95 results on '"Bianca Serio"'
Search Results
52. Low-Density Granulocytes Are Decreased in Acute Myeloid Leukemia and in Myelodysplastic Syndromes with Negative Prognostic Factors
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Valentina Giudice, Rossella Marcucci, Maddalena Langella, Rita Pepe, Carmine Selleri, Maria Teresa Buonanno, Rosa Vitolo, Matteo D'Addona, Maria Carmen Martorelli, Bianca Serio, Marisa Gorrese, Idalucia Ferrara, Angela Bertolini, and Paola Manzo
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business.industry ,Myelodysplastic syndromes ,Immunology ,medicine ,Cancer research ,Low density ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,business ,Biochemistry - Abstract
Introduction. Myelodysplastic syndromes (MDS), a group of clonal hematological diseases, are characterized by ineffective hematopoiesis, progressive peripheral blood (PB) cytopenia(s), and increased risk of developing acute myeloid leukemia (AML). Classification and risk stratification are constantly under revision for a better estimation of prognosis in those patients. Investigation of immune biomarkers is needed, because immune dysregulation also plays an important role in dysplastic hemopoiesis and immunological escape of neoplastic clones. Here, we studied frequency of low-density granulocytes (LDGs), a neutrophil subset with immunoregulatory functions, in MDS and AML at diagnosis and during treatments. Methods. A total of 17 patients (M/F, 14/12; median age, 69 years old; range, 21-84 years) and seven healthy subjects were enrolled at the Hematology and Transplant Center, University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy, between October 2020 and July 2021. Patients were diagnosed with AML (N = 7), or MDS (N = 10) according to the 2016 World Health Organization criteria. For immunophenotyping, fresh EDTA whole PB was stained with the ollowing antibodies: CD45; HLA-DR; CD15; CD3; CD56; CD19; CD11b; CD33; CD34; CD14; and CD16 (all from Beckman Coulter, Brea, CA). Acquisition was carried out using a Navios EX flow cytometer, and Navios software v1.3 (Beckman Coulter). Post-acquisition compensation and analysis were performed using FlowJo software (v.10.7.1, Becton Dickinson). LDGs were identified as CD3-CD56-CD19-CD11b+CD33+CD14-CD15+ cells, following previously published gating strategies (Rahman S, et al. Ann Rheum Dis. 2019). Data were analyzed using Prism (GraphPad software, La Jolla, CA). A P < 0.05 was considered statistically significant. Results. Frequencies of circulating LDGs were significantly reduced in AML patients at diagnosis compared to controls (P = 0.0018) and MDS (P = 0.0077) and were slightly decreased compared to AML in complete remission (P = 0.1605). MDS patients were then divided based on Revised International Prognostic Scoring System (IPSS-R), and very-low and low-risk MDS patients displayed significantly higher circulating LDG frequencies compared to AML at diagnosis (P = 0.0083), while no differences were described between AML at baseline and intermediate-risk MDS (P = 0.1103). Subsequently, LDGs were correlated with clinical and phenotypic features by correlation analysis showing significant negative correlations between LDGs and blasts identified by flow cytometry (r = -0.5463; P = 0.0057) but not by cytology (P = 0.1346), between LDGs and lymphocytes (r = -0.4407; P = 0.0311) or flow cytometric normalized blast count (NBC; r = -0.5283; P = 0.0096) as previously defined (Giudice V, et al. Biomedicines. 2021). A slight negative correlation was described between LDGs and WT1 expression levels (r = -0.5369; P = 0.0719), particularly evident in MDS patients (r = -0.9980; P = 0.0402), supporting our previous findings of negative prognostic impact of WT1 expression in MDS and AML. Finally, we investigated CD16 expression on LDGs, because CD16 is essential for neutrophil degranulation. Despite no differences were described between percentage of LDG subsets among patients' groups, various correlations were identified by Pearson analysis. In particular, CD16+ LDGs negatively correlated with blasts (P = 0.0229), while positively correlated with lymphocytes (P = 0.0404) detected by flow cytometry. Conversely, CD16int and CD16- LDGs negatively correlated with lymphocytes (P = 0.0109 and P = 0.0021, respectively) and positively correlated with granulocytes identified by flow cytometry (P = 0.0024 and P = 0.0008, respectively). In addition, CD16int LDGs negatively correlated with blasts detected by flow cytometry (r = -0.65; P = 0.0414). Conclusions. Our preliminary results suggested a possible role of LDGs in prognostic definition of AML and MDS patients especially when combined with other biomarkers, such as WT1 expression levels or NBC. Moreover, our data supported the hypothesis of biological heterogeneity of granulocytes, as LDG subsets variously correlated with lymphocytes and leukemic cells suggesting different roles in suppression or activation of immune responses. However, our findings need further validation in larger cohorts and in in vitro studies. Disclosures No relevant conflicts of interest to declare.
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- 2021
53. Wt1 expression levels combined with flow cytometry blast counts for risk stratification of acute myeloid leukemia and myelodysplastic syndromes
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Roberto Guariglia, Nunzia Montuori, Rossella Marcucci, Maddalena Langella, Rosa Vitolo, Antonio Pedicini, Rita Pepe, Bianca Serio, Valentina Giudice, Idalucia Ferrara, Barbara Izzo, Marisa Gorrese, Carmine Selleri, Angela Bertolini, Francesca D'Alto, Giudice, V., Gorrese, M., Vitolo, R., Bertolini, A., Marcucci, R., Serio, B., Guariglia, R., Ferrara, I., Pepe, R., D'Alto, F., Izzo, B., Pedicini, A., Montuori, N., Langella, M., and Selleri, C.
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Oncology ,medicine.medical_specialty ,Wilms’ tumor 1 ,Prognosi ,Medicine (miscellaneous) ,Article ,General Biochemistry, Genetics and Molecular Biology ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Hematologic disorders ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Mutational status ,lcsh:QH301-705.5 ,Acute myeloid leukemia ,medicine.diagnostic_test ,business.industry ,Myelodysplastic syndromes ,Myeloid leukemia ,Retrospective cohort study ,medicine.disease ,Haematopoiesis ,lcsh:Biology (General) ,030220 oncology & carcinogenesis ,Risk stratification ,prognosis ,business ,Myelodysplastic syndrome ,030215 immunology - Abstract
Wilm’s tumor 1 (WT1), a zinc-finger transcription factor and an epigenetic modifier, is frequently overexpressed in several hematologic disorders and solid tumors, and it has been proposed as diagnostic and prognostic marker of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the exact role of WT1 in leukemogenesis and disease progression remains unclear. In this real-world evidence retrospective study, we investigated prognostic role of WT1-mRNA expression levels in AML and MDS patients and correlations with complete blood counts, flow cytometry counts, and molecular features. A total of 71 patients (AML, n = 46, and MDS, n = 25) were included in this study, and WT1 levels were assessed at diagnosis, during treatment and follow-up. We showed that WT1 expression levels were inversely correlated with normal hemopoiesis in both AML and MDS, and positively associated with blast counts. Flow cytometry was more sensitive and specific in distinguishing normal myeloid cells from neoplastic counterpart even just using linear parameters and CD45 expression. Moreover, we showed that a simple integrated approach combining blast counts by flow cytometry, FLT3 mutational status, and WT1 expression levels might be a useful tool for a better prognostic definition in both AML and MDS patients.
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- 2021
54. A case series of blastic plasmacytoid dendritic cell neoplasia
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Francesca D'Alto, Carmine Selleri, Bianca Serio, Marisa Gorrese, Daniela Pellegrino, Roberto Guariglia, Maddalena Langella, Valentina Giudice, Bianca Cuffa, Matteo D'Addona, and Angela Bertolini
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Chemotherapy ,Myeloid ,business.industry ,flow cytometry ,Lineage markers ,medicine.medical_treatment ,blastic plasmacytoid dendritic cell neoplasm ,Articles ,Plasmacytoid dendritic cell ,Hematopoietic stem cell transplantation ,chemotherapy ,Fludarabine ,medicine.anatomical_structure ,medicine ,Cancer research ,Cytarabine ,General Earth and Planetary Sciences ,Idarubicin ,transplant ,business ,General Environmental Science ,medicine.drug - Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN), an extremely rare and aggressive tumor, derives from plasmacytoid dendritic cell precursors and is characterized by CD4 and CD56 positivity accompanied by the expression of isolated myeloid, B- or T-cell lineage markers. Despite the recent introduction of specific targeted therapies, prognosis is still poor with a median overall survival of one year, and allogeneic bone marrow transplantation remains the only curative treatment in eligible patients. In this series, we described two cases of adult BPDCN treated with high dose cytarabine and methotrexate and autologous hematopoietic stem cell transplantation, or fludarabine, cytarabine, and idarubicin achieving the first a complete lasting remission, while the second only a transient improvement in skin lesions.
