although limited, advantage in the cell-treated group. This may be due to the choice of the wrong BM cell type: other candidates would be e.g. CD34(+) HSCs, or non-hematopoietic Mesenchymal Stem Cells. After positive results from the experimental studies, phase I/II clinical trials are currently on-going for both. Ideally, the best cell to use to regenerate the heart would be a precursor of all cardiac lineages; until the isolation and expansion of Cardiac Stem Cells (CSCs), such a cell was thought to exist only during embryogenesis. Using CSCs researchers managed to generate electrically-coupled contractile tissue within the infarct of animal models. Still, some doubts persist over the possibility to translate such results in real-life patients. Another approach, therefore, involves the use of induced Pluripotent Stem Cells (iPS) obtained from fibroblasts after genetic reprogramming. This new type of cell would combine the pluripotency of embryonal stem cells with the advantages of an autologous use. Nevertheless, iPS cells form teratomas, and their effective differentiation in vivo is largely unknown. This review will critically compare the data from the Literature concerning cell therapy after myocardial infarction. Can we name the best cell?
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http://dx.doi.org/10.2174/187152510792481216DOI Listing
October 2010

Human bone marrow and adipose tissue mesenchymal stem cells: a user's guide.

Stem Cells Dev 2010 Oct;19(10):1449-70

Stem Cell Research Laboratory, Section of Hematology, Department of Medicine, Policlinico G.B. Rossi-University of Verona, Verona, Italy.

Mesenchymal stem cells (MSCs) are adult stem cells that hold great promise in the field of regenerative medicine. They can be isolated from almost any tissue of the body and display, after expansion, very similar properties and minor differences, probably due to their microenvironment of origin. Expansion in vitro can be obtained in cytokine-free, serum-enriched media, as well as in serum-free, basic fibroblast growth factor-enriched media. A detailed immunophenotypic analysis is required to test the purity of the preparation, but no unique distinguishing marker has been described as yet. Functional assays, that is, differentiation studies in vitro, are needed to prove multilineage differentiation of expanded cells, and demonstration of pluripotency is necessary to identify most immature precursors. MSCs show powerful immunomodulative properties toward most of the cells of the immune system: this strengthens the theoretical rationale for their use also in an allogeneic setting across the major histocompatibility complex (MHC) immunological barriers. Systemic intravenous injection and local use have been tried: after systemic injection, MSCs show a high degree of chemotaxis based on pro-inflammatory cytokines, and localize at inflamed and neoplastic tissues; local regeneration has been improved using synthetic, as well as organic scaffolds. On the other hand, inadequate heterotopic in vivo differentiation and neoplastic transformation are potential risks of this form of cell therapy, even if evidence of this sort has been collected only from studies in mice, and generally after prolonged in vitro expansion. This review tries to provide a detailed technical overview of the methods used for human bone-marrow (BM)-derived and adipose-tissue (AT)-derived MSC isolation, in vitro expansion, and characterization for tissue repair. We chose to use BM-MSCs as a model to describe techniques that have been used for MSC isolation and expansion from very different sources, and AT-MSCs as an example of a reliable and increasingly common alternative source.
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http://dx.doi.org/10.1089/scd.2010.0140DOI Listing
October 2010

IFN-gamma-mediated upmodulation of MHC class I expression activates tumor-specific immune response in a mouse model of prostate cancer.

Vaccine 2010 Apr 19;28(20):3548-57. Epub 2010 Mar 19.

Department of Pathology and Diagnostics, Immunology Section, University of Verona, Italy.

De novo expression of B7-1 impaired tumorigenicity of TRAMP-C2 mouse prostate adenocarcinoma (TRAMP-C2/B7), but it did not elicit a protective response against TRAMP-C2 parental tumor, unless after in vitro treatment with IFN-gamma. TRAMP-C2 cells secrete TGF-beta and show low MHC-I expression. Treatment with IFN-gamma increased MHC-I expression by induction of some APM components and antagonizing the immunosuppressant activity of TGF-beta. Thus, immunization with TRAMP-C2/B7 conferred protection against TRAMP-C2-derived tumors in function of the IFN-gamma-mediated fine-tuned modulation of either APM expression or TGF-beta signaling. To explore possible clinical translation, we delivered IFN-gamma to TRAMP-C2 tumor site by means of genetically engineered MSCs secreting IFN-gamma.
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http://dx.doi.org/10.1016/j.vaccine.2010.03.007DOI Listing
April 2010

Progenitor cells from the explanted heart generate immunocompatible myocardium within the transplanted donor heart.

Circ Res 2009 Nov 8;105(11):1128-40. Epub 2009 Oct 8.

Department of Cardiothoracic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, New York, USA.

Rationale: Chronic rejection, accelerated coronary atherosclerosis, myocardial infarction, and ischemic heart failure determine the unfavorable evolution of the transplanted heart in humans.

Objective: Here we tested whether the pathological manifestations of the transplanted heart can be corrected partly by a strategy that implements the use of cardiac progenitor cells from the recipient to repopulate the donor heart with immunocompatible cardiomyocytes and coronary vessels.

Methods And Results: A large number of cardiomyocytes and coronary vessels were created in a rather short period of time from the delivery, engraftment, and differentiation of cardiac progenitor cells from the recipient. A proportion of newly formed cardiomyocytes acquired adult characteristics and was integrated structurally and functionally within the transplant. Similarly, the regenerated arteries, arterioles, and capillaries were operative and contributed to the oxygenation of the chimeric myocardium. Attenuation in the extent of acute damage by repopulating cardiomyocytes and vessels decreased significantly the magnitude of myocardial scarring preserving partly the integrity of the donor heart.

Conclusions: Our data suggest that tissue regeneration by differentiation of recipient cardiac progenitor cells restored a significant portion of the rejected donor myocardium. Ultimately, immunosuppressive therapy may be only partially required improving quality of life and lifespan of patients with cardiac transplantation.
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http://dx.doi.org/10.1161/CIRCRESAHA.109.207266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801080PMC
November 2009

Immune regulation by mesenchymal stem cells derived from adult spleen and thymus.

Stem Cells Dev 2007 Oct;16(5):797-810

Department of Clinical and Experimental Medicine, Section of Haematology, University of Verona, Italy.

We show here that human and mouse mesenchymal stem cells (MSCs) can be obtained not only from bone marrow (BM), but also from adult spleen and thymus. In vitro, both human and mouse spleen- and thymus-derived MSCs exhibit immunophenotypic characteristics and differentiation potential completely comparable to BM-MSCs. In addition, they can inhibit immune responses mediated by activated T lymphocytes with efficiency comparable to BM-MSCs. In vivo, mouse MSCs from BM, spleen, and thymus, if injected together with a genetically modified tumor cell vaccine, can equally prevent the onset of an anti-tumor memory immune response, thus leading to tumor growth in normally resistant mice. Our data suggest that not only do spleen and thymus have a stem cell reservoir to build up their stromal architecture, but also contain microenviromental immunoregulatory cells with the same properties of BM-MSCs.
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http://dx.doi.org/10.1089/scd.2007.0024DOI Listing
October 2007

ERK1/2 phosphorylation is an independent predictor of complete remission in newly diagnosed adult acute lymphoblastic leukemia.

Blood 2007 Jun 9;109(12):5473-6. Epub 2007 Mar 9.

Division of Hematology, Department of Cellular Biotechnologies and Hematology, University La Sapienza of Rome, Italy.

Extracellular signal-regulated kinase-1/2 (ERK1/2) is frequently found constitutively activated (p-ERK1/2) in hematopoietic diseases, suggesting a role in leukemogenesis. The aim of this study was to assess the expression and clinical role of p-ERK1/2 in adult acute lymphoblastic leukemia (ALL). In 131 primary samples from adult de novo ALL patients enrolled in the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) Leucemia Acute Linfoide (LAL) 2000 protocol and evaluated by flow cytometry, constitutive ERK1/2 activation was found in 34.5% of cases; these results were significantly associated with higher white blood cell (WBC) values (P=.013). In a multivariate analysis, p-ERK1/2 expression was an independent predictor of complete remission achievement (P=.027). Effective approaches toward MEK inhibition need to be explored in order to evaluate whether this may represent a new therapeutic strategy for adult ALL patients.
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http://dx.doi.org/10.1182/blood-2006-05-021071DOI Listing
June 2007

Adolescent feline heart contains a population of small, proliferative ventricular myocytes with immature physiological properties.

Circ Res 2007 Mar 1;100(4):536-44. Epub 2007 Feb 1.

Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.

Recent studies suggest that rather than being terminally differentiated, the adult heart is a self-renewing organ with the capacity to generate new myocytes from cardiac stem/progenitor cells (CS/PCs). This study examined the hypotheses that new myocytes are generated during adolescent growth, to increase myocyte number, and these newly formed myocytes are initially small, mononucleated, proliferation competent, and have immature properties. Ventricular myocytes (VMs) and cKit(+) (stem cell receptor) CS/PCs were isolated from 11- and 22-week feline hearts. Bromodeoxyuridine incorporation (in vivo) and p16(INK4a) immunostaining were measured to assess myocyte cell cycle activity and senescence, respectively. Telomerase activity, contractions, Ca(2+) transients, and electrophysiology were compared in small mononucleated (SMMs) and large binucleated (LBMs) myocytes. Heart mass increased by 101% during adolescent growth, but left ventricular myocyte volume only increased by 77%. Most VMs were binucleated (87% versus 12% mononucleated) and larger than mononucleated myocytes. A greater percentage of SMMs was bromodeoxyuridine positive (SMMs versus LBMs: 3.1% versus 0.8%; P<0.05), and p16(INK4a) negative and small myocytes had greater telomerase activity than large myocytes. Contractions and Ca(2+) transients were prolonged in SMMs versus LBMs and Ca(2+) release was disorganized in SMMs with reduced transient outward current and T-tubule density. The T-type Ca(2+) current, usually seen in fetal/neonatal VMs, was found exclusively in SMMs and in myocytes derived from CS/PC. Myocyte number increases during adolescent cardiac growth. These new myocytes are initially small and functionally immature, with patterns of ion channel expression normally found in the fetal/neonatal period.
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http://dx.doi.org/10.1161/01.RES.0000259560.39234.99DOI Listing
March 2007

Induction of neural-like differentiation in human mesenchymal stem cells derived from bone marrow, fat, spleen and thymus.

Bone 2007 Feb 16;40(2):382-90. Epub 2006 Oct 16.

Department of Clinical, Section of Haematology, University of Verona, Italy.

Mesenchymal stem cells (MSCs) from bone marrow (BM) and sub-cutaneous fat are known to differentiate into neural cells under appropriate stimuli. We describe here the neural-like differentiation of human MSCs obtained from spleen and thymus, induced either with chemical factors or with co-culture with human Schwann cells (Sc). Under the effect of neural differentiation medium, most MSCs from BM, fat, spleen and thymus acquired morphological changes suggestive of cells of astrocytic/neuronal and oligodendroglial lineages with general up-regulation of neural molecules not correlated with morphological changes. The process was transient and reversible, as MSCs recovered basal morphology and phenotype, as well as their multilineage differentiation potential. Thus, we hypothesized that chemical factors may prime MSCs for neural differentiation, by inducing initial and poorly specific changes. By contrast, co-cultures of MSCs of different origin with Sc induced long-lasting and Sc differentiation, i.e., the expression of Sc myelin proteins for up to 12 days. Our results show that a MSC reservoir is present in tissues other than BM and fat, and that MSCs of different origin have similar neural differentiation potential. This evidence provides new insights into BM-like tissue plasticity and may have important implications for future therapeutic interventions in chronic neuropathies.
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http://dx.doi.org/10.1016/j.bone.2006.09.006DOI Listing
February 2007

Remission of severe antiphospholipid syndrome associated with non-Hodgkin's B-cell lymphoma after combined treatment with rituximab and chemotherapy.

Haematologica 2005 Nov;90 Suppl:ECR37

Dipartimento di Medicina Clinica e Sperimentale, Sezione di Ematologia, Università di Verona, Italy.

The association of lymphoid neoplasms and antiphospolipid antibodies (APA), with or without thromboembolic complications, has been reported in several cases. We describe one case of B-cell non-Hodgkinís lymphoma (NHL) in which the combination of rituximab with standard chemotherapy led to the complete remission of a severe hypercoagulable state associated with APA.
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November 2005