41 results on '"Rambaldi B"'
Search Results
2. NEONATAL BONE MARROW TRANSPLANTATION STRATEGY FOR THE CURE OF HURLER DISEASE SKELETAL PHENOTYPE: PH-P107
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Pievani, A., Azario, I., Rambaldi, B., Cersosimo, S., Scagliotti, V., Biondi, A., Tomatsu, S., Riminucci, M., and Serafini, M.
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- 2014
3. FUNCTIONAL RECONSTITUTION OF BONE/BONE MARROW MICROENVIRONMENT FOLLOWING IN VIVO IMPLANTATION OF CARTILAGE PELLETS DIFFERENTIATED FROM HUMAN BONE MARROW- AND CORD BLOOD- DERIVED MESENCHYMAL STEM CELLS (MSCS): PH-O017
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Serafini, M., Pievani, A., Sacchetti, B., Azario, I., Rambaldi, B., Biondi, A., Riminucci, M., and Bianco, P.
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- 2014
4. Biological versus Clinical Risk Factors in Acute Myeloid Leukemia: Is There a Winner?
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Malagola, M., Polverelli, N., Cancelli, V., Morello, E., Turra, A., Borlenghi, E., Cattina, F., Rambaldi, B., Bernardi, S., Zanaglio, C., Dereli Eke, Elif, Gandolfi, L., Farina, M., and Russo, D.
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Article Subject ,hemic and lymphatic diseases - Abstract
We present a case of a patient with a three-month history of peripheral blood cytopenia without a confirmed diagnosis of myelodysplastic syndrome, who developed a favourable-risk acute myeloid leukemia (AML), according to the European Leukemia Net (ELN) criteria. The patient achieved a complete remission with incomplete platelet recovery (CRi) after induction. The patient achieved the morphological CR after the first consolidation and completed the first-line treatment with a syngeneic stem cell transplantation (SCT). A disease relapse occurred after one year of CR (blast cell count in the bone marrow 15%), and the patient was offered a haplo-SCT, which he refused due to personal reasons. In this paper, we discuss the interplay between clinical and biological risk factors in non-high-risk AML patients and speculate that some old clinical risk factors (e.g., age of the patient, achievement of CR after induction, and previous history of myelodysplastic syndrome) may still impact on the treatment decision algorithm of some of these patients.
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- 2019
- Full Text
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5. 'Real-life' analysis of the role of antifungal prophylaxis in preventing invasive aspergillosis in AML patients undergoing consolidation therapy: Sorveglianza Epidemiologica Infezioni nelle Emopatie (SEIFEM) 2016 study
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Del Principe, Maria Ilaria, Dragonetti, Giulia, Verga, Luisa, Candoni, Anna, Marchesi, Francesco, Cattaneo, Chiara, Delia, Mario, Potenza, Leonardo, Farina, Francesca, Ballanti, Stelvio, Decembrino, Nunzia, Castagnola, Carlo, Nadali, Gianpaolo, Fanci, Rosa, Orciulo, Enrico, Veggia, Barbara, Offidani, Massimo, Melillo, Lorella, Manetta, Sara, Tumbarello, Mario, Venditti, Adriano, Busca, Alessandro, Aversa, Franco, Pagano, Livio, Picardi, M, Della Pepa, R, Ferrari, A, Piedimonte, M, Fracchiolla, Ns, Sciumè, M, Lessi, F, Prezioso, L, Spolzino, A, Rambaldi, B, Russo, D, Maracci, L, di Ematologia, C, Sarlo, C, Annibali, O, Cefalo, M, Zizzari, A, Di Blasi, R, di Ematologia, I, Zama, D, Mancini, V, Salutari, P, Cesaro, S, Chiara Tisi, M, Garzia, Mg, Vacca, A, Dargenio, M, Invernizzi, R, Perruccio, K, Mitra, Me, Quinto, Am, Chierichini, A, and Spadea, A.
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0301 basic medicine ,Microbiology (medical) ,Adult ,Male ,medicine.medical_specialty ,Antifungal Agents ,AML, SEIFEM, Invasive Aspergillosis, consolidation therapy, antifumgal prophylaxis, antifungal therapy ,030106 microbiology ,SEIFEM ,antifumgal prophylaxis ,Comorbidity ,Aspergillosis ,03 medical and health sciences ,0302 clinical medicine ,AML ,Risk Factors ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Prospective cohort study ,Aged ,Pharmacology ,business.industry ,Incidence (epidemiology) ,Mortality rate ,Consolidation Chemotherapy ,Induction Chemotherapy ,Middle Aged ,medicine.disease ,antifungal therapy ,Leukemia, Myeloid, Acute ,Infectious Diseases ,Number needed to treat ,Cytarabine ,Invasive Aspergillosis ,Female ,business ,consolidation therapy ,Settore MED/15 - Malattie del Sangue ,Invasive Fungal Infections ,medicine.drug - Abstract
Background We evaluated the incidence of proven/probable invasive aspergillosis (IA) and the role of antifungal prophylaxis (AP) in a 'real-life' setting of patients with AML receiving intensive consolidation therapy. Methods Cases of IA, observed during consolidation in adult/paediatric patients with AML between 2011 and 2015, were retrospectively collected in a multicentre Italian study. Results Of 2588 patients, 56 (2.2%) developed IA [43 probable (1.7%) and 13 proven (0.5%)]. IA was diagnosed in 34 of 1137 (2.9%) patients receiving no AP and in 22 of 1451 (1.5%) who were given AP (P = 0.01). Number-needed-to-treat calculation indicates that, on average, 71 patients should have received AP (instead of no AP) for one additional patient to not have IA. Initial antifungal therapy was 'pre-emptive' in 36 (64%) patients and 'targeted' in 20 (36%) patients. A good response to first-line therapy was observed in 26 (46%) patients, mainly those who received AP [16 of 22 (73%) versus 10 of 34 (29%); P = 0.001]. The overall mortality rate and the mortality rate attributable to IA by day 120 were 16% and 9%, respectively. In multivariate analysis, age ≥60 years (OR = 12.46, 95% CI = 1.13-136.73; P = 0.03) and high-dose cytarabine treatment (OR = 10.56, 95% CI = 1.95-116.74; P = 0.04) independently affected outcome. Conclusions In our experience, AP appears to prevent IA from occurring during consolidation. However, although the incidence of IA was low, mortality was not negligible among older patients. Further prospective studies should be carried out particularly in elderly patients treated with high-dose cytarabine to confirm our data and to identify subsets of individuals who may require AP.
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- 2019
6. Identification of a Novel Mutation Predisposing to Familial AML and MDS Syndrome By a NGS Approach
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Bernardi, S., Zanaglio, C., DERELI EKE, Elif, Cattina, F., Farina, Marco, Masneri, S., Rambaldi, B, Schieppati, F., Turra, A., Polverelli, N., Morello, E., Malagola, M., and Russo, D.
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- 2018
7. PS1540 MULTIPARAMETRIC PREDICTIVE SCORE FOR GRAFT VERSUS HOST DISEASE (GVHD) IN PATIENTS SUBMITTED TO ALLOGENEIC STEM CELLS TRANSPLANTATION (SCT)
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Turra, A., primary, Polverelli, N., additional, Corvini, F., additional, Morello, E., additional, Malagola, M., additional, Arena, F., additional, Andreoli, M., additional, Bertulli, A., additional, Farina, M., additional, Cattina, F., additional, Rambaldi, B., additional, Gandolfi, L., additional, Zollner, T., additional, Buttini, E. Accorsi, additional, Bernardi, S., additional, Zanaglio, C., additional, Foroni, C., additional, Re, F., additional, and Russo, D., additional
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- 2019
- Full Text
- View/download PDF
8. PARAMETERS OF PROTEIN METABOLISM AND THYROID FUNCTION AS PREDICTORS OF A SCORING SYSTEM FOR ACUTE AND CHRONIC GRAFT-VERSUS-HOST DISEASE
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Skert, C., Turra, A., Malagola, M., Perucca, S., Cattina, F., Cancelli, V., Rambaldi, B., Fili, C., Pagani, C., Nicola Polverelli, Di Palma, A., Bernardi, S., and Russo, D.
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- 2015
9. SEIFEM 2016 STUDY: INCIDENCE OF PROBABLE AND PROVEN INVASIVE ASPERGILLOSIS IN PATIENTS WITH ACUTE MYELOID LEUKEMIA DURING CONSOLIDATION THERAPY
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Del Principe, M. I., Di Blasi, R., Verga, L., anna candoni, Potenza, L., Ballanti, S., Cattaneo, C., Delia, M., Decembrino, N., Melillo, L., Castagnola, C., Nadali, G., Fanci, R., Ferrari, A., Fracchiolla, N. S., Iovino, L., Lessi, F., Veggia, B., Offidani, M., Picardi, M., Prezioso, L., Rambaldi, B., Marchesi, F., Annibali, O., Zama, D., Mancini, V., Salutari, P., Garzia, M. G., Vacca, A., Cesaro, S., Paolis, M. R., Invernizzi, R., Perruccio, K., Mitra, M. E., Quinto, A. M., Venditti, A., Busca, A., Aversa, F., and Pagano, L.
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acute myeloid leukemia, aspergillosis, chemotherapy ,aspergillosis ,acute myeloid leukemia ,chemotherapy
10. EXTRACORPOREAL PHOTOPHERESIS FOR THE TREATEMENT OF ACUTE AND CHRONIC GRAFT VERSUS HOST DISEASE: A RETROSPECTIVE MULTICENTRIC ANALYSIS ON 94 PATIENTS
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Malagola, M., Cancelli, V., Skert, C., Lealia, P. Ferremi, Ferrari, E., Tiburzi, A., Sala, M. L., Donini, I., Patrizia Chiusolo, Muffetti, A., Battista, M., Polverelli, N., Turra, A., Cattina, F., Rambaldi, B., Schieppati, F., Bosi, A., Sica, S., Corradini, P., Patriarca, F., Marini, M., and Russo, D.
11. Extracorporeal Photopheresis for Treatment of Acute and Chronic Graft Versus Host Disease: An Italian Multicentric Retrospective Analysis on 94 Patients on Behalf of the Gruppo Italiano Trapianto di Midollo Osseo
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Malagola M, Cancelli V, Skert C, Pf, Leali, Ferrari E, Tiburzi A, Ml, Sala, Donnini I, Chiusolo P, Mussetti A, Battista M, Turra A, Cattina F, Rambaldi B, Schieppati F, Nicola Polverelli, Bernardi S, Perucca S, Marini M, and Laszlo D
12. IN VIVO STUDY (MYCEC0617) OF CD34+-HSC AND CEC MUTATIONAL PROFILE FOR INVESTIGATING CELL ORIGIN AND PATHOGENESIS OF PRIMARY MYELOFIBROSIS (PMF)
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Farina, M., Bernardi, S., D Adda, M., Foroni, C., Zanaglio, C., Dunbar, A., Re, F., Cattina, F., Rambaldi, B., Zollner, T., Turra, A., Morello, E., Malagola, M., Levine, R. L., Rossi, G., Nicola Polverelli, and Russo, D.
13. Understanding T and NK cell reconstitution after allogeneic hematopoietic cell transplantation: a path to improve graft versus leukemia and minimize graft versus host disease
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RAMBALDI, BENEDETTA, Rambaldi, B, BECCHETTI, ANDREA, and BIONDI, ANDREA
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checkpoint inhibitor ,immunoricostituzione ,HCT ,GVHD ,terapia cellulare NK ,NK cell therapy ,MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,immunereconstitution ,checkpoint inibitore - Abstract
Il trapianto di cellule ematopoietiche (HCT) rappresenta una terapia cardine per il trattamento delle neoplasie ematologiche altrimenti incurabili. Tuttavia, la procedura di trapianto può essere gravata dalla recidiva della malattia, dalla malattia del trapianto contro l'ospite (GVHD) e dalle infezioni. Le cellule T e NK che ricostituiscono dopo l'HCT proteggono da infezioni e recidive, ma sono anche coinvolte nella patogenesi della GVHD. Gli obiettivi del mio progetto di dottorato erano di migliorare la comprensione della ricostituzione delle cellule T e NK, utilizzando campioni di donatori sani e pazienti dopo il trapianto e diversi approcci tecnici (citometria a flusso, citometria di massa, sequenziamento dell'RNA e test funzionale ex vivo) e sviluppare nuove strategie immunoterapiche basate sui linfociti T e NK dopo HCT. In primo luogo, abbiamo dimostrato che un ritardo nel recupero dei linfociti T, un rapporto Treg/Tcon più elevato, un'aumentata espressione di PD-1 sui linfociti T di memoria e un arricchimento di cellule NK a fenotipo immaturo sono stati osservati dopo HCT aploidentico (aplo-HCT) con l’utilizzo di ciclofosfamide post-trapianto. Inoltre, la funzione delle cellule NK CD56brightCD16+ immature funzionalmente alterate dopo aplo-HCT può essere migliorata con l’utilizzo dell'interleuchina-15 in vitro. In secondo luogo, abbiamo avviato uno studio di fase I sulle cellule cytokine-induced memory-like (CIML) NK infuse da donatore haploidentico in pazienti con neoplasie mieloidi che hanno avuto una recidiva dopo aplo-HCT. Nei primi 6 pazienti arruolati, l'infusione di cellule CIML-NK ha portato a una rapida espansione in vivo da 10 a 50 volte, che è stata mantenuta per mesi. L'infusione è stata ben tollerata, con febbre e pancitopenia come eventi avversi più comuni. Sulla base di questi dati preliminari, le cellule CIML-NK possono fungere da piattaforma per il trattamento della recidiva post-trapianto delle patologie mieloidi. Infine, ci siamo concentrati sul bilanciamento della risposta dei linfociti T per controllare l’incidenza di GVHD. CD6, un recettore co-stimolatorio dei linfociti T, che aiuta a stabilizzare la sinapsi immunologica tra la cellula T e l'APC, dopo legame con il suo ligando, la molecola di adesione delle cellule leucocitarie attivate (ALCAM). In questo contesto, il legame CD6-ALCAM promuove l'attivazione, la proliferazione e la maturazione delle cellule T. Abbiamo dimostrato che le cellule T CD6 ricostituivano subito dopo il trapianto, con le cellule Treg che esprimono livelli inferiori di CD6 rispetto alle cellule Tcon e cellule T CD8+. Dopo l'insorgenza della aGVHD, l'espressione sia di CD6 che di ALCAM è stata mantenuta. Itolizumab ha inibito l'attivazione e la proliferazione delle cellule T CD4+ e CD8+ nell'ambito di aGVHD in esperimenti ex vivo, senza mediare l'attività citolitica diretta o la citotossicità anticorpo-dipendente. I nostri risultati identificano la via di CD6-ALCAM come potenziale bersaglio per il controllo dell'aGVHD. Uno studio di fase I/II che utilizza itolizumab come trattamento di prima linea in combinazione con steroidi per i pazienti con aGVHD è attualmente in corso. In conclusione, questi risultati evidenziano la necessità di bilanciare le proprietà effettrici e tolerogeniche del sistema immunitario che si ricostituisce dopo HCT e suggeriscono differenti strategie per promuovere o moderare le funzioni delle cellule T e NK. Hematopoietic cell transplantation (HCT) represents a cardinal therapy for hematological malignancy otherwise incurable. However, HCT can be complicated by disease recurrence, graft versus host disease (GVHD) and infections. After HCT, reconstituting T and NK cells protect against infection and relapse, but they are also involved in the pathogenesis of GVHD. The aims of my PhD project were to improve the understanding of T and NK-cell reconstitution, using samples from both healthy donor and patients after transplant and different technical approaches (flow cytometry, mass cytometry, RNA sequencing, and ex vivo functional assay) and to develop post-transplant T and NK cell-based immunotherapeutic strategies. First, we showed that delayed early T-cell recovery, a higher Treg/ Tcon ratio, an increased PD-1 expression on memory T cells, and an enriched immature NK phenotype were observed after haploidentical HCT (haplo-HCT) with post-transplant cyclophosphamide. In addition, the expansion of functionally impaired immature CD56brightCD16+ NK cells after haplo-HCT can be enhanced with in vitro interleukin-15 priming. Second, we initiated a phase I trial of adoptively transferred cytokine-induced memory-like (CIML) NK cells in patients with myeloid malignancies who relapsed after haplo-HCT. In the first 6 enrolled patients, infusion of CIML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events. Based on these preliminary data, CIML NK cells may serve as a promising platform for the treatment of posttransplant relapse of myeloid disease. Finally, we focused on the balancing of T cell response to control GVHD occurrence. CD6, a pan-T cell co-stimulatory receptor, helps to stabilize the immunological synapse between the T cell and the APC, upon ligation, with its ligand, activated leukocyte cell adhesion molecule (ALCAM). In this context, CD6-ALCAM binding promotes T cell activation, proliferation, maturation. We showed that CD6 T cells reconstituted early after transplant with Treg expressing lower levels of CD6 compared to Tcon and CD8+ T cells. After onset of aGVHD, both CD6 and ALCAM expression was maintained. Itolizumab inhibited CD4+ and CD8+ T cell activation and proliferation in the setting of aGVHD in ex vivo experiments, without mediate direct cytolytic activity or antibody-dependent cytotoxicity. Our results identify the CD6-ALCAM pathway as a potential target for aGVHD control. A phase I/II study using itolizumab as first line treatment in combination with steroids for patients with aGVHD is currently ongoing. In conclusion, these results highlight the need of balancing the effector and tolerogenic properties of the immune system reconstituting after HCT and suggest different strategies to enhance or moderate the T and NK cells functions.
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- 2023
14. A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies
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Chiara Tomasoni, Alice Pievani, Benedetta Rambaldi, Andrea Biondi, Marta Serafini, Tomasoni, C, Pievani, A, Rambaldi, B, Biondi, A, and Serafini, M
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Bone Marrow Stromal Niche ,Hematology ,Myeloid Malignancies - Abstract
Until a few years ago, the onset of acute myeloid leukemia (AML) was entirely ascribed to genetic lesions in hematopoietic stem cells. These mutations generate leukemic stem cells, which are known to be the main ones responsible for chemoresistance and relapse. However, in the last years, increasing evidence demonstrated that dynamic interplay between leukemic cells and bone marrow (BM) niche is of paramount relevance in the pathogenesis of myeloid malignancies, including AML. Specifically, BM stromal niche components, such as mesenchymal stromal cells (MSCs) and their osteoblastic cell derivatives, play a key role not only in supporting normal hematopoiesis but also in the manifestation and progression of myeloid malignancies. Here, we reviewed recent clinical and experimental findings about how genetic and functional alterations in MSCs and osteolineage progeny can contribute to leukemogenesis and how leukemic cells in turn generate a corrupted niche able to support myeloid neoplasms. Moreover, we discussed how the newest single-cell technologies may help dissect the interactions between BM stromal cells and malignant hematopoiesis. The deep comprehension of the tangled relationship between stroma and AML blasts and their modulation during disease progression may have a valuable impact on the development of new microenvironment-directed therapeutic strategies, potentially useful for a wide cohort of patients.
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- 2023
15. Heterogeneity of the bone marrow niche in patients with myeloproliferative neoplasms: ActivinA secretion by mesenchymal stromal cells correlates with the degree of marrow fibrosis
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Alice Pievani, Elena Maria Elli, Mara Riminucci, Andrea Biondi, Noemi Di Marzo, Federica Mottadelli, Pietro Pioltelli, Erica Dander, Elisa Diral, Samantha Donsante, Giovanna D'Amico, Giuseppe Isimbaldi, Lucia Cardinale, Marta Serafini, Benedetta Rambaldi, Rambaldi, B, Diral, E, Donsante, S, Di Marzo, N, Mottadelli, F, Cardinale, L, Dander, E, Isimbaldi, G, Pioltelli, P, Biondi, A, Riminucci, M, D'Amico, G, Elli, E, Pievani, A, and Serafini, M
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Adult ,Male ,Myeloid ,Stromal cell ,Myeloproliferative neoplasm ,myelofibrosis ,myeloproliferative neoplasms ,Cohort Studies ,03 medical and health sciences ,ActivinA ,0302 clinical medicine ,Polycythemia vera ,Fibrosis ,Bone Marrow ,medicine ,Humans ,Myelofibrosis ,mesenchymal stromal cells ,Polycythemia Vera ,Cells, Cultured ,Aged ,Myeloproliferative Disorders ,Essential thrombocythemia ,business.industry ,Mesenchymal stromal cell ,Mesenchymal stem cell ,Myelofibrosi ,Cell Differentiation ,Mesenchymal Stem Cells ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Activins ,medicine.anatomical_structure ,Primary Myelofibrosis ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Bone marrow ,business ,030215 immunology ,Thrombocythemia, Essential - Abstract
Mesenchymal stromal cells (MSCs) represent an essential component of the bone marrow (BM) niche and display disease-specific alterations in several myeloid malignancies. The aim of this work was to study possible MSC abnormalities in Philadelphia-negative myeloproliferative neoplasms (MPNs) in relationship to the degree of BM fibrosis. MSCs were isolated from BM of 6 healthy donors (HD) and of 23 MPN patients, classified in 3 groups according to the diagnosis and the grade of BM fibrosis: polycythemia vera and essential thrombocythemia (PV/ET), low fibrosis myelofibrosis (LF-MF), and high fibrosis MF (HF-MF). MSC cultures were established from 21 of 23 MPN patients. MPN-derived MSCs did not exhibit any functional impairment in their adipogenic/osteogenic/chondrogenic differentiation potential and displayed a phenotype similar to HD-derived MSCs but with a decreased expression of CD146. All MPN-MSC lines were negative for the patient-specific hematopoietic clone mutations (JAK2, MPL, CALR). MSCs derived from HF-MF patients displayed a reduced clonogenic potential and a lower growth kinetic compared to MSCs from HD, LF-MF, and PV/ET patients. mRNA levels of hematopoiesis regulatory molecules were unaffected in MSCs from HF-MF compared to HD. Finally, in vitro ActivinA secretion by MSCs was increased in HF-MF compared to LF-MF patients, in association with a lower hemoglobin value. Increased ActivinA immunolabeling on stromal cells and erythroid precursors was also observed in HF-MF BM biopsies. In conclusion, higher grade of BM fibrosis is associated with functional impairment of MSCs and the increased secretion of ActivinA may represent a suitable target for anemia treatment in MF patients.
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- 2020
16. CMV management with specific immunoglobulins: A multicentric retrospective analysis on 92 allotransplanted patients
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Peccatori, Jacopo, Russo, Domenico, Ciceri, Fabio, Foà, Robin, Velardi, Andrea, Milone, Giuseppe, Natale, Annalisa, Serio, Francesca, Lorentino, Francesca, Rambaldi, Benedetta, Gandolfi, Lisa, Cattina, Federica, Turra, Alessandro, Polverelli, Nicola, Morello, Enrico, Bernardi, Simon, Pierini, Antonio, Carotti, Alessandra, Leotta, Salvatore, Antonella, Bruzzese, Barberi, Walter, Quatrocchi, Luisa, Iori, Anna Paola, Santarone, Stella, Greco, Raffaella, Malagola, Michele, Bernardi, Simona, Malagola, M., Greco, R., Santarone, S., Natale, A., Iori, A. P., Quatrocchi, L., Barbieri, W., Bruzzese, A., Leotta, S., Carotti, A., Pierini, A., Bernardi, S., Morello, E., Polverelli, N., Turra, A., Cattina, F., Gandolfi, L., Rambaldi, B., Lorentino, F., Serio, F., Milone, G., Velardi, A., Foa, R., Ciceri, F., Russo, D., and Peccatori, J.
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Drug ,medicine.medical_specialty ,media_common.quotation_subject ,Viremia ,Pre-emptive treatement ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Risk factor ,Adverse effect ,media_common ,Specific immunoglobulins ,business.industry ,lcsh:RC633-647.5 ,Prophylaxis ,virus diseases ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,medicine.disease ,Cytomegalovirus infection ,Transplantation ,Infectious Diseases ,CMV disease ,CMV infection ,030220 oncology & carcinogenesis ,Toxicity ,Original Article ,business ,030215 immunology - Abstract
CMV represents one of the most serious life-threatening complications of allogeneic stem cell transplantaion (allo-SCT). Pre-emptive treatment is highly effective, but toxicity and repetitive reactivation of CMV represent a major challenge in the clinical practice. The use of anti-CMV specific immunoglobulins (Megalotect) is controversial. We retrospectively collected data on 92 patients submitted to allo-SCT for hematological malignancies, in whom Megalotect was used either for prophylaxis (n=14) or with pre-emptive therapy (n=78). All the patients were considered at high-risk of developing CMV reactivation and CMV disease. The treatment was well tolerated, with no reported infusion reactions, nor other adverse events. None of the 14 cases treated with Megalotect as prophylaxis developed CMV reactivation. 51/78 (65%) patients who received Megalotect during pre-emptive treatment achieved complete clearance of CMV viremia, and 14/51 patients (29%) developed a breakthroug CMV infection. 7/78 patients (9%) developed CMV disease. The projected 1-year OS, 1-year TRM and 1-year RR is 74%, 15% and 19%, respectively. No differences were observed in terms of OS, TRM and RR by comparing patients who achieved a complete response after treatment versus those who did not.. These retrospective data suggest that Megalotect is safe and well tolerated. When used as prophylaxis, no CMV reactivation was recorded. We have no conclusive data regarding its efficacy in reducing the cumulative dose of anti-CMV specific drugs in the pre-emptive setting. Further prospective trials are warrented to identify the best setting of patients who can benefit from Megalotect alone or in addition to anti-CMV specific drugs.
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- 2019
17. Fludarabine as a cost-effective adjuvant to enhance engraftment of human normal and malignant hematopoiesis in immunodeficient mice
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Francesco Dazzi, A. Pievani, Marta Serafini, Benedetta Rambaldi, Ilaria M. Michelozzi, Alessandro Corsi, Andrea Biondi, V. Granata, Pievani, A, Michelozzi, I, Rambaldi, B, Granata, V, Corsi, A, Dazzi, F, Biondi, A, and Serafini, M
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0301 basic medicine ,Myeloid ,Transplantation Conditioning ,Xenotransplantation ,medicine.medical_treatment ,lcsh:Medicine ,Hematopoietic stem cell transplantation ,Mice, SCID ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,lcsh:Science ,Multidisciplinary ,business.industry ,lcsh:R ,Graft Survival ,fludarabin, hematopoiesis, immunodeficient mice ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Neoplasms, Experimental ,Fludarabine ,Hematopoiesis ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,lcsh:Q ,Bone marrow ,Stem cell ,business ,in vivo model of human normal and malignant haematopoiesis ,Neoplasm Transplantation ,Vidarabine ,030215 immunology ,medicine.drug - Abstract
There is still an unmet need for xenotransplantation models that efficiently recapitulate normal and malignant human hematopoiesis. Indeed, there are a number of strategies to generate humanized mice and specific protocols, including techniques to optimize the cytokine environment of recipient mice and drug alternatives or complementary to the standard conditioning regimens, that can be significantly modulated. Unfortunately, the high costs related to the use of sophisticated mouse models may limit the application of these models to studies that require an extensive experimental design. Here, using an affordable and convenient method, we demonstrate that the administration of fludarabine (FludaraTM) promotes the extensive and rapid engraftment of human normal hematopoiesis in immunodeficient mice. Quantification of human CD45+ cells in bone marrow revealed approximately a 102-fold increase in mice conditioned with irradiation plus fludarabine. Engrafted cells in the bone marrow included hematopoietic stem cells, as well as myeloid and lymphoid cells. Moreover, this model proved to be sufficient for robust reconstitution of malignant myeloid hematopoiesis, permitting primary acute myeloid leukemia cells to engraft as early as 8 weeks after the transplant. Overall, these results present a novel and affordable model for engraftment of human normal and malignant hematopoiesis in immunodeficient mice.
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- 2018
18. Comparative analysis of multilineage properties of mesenchymal stromal cells derived from fetal sources shows an advantage of mesenchymal stromal cells isolated from cord blood in chondrogenic differentiation potential
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Eugenio Erba, Andrea Biondi, Marta Serafini, Benedetta Rambaldi, Isabella Azario, Benedetto Sacchetti, Simona Marzorati, Giovanni Giudici, Francesca Russo, Mara Riminucci, Valeria Scagliotti, Patrizia Vergani, Alice Pievani, Pievani, A, Scagliotti, V, Russo, F, Azario, I, Rambaldi, B, Sacchetti, B, Marzorati, S, Erba, E, Giudici, G, Riminucci, M, Biondi, A, Vergani, P, and Serafini, M
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Cancer Research ,Pathology ,medicine.medical_specialty ,Amniotic fluid ,Stromal cell ,Cellular differentiation ,MED/40 - GINECOLOGIA E OSTETRICIA ,Immunology ,Biology ,mesenchymal stromal cells, fetal, cord blood ,amniotic fluid, chondrogenic differentiation, cord blood, mesenchymal stromal cells ,Fetus ,Tissue engineering ,Pregnancy ,medicine ,Immunology and Allergy ,Humans ,Cell Lineage ,chondrogenic differentiation ,Genetics (clinical) ,In Situ Hybridization, Fluorescence ,Transplantation ,Original Paper ,Mesenchymal Stromal Cells ,Tissue Engineering ,Mesenchymal stem cell ,amniotic fluid ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Chondrogenesis ,Fetal Blood ,Cell biology ,Oncology ,Cord blood ,cord blood ,Molecular Medicine ,Female - Abstract
Background aims: Cord blood (CB) and amniotic fluid (AF) could represent new and attractive mesenchymal stromal cell (MSC) sources, but their potential therapeutic applications are still limited by lack of standardized protocols for isolation and differentiation. In particular, chondrogenic differentiation has never been deeply investigated. Methods: MSCs were obtained from CB and AF samples collected during cesarean sections at term and compared for their biological and differentiation properties, with particular interest in cartilage differentiation, in which quantitative real-time polymerase chain reaction and immunohistochemical analyses were performed to evaluate the expression of type 2 collagen, type 10 collagen, SRY-box9 and aggrecan. Results: We were able to isolate MSCs from 12 of 30 (40%) and 5 of 20 (25%) CB and AF units, respectively. Fluorescence in situ hybridization analysis indicated the fetal origin of isolated MSC strains. Both populations expressed mesenchymal but not endothelial and hematopoietic markers, even though we observed a lower expression of human leukocyte antigen (HLA) I in CB-MSCs. No differences in proliferation rate and cell cycle analysis could be detected. After osteogenic induction, both populations showed matrix mineralization and typical marker expression. Under chondrogenic conditions, pellets derived from CB-MSCs, in contrast with AF-MSCs pellets, were significantly larger, showed cartilage-like morphology and resulted positive for chondrocyte-associated markers, such as type 2 collagen, type 10 collagen, SRY-box9 and aggrecan. Conclusions: Our results show that CB-MSCs and AF-MSCs collected at term differ from each other in their biological and differentiation properties. In particular, only CB-MSCs showed a clear chondrogenic potential and thus could represent an ideal candidate for cartilage-tissue engineering.
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- 2014
19. Human umbilical cord blood-borne fibroblasts contain marrow niche precursors that form a bone/marrow organoid
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Samantha Donsante, Marta Serafini, Benedetta Rambaldi, Alice Pievani, Mara Riminucci, Andrea Biondi, Valeria Scagliotti, Alessandro Corsi, Patrizia Vergani, Benedetto Sacchetti, Cristina Remoli, Pamela Gehron Robey, Pievani, A, Sacchetti, B, Corsi, A, Rambaldi, B, Donsante, S, Scagliotti, V, Vergani, P, Remoli, C, Biondi, A, Robey, P, Riminucci, M, and Serafin, M
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0301 basic medicine ,Adult ,Cord blood-borne fibroblast ,Hematopoietic stem cell niche ,Human Development ,CD34 ,Bone Marrow Cells ,Biology ,Umbilical cord blood ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Homeostasis ,Humans ,Progenitor cell ,Stem Cell Niche ,Child ,Molecular Biology ,Hematopoietic Tissue ,Hematopoietic Stem Cell Transplantation ,Hematopoietic stem cell ,Bone marrow organoid ,Cord blood-borne fibroblasts ,Fibroblasts ,Fetal Blood ,Hematopoietic Stem Cells ,Cell biology ,Cell Compartmentation ,Developmental Biology ,Transplantation ,Organoids ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Bone marrow ,Stromal Cells - Abstract
Human umbilical cord blood (CB) has attracted much attention as a reservoir for functional hematopoietic stem and progenitor cells, and, recently, as a source of blood-borne fibroblasts (CB-BFs). Previously, we demonstrated that bone marrow stromal cell (BMSC) and CB-BF pellet cultures make cartilage in vitro. Furthermore, upon in vivo transplantation, BMSC pellets remodelled into miniature bone/marrow organoids. Using this in vivo model, we asked whether CB-BF populations that express characteristics of the hematopoietic stem cell (HSC) niche contain precursors that reform the niche. CB ossicles were regularly observed upon transplantation. Compared with BM ossicles, CB ossicles showed a predominance of red marrow over yellow marrow, as demonstrated by histomorphological analyses and the number of hematopoietic cells isolated within ossicles. Marrow cavities from CB and BM ossicles included donor-derived CD146-expressing osteoprogenitors and host-derived mature hematopoietic cells, clonogenic lineage-committed progenitors and HSCs. Furthermore, human CD34+ cells transplanted into ossicle-bearing mice engrafted and maintained human HSCs in the niche. Our data indicate that CB-BFs are able to recapitulate the conditions by which the bone marrow microenvironment is formed and establish complete HSC niches, which are functionally supportive of hematopoietic tissue.
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- 2016
20. Neonatal bone marrow transplantation prevents bone pathology in a mouse model of mucopolysaccharidosis type I
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Pravin Patel, Marta Serafini, Benedetta Rambaldi, Shunji Tomatsu, Alice Pievani, Laura Antolini, Cristina Remoli, Tsutomu Shimada, Mara Riminucci, Maria Grazia Valsecchi, Andrea Biondi, Isabella Azario, Pievani, A, Azario, I, Antolini, L, Shimada, T, Patel, P, Remoli, C, Rambaldi, B, Valsecchi, M, Riminucci, M, Biondi, A, Tomatsu, S, and Serafini, M
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Male ,Pathology ,medicine.medical_specialty ,Bone pathology ,Mucopolysaccharidosis I ,Long bone ,Immunology ,Hurler syndrome, bone marrow transplantation, bone ,Biochemistry ,Bone and Bones ,Mucopolysaccharidosis type I ,Iduronidase ,Mice ,medicine ,Animals ,Humans ,Hurler syndrome ,Bone Marrow Transplantation ,Glycosaminoglycans ,Mice, Knockout ,Bone Diseases, Developmental ,business.industry ,mucopolysaccharidosis type I ,Age Factors ,Infant, Newborn ,Cell Biology ,Hematology ,medicine.disease ,Transplantation ,Mice, Inbred C57BL ,Disease Models, Animal ,surgical procedures, operative ,medicine.anatomical_structure ,Animals, Newborn ,Female ,Bone marrow ,business ,Busulfan ,medicine.drug - Abstract
Neonatal bone marrow transplantation (nBMT) could offer a novel therapeutic opportunity for genetic disorders by providing sustainable levels of the missing protein at birth, thus preventing tissue damage. We tested this concept in Mucopolysaccharidosis type I (MPS IH, Hurler syndrome), a lysosomal storage disorder caused by deficiency of α-L-iduronidase (IDUA). MPS IH is characterized by a broad spectrum of clinical manifestations including severe progressive skeletal abnormalities. Although BMT increases the life span of MPS IH patients, musculoskeletal manifestations are only minimally responsive if the timing of BMT delays, suggesting already irreversible bone damage. In this study, we tested the hypothesis that transplanting normal bone marrow into newborn MPS I mice, soon after birth, can prevent skeletal dysplasia. 1- to 2-day-old mutant mice were conditioned using a single administration of 20 mg/kg busulfan and then injected via the superficial temporal vein with 2 x 106 bone marrow cells from wild type (WT) donors. Age-matched WT and untreated MPS I mice were used as controls. Transplantation of normal bone marrow cells into preconditioned MPS I and WT neonates led to a similar engraftment level at 37 weeks after nBMT (peripheral blood, median MPS I nBMT 81.30%, range from 0.80% to 95.80% vs. median WT nBMT 67.45%, range from 16.00% to 95.86%, p = 0.714). Spleen, PB and thymus cells of nBMT MPS I mice were repopulated with committed lymphoid and myeloid populations similar to the transplanted WT mice. The >50% replacement of the hematopoiesis resulted in a measurable increase in IDUA activity in visceral organs, especially in the spleen, showing a correlation between engraftment levels and enzyme activity with clearance of GAGs from blood and tissues. At the time of euthanasia (37-week-old), reconstitution of normal hematopoiesis in MPS I mice was associated with a consistent amelioration of bone pathology, as revealed by radiographic skeletal examination. Radiographic analysis has shown that the width of the humerus, radius/ulna, femur and tibia of untreated MPS I mice was significantly larger at comparison with WT littermates. For MPS I nBMT mice, long bone widths, including the humerus (p = 0.0014, vs. untreated MPS I mice), the radius/ulna (p = 0.0003, vs. untreated MPS I mice), the femur (p = 0.0003, vs. untreated MPS I mice), and the tibia (p = 0.0003, vs. untreated MPS I mice) significantly decreased, compared to untreated MPS I mice. Furthermore, several three-dimensional architectural parameters in femurs such as trabecular number and separation, cortical thickness and bone mineral volume were analyzed by micro-CT, resulting in a significant difference between untreated and nBMT MPS I mice. All examined nBMT MPS I mice displayed bone parameter values comparable to WT mice, confirming that nBMT mice had significant improvements in skeletal phenotype approaching complete normalization of each parameter tested. Histologically, in MPS I cortical bone, osteocytes were increased and contained vacuoles, likely reflecting GAGs storage. Histological amelioration of these features was consistently observed in femurs of all nBMT mice with a definite reduction in both hyperosteocytosis and lysosomal vacuolization, confirming that the perinatal treatment of the disease can positively impact the skeletal phenotype in MPS I. We also evaluated KS levels in the blood as a biomarker of MPS with skeletal dysplasia. Normalization of blood KS level strongly supports the notion that nBMT corrects the pathological and clinical bone lesions in nBMT MPS I mice. Our findings demonstrate that nBMT prevents some of the relevant abnormalities of the skeletal pathology in the MPS I mouse model. Moreover, improvements in bone parameters correlated with high levels of bone marrow-derived cell engraftment in multiple hematopoietic compartments, suggesting that the early and complete restoration of normal hematopoiesis can have significant impact on the bone development of newborn MPS I mice. Future clinical trials are needed to confirm our findings. Disclosures No relevant conflicts of interest to declare.
- Published
- 2015
21. Safety and efficacy of narsoplimab in pediatric and adult patients with transplant-associated thrombotic microangiopathy: a real-world experience.
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Castelli M, Micò MC, Grassi A, Algarotti A, Lussana F, Finazzi MC, Rambaldi B, Pavoni C, Rizzuto G, Tebaldi P, Vendemini F, Verna M, Bonanomi S, Biondi A, Balduzzi A, Rambaldi A, and Gotti G
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- Humans, Adult, Male, Female, Child, Adolescent, Middle Aged, Child, Preschool, Young Adult, Aged, Antibodies, Monoclonal, Humanized therapeutic use, Thrombotic Microangiopathies etiology, Thrombotic Microangiopathies therapy, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication following hematopoietic stem cell transplantation (HSCT). No approved treatments are currently available. This study presents real-world data obtained with narsoplimab, a human immunoglobulin G4 monoclonal antibody that inhibits MASP-2, the effector enzyme of the lectin pathway of the complement system. Between January 2018 and August 2023, 20 (13 adult and 7 pediatric) patients diagnosed with TA-TMA received narsoplimab under an ongoing compassionate use program. The diagnosis was based on internationally defined criteria for pediatric and adult patients. Fifteen patients fulfilled the criteria recently established by an international consensus on TA-TMA. Nineteen patients exhibited high-risk characteristics. Thirteen patients (65%) responded to narsoplimab, achieving transfusion independence and significant clinical improvement. The one-hundred-day Overall Survival (OS) post-TA-TMA diagnosis was 70%, and 100% for responders. Narsoplimab proved to be effective and safe in the treatment of high-risk TA-TMA, with no increased infectious complications or other safety signals of concern across all age groups. The high response rates and the encouraging survival outcomes underscore the potential of narsoplimab as a valuable therapeutic option, particularly for high-risk cases., (© 2024. The Author(s).)
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- 2024
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22. Optimization and validation of in vivo flow cytometry chimeric antigen receptor T cell detection method using CD19his indirect staining.
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Zaninelli S, Meli C, Borleri G, Quaroni M, Pavoni C, Gaipa G, Biondi A, Introna M, Golay J, Rambaldi A, and Rambaldi B
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- Humans, Flow Cytometry methods, Immunotherapy, Adoptive methods, Antigens, CD19, Antibodies, T-Lymphocytes, Receptors, Chimeric Antigen genetics
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CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy has shown unprecedented results in patients with B cell relapsed/refractory acute lymphoblastic leukemia (R/R-ALL) and B cell non-Hodgkin lymphomas where no other curative options are available. In vivo monitoring of CAR-T cell kinetics is fundamental to understand the correlation between CAR-T cells expansion and persistence with treatment response and toxicity development. The aim of this study was to define a robust, sensitive, and universal method for CAR-T cell detection using flow cytometry. We set up and compared with each other three assays for CD19 CAR-T cell detection, all based on commercially available reagents. All methods used a recombinant human CD19 protein fragment recognized by the single-chain variable fragment of the CAR construct. The two indirect staining assays (CD19his + APC-conjugated antihistidine antibody and CD19bio + APC-conjugated antibiotin antibody) showed better sensitivity and specificity compared with the direct staining with CD19-FITC, and CD19his had a better cost-effective profile. We validated CAR detection with CD19his with parallel quantitative real-time polymerase chain reaction data and we could demonstrate a strong positive correlation. We also showed that CD19his staining can be easily included in a multicolor flow cytometry panel to achieve additional information about the cell phenotype of CAR-T cell positive subpopulations. Finally, this method can be used for different anti-CD19 CAR-T cell products and for different sample sources. These data demonstrate that detection of CAR-T cells by CD19his flow cytometry staining is a reliable, robust, and broadly applicable tool for in vivo monitoring of CAR-T cells., (© 2023 The Authors. Cytometry Part A published by Wiley Periodicals LLC on behalf of International Society for Advancement of Cytometry.)
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- 2024
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23. A Question of Frame: The Role of the Bone Marrow Stromal Niche in Myeloid Malignancies.
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Tomasoni C, Pievani A, Rambaldi B, Biondi A, and Serafini M
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Until a few years ago, the onset of acute myeloid leukemia (AML) was entirely ascribed to genetic lesions in hematopoietic stem cells. These mutations generate leukemic stem cells, which are known to be the main ones responsible for chemoresistance and relapse. However, in the last years, increasing evidence demonstrated that dynamic interplay between leukemic cells and bone marrow (BM) niche is of paramount relevance in the pathogenesis of myeloid malignancies, including AML. Specifically, BM stromal niche components, such as mesenchymal stromal cells (MSCs) and their osteoblastic cell derivatives, play a key role not only in supporting normal hematopoiesis but also in the manifestation and progression of myeloid malignancies. Here, we reviewed recent clinical and experimental findings about how genetic and functional alterations in MSCs and osteolineage progeny can contribute to leukemogenesis and how leukemic cells in turn generate a corrupted niche able to support myeloid neoplasms. Moreover, we discussed how the newest single-cell technologies may help dissect the interactions between BM stromal cells and malignant hematopoiesis. The deep comprehension of the tangled relationship between stroma and AML blasts and their modulation during disease progression may have a valuable impact on the development of new microenvironment-directed therapeutic strategies, potentially useful for a wide cohort of patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)
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- 2023
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24. Phenotypic and functional characterization of the CD6-ALCAM T-cell co-stimulatory pathway after allogeneic cell transplantation.
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Rambaldi B, Kim HT, Arihara Y, Asano T, Reynolds C, Manter M, Halpern M, Weber A, Koreth J, Cutler C, Gooptu M, Nikiforow S, Ho VT, Antin JH, Romee R, Ampudia J, Ng C, Connelly S, Soiffer RJ, and Ritz J
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- Humans, Antigens, Differentiation, T-Lymphocyte, Lymphocyte Activation, Antibodies, Monoclonal pharmacology, Fetal Proteins, Antigens, CD, Cell Adhesion Molecules, Neuronal, Activated-Leukocyte Cell Adhesion Molecule metabolism, Hematopoietic Stem Cell Transplantation
- Abstract
CD6 is a co-stimulatory receptor expressed on T cells that binds activated leukocyte cell adhesion molecule (ALCAM), expressed on antigen presenting cells, epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T-cell activation, proliferation, and trafficking. In this study we examined expression of CD6 by reconstituting T cells in 95 patients after allogeneic cell transplantation and evaluated the effects of itolizumab, an anti- CD6 monoclonal antibody, on T-cell activation. CD6 T cells reconstituted early after transplant with CD4 regulatory T cells (Treg)-expressing lower levels of CD6 compared to conventional CD4 T cells (Tcon) and CD8 T cells. After onset of acute graft-versus-host disease (aGvHD), CD6 expression was further reduced in Treg and CD8 T cells compared to healthy donors, while no difference was observed for Tcon. ALCAM expression was highest in plasmacytoid dendritic cells (pDC), lowest in myeloid dendritic cells (mDC) and intermediate in monocytes and was generally increased after aGvHD onset. Itolizumab inhibited CD4 and CD8 T-cell activation and proliferation in preGvHD samples, but inhibition was less prominent in samples collected after aGvHD onset, especially for CD8 T cells. Functional studies showed that itolizumab did not mediate direct cytolytic activity or antibody-dependent cytotoxicity in vitro. However, itolizumab efficiently abrogated the costimulatory activity of ALCAM on T-cell proliferation, activation and maturation. Our results identify the CD6-ALCAM pathway as a potential target for aGvHD control and a phase I/II study using itolizumab as first line treatment in combination with steroids for patients with aGvHD is currently ongoing (clinicaltrials gov. Identifier: NCT03763318).
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- 2022
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25. Expansion, persistence, and efficacy of donor memory-like NK cells infused for posttransplant relapse.
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Shapiro RM, Birch GC, Hu G, Vergara Cadavid J, Nikiforow S, Baginska J, Ali AK, Tarannum M, Sheffer M, Abdulhamid YZ, Rambaldi B, Arihara Y, Reynolds C, Halpern MS, Rodig SJ, Cullen N, Wolff JO, Pfaff KL, Lane AA, Lindsley RC, Cutler CS, Antin JH, Ho VT, Koreth J, Gooptu M, Kim HT, Malmberg KJ, Wu CJ, Chen J, Soiffer RJ, Ritz J, and Romee R
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- Humans, Killer Cells, Natural, Recurrence, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation, Interleukin-2
- Abstract
BackgroundResponses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell-based therapy is a promising modality to treat post-HCT relapse.MethodsWe initiated this ongoing phase I trial of adoptively transferred cytokine-induced memory-like (CIML) NK cells in patients with myeloid malignancies who relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5 to 10 million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. High-resolution profiling with mass cytometry and single-cell RNA sequencing characterized the expanding and persistent NK cell subpopulations in a longitudinal manner after infusion.ResultsIn the first 6 enrolled patients on the trial, infusion of CIML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events. Expansion of NK cells was distinct from IL-2 effects on endogenous post-HCT NK cells, and not dependent on CMV viremia. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires.ConclusionGiven their rapid expansion and long-term persistence in an immune-compatible environment, CIML NK cells serve as a promising platform for the treatment of posttransplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T cells and tumor targets will lead to improvements in cell-based immunotherapies.Trial RegistrationClinicalTrials.gov NCT04024761.FundingDunkin' Donuts, NIH/National Cancer Institute, and the Leukemia and Lymphoma Society.
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- 2022
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26. Treatment of immune thrombocytopenia (ITP) secondary to malignancy: a systematic review.
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Podda GM, Fiorelli EM, Birocchi S, Rambaldi B, Di Chio MC, Casazza G, and Cattaneo M
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- Humans, Purpura, Thrombocytopenic, Idiopathic pathology, Neoplasms complications, Purpura, Thrombocytopenic, Idiopathic etiology, Purpura, Thrombocytopenic, Idiopathic therapy
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Immune thrombocytopenia (ITP) can be associated with lymphoproliferative diseases (LPD) or solid tumors. A systematic review of published literature was conducted to evaluate response to treatment of ITP secondary to malignancy. Primary outcome was overall response (complete response+response) to first-line treatments [steroids alone or in combination with intravenous immunoglobulins (IVIg)]. Among secondary outcomes, overall response to second-line treatments [splenectomy, rituximab or thrombopoietin receptor agonists (TPO-RA)] and death were evaluated. Of the retrieved 238 text articles, 108 were analyzable, for a total of 154 patients: 142 in 105 case reports and 12 in 3 observational studies. Thirty-nine patients had solid tumors, 114 LPD, and 1 both. The median follow up was 19 months (IQR, 9-40). The overall response was 50% (62% in solid tumors, 46% in LPD) after steroids and 47% (67% in solid tumors, 36% in LPD) after steroids+IVIg, which are lower than historical responses observed in primary ITP (≈80%). The overall responses to rituximab (used in LPD only), splenectomy and TPO-RA (70%, 73% and 92%, respectively) were similar to those observed in primary ITP. Seven patients (6%) died due to bleeding events. ITP secondary to malignancy appears to be associated with unsatisfactory response to first-line treatments.
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- 2022
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27. Impaired T- and NK-cell reconstitution after haploidentical HCT with posttransplant cyclophosphamide.
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Rambaldi B, Kim HT, Reynolds C, Chamling Rai S, Arihara Y, Kubo T, Buon L, Gooptu M, Koreth J, Cutler C, Nikiforow S, Ho VT, Alyea EP, Antin JH, Wu CJ, Soiffer RJ, Ritz J, and Romee R
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- Cyclophosphamide therapeutic use, Humans, Killer Cells, Natural, Graft vs Host Disease, Hematopoietic Stem Cell Transplantation, Immune Reconstitution
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Administration of posttransplant cyclophosphamide (PTCy) has significantly expanded the number of patients undergoing HLA-haploidentical hematopoietic cell transplantation (haplo-HCT). To examine immune reconstitution in these patients, we monitored T- and natural killer (NK)-cell recovery in 60 patients receiving bone marrow or peripheral blood stem cell (PBSC) grafts after haplo-HCT with PTCy and 35 patients receiving HLA-matched donor PBSC grafts with standard graft-versus-host disease (GVHD) prophylaxis. Compared with HLA-matched recipients, early T-cell recovery was delayed in haplo-HCT patients and skewed toward effector memory T cells with markedly reduced naive T cells. We found higher regulatory T (Treg)-cell/conventional T (Tcon)-cell ratios early after HCT and increased PD-1 expression on memory T cells. Within the haplo-HCT, patients who did not develop chronic GVHD (cGVHD) had higher PD-1 expression on central and effector memory CD4+ Treg cells at 1 month after transplant. These findings suggest an immunologic milieu that promotes immune tolerance in haplo-HCT patients. NK cells were decreased early after haplo-HCT with preferential expansion of immature CD56brightCD16- NK cells compared with matched donor transplants. One month after transplant, mass cytometry revealed enrichment of immature NK-cell metaclusters with high NKG2A, low CD57, and low killer-cell immunoglobulin-like receptor expression after haplo-HCT, which partially recovered 3 months post-HCT. At 2 months, immature NK cells from both groups were functionally impaired, but interleukin-15 priming corrected these defects in vitro. Increased immature/mature NK-cell ratios were associated with cytomegalovirus reactivation and increased incidence of cGVHD after haplo-HCT. These homeostatic imbalances in T- and NK-cell reconstitution after haplo-HCT reveal opportunities for early immune-based interventions to optimize clinical outcomes., (© 2021 by The American Society of Hematology.)
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- 2021
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28. Heterogeneity of the bone marrow niche in patients with myeloproliferative neoplasms: ActivinA secretion by mesenchymal stromal cells correlates with the degree of marrow fibrosis.
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Rambaldi B, Diral E, Donsante S, Di Marzo N, Mottadelli F, Cardinale L, Dander E, Isimbaldi G, Pioltelli P, Biondi A, Riminucci M, D'Amico G, Elli EM, Pievani A, and Serafini M
- Subjects
- Adult, Aged, Bone Marrow pathology, Cell Differentiation physiology, Cells, Cultured, Cohort Studies, Female, Humans, Male, Mesenchymal Stem Cells pathology, Middle Aged, Myeloproliferative Disorders pathology, Polycythemia Vera metabolism, Polycythemia Vera pathology, Primary Myelofibrosis pathology, Thrombocythemia, Essential metabolism, Thrombocythemia, Essential pathology, Activins metabolism, Bone Marrow metabolism, Mesenchymal Stem Cells metabolism, Myeloproliferative Disorders metabolism, Primary Myelofibrosis metabolism
- Abstract
Mesenchymal stromal cells (MSCs) represent an essential component of the bone marrow (BM) niche and display disease-specific alterations in several myeloid malignancies. The aim of this work was to study possible MSC abnormalities in Philadelphia-negative myeloproliferative neoplasms (MPNs) in relationship to the degree of BM fibrosis. MSCs were isolated from BM of 6 healthy donors (HD) and of 23 MPN patients, classified in 3 groups according to the diagnosis and the grade of BM fibrosis: polycythemia vera and essential thrombocythemia (PV/ET), low fibrosis myelofibrosis (LF-MF), and high fibrosis MF (HF-MF). MSC cultures were established from 21 of 23 MPN patients. MPN-derived MSCs did not exhibit any functional impairment in their adipogenic/osteogenic/chondrogenic differentiation potential and displayed a phenotype similar to HD-derived MSCs but with a decreased expression of CD146. All MPN-MSC lines were negative for the patient-specific hematopoietic clone mutations (JAK2, MPL, CALR). MSCs derived from HF-MF patients displayed a reduced clonogenic potential and a lower growth kinetic compared to MSCs from HD, LF-MF, and PV/ET patients. mRNA levels of hematopoiesis regulatory molecules were unaffected in MSCs from HF-MF compared to HD. Finally, in vitro ActivinA secretion by MSCs was increased in HF-MF compared to LF-MF patients, in association with a lower hemoglobin value. Increased ActivinA immunolabeling on stromal cells and erythroid precursors was also observed in HF-MF BM biopsies. In conclusion, higher grade of BM fibrosis is associated with functional impairment of MSCs and the increased secretion of ActivinA may represent a suitable target for anemia treatment in MF patients.
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- 2021
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29. Case Report: Late Onset of Myelodysplastic Syndrome From Donor Progenitor Cells After Allogeneic Stem Cell Transplantation. Which Lessons Can We Draw From the Reported Case?
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Farina M, Bernardi S, Gandolfi L, Zanaglio C, Morello E, Turra A, Zollner T, Gramegna D, Rambaldi B, Cattina F, Polverelli N, Malagola M, and Russo D
- Abstract
Background: Myelodysplastic syndromes and acute leukemias after allogeneic stem cell transplantation (allo-SCT) are mainly caused by recurrence of the primitive leukemic clones. More rarely, they originate from donor hematopoietic stem cells, developing the so-called donor cell leukemia (DCL) or myelodysplastic syndromes (DC-MDSs). DCL and DC-MDS can be considered as an in vivo model of leukemogenesis, and even if the pathogenetic mechanisms remain speculative, a genetic predisposition of donor progenitor cells, an altered host microenvironment, and the impairment of immune surveillance are considered the main causes., Case Presentation: We report a case of DC-MDS diagnosed 5 years after an allo-SCT from a matched related donor (patient's sister) in a patient with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL). The sex-mismatch allowed us to identify the donor cell origin. At the onset, the DC-MDS was characterized by chromosome seven monosomy and NRAS , RUNX1 , and BCOR mutations. Because of a familiar history of colorectal neoplasia and the variant allele frequency (VAF) of NRAS mutation at the onset, this mutation was searched on germline DNA in both the donor and the recipient, but the result was negative. Moreover, after transplant (+4 months), the patient developed severe and long-lasting chronic graft-versus-host disease (cGVHD), requiring multiple lines of treatments. Because of the severe immunosuppression, recurrent infections occurred and, lately, the patient died due to septic shock., Conclusion: This case report highlights the need, whenever possible, to evaluate the donor origin of the posttransplant myelodysplasia and acute leukemias. The potential key role of the impaired immune surveillance and of long-lasting immunosuppression appears to be emerging in the development of this case of DC-MDS. Finally, this case reminds the importance to investigate the familiar genetic predisposition in donors with a familiar history of neoplasia., (Copyright © 2020 Farina, Bernardi, Gandolfi, Zanaglio, Morello, Turra, Zollner, Gramegna, Rambaldi, Cattina, Polverelli, Malagola and Russo.)
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- 2020
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30. Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation.
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Baumeister SHC, Rambaldi B, Shapiro RM, and Romee R
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- Cyclophosphamide therapeutic use, Graft vs Host Disease etiology, Histocompatibility Testing, Humans, Immunity, Innate, Immunosuppression Therapy, Immunotherapy, Adoptive, Lymphocyte Depletion methods, Lymphocyte Transfusion, Neutrophils immunology, T-Lymphocytes immunology, Hematopoietic Stem Cell Transplantation adverse effects, Transplantation, Haploidentical adverse effects
- Abstract
Hematopoietic stem cell transplantation from a haploidentical donor is increasingly used and has become a standard donor option for patients lacking an appropriately matched sibling or unrelated donor. Historically, prohibitive immunological barriers resulting from the high degree of HLA-mismatch included graft-vs.-host disease (GVHD) and graft failure. These were overcome with increasingly sophisticated strategies to manipulate the sensitive balance between donor and recipient immune cells. Three different approaches are currently in clinical use: (a) ex vivo T-cell depletion resulting in grafts with defined immune cell content (b) extensive immunosuppression with a T-cell replete graft consisting of G-CSF primed bone marrow and PBSC (GIAC) (c) T-cell replete grafts with post-transplant cyclophosphamide (PTCy). Intriguing studies have recently elucidated the immunologic mechanisms by which PTCy prevents GVHD. Each approach uniquely affects post-transplant immune reconstitution which is critical for the control of post-transplant infections and relapse. NK-cells play a key role in haplo-HCT since they do not mediate GVHD but can successfully mediate a graft-vs.-leukemia effect. This effect is in part regulated by KIR receptors that inhibit NK cell cytotoxic function when binding to the appropriate HLA-class I ligands. In the context of an HLA-class I mismatch in haplo-HCT, lack of inhibition can contribute to NK-cell alloreactivity leading to enhanced anti-leukemic effect. Emerging work reveals immune evasion phenomena such as copy-neutral loss of heterozygosity of the incompatible HLA alleles as one of the major mechanisms of relapse. Relapse and infectious complications remain the leading causes impacting overall survival and are central to scientific advances seeking to improve haplo-HCT. Given that haploidentical donors can typically be readily approached to collect additional stem- or immune cells for the recipient, haplo-HCT represents a unique platform for cell- and immune-based therapies aimed at further reducing relapse and infections. The rapid advancements in our understanding of the immunobiology of haplo-HCT are therefore poised to lead to iterative innovations resulting in further improvement of outcomes with this compelling transplant modality., (Copyright © 2020 Baumeister, Rambaldi, Shapiro and Romee.)
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- 2020
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31. CMV Management with Specific Immunoglobulins: A Multicentric Retrospective Analysis on 92 Allotransplanted Patients.
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Malagola M, Greco R, Santarone S, Natale A, Iori AP, Quatrocchi L, Barbieri W, Bruzzese A, Leotta S, Carotti A, Pierini A, Bernardi S, Morello E, Polverelli N, Turra A, Cattina F, Gandolfi L, Rambaldi B, Lorentino F, Serio F, Milone G, Velardi A, Foà R, Ciceri F, Russo D, and Peccatori J
- Abstract
CMV represents one of the most severe life-threatening complications of allogeneic stem cell transplantation (allo-SCT). Pre-emptive treatment is highly effective, but toxicity and repetitive reactivation of CMV represent a significant challenge in the clinical practice. The use of anti-CMV specific immunoglobulins (Megalotect) is controversial. We retrospectively collected data on 92 patients submitted to allo-SCT for hematological malignancies, in whom Megalotect was used either for prophylaxis (n=14) or with pre-emptive therapy, together with an anti-CMV specific drug (n=78). All the patients were considered at high-risk, due to the presence of at least one risk factor for CMV reactivation. The treatment was well tolerated, with no reported infusion reactions, nor other adverse events, none of the 14 cases treated with Megalotect as prophylaxis developed CMV reactivation. 51/78 (65%) patients who received Megalotect during pre-emptive treatment achieved complete clearance of CMV viremia, and 14/51 patients (29%) developed a breakthrough CMV infection. 7/78 patients (9%) developed CMV disease. The projected 1-year OS, 1-year TRM, and 1-year RR is 74%, 15%, and 19%, respectively. No differences were observed in terms of OS, TRM, and RR by comparing patients who achieved a complete response after treatment versus those who did not. These retrospective data suggest that Megalotect is safe and well-tolerated. When used as prophylaxis, no CMV reactivation was recorded. Further prospective trials are warranted to identify the best set of patients who can benefit from Megalotect alone or in addition to anti-CMV specific drugs., Competing Interests: Competing interests: MM, RG, SS, AI, SL, AP, FC and JP are included in the Advisory Board of Biotest. All the remaining Authors declare no potential Conflict of Interest.
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- 2019
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32. Inducing Fat to Feed a Natural Killer of Malignancy.
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Rambaldi B and Romee R
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- Adipocytes, Genes, Neoplasm, Humans, Killer Cells, Natural, Interleukin-15, Neoplasms
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- 2019
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33. Comparative study on ATG-thymoglobulin versus ATG-fresenius for the graft-versus-host disease (GVHD) prophylaxis in allogeneic stem cell transplantation from matched unrelated donor: a single-centre experience over the contemporary years.
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Polverelli N, Malagola M, Turra A, Skert C, Perucca S, Chiarini M, Cattina F, Rambaldi B, Cancelli V, Morello E, Schieppati F, Bernardi S, Zanaglio C, Sottini A, Giustini V, Imberti L, Montanelli A, and Russo D
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- Adult, Aged, Female, Follow-Up Studies, Hematologic Neoplasms pathology, Humans, Male, Middle Aged, Prognosis, Retrospective Studies, Survival Rate, Transplantation, Homologous, Unrelated Donors, Antilymphocyte Serum administration & dosage, Graft vs Host Disease prevention & control, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation mortality, Immunosuppressive Agents administration & dosage
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- 2018
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34. Clinical Care of Hematological Patients in a Bone Marrow Transplant Unit: Do Human Resources Influence Infection Incidence?
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Malagola M, Rambaldi B, Ravizzola G, Polverelli N, Turra A, Morello E, Skert C, Cancelli V, Cattina F, Bernardi S, Perucca S, Signorini L, Stellini R, Castelli F, Caruso A, and Russo D
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- 2017
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35. Bacterial Blood Stream Infections Negatively Impact on Outcome of Patients Treated with Allogeneic Stem Cell Transplantation: 6 Years Single-Centre Experience.
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Malagola M, Rambaldi B, Ravizzola G, Cattaneo C, Borlenghi E, Polverelli N, Turra A, Morello E, Skert C, Cancelli V, Cattina F, Giannetta G, Bernardi S, Perucca S, Almici C, Roccaro A, Signorini L, Stellini R, Castelli F, Caruso A, and Russo D
- Abstract
Background: Blood stream infections (BSIs) represent a major complication of allo-SCT and are a major cause of morbidity and mortality during and after bone marrow aplasia., Objectives: The objective of this study was to describe the incidence and outcome of BSIs in a cohort of patients submitted to allo-SCT, in order to track changes of the epidemiology and bacteria resistance., Methods: We retrospectively analyzed the microbiological data of 162 patients allotransplanted in Brescia University Hospital, over a period of 6 years., Results: Eighty patients experienced a BSIs for a total of 119 isolates. In 77 cases (65%) a Gram positive bacteria was isolated, being coagulase negative Staphilococci the most frequent species (77% of the cases). In 42 cases (35%) a Gram negative bacteria was isolated ( E . coli 57% and P. aeruginosa 24%). Fluoroquinolones resistance was frequent (90% for S. epidermidis , 92% for E. coli , 90% for P. aeruginosa ). Methycillin resistance of S. epidermidis was 100%, 76% of E. coli were ESBL positive and among P. aeruginosa resistance to carbapenems was 40%. The 2 years overall survival of patients with BSIs vs patients without BSIs was 46% vs 60% (HR1,48, p=0,07). P. aeruginosa and E. coli were the species with the highest mortality (50% and 33%, respectively)., Conclusions: These data confirm that BSIs, mainly sustained by Gram positive bacteria, are frequent in allotransplanted patients (50% of the cases) and may influence the outcome of allotransplanted patients, being antibiotics resistance highly frequent among these bacteria., Competing Interests: Competing interests: The authors have declared that no competing interests exist.
- Published
- 2017
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36. Sequential monitoring of lymphocyte subsets and of T-and-B cell neogenesis indexes to identify time-varying immunologic profiles in relation to graft-versus-host disease and relapse after allogeneic stem cell transplantation.
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Skert C, Perucca S, Chiarini M, Giustini V, Sottini A, Ghidini C, Martellos S, Cattina F, Rambaldi B, Cancelli V, Malagola M, Turra A, Polverelli N, Bernardi S, Imberti L, and Russo D
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- Adolescent, Adult, Aged, Female, Flow Cytometry, Humans, Male, Middle Aged, Recurrence, Transplantation, Homologous, Young Adult, B-Lymphocytes cytology, Graft vs Host Disease immunology, Hematopoietic Stem Cell Transplantation, Lymphocyte Subsets, T-Lymphocytes cytology
- Abstract
T and B lymphocyte subsets have been not univocally associated to Graft-versus-host disease (GVHD) and relapse of hematological malignancies after stem cell transplantation (SCT). Their sequential assessment together with B and T cell neogenesis indexes has been not thoroughly analysed in relation to these changing and interrelated immunologic/clinic events yet. Lymphocyte subsets in peripheral blood (PB) and B and T cell neogenesis indexes were analysed together at different time points in a prospective study of 50 patients. Principal component analysis (PCA) was used as first step of multivariate analysis to address issues related to a high number of variables versus a relatively low number of patients. Multivariate analysis was completed by Fine-Gray proportional hazard regression model. PCA identified 3 clusters of variables (PC1-3), which correlated with acute GVHD: PC1 (pre-SCT: KRECs≥6608/ml, unswitched memory B <2.4%, CD4+TCM cells <45%; HR 0.5, p = 0.001); PC2 (at aGVHD onset: CD4+>44%, CD8+TCM cells>4%; HR 1.9, p = 0.01), and PC3 (at aGVHD onset: CD4+TEMRA<1, total Treg<4, TregEM <2 cells/μl; HR 0.5, p = 0.002). Chronic GVHD was associated with one PC (TregEM <2 cells/μl at day+28, CD8+TEMRA<43% at day+90, immature B cells<6 cells/μl and KRECs<11710/ml at day+180; HR 0.4, P = 0.001). Two PC correlated with relapse: PC1 (pre-SCT: CD4+ <269, CD4+TCM <120, total Treg <18, TregCM <8 cells/μl; HR 4.0, p = 0.02); PC2 (pre-SCT mature CD19+ >69%, switched memory CD19+ = 0 cells and KRECs<6614/ml at +90; HR 0.1, p = 0.008). All these immunologic parameters were independent indicators of chronic GVHD and relapse, also considering the possible effect of previous steroid-therapy for acute GVHD. Specific time-varying immunologic profiles were associated to GVHD and relapse. Pre-SCT host immune-microenvironment and changes of B cell homeostasis could influence GVH- and Graft-versus-Tumor reactions. The paradoxical increase of EM Treg in PB of patients with GVHD could be explained by their compartmentalization outside lymphoid tissues, which are of critical relevance for regulation of GVH reactions.
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- 2017
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37. Human umbilical cord blood-borne fibroblasts contain marrow niche precursors that form a bone/marrow organoid in vivo .
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Pievani A, Sacchetti B, Corsi A, Rambaldi B, Donsante S, Scagliotti V, Vergani P, Remoli C, Biondi A, Robey PG, Riminucci M, and Serafini M
- Subjects
- Adult, Cell Compartmentation, Child, Fibroblasts transplantation, Hematopoietic Stem Cell Transplantation, Homeostasis, Humans, Stromal Cells cytology, Bone Marrow Cells cytology, Fetal Blood cytology, Fibroblasts cytology, Hematopoietic Stem Cells cytology, Organoids cytology, Stem Cell Niche genetics
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Human umbilical cord blood (CB) has attracted much attention as a reservoir for functional hematopoietic stem and progenitor cells, and, recently, as a source of blood-borne fibroblasts (CB-BFs). Previously, we demonstrated that bone marrow stromal cell (BMSC) and CB-BF pellet cultures make cartilage in vitro Furthermore, upon in vivo transplantation, BMSC pellets remodelled into miniature bone/marrow organoids. Using this in vivo model, we asked whether CB-BF populations that express characteristics of the hematopoietic stem cell (HSC) niche contain precursors that reform the niche. CB ossicles were regularly observed upon transplantation. Compared with BM ossicles, CB ossicles showed a predominance of red marrow over yellow marrow, as demonstrated by histomorphological analyses and the number of hematopoietic cells isolated within ossicles. Marrow cavities from CB and BM ossicles included donor-derived CD146-expressing osteoprogenitors and host-derived mature hematopoietic cells, clonogenic lineage-committed progenitors and HSCs. Furthermore, human CD34
+ cells transplanted into ossicle-bearing mice engrafted and maintained human HSCs in the niche. Our data indicate that CB-BFs are able to recapitulate the conditions by which the bone marrow microenvironment is formed and establish complete HSC niches, which are functionally supportive of hematopoietic tissue., (© 2017. Published by The Company of Biologists Ltd.)- Published
- 2017
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38. Defining Invasive Fungal Infection Risk in Hematological Malignancies: A New Tool for Clinical Practice.
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Rambaldi B, Russo D, and Pagano L
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- 2017
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39. Extracorporeal Photopheresis for Treatment of Acute and Chronic Graft Versus Host Disease: An Italian Multicentric Retrospective Analysis on 94 Patients on Behalf of the Gruppo Italiano Trapianto di Midollo Osseo.
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Malagola M, Cancelli V, Skert C, Leali PF, Ferrari E, Tiburzi A, Sala ML, Donnini I, Chiusolo P, Mussetti A, Battista M, Turra A, Cattina F, Rambaldi B, Schieppati F, Polverelli N, Bernardi S, Perucca S, Marini M, Laszlo D, Savignano C, Patriarca F, Corradini P, Piccirillo N, Sica S, Bosi A, and Russo D
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- Adult, Aged, Algorithms, Female, Follow-Up Studies, Graft vs Host Disease etiology, Humans, Inflammation, Italy, Male, Middle Aged, Remission Induction, Retrospective Studies, Stem Cell Transplantation, Steroids therapeutic use, Time Factors, Transplantation, Homologous, Treatment Outcome, Young Adult, Graft vs Host Disease therapy, Hematopoietic Stem Cell Transplantation adverse effects, Photopheresis methods, Transplantation Conditioning methods
- Abstract
Background: Extracorporeal photopheresis (ECP) is considered a valid second-line treatment for acute and chronic graft versus host disease (GVHD)., Methods: Ninety-four patients with acute GVHD (aGVHD) (n = 45) and chronic GVHD (cGVHD) (n = 49), retrospectively recruited in 6 Italian centers, were submitted to ECP for second-line treatment. At the time of ECP, 22 (49%) and 23 (51%) of 45 patients with aGHVD were nonresponsive and in partial remission (PR) after steroids, respectively, and all the 49 patients with cGVHD were steroid refractory., Results: Forty-one (91%) of 45 patients with aGVHD achieved complete remission (CR) after ECP. Fifteen (33%) of 45 patients developed cGVHD. The CR rate in patients who started ECP being nonresponsive and in PR after steroid was 86% and 96%, respectively. After a median follow-up of 20 months (range, 2-72), 15 (33%) of 45 patients developed cGHVD and 16 (35%) of 45 patients died, in 3 cases for aGVHD. A trend for a better survival was seen among patients who started ECP in PR after steroid (80% vs 50% at 2 years; P = 0.07). Overall, 22 (45%) of 49 patients and 17 (35%) of 49 patients with steroid refractory cGHVD achieved CR and PR after ECP, respectively. After a median follow-up of 27 months, 44 (90%) of 49 patients are alive, 21 of whom (48%) are on steroid., Conclusions: Extracorporeal photopheresis is confirmed as an effective second-line treatment in both aGVHD and cGVHD, because it can induce a response in more than 80% of the patients and a long-term survival in at least 50% of the cases.
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- 2016
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40. Neonatal bone marrow transplantation prevents bone pathology in a mouse model of mucopolysaccharidosis type I.
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Pievani A, Azario I, Antolini L, Shimada T, Patel P, Remoli C, Rambaldi B, Valsecchi MG, Riminucci M, Biondi A, Tomatsu S, and Serafini M
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- Age Factors, Animals, Animals, Newborn, Bone Diseases, Developmental metabolism, Bone Diseases, Developmental pathology, Bone and Bones metabolism, Bone and Bones pathology, Disease Models, Animal, Female, Glycosaminoglycans blood, Glycosaminoglycans metabolism, Humans, Iduronidase genetics, Iduronidase metabolism, Infant, Newborn, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mucopolysaccharidosis I genetics, Bone Diseases, Developmental prevention & control, Bone Marrow Transplantation methods, Mucopolysaccharidosis I pathology, Mucopolysaccharidosis I therapy
- Abstract
Neonatal bone marrow transplantation (BMT) could offer a novel therapeutic opportunity for genetic disorders by providing sustainable levels of the missing protein at birth, thus preventing tissue damage. We tested this concept in mucopolysaccharidosis type I (MPS IH; Hurler syndrome), a lysosomal storage disorder caused by deficiency of α-l-iduronidase. MPS IH is characterized by a broad spectrum of clinical manifestations, including severe progressive skeletal abnormalities. Although BMT increases the life span of patients with MPS IH, musculoskeletal manifestations are only minimally responsive if the timing of BMT delays, suggesting already irreversible bone damage. In this study, we tested the hypothesis that transplanting normal BM into newborn MPS I mice soon after birth can prevent skeletal dysplasia. We observed that neonatal BMT was effective at restoring α-l-iduronidase activity and clearing elevated glycosaminoglycans in blood and multiple organs. At 37 weeks of age, we observed an almost complete normalization of all bone tissue parameters, using radiographic, microcomputed tomography, biochemical, and histological analyses. Overall, the magnitude of improvements correlated with the extent of hematopoietic engraftment. We conclude that BMT at a very early stage in life markedly reduces signs and symptoms of MPS I before they appear., (© 2015 by The American Society of Hematology.)
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- 2015
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41. Comparative analysis of multilineage properties of mesenchymal stromal cells derived from fetal sources shows an advantage of mesenchymal stromal cells isolated from cord blood in chondrogenic differentiation potential.
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Pievani A, Scagliotti V, Russo FM, Azario I, Rambaldi B, Sacchetti B, Marzorati S, Erba E, Giudici G, Riminucci M, Biondi A, Vergani P, and Serafini M
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- Cell Lineage genetics, Female, Fetus, Humans, In Situ Hybridization, Fluorescence, Pregnancy, Tissue Engineering, Cell Differentiation genetics, Chondrogenesis genetics, Fetal Blood cytology, Mesenchymal Stem Cells cytology
- Abstract
Background Aims: Cord blood (CB) and amniotic fluid (AF) could represent new and attractive mesenchymal stromal cell (MSC) sources, but their potential therapeutic applications are still limited by lack of standardized protocols for isolation and differentiation. In particular, chondrogenic differentiation has never been deeply investigated., Methods: MSCs were obtained from CB and AF samples collected during cesarean sections at term and compared for their biological and differentiation properties, with particular interest in cartilage differentiation, in which quantitative real-time polymerase chain reaction and immunohistochemical analyses were performed to evaluate the expression of type 2 collagen, type 10 collagen, SRY-box9 and aggrecan., Results: We were able to isolate MSCs from 12 of 30 (40%) and 5 of 20 (25%) CB and AF units, respectively. Fluorescence in situ hybridization analysis indicated the fetal origin of isolated MSC strains. Both populations expressed mesenchymal but not endothelial and hematopoietic markers, even though we observed a lower expression of human leukocyte antigen (HLA) I in CB-MSCs. No differences in proliferation rate and cell cycle analysis could be detected. After osteogenic induction, both populations showed matrix mineralization and typical marker expression. Under chondrogenic conditions, pellets derived from CB-MSCs, in contrast with AF-MSCs pellets, were significantly larger, showed cartilage-like morphology and resulted positive for chondrocyte-associated markers, such as type 2 collagen, type 10 collagen, SRY-box9 and aggrecan., Conclusions: Our results show that CB-MSCs and AF-MSCs collected at term differ from each other in their biological and differentiation properties. In particular, only CB-MSCs showed a clear chondrogenic potential and thus could represent an ideal candidate for cartilage-tissue engineering., (Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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