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- 2020
55. Axitinib in Ponatinib-Resistant B-Cell Acute Lymphoblastic Leukemia Harboring a T315L Mutation
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Andrea Ghelli Luserna di Rorà, Roberto Guariglia, Giovanni Martinelli, Maria Benedetta Giannini, Bianca Serio, Carmine Selleri, Anna Maria Ferrari, Valentina Giudice, and Giorgia Simonetti
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Oncology ,medicine.medical_specialty ,axitinib ,Salvage therapy ,Case Report ,acute lymphoblastic leukemia ,Philadelphia chromosome ,Catalysis ,Inorganic Chemistry ,lcsh:Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,hemic and lymphatic diseases ,medicine ,ponatinib ,Physical and Theoretical Chemistry ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,ABL ,business.industry ,Organic Chemistry ,Ponatinib ,General Medicine ,medicine.disease ,Computer Science Applications ,Clinical trial ,Axitinib ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,030220 oncology & carcinogenesis ,Adult Acute Lymphoblastic Leukemia ,TKI inhibitor ,business ,Tyrosine kinase ,030215 immunology ,medicine.drug - Abstract
Adult acute lymphoblastic leukemia (ALL) with BCR-ABL1 rearrangement (Philadelphia chromosome, Ph) is a hematological aggressive disease with a fatal outcome in more than 50% of cases. Tyrosine kinase inhibitors (TKIs) targeting the activity of BCR-ABL1 protein have improved the prognosis; however, relapses are frequent because of acquired somatic mutations in the BCR-ABL1 kinase domain causing resistance to first, second and third generation TKIs. Axitinib has shown in vitro and ex vivo activity in blocking ABL1; however, clinical trials exploring its efficacy in ALL are missing. Here, we presented a 77-year-old male with a diagnosis of Ph positive ALL resistant to ponatinib and carrying a rare threonine to leucine (T315L) mutation on BCR-ABL1 gene. The patient was treated with axitinib at 5 mg/twice daily as salvage therapy showing an immediate although transient benefit with an overall survival of 9.3 months. Further dose-finding and randomized clinical trials are required to assess the real efficacy of axitinib for adult Ph positive ALL resistant to third generation TKIs.
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- 2020
56. Hemopoiesis and Immune Cell Perturbations during Venetoclax Plus Azacytidine Treatment in Acute Myeloid Leukemia
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Serena Luponio, Angela Bertolini, Francesca D'Alto, Bianca Cuffa, Bianca Serio, Roberto Guariglia, Carmine Selleri, Laura Mettivier, Idalucia Ferrara, L Pezzullo, Marisa Gorrese, Valentina Giudice, Matteo D'Addona, and Danilo De Novellis
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Venetoclax ,business.industry ,Immunology ,Cell ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,chemistry.chemical_compound ,Haematopoiesis ,medicine.anatomical_structure ,Immune system ,chemistry ,medicine ,Cancer research ,business - Abstract
Treatment of acute myeloid leukemia (AML) in elderly is still challenging. Indeed, high-dose chemotherapy followed by hematopoietic stem cell transplantation with myeloablative regimens is not always feasible because patients are often unfit and have several comorbidities; however, they frequently show multiple negative prognostic factors and have a worse overall survival compared to younger adults. Venetoclax, the first-in-class Bcl-2 antagonist and first approved for treatment of chronic lymphocytic leukemia, inhibits the anti-apoptotic functions of Bcl-2 inducing apoptosis and tumor growth arrest. Venetoclax is also used in combination with azacytidine, or decitabine, or low-dose cytarabine for treatment of elderly newly diagnosed AML. However, several mechanisms of resistance have already been described, such as increased expression of other anti-apoptotic proteins by the leukemic clone. In this case series, we investigated hematopoiesis and immune cell perturbations during venetoclax plus azacytidine treatment in elderly AML patients. A total of six AML patients (M/F, 2/4; median age, 71 years old; range, 63-79 years) were retrospectively evaluated at the Hematology and Transplant Center, University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno, Italy. Patients received a diagnosis of AML based on the 2016 World Health Organization (WHO) criteria and chemotherapy with azacytidine 75 mg/m 2 daily for 7 days per cycle and venetoclax 70 mg/daily. Two patients were NPM1 mutated (one of them also had mutated IDH1, VAF 27.2%), while all subjects had FLT3 wild type. Based on the 2017 European LeukemiaNet risk classification, two patients had favorable risk and four intermediate. Median follow-up was 10.1 months (range, 4.9-16.6 months), and all patients were in partial or complete remission at the time of writing. Flow cytometry immunophenotype, complete blood counts (CBCs), and WT1 expression levels were performed at diagnosis and after every cycle of therapy as per our institutional guidelines. In our case series, leukemic cells were already decreased after the first cycle of therapy (blasts by flow cytometry + SD, 54.7+39.9% vs 4.2+5.4%, diagnosis vs post I cycle; P = 0.0671; paired t-test performed), while normal granulocytes detected by flow cytometry recovered only after the third cycle of therapy (20.7+23.7% vs 53+6.6%, diagnosis vs post III cycle; P = 0.1396; uncorrected Fisher's mixed model performed). Treated patients also displayed a contextual decreased in WT1 expression levels (normalized WT1 copy number + SD, 1810+2723 copies vs 201+132.9 copies, diagnosis vs post I cycle; P = 0.2660; paired t-test performed). Platelet count tended to increase after the first cycle (P = 0.0680); however, at the end of the second cycle, half of patients were again thrombocytopenic (platelets < 100 x 10 3/µL). Interestingly, percentage of lymphocytes detected by flow cytometry were significantly increased after the second cycle of azacytidine plus venetoclax compared to baseline and after the first cycle of therapy (mean+SD, 13.5+13.3% vs 48+8.7%, diagnosis vs post II cycle; P = 0.0167; and vs 28+11.3%, vs post III cycle; P = 0.0480), likely because an increase in Natural Killer (NK) cell frequency peaking after the second cycle (mean+SD, 19.4+4.4% vs 32.5+15.1%, diagnosis vs post II cycle; P = 0.1383). Moreover, five out of six patients displayed expansion of plasma cells detected by flow cytometry in the bone marrow after the first cycle: in particular, one case patient had expansion of aberrant CD45-/dimCD38++CD138++CD56+CD19- plasma cells, while one subject showed only a transient appearance of clonal plasma cells after the second cycle. No differences in bone marrow monocyte frequencies were described during treatment. Our preliminary results added evidence to efficacy and safety of the combination of venetoclax and azacytidine in treatment of elderly AML in a real-world setting. These drugs might synergistically function on hematopoiesis by inducing apoptosis of neoplastic cells while favoring differentiation of other lineages, as suggested by the expansion of plasma cells, or triggering NK-mediated immunosurveillance. However, prognostic and clinical significance of plasma cell and NK cell expansion in the setting of AML treatment needs to be further explored in larger prospective cohorts. Disclosures No relevant conflicts of interest to declare.
- Published
- 2021
57. INCREASED CYTOMEGALOVIRUS (CMV) REACTIVATION IN PATIENTS TREATED WITH BENDAMUSTINE BASED REGIMEN IS CORRELATE WITH DRAMATICAL REDUCTION OF CD4+ T LYMPHOCITES
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M.C. Martorelli, R Rosamilio, R. bianco, R. Guariglia, E. Vaccaro, Carmine Selleri, A. Bruno, G Villani, R Fontana, Bianca Serio, L Pezzullo, and G. cassiodoro
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Bendamustine ,Cancer Research ,medicine.medical_specialty ,business.industry ,Congenital cytomegalovirus infection ,Hematology ,General Medicine ,medicine.disease ,Cmv reactivation ,Gastroenterology ,Regimen ,Oncology ,Internal medicine ,medicine ,In patient ,business ,medicine.drug - Published
- 2019
58. Role of Laparoscopic Splenectomy in Elderly Immune Thrombocytopenia
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Vincenzo Pilone, Amato de Paulis, R Rosamilio, Carmine Selleri, Francesca Wanda Rossi, Valentina Giudice, Rosa Maria Di Crescenzo, Bianca Serio, Giudice, Valentina, Rosamilio, Rosa, Serio, Bianca, Di Crescenzo, Rosa Maria, Rossi, FRANCESCA WANDA, DE PAULIS, Amato, Pilone, Vincenzo, and Selleri, Carmine
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Pediatrics ,medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Splenectomy ,Review Article ,Laparoscopic splenectomy ,03 medical and health sciences ,0302 clinical medicine ,Elderly ,medicine ,Laparoscopy ,medicine.diagnostic_test ,business.industry ,Immune thrombocytopenia ,General Medicine ,030220 oncology & carcinogenesis ,Concomitant ,Corticosteroid ,Medicine ,Rituximab ,business ,Complication ,030215 immunology ,medicine.drug - Abstract
The management of older patients with chronic primary immune thrombocytopenia (ITP) is still very challenging because of the fragility of older patients who frequently have severe comorbidities and/or disabilities. Corticosteroid-based first-line therapies fail in most of the cases and patients require a second-line treatment, choosing between rituximab, thrombopoietin-receptor agonists and splenectomy. The choice of the best treatment in elderly patients is a compromise between effectiveness and safety and laparoscopic splenectomy may be a good option with a complete remission rate of 67% at 60 months. But relapse and complication rates remain higher than in younger splenectomized ITP patients because elderly patients undergo splenectomy with unfavorable conditions (age >60 year-old, presence of comorbidities, or multiple previous treatments) which negatively influence the outcome, regardless the hematological response. For these reasons, a good management of concomitant diseases and the option to not use the splenectomy as the last possible treatment could improve the outcome of old splenectomized patients.
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- 2016
59. Involvement of urokinase receptor in the cross-talk between human hematopoietic stem cells and bone marrow microenvironment
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Patrizia Ricci, Nunzia Montuori, Bianca Serio, Annamaria Salvati, Gunilla Høyer-Hansen, Ada Pesapane, Anna Gorrasi, Pia Ragno, Carmine Selleri, Anna Li Santi, Selleri, Carmine, Montuori, Nunzia, Salvati, Annamaria, Serio, Bianca, Pesapane, Ada, Ricci, Patrizia, Gorrasi, Anna, Li Santi, Anna, Hoyer-Hansen, Gunilla, and Ragno, Pia
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Adult ,0301 basic medicine ,Transplantation Conditioning ,Bone Marrow Cells ,Receptors, Urokinase Plasminogen Activator ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Bone Marrow ,Cell Line, Tumor ,medicine ,urokinase receptor ,Humans ,Bone marrow microenvironment ,Hematopoietic stem cells ,Leukemia ,UPAR ,Urokinase receptor ,Oncology ,Stem Cell Niche ,Cells, Cultured ,Cell Proliferation ,bone marrow microenvironment ,business.industry ,Hematopoietic Stem Cell Transplantation ,leukemia ,Middle Aged ,medicine.disease ,Transplantation ,Leukemia, Myeloid, Acute ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,SuPAR ,030220 oncology & carcinogenesis ,Immunology ,hematopoietic stem cell ,Bone marrow ,Stem cell ,Peptides ,business ,uPAR ,Research Paper ,Homing (hematopoietic) - Abstract
// Carmine Selleri 1, * , Nunzia Montuori 2, * , Annamaria Salvati 3 , Bianca Serio 1 , Ada Pesapane 2 , Patrizia Ricci 1 , Anna Gorrasi 3 , Anna Li Santi 3 , Gunilla Hoyer-Hansen 4 , Pia Ragno 3 1 Department of Medicine and Surgery, University of Salerno, Salerno, Italy 2 Department of Translational Medical Sciences, “Federico II” University, Naples, Italy 3 Department of Chemistry and Biology, University of Salerno, Salerno, Italy 4 The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark * These authors have contributed equally to this work Correspondence to: Pia Ragno, email: pragno@unisa.it Keywords: urokinase receptor, uPAR, hematopoietic stem cells, bone marrow microenvironment, leukemia Received: January 04, 2016 Accepted: July 18, 2016 Published: August 08, 2016 ABSTRACT Hematopoietic stem cells (HSCs) reside in bone marrow (BM) and can be induced to mobilize into the circulation for transplantation. Homing and lodgement into BM of transplanted HSCs are the first critical steps in their engraftment and involve multiple interactions between HSCs and the BM microenvironment. uPAR is a three domain receptor (DIDIIDIII) which binds urokinase, vitronectin, integrins. uPAR can be cleaved and shed from the cell surface generating full-length and cleaved soluble forms (suPAR and DIIDIII-suPAR). DIIDIII-suPAR can bind fMLF receptors through the SRSRY sequence (residues 88-92). We previously reported the involvement of soluble uPAR in HSC mobilization. We now investigate its possible role in HSC homing and engraftment. We show similar levels of circulating full-length suPAR in healthy donors and in acute myeloid leukemia (AML) patients before and after the pre-transplant conditioning regimen. By contrast, levels of circulating DIIDIII-suPAR in AML patients are higher as compared to controls and significantly decrease after the conditioning. We found that suPAR and uPAR 84-95 , a uPAR-derived peptide which mimics active DIIDIII-suPAR, induce a significant increase in Long Term Culture (LTC)-Initiating Cells (ICs) and in the release of clonogenic progenitors from LTCs of CD34 + HSCs. Further, suPAR increases adhesion and survival of CD34 + KG1 AML cells, whereas uPAR 84-95 increases their proliferation. Thus, circulating DIIDIII-suPAR, strongly increased in HSC mobilization, is indeed down-regulated by pre-transplant conditioning, probably to favour HSC homing. BM full-length suPAR and DIIDIII-suPAR may be involved in HSC lodgement within the BM by contributing to a suitable microenvironment.
- Published
- 2016
60. Double-negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation
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Marcin W. Wlodarski, Brian J. Bolwell, J. Maciejewski, Jennifer Powers, Christine L. O'Keefe, Tao Jin, Zachariah A. McIver, Andrew Dunbar, Bianca Serio, and Ronald Sobecks
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Adult ,Male ,medicine.medical_treatment ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Hematopoietic stem cell transplantation ,Biology ,Severity of Illness Index ,T-Lymphocytes, Regulatory ,Immune tolerance ,T-Lymphocyte Subsets ,immune system diseases ,Immune Tolerance ,medicine ,Humans ,Aged ,Hematopoietic Stem Cell Transplantation ,Peripheral tolerance ,Forkhead Transcription Factors ,hemic and immune systems ,Hematology ,Middle Aged ,medicine.disease ,Transplantation ,Haematopoiesis ,surgical procedures, operative ,Graft-versus-host disease ,Immunology ,Female ,Stem cell ,CD8 ,Follow-Up Studies - Abstract
Double-negative (DN) regulatory T cells (Tregs) are specialized T lymphocytes involved in the down-modulation of immune responses, resulting in allotolerance after allogeneic haematopoietic stem cell transplantation (HSCT). Most of the properties of DN Tregs were identified in murine models, including the unique ability to suppress alloreactive syngeneic effector T cells in an antigen-specific manner via Fas/Fas-ligand interactions. We investigated the behaviour of DN Tregs following human allogeneic HSCT with regard to occurrence of graft-versus-host disease (GvHD) and restoration of T-cell receptor repertoire in a cohort of 40 patients. The frequency of DN Tregs and CD4/CD8 TCR repertoire was measured serially and at the time of diagnosis of GvHD by flow cytometry. Analysis demonstrated a positive correlation between degree of alloreactivity, as measured by grade of GvHD, and the number of variable beta chain (Vbeta) family expansions in both T-cell populations. We also found that a deficiency of DN Tregs was associated with an increased number of Vbeta family expansions, and most importantly, with the occurrence of GvHD. All individuals who demonstrated more than 1% DN Tregs did not develop GvHD, providing evidence that DN Tregs participate in peripheral tolerance to prevent GvHD when expanded after allogeneic HSCT.
- Published
- 2008
61. Hemochromatosis-associated gene mutations in patients with myelodysplastic syndromes with refractory anemia with ringed sideroblasts
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Bianca Serio, Karl S. Theil, Alan E. Lichtin, Hadrian Szpurka, Jaroslaw P. Maciejewski, Zachary P. Nearman, Ilka Warshawksy, and Mikkael A. Sekeres
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medicine.medical_specialty ,Erythroblasts ,Genotype ,Anemia ,Restriction Mapping ,Genes, Recessive ,Refractory anemia with ringed sideroblasts ,Gene mutation ,Biology ,Polymerase Chain Reaction ,Gastroenterology ,Cohort Studies ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Allele ,Hemochromatosis ,DNA Primers ,Thrombocytosis ,Myelodysplastic syndromes ,Genetic Variation ,Hematology ,medicine.disease ,Anemia, Sideroblastic ,Amino Acid Substitution ,Myelodysplastic Syndromes ,Mutation ,Immunology - Abstract
We observed increased ferritin levels in newly diagnosed MDS-RARS patients without transfusional iron-overload. Hence, we hypothesized RARS patients may harbor hemochromatosis-related mutations, which could contribute to the pathophysiology of this myelodysplastic syndromes (MDS) subset. We studied a cohort of 140 MDS patients: 42 with RARS, 10 with increased ringed sideroblasts, and 96 with other forms of MDS (43 RA, 27 RAEB, 17 RAEB-T, 8 MDS/MPD, 1 CMML). Patients were genotyped using restriction fragment length polymorphism, designed to detect C282Y and H63D mutations of the HFE gene. We found significantly higher frequency of heterozygosity for C282Y mutation in RARS patients compared with a large control population of matched race individuals (21 vs. 9.8% in controls, P = 0.03); H63D genotype was not significantly increased. Frequency of HFE variation in other MDS subtypes failed to differ significantly from controls. Within this group, we included patients with a rare form of MDS, provisionally subclassified by WHO as RARS with thrombocytosis (RARSt). 10/14 RARSt patients were carriers of either C282Y or H63D allele significantly increased compared with the combined prevalence in a healthy population (71 vs. 33%, P < 0.01). We found expected distribution of mutant HFE alleles in patients with other forms of MDS (9.1 vs. 9.8%, P = 0.82). Increased prevalence of HFE gene mutations is not a generalized feature of MDS, but some subgroups of MDS, especially those characterized by excessive accumulation of ringed sideroblasts, exhibit C282Y mutations at a higher frequency than in other forms of MDS and healthy controls.
- Published
- 2007
62. Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization
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Pia Ragno, Patrizia Ricci, Nunzia Montuori, Guido Rossi, Carmine Selleri, Francesco Blasi, Bianca Serio, Maria Vincenza Carriero, Bruno Rotoli, Valeria Visconte, Nicolai Sidenius, C., Selleri, Montuori, Nunzia, P., Ricci, V., Visconte, M. V., Carriero, N., Sideniu, Serio, Bianca, F., Blasi, Rotoli, Bruno, Rossi, Guido, and P., Ragno
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medicine.medical_specialty ,Sialic Acid Binding Ig-like Lectin 3 ,Immunology ,Lipopolysaccharide Receptors ,Antigens, Differentiation, Myelomonocytic ,Receptors, Cell Surface ,Biochemistry ,CXCR4 ,Receptors, Urokinase Plasminogen Activator ,Antigens, CD ,Cell Movement ,Internal medicine ,Granulocyte Colony-Stimulating Factor ,medicine ,Humans ,Progenitor cell ,Hematopoietic Stem Cell Mobilization ,Chemistry ,uPAR ,hematopoietic stem cell ,Hematopoietic stem cell ,Cell Biology ,Hematology ,Hematopoietic Stem Cells ,Receptors, Formyl Peptide ,Tissue Donors ,Up-Regulation ,Urokinase receptor ,Haematopoiesis ,Endocrinology ,medicine.anatomical_structure ,SuPAR ,Cancer research ,Stem cell - Abstract
We investigated the involvement of the urokinase-type plasminogen-activator receptor (uPAR) in granulocyte–colony-stimulating factor (G-CSF)–induced mobilization of CD34+ hematopoietic stem cells (HSCs) from 16 healthy donors. Analysis of peripheral blood mononuclear cells (PBMNCs) showed an increased uPAR expression after G-CSF treatment in CD33+ myeloid and CD14+ monocytic cells, whereas mobilized CD34+ HSCs remained uPAR negative. G-CSF treatment also induced an increase in serum levels of soluble uPAR (suPAR). Cleaved forms of suPAR (c-suPAR) were released in vitro by PBMNCs and were also detected in the serum of G-CSF–treated donors. c-suPAR was able to chemoattract CD34+ KG1 leukemia cells and CD34+ HSCs, as documented by their in vitro migratory response to a chemotactic suPAR-derived peptide (uPAR84-95). uPAR84-95 induced CD34+ KG1 and CD34+ HSC migration by activating the high-affinity fMet-Leu-Phe (fMLP) receptor (FPR). In addition, uPAR84-95 inhibited CD34+ KG1 and CD34+ HSC in vitro migration toward the stromal-derived factor 1 (SDF1), thus suggesting the heterologous desensitization of its receptor, CXCR4. Finally, uPAR84-95 treatment significantly increased the output of clonogenic progenitors from long-term cultures of CD34+ HSCs. Our findings demonstrate that G-CSF–induced upregulation of uPAR on circulating CD33+ and CD14+ cells is associated with increased uPAR shedding, which leads to the appearance of serum c-suPAR. c-suPAR could contribute to the mobilization of HSCs by promoting their FPR-mediated migration and by inducing CXCR4 desensitization.
- Published
- 2005
63. Long-Lasting Bone Damage Detected by Dual-Energy X-Ray Absorptiometry, Phalangeal Osteosonogrammetry, andin VitroGrowth of Marrow Stromal Cells after Allogeneic Stem Cell Transplantation
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Gaetano Lombardi, Libuse Tauchmanovà, Carmine Selleri, Antonio M. Risitano, Bruno Rotoli, Bianca Serio, Annamaria Colao, Antonio Del Puente, Gennaro De Rosa, and Antonella Esposito
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Adult ,Male ,medicine.medical_specialty ,Bone density ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Osteoporosis ,Graft vs Host Disease ,Bone Marrow Cells ,Biochemistry ,Colony-Forming Units Assay ,Necrosis ,Absorptiometry, Photon ,Endocrinology ,Bone Density ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Cells, Cultured ,Dual-energy X-ray absorptiometry ,Aged ,Ultrasonography ,Femoral neck ,Bone mineral ,biology ,medicine.diagnostic_test ,business.industry ,Biochemistry (medical) ,medicine.disease ,Transplantation ,Cross-Sectional Studies ,medicine.anatomical_structure ,Cyclosporine ,Osteocalcin ,biology.protein ,Female ,Bone Diseases ,Stromal Cells ,Densitometry ,business ,Immunosuppressive Agents ,Stem Cell Transplantation - Abstract
Bone complications after allogeneic stem cell transplant (alloSCT) include osteoporosis, fractures, and osteonecrosis. We investigated bone abnormalities in long-term survivors after busulfan cyclophosphamide-conditioning regimen, followed by human leukocyte antigen-identical sibling SCT. Bone density was measured by dual-energy x-ray absorptiometry at lumbar spine (LS) and femoral neck (FN) and phalangeal osteosonogrammetry (OSG) in 41 patients 1–10 yr after allo-SCT. Using colony-forming units-fibroblast (CFU-F) assay, we analyzed the repopulating capacity of clonogenic fibroblast progenitors belonging to the osteogenic stromal lineage. LS and FN bone mineral density (BMD) and phalangeal densitometric values were significantly reduced, compared with 188 healthy controls (P < 0.001). Decrease in T-score less than 1 SD was documented in 29% and 52% of patients at the LS and FN, respectively. OSG detected densitometric values with a Tscore less than 1 SD in 68% of transplanted patients. The patients examined within the first 3 yr after transplant showed low BMD, which remained stable at FN and improved at LS. Phalangeal densitometry was low up to 10 yr after transplant. CFU-F was found permanently depressed and unable to give rise to a confluent stroma. Low serum osteocalcin levels were present throughout the whole follow-up period. A significant correlation was found between densitometric values detected by both techniques and CFU-F growth in vitro. Osteonecrosis was associated with lower FN BMD, and phalangeal densitometry correlated inversely with duration of amenorrhea and chronic graft vs. host disease requiring long-lasting steroid therapy. In conclusion, dual-energy x-ray absorptiometry and phalangeal OSG may provide complementary information on bone density after allo-SCT. Prolonged severe impairment of femoral BMD and phalangeal densitometry suggest that bone loss may persist for many years after transplant. Inability to regenerate a normal number of osteoblastic precursors in the stromal stem cell compartment may in part account for severe long-lasting posttransplant decrease in bone mass. (J Clin Endocrinol Metab 87: 5058 –5065, 2002)
- Published
- 2002
64. The Role of B Regulatory Cells in the Immunological Escape of Tumor Cells in Hodgkin Lymphoma
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M Rocco, G Villani, Valentina Giudice, Carmine Selleri, R Rosamilio, L Pezzullo, Bianca Serio, and Idalucia Ferrara
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biology ,business.industry ,T cell ,Dacarbazine ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,CD19 ,Vinblastine ,Interleukin 10 ,medicine.anatomical_structure ,biology.protein ,Medicine ,Cytotoxic T cell ,IL-2 receptor ,business ,CD8 ,medicine.drug - Abstract
Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin Lymphoma (HL) are surrounded by a rich inflammatory infiltrate which aids in their survival and escape from cytotoxic CD8+ T cells (CTLs) and Natural Killer cells (NKs). Within HL environment, T regulatory cells (Tregs) directly suppress the activity of CTLs and NKs, enhancing the tolerance against HRS cells. B regulatory cells (Bregs) have been shown to support the differentiation of Tregs through IL-10 production; thus, we hypothesized that they could have a role in the pathophysiology of HL. We evaluated 30 classic HL patients (M/F: 18/12; median age, 31 years, range 15-62) and 5 healthy controls (HC) for circulating peripheral blood (PB) Bregs, Tregs, CTLs, NKs, and NKTs. Twenty-four of them were new-diagnosed patients (NwHL) and 6 received a previous diagnosis of HL but were in complete remission (CR) for more than 12 months (PvHL). NwHL patients were divided according to the International Prognostic Score (IPS) and the Ann-Arbor Staging System. All subjects were treated following the ABVD protocol (doxorubicin 25 mg/m2, bleomycin 10 U/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2). Flow cytometry was performed on heparinized PB samples with a 5-color Beckman Coulter Cytomics FC500 flow cytometer. Breg (CD19+CD24+), Treg (CD3+CD4+CD25+), CTL (CD3+CD8+), NK (CD3-CD56+), and NKT (CD3+CD56+) levels were measured simultaneously with the PET/CT evaluations, ie at diagnosis, at the end of the second ABVD administration, at the end of treatment, and at 6 and/or 12 months off-therapy. Moreover, Breg levels were compared to IPS and Ann-Arbor staging groups, and also were correlated to the erythrocyte sedimentation rate (ESR) and to the absolute lymphocyte count (ALC). We found decreased circulating Bregs in NwHL and PvHL patients compared to controls (0.39% vs 0.875% vs 1.813%, respectively, p Our preliminary data suggest involvement of Bregs in the escape and survival of HRS cells during active disease. Peripheral blood may mirror disease activity in lymphoid tissues. Thus, the decrease of circulating Bregs may be related to the recruitment of these cells to the tumor site; amplification of the Bregs/Tregs ratio may result in a greater Breg-dependent Treg activation with subsequent inhibition of CTL and NK function. Additionally, the normalization of Bregs and the Bregs/Tregs ratio after chemotherapy could be used to predict disease remission. While larger prospective studies are required to validate these results, we present intriguing evidence of the involvement of Bregs in the pathophysiology of HL. Disclosures No relevant conflicts of interest to declare.
- Published
- 2016
65. How to Improve the Definition of Chronic Lymphocytic Leukemia Outcome Using a Simple Flow Cytometric Score Based on CD49d and Homing Marker Expression
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Bianca Serio, G Villani, Luigi Marino, Valentina Giudice, S Annunziata, Carmine Selleri, Idalucia Ferrara, R Rosamilio, L Pezzullo, R Fontana, and M Rocco
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Oncology ,medicine.medical_specialty ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,CD49d ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Immunophenotyping ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Platelet Count measurement ,Hemoglobin measurement ,business ,Homing (hematopoietic) - Abstract
The identification of new molecular markers in Chronic Lymphocytic Leukemia (CLL) allowed to better define prognosis and clinical outcome. The actual staging systems could estimate the prognosis, but not the rapidity of disease evolution. Neither the identification of new molecular markers did allow to foresee the evolution and clinical response, because discordant findings were mostly reported. The aim of the present study was (1) to confirm the independent prognostic role of CD49d as a single marker in CLL patients, (2) to investigate the relationship between CD49d and other well-established CLL-membrane predictor markers (CD5, CD11c, CD20 and CD38) or clinical staging systems and (3) to evaluate the role of an immunophenotypic score based on the flow-cytometric detection of CD5, CD11c, CD20, CD38 and CD49d in the work up of CLL staging. Heparinized whole blood was collected from 68 CLL patients for immunophenotyping using the following antibodies: anti kappa, anti-lambda, CD5, CD11c, CD19, CD20, CD23, CD38, CD45, CD49d. A scoring system was elaborated combining 5 membrane markers: CD5, CD11c, CD20, CD38 and CD49d. Antigens were divided in two groups, favorable (CD5 and CD20) and unfavorable (CD11c, CD38 and CD49d) prognostic markers, and the cut-off of positivity was chosen according to the literature (30% for CD5, CD11c, CD20 and CD38, and 45% for CD49d). A value of "0" or "1" ("2" only for CD49d positivity) was assigned according to antigen expression. Finally, we defined a favorable phenotype when the sum of all the cytometric features was equal or less than 2, conversely the unfavorable phenotype was defined for a sum equal or greater than 3 (between 3 and 6). Flow cytometric analysis showed high CD49d expression in CD19+ cells in 47% of patients (n=32), and high CD38 expression in 44% of subjects (n=30), simultaneously expressed in 28% of patients (n=19). The 19% (n=13) of all CLL patients were CD5-, and interestingly the 85% of them showed higher expression of CD49d. Linear correlation was found between CD49d and CD38 (r2=0.08772, p=0.0142), and between CD49d and CD20 expression (r2=0.2490, p45% of CD49d positive cells. Four patients with Unfavorable Phenotype received chemotherapy with an ORR of 25%. Furthermore, a small population (n=16) of our CLL cohort was also studied for genetic abnormalities using FISH technique. According to FISH analysis, 25% of studied patients were classifies as very low-risk and, interestingly, no one of them showed an Unfavorable Phenotype (only one patient carried CD49d as unique negative marker). In our cohort, 50% of patients were low-risk with no genetic abnormalities or +12, but 63% of them showed an Unfavorable Phenotype with high CD49d and CD38 expression in 100% and 60% of cases, respectively. Our data confirm the independent negative prognostic role of CD49d and suggest a stronger prognostic power compared to CD38 in the definition of CLL outcome, because of its complex activity as homing marker, signaling receptor and anti-apoptotic molecule. Thus, the prognostic significance of CD49d may be enhanced when considered in comparison with other established markers, as CD11c and CD38. In conclusion, our results propose the use of the CD49d marker in combination with other B-cell membrane antigens as an additional tool for routine diagnosis and risk-stratification of CLL patients. Identification of high-risk phenotype with a simple scoring method could improve the treatment of these patients, who could take advantage of the most recent molecular targeting therapies. Disclosures No relevant conflicts of interest to declare.
- Published
- 2016
66. Endocrinopathies after allogeneic and autologous transplantation of hematopoietic stem cells
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Libuse Tauchmanovà, Giovanna Muscogiuri, Valentina Giudice, Stefano Palomba, Idalucia Ferrara, Annamaria Colao, Bianca Serio, Carmine Selleri, Francesco Orio, Mariarosaria Sessa, Orio, Francesco, Muscogiuri, Giovanna, Palomba, S, Serio, B, Sessa, M, Giudice, V, Ferrara, I, Tauchmanovà, L, Colao, Annamaria, and Selleri, 4.
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Oncology ,Male ,medicine.medical_specialty ,endocrine system ,lcsh:Medicine ,Review Article ,Endocrine System Diseases ,lcsh:Technology ,Transplantation, Autologous ,General Biochemistry, Genetics and Molecular Biology ,Sex Factors ,Risk Factors ,Internal medicine ,Autologous Transplantation ,medicine ,Adrenal insufficiency ,Endocrine system ,Autologous transplantation ,Humans ,Transplantation, Homologous ,lcsh:Science ,Endocrinopathies ,Chronic thyroiditis ,Allogeneic ,General Environmental Science ,Subclinical infection ,lcsh:T ,business.industry ,lcsh:R ,Thyroid ,Hematopoietic Stem Cell Transplantation ,General Medicine ,Total body irradiation ,Hematopoietic Stem Cells ,medicine.disease ,Thyroid Diseases ,Transplantation ,medicine.anatomical_structure ,surgical procedures, operative ,Infertility ,Immunology ,lcsh:Q ,Female ,business ,Hypothalamic Diseases - Abstract
Early and late endocrine disorders are among the most common complications in survivors after hematopoietic allogeneic- (allo-) and autologous- (auto-) stem cell transplant (HSCT). This review summarizes main endocrine disorders reported in literature and observed in our center as consequence of auto- and allo-HSCT and outlines current options for their management. Gonadal impairment has been found early in approximately two-thirds of auto- and allo-HSCT patients: 90–99% of women and 60–90% of men. Dysfunctions of the hypothalamus-pituitary-growth hormone/insulin growth factor-I axis, hypothalamus-pituitary-thyroid axis, and hypothalamus-pituitary-adrenal axis were documented as later complicances, occurring in about 10, 30, and 40–50% of transplanted patients, respectively. Moreover, overt or subclinical thyroid complications (including persistent low-T3 syndrome, chronic thyroiditis, subclinical hypo- or hyperthyroidism, and thyroid carcinoma), gonadal failure, and adrenal insufficiency may persist many years after HSCT. Our analysis further provides evidence that main recognized risk factors for endocrine complications after HSCT are the underlying disease, previous pretransplant therapies, the age at HSCT, gender, total body irradiation, posttransplant derangement of immune system, and in the allogeneic setting, the presence of graft-versus-host disease requiring prolonged steroid treatment. Early identification of endocrine complications can greatly improve the quality of life of long-term survivors after HSCT.
- Published
- 2013
67. Cytomegalovirus reactivation prophylaxis with low dose valgancyclovir after hematopoietic stem cell transplantation
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Ciro De Luca, R Fontana, Carmine Selleri, M Rocco, Valentina Giudice, S Annunziata, Mariarosaria Sessa, R Rosamilio, L Pezzullo, Bianca Serio, and Idalucia Ferrara
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medicine.medical_specialty ,Acute leukemia ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Asymptomatic ,Gastroenterology ,Surgery ,Cyclosporin a ,Internal medicine ,medicine ,Methotrexate ,medicine.symptom ,Complication ,business ,Viral load ,Multiple myeloma ,medicine.drug - Abstract
Cytomegalovirus (CMV) reactivation is one of the most frequent complication after hematopoietic stem cell transplantation (HSCT). Pre-transplant CMV-positive recipient serostatus is the most significant independent variable for viral reactivation. Oral valgancyclovir (VGCV) is a prodrug of intravenous gancyclovir (GCV) and is an effective and safety alternative for the management of CMV reactivation prophylaxis and preemptive therapy. However, VGCV at standard dose (900 mg twice a day) increases risk of myelosuppression in HSCT recipients. The efficacy of low dose (LD, 450 mg daily) oral VGCV was retrospectively evaluated in 30 allogeneic HLA-matched related patients and 2 unrelated, with a median age of 40 years (range, 18-59) and a median follow-up of 30 months (range, 3-56). Primary diseases were acute myeloid leukemia (AML, n=19), acute lymphoblastic leukemia (n=4), non-Hodgkin’s lymphoma (n=3), multiple myeloma (n=3) and myelodysplastic syndrome (n=3). Seventeen of twenty-three acute leukemia (AL) patients were transplanted in first complete remission (CR), while the remaining (n=6) were transplanted in 2nd CR. Five patients suffered from AML secondary to long-lasting MDS (n=3) or Hodgkin disease and breast cancer (n=2). Based upon CMV serostatus (D/R, donor/recipient), thirty (94%) of HSCT recipients were classified as high risk (D-/R+ = 3 and D+/R+ = 27) for CMV reactivation and only 6% as low risk (D-/R- = 2); none of the patients was in the intermediate risk group (D+/R-). Fifteen and 17 patients received a myeloablative and RIC regimens, respectively. Twenty-one patients received GvHD prophylaxis with cyclosporin A (CsA, 1 mg/kg intravenously from day -1 to +21, then 8 mg/kg orally for at least 6 months) and short-course methotrexate (MTX, 10 mg/kg on days +1, +3, +6 and +11). The others (n=11) received CsA with MTX and antithymocyte globulin (ATG, as a part of the conditioning regimen at 10 mg/kg at days -3, -2 and -1). According to the Glucksberg scoring system, thirteen patients experienced grade I-II and two grade III-IV acute GvHD, while 7 patients developed limited (n=6, 18%) and extensive (n=3, 10%) chronic GvHD. Starting from time of engraftment, LD oral VGCV was given prophylactically for at least 6 months. CMV infection was monitored weekly using polymerase chain reaction (PCR) in high risk seropositive recipients and we started preemptive therapy when the peak viral load exceeding 1000 copies/mL in two consecutive plasma samples. Six patients (4 early and 2 late) developed a positive PCR after a mean of 59 days post-HSCT successfully treated with 900 mg of VGCV twice a day for at least when PCR negative (in a median of 12 days). Only one patient developed late fatal gastrointestinal CMV disease. Indeed, asymptomatic early and late CMV-DNA PCR reactivation occurred only in 17% (n=5) of high risk seropositive HSCT recipients, in contrast to 37% and 18% of early and late CMV reactivation observed in matched gender, disease phase, graft source and CMV serostatus cohort of 32 HSCT recipients treated prophylactically with oral acyclovir (ACV, 15 mg/kg daily) and high dose intravenous immunoglobulins (IVIG, 0.4 gr/kg weekly for at least 6 months) . Seven patients presented hematological toxicity do not requiring drug discontinuation. The rate of non CMV-related infections was 25% and was similar in both groups with and without CMV reactivation. At the end of the follow-up, 18 of 32 (56%) patients were alive with a median follow-up of 31 months (range, 2-56). Relapsed-related mortality was 20%, transplant-related mortality was 9% and did not differ between group with and without CMV reactivation. Our data provide evidence that LD-VGCV is safe and effective as CMV reactivation prophylaxis in allogeneic HSCT recipients. These results require further validation in randomized studies. Disclosures: No relevant conflicts of interest to declare.
- Published
- 2013
68. Novel immunosuppressive strategies for bone marrow failure syndromes: a focus on alemtuzumab
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Am Risitano, Bianca Serio, Carmine Selleri, Selleri, C, Serio, B, and Risitano, ANTONIO MARIA
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Anemia ,Antibodies, Neoplasm ,medicine.medical_treatment ,Hemoglobinuria, Paroxysmal ,Antibodies, Monoclonal, Humanized ,Drug Discovery ,medicine ,Humans ,Aplastic anemia ,Alemtuzumab ,Bone Marrow Diseases ,Pharmacology ,Cytopenia ,Clinical Trials as Topic ,business.industry ,Myelodysplastic syndromes ,Bone marrow failure ,Anemia, Aplastic ,Antibodies, Monoclonal ,Immunosuppression ,General Medicine ,Bone Marrow Failure Disorders ,medicine.disease ,medicine.anatomical_structure ,Myelodysplastic Syndromes ,Immunology ,Bone marrow ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
Acquired bone marrow failure syndromes (BMFS) are a heterogeneous group of hematological disorders characterized by impaired bone marrow function and subsequent cytopenia of one or more blood cell lineages [1,2]. The well-accepted pathogenic mechanism of the typical bone marrow failure - aplastic anemia (AA)- is a T cell mediated immune attack targeting the hematopoietic tissue [3]. This pathogenic mechanism is at least partially shared by other bone marrow failure syndromes, such as lineage-restricted aplasias and some myelodysplastic syndromes. Thus, for these disorders immunosuppression (IS) is the pivotal etiologic treatment. While the standard IS regimen include the heterologous anti-thymocyte globulin [4], here we review the recent data on the anti-CD52 monoclonal antibody alemtuzumab as a novel IS agent for marrow failures. Alemtuzumab led to objective responses in aplastic anemia patients in 3 recent prospective studies, with overall response rates ranging between 37% and 72%. Adverse events were irrelevant, ruling out even the concerns about the risk of infectious complications. Alemtuzumab was effective even for the treatment of lineage-restricted marrow failure, with very acceptable toxicity and excellent response rates (as high as 80%). More recently, even patients suffering from myelodysplastic syndromes showed a remarkable hematological response to alemtuzumab-based IS treatment. Thus, alemtuzumab is a novel IS agent representing an excellent alternative to ATG for all immune-mediated marrow failure syndromes. Even if the dose and the schedule may still require further refining, the available data support the need of large prospective trials comparing alemtuzumab to current standard IS regimens.
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- 2011
69. Impact of immunogenetic polymorphisms in bone marrow failure syndromes
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Jaroslaw P. Maciejewski, Carmine Selleri, and Bianca Serio
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Adult ,Adolescent ,Genotype ,Hemoglobinuria, Paroxysmal ,Single-nucleotide polymorphism ,Human leukocyte antigen ,Biology ,Polymorphism, Single Nucleotide ,Cohort Studies ,Interferon-gamma ,Gene Frequency ,Receptors, KIR ,Transforming Growth Factor beta ,hemic and lymphatic diseases ,Drug Discovery ,medicine ,Humans ,Aplastic anemia ,Receptors, Cytokine ,Child ,Bone Marrow Diseases ,Aged ,Pharmacology ,Myelodysplastic syndromes ,Haplotype ,Anemia, Aplastic ,General Medicine ,Bone Marrow Failure Disorders ,Middle Aged ,medicine.disease ,Phenotype ,Interleukin-10 ,Child, Preschool ,Myelodysplastic Syndromes ,Immunology ,Cytokines ,Cytokine receptor - Abstract
Aim: To explore whether predisposition to bone marrow failure syndromes (BMF), such aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH) and myelosysplastic syndromes (MDS), is found in killer cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) ligand (KIR-L) gene variations or cytokine polymorphisms. Patients: We studied a cohort of 77 patients with AA, 129 with MDS and 285 healthy controls for the frequencies of KIRL and KIR genotypes and 22 selected single nucleotide polymorphisms (SNPs) located within 10 cytokine (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL12, IFN-γ, TNF-α, TGF-β) and 3 cytokine receptor (IL-1R, IL-1RA, IL-4Rα) genes. Results: In AA we found a decreased frequency of inhibitory KIR-2DL3 genes. In MDS, no difference in the frequency of KIR genotype was identified; however, a decreased frequency of 2DL3 was found in hypocellular MDS. Analysis of the KIR genotype in correlation with the corresponding KIR-L profile, revealed a decreased frequency of stimulatory 2DS1/C2 mismatch both in AA and MDS. In AA and MDS cohorts, compared to controls, we found a higher frequency of TT codon 10 variant and of GG codon 25 variant of TGF-β gene, consistent with a high secretory phenotype. This relationship was even more pronounced in PNH and hypocellular MDS. We confirm that the hypersecretory genotype T/T at position -874 of INF-γ gene was overrepresented only in AA and correlates with presence of a PNH clone. Instead in MDS patients, the frequency of G/A polymorphism at position – 308 on the TNF-α gene promoter, which correlates with higher TNF-α production, was found significantly higher. Moreover, hypocellular MDS was characterized by a higher prevalence of IL-10 GCC/GCC haplotype, which is functionally associated with a low secretor phenotype. Conclusion: Our findings suggest that alterations in KIR/KIR-L matching, such as increased 3DL2 and decreased 2DS1 mismatch, and in the polymorphisms of TGFβ1, IFN-γ, TNF-α and IL-10 may account for the propensity to immunemediated killing of hematopoietic stem cells and/or ineffective hematopoiesis characteristic of AA and MDS. Further studies are needed to elucidate whether these immunogenetic traits may be involved in increased risk of developing immune-mediated BMF.
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- 2010
70. Alemtuzumab is safe and effective as immunosuppressive treatment for aplastic anaemia and single-lineage marrow failure: a pilot study and a survey from the EBMT WPSAA
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A. D. Kulagin, Judith C. W. Marsh, Vikas Gupta, Bruno Rotoli, Jörg Halter, Antonio M. Risitano, André Tichelli, Carmine Selleri, Andrea Bacigalupo, Sébastien Maury, Giovanni Fernando Torelli, Hubert Schrezenmeier, Gérard Socié, Jakob Passweg, Bianca Serio, and Marrow Transplantation
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Adult ,Male ,medicine.medical_specialty ,Antibodies, Neoplasm ,medicine.medical_treatment ,Injections, Subcutaneous ,Pure red cell aplasia ,Antibodies, Monoclonal/adverse effects/*therapeutic use ,Pilot Projects ,Bone Marrow Aplasia ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,Internal medicine ,Anemia, Aplastic/*drug therapy ,Medicine ,Humans ,Prospective Studies ,Aplastic anemia ,Antibodies, Neoplasm/adverse effects/*therapeutic use ,Alemtuzumab ,Aged ,Cyclosporine/therapeutic use ,ddc:616 ,Aged, 80 and over ,business.industry ,Bone marrow failure ,Anemia, Aplastic ,Antibodies, Monoclonal ,Immunosuppression ,Hematology ,Middle Aged ,medicine.disease ,Immunosuppressive Agents/adverse effects/*therapeutic use ,Surgery ,Regimen ,Leukemia ,Cyclosporine ,Drug Therapy, Combination ,Female ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
An alemtuzumab-based experimental immunosuppressive treatment (IST) regimen was investigated in 35 patients with severe aplastic anaemia (SAA), pure red cell (PRCA) or pure white cell aplasia (PWCA). Alemtuzumab total dose was 73-103 mg s.c., followed by cyclosporine. No serious toxicity due to the regimen was observed. Adverse events were clinically irrelevant; infectious events were rare. The total response rate was 58%, 84% and 100% in SAA, PRCA and PWCA, respectively, with corresponding 6 months cumulative response probabilities of 84%, 84% and 100%. Subcutaneous alemtuzumab is a feasible and sufficiently safe IST regimen for patients suffering from immune-mediated marrow failures.
- Published
- 2010
71. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab
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Lucio Luzzatto, Patrizia Ricci, Giorgio Fratellanza, Anna Paola Iori, Angela Amendola, Antonio M. Risitano, Giacomo Gianfaldoni, Francesco Rodeghiero, Andrea Camera, Rosario Notaro, Filippo Barbano, Eros Di Bona, Fiorella Alfinito, Ludovica Marando, Bruno Rotoli, Carla Boschetti, Elisa Seneca, Bianca Serio, Carmine Selleri, Alberto Zanella, Danilo Ranaldi, Risitano, ANTONIO MARIA, Notaro, R, Marando, L, Serio, B, Ranaldi, D, Seneca, E, Ricci, P, Alfinito, Fiorella, Camera, A, Gianfaldoni, G, Amendola, A, Boschetti, C, Di Bona, E, Fratellanza, Giorgio, Barbano, F, Rodeghiero, F, Zanella, A, Iori, Ap, Selleri, Carmine, Luzzatto, L, and Rotoli, B.
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Hemolytic anemia ,Male ,medicine.medical_specialty ,Erythrocytes ,Cell Survival ,Immunology ,Hemoglobinuria, Paroxysmal ,CD59 ,Antibodies, Monoclonal, Humanized ,Biochemistry ,Blood cell ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Hematology ,biology ,business.industry ,Antibodies, Monoclonal ,hemic and immune systems ,Cell Biology ,Complement C3 ,Eculizumab ,medicine.disease ,Flow Cytometry ,Red blood cell ,medicine.anatomical_structure ,Paroxysmal nocturnal hemoglobinuria ,biology.protein ,Female ,Immunotherapy ,Antibody ,business ,circulatory and respiratory physiology ,medicine.drug - Abstract
In paroxysmal nocturnal hemoglobinuria (PNH) hemolytic anemia is due mainly to deficiency of the complement regulator CD59 on the surface of red blood cells (RBCs). Eculizumab, an antibody that targets complement fraction 5 (C5), has proven highly effective in abolishing complement-mediated intravascular hemolysis in PNH; however, the hematologic benefit varies considerably among patients. In the aim to understand the basis for this variable response, we have investigated by flow cytometry the binding of complement fraction 3 (C3) on RBCs from PNH patients before and during eculizumab treatment. There was no evidence of C3 on RBCs of untreated PNH patients; by contrast, in all patients on eculizumab (n = 41) a substantial fraction of RBCs had C3 bound on their surface, and this was entirely restricted to RBCs with the PNH phenotype (CD59−). The proportion of C3+ RBCs correlated significantly with the reticulocyte count and with the hematologic response to eculizumab. In 3 patients in whom 51Cr labeling of RBCs was carried out while on eculizumab, we have demonstrated reduced RBC half-life in vivo, with excess 51Cr uptake in spleen and in liver. Binding of C3 by PNH RBCs may constitute an additional disease mechanism in PNH, strongly enhanced by eculizumab treatment and producing a variable degree of extravascular hemolysis.
- Published
- 2009
72. Valganciclovir as CMV reactivation prophylaxis in patients receiving alemtuzumab for marrow failure syndromes
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Bianca Serio, Antonio M. Risitano, Carmine Selleri, Bruno Rotoli, Risitano, ANTONIO MARIA, Serio, B, Selleri, C, and Rotoli, B.
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Ganciclovir ,medicine.medical_specialty ,Antibodies, Neoplasm ,medicine.medical_treatment ,Pure red cell aplasia ,Antineoplastic Agents ,Neutropenia ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,Antiviral Agents ,Clinical Trials, Phase II as Topic ,Recurrence ,Internal medicine ,medicine ,Humans ,Valganciclovir ,Aplastic anemia ,Alemtuzumab ,Bone Marrow Diseases ,business.industry ,Bone marrow failure ,Antibodies, Monoclonal ,Immunosuppression ,Hematology ,General Medicine ,Syndrome ,medicine.disease ,Immunology ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
Dear Editor, Elter et al. recently published in your journal a comprehensive report on the management of infectious risk during treatment by alemtuzumab [1]. Their paper referred exclusively to chronic lymphocytic leukemia patients. Marrow failure syndromes are a group of hematological disorders sharing an immune pathophysiology and may benefit from intense immunosuppressive treatment including antilymphocyte antibodies, such as heterologous antithymocyte globulin (ATG), and cyclosporine A (CyA) [2]. However, given its potent lympholytic effect, alemtuzumab may also be appropriate for patients requiring intense immunosuppression. We recently developed an alemtuzumab-based immunosuppressive treatment for patients suffering from aplastic anemia or singlelineage bone marrow failure disorders [3], with the aim of inducing a more potent and prolonged immunosuppression and allowing retreatment in case of relapse (retreatment is difficult to attempt when using heterologous antisera). We wish to add our own experience in this particular setting, with specific attention to prophylaxis of cytomegalovirus (CMV) reactivation, which remains a major problem limiting a broader use of alemtuzumab. A cohort of consecutive patients suffering from either severe aplastic anemia (SAA), pure red cell aplasia (PRCA) or pure white cell aplasia (PWCA) were enrolled in a prospective phase II clinical trial with alemtuzumabbased immunosuppression (EUDRACT number 2008001151-22). The drug was administered subcutaneously as a single course, at 3–10–30–30–(30) mg doses on four (five) consecutive days (non-SAA patients received the 4day dose), followed by low-dose (1 mg/kg) cyclosporine A starting from day 7; retreatment by alemtuzumab (as complete courses or single shoots) was allowed in case of relapse. Anti-CMV prophylaxis was administered per protocol to all seropositive patients starting day 7, using oral valganciclovir at the dose of 450 mg, bidaily. Initially, anti-CMV prophylaxis was scheduled until CD4+ T cells reached 250 per microliter; however, since after assessment of immune reconstitution performed in the first patients CD4+count sometimes remained below the planned cutoff for many months, the protocol was amended to withdraw valganciclovir at CD4+ levels above 100 per microliter, and in any case 3 months after treatment. All patients received also anti-Pneumocystisjiroveci prophylaxis by low-dose oral trimethoprimsulfamethoxazole (bidaily three times per week), as well as standard antibacterial and antifungal prophylaxis in case of severe (
- Published
- 2008
73. Role of the Urokinase Receptor (uPAR) in the Cross-Talk of Hematopoietic Stem Cells with the Bone Marrow Microenvironment
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Claudio La Penna, Pia Ragno, Nunzia Montuori, Antonio M. Risitano, Valeria Visconte, Patrizia Ricci, Guido Rossi, Carmine Selleri, Bruno Rotoli, Ada Pesapane, Bianca Serio, Montuori, Nunzia, Ricci, P, Serio, B, Visconte, V, La Penna, C, Pesapane, A, Risitano, ANTONIO MARIA, Rotoli, B, Rossi, G, Ragno, P, and Selleri, C.
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Stromal cell ,Immunology ,Hematopoietic stem cell ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Molecular biology ,Cell biology ,Urokinase receptor ,medicine.anatomical_structure ,SuPAR ,medicine ,Stem cell ,Progenitor cell ,Cell adhesion ,Homing (hematopoietic) - Abstract
The urokinase-type plasminogen activator receptor (uPAR) is a cell-surface receptor involved in cell adhesion and migration. uPAR binds urokinase (uPA) and vitronectin (VN) and interacts with integrins and chemotaxis receptors. Soluble forms of uPAR (suPAR) have been detected in human plasma and urine. A cleaved form of suPAR (c-suPAR), lacking the N-terminal domain and exposing the sequence SRSRY (aa 88–92), stimulates cell migration by activating fMLP receptors. We recently demonstrated uPAR involvement in G-CSF-induced CD34+ hematopoietic stem cell (HSC) mobilization. We also demonstrated that c-suPAR could induce mobilization of hematopoietic stem/progenitor cells in mice. Since HSC mobilization and homing to bone marrow (BM) are mirror image processes which utilize the same mediators and similar signaling pathways, we investigated whether uPAR and its ligands could play a role in regulating CD34+ HSC interactions with the BM stroma, thus also contributing to HSC homing and engraftment to the BM. We found expression of uPA and VN in cultures of human BM stroma cells. Interestingly, stroma cells also produced suPAR and high amounts of c-suPAR, exposing the chemotactic SRSRY sequence. The role of the different soluble forms of uPAR produced by stroma cells in regulating HSC interactions with the BM microenvironment was analyzed by long term cultures (LTC) of BM and G-CSF mobilized CD34+ HSCs, in the presence of suPAR or the uPAR-derived uPAR84–95 peptide, corresponding to the active site of c-suPAR. Both suPAR and the uPAR84–95 peptide increased the number of adherent and released clonogenic progenitors from LTC of BM and G-CSF mobilized HSCs. To elucidate the mechanism of suPAR and c-suPAR effects on CD34+ HSC interactions with the stromal microenvironment, in vitro adhesion and proliferation assays were performed on CD34+ KG1 cells. suPAR treatment determined a significant increase in CD34+ KG1 cell adhesion whereas c-suPAR increased cell proliferation. Taken together, our results indicate that BM stroma produces soluble forms of uPAR that regulate CD34+ HSC interactions with BM microenvironment, their local proliferation and trafficking from and to BM.
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- 2008
74. Short-term zoledronic acid treatment increases bone mineral density and marrow clonogenic fibroblast progenitors after allogeneic stem cell transplantation
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Bianca Serio, Libuse Tauchmanovà, Gaetano Lombardi, Carmine Selleri, Annamaria Colao, Patrizia Ricci, Bruno Rotoli, L., Tauchmanovà, P., Ricci, Serio, Bianca, Lombardi, Gaetano, Colao, Annamaria, Rotoli, Bruno, and Selleri, Carmine
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Osteoporosis ,Bone Marrow Cells ,Biochemistry ,Zoledronic Acid ,Bone remodeling ,Endocrinology ,Bone Density ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Progenitor cell ,Infusions, Intravenous ,Femoral neck ,Bone mineral ,Leukemia ,Diphosphonates ,business.industry ,Stem Cells ,Biochemistry (medical) ,Imidazoles ,Fibroblasts ,Middle Aged ,medicine.disease ,Transplantation ,Osteopenia ,medicine.anatomical_structure ,Zoledronic acid ,Female ,business ,medicine.drug ,Stem Cell Transplantation - Abstract
Although osteoporosis is a relatively common complication after allogeneic stem cell transplantation, the role of bisphosphonates in its management has not yet been completely established. Thirty-two patients who underwent allogeneic stem cell transplantation were prospectively evaluated for bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN) after a median period of 12.2 months. Then, 15 of the patients with osteoporosis or rapidly progressing osteopenia (bone loss > 5%/yr) received three monthly doses of 4 mg zoledronic acid iv. Fifteen patients were followed up without treatment, and all 30 patients were reevaluated after 12 months for BMD and bone turnover markers. By using enriched mesenchymal stem cells in the colony-forming units fibroblast (CFU-F) assay, we evaluated the osteogenic stromal lineage. This procedure was performed in both groups of patients at study entry and after 12 months. The average BMD loss was 3.42% at LS and 3.8% at FN during a 1-yr longitudinal evaluation in 32 patients. Subsequently, BMD increased at both LS and FN (9.8 and 6.4%, respectively) in the zoledronic acid-treated cohort. Hydroxyproline excretion decreased, and serum bone-specific alkaline phosphatase increased significantly, whereas serum osteocalcin increase did not reach the limit of significance. A significant increase in CFU-F growth in vitro was induced by in vivo zoledronic acid administration. In the untreated group, no significant change was observed in bone turnover markers, LS BMD (–2.1%), FN BMD (–2.3%), and CFU-F colony number. In conclusion, short-term zoledronic acid treatment consistently improved both LS and FN BMD in transplanted patients who were at high risk for fast and/or persistent bone loss, partly by increasing the osteogenic progenitors in the stromal cell compartment.
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- 2005
75. High serum leptin in patients with chronic graft-versus-host disease after hematopoietic stem cell transplantation
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Patrizia Ricci, Annamaria Colao, Giuseppe Matarese, Carlo Carella, Gennaro De Rosa, Bruno Rotoli, Libose Tauchmanovà, Carmine Selleri, Gaetano Lombardi, Bianca Serio, Tauchmanovà, L., Matarese, G., Carella, C., DE ROSA, Gennaro, Serio, Bianca, Ricci, P., Lombardi, Gaetano, Rotoli, Bruno, Colao, Annamaria, and Selleri, Carmine
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Adult ,Leptin ,Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,CD4-CD8 Ratio ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Biology ,Internal medicine ,Blocking antibody ,medicine ,Humans ,Interferon gamma ,Transplantation ,digestive, oral, and skin physiology ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,medicine.disease ,Mixed lymphocyte reaction ,Endocrinology ,Graft-versus-host disease ,Chronic Disease ,Immunology ,Cytokines ,Female ,Lymphocyte Culture Test, Mixed ,Stem cell ,Body mass index ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
Background. Increased serum leptin has been described after various organ transplants, with a mechanism that is still unclear. Methods. We measured serum leptin in 60 patients before and after allogeneic (allo) or autologous (auto) stem cell transplant (SCT) and in 60 healthy controls, matched for age and body mass index (BMI). Results. Serum leptin was higher in patients after SCT than before and in controls. Leptin production was higher after allo- than after auto-SCT; the presence of chronic graft-versus-host disease (cGVHD) was associated with the highest values. The physiological correlation with BMI was lost in the allogeneic setting, indicating a strong influence of factors other than the nutritional status on circulating leptin. No relationship was found between serum leptin levels and time from transplant, age, cortisol, C-reactive protein, and T-lymphocyte CD4-to-CD8 ratio. Among the cytokines secreted by type-1/type-2 T-helper lymphocytes, only serum interferon-gamma significantly correlated with serum leptin levels. Anti-leptin blocking antibodies partially inhibited T-cell activation in mixed lymphocyte reaction, suggesting a link between leptin and T-lymphocyte activation in the allo-SCT setting. Conclusion. Taken together, these findings suggest that increased serum leptin concentrations may contribute to T-cell activation during development of cGVHD.
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- 2004
76. Late relapse of acute promyelocytic leukemia treated with all- trans retinoic acid and chemotherapy: report of two cases
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Felicetto Ferrara, Giuseppina Mele, Barbara Pocali, Carmine Selleri, Salvatore Palmieri, Fabrizio Pane, Bianca Serio, Bruno Rotoli, F., Ferrara, Selleri, Carmine, G., Mele, Serio, Bianca, S., Palmieri, B., Pocali, Pane, Fabrizio, and Rotoli, Bruno
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Adult ,Male ,Acute promyelocytic leukemia ,medicine.medical_specialty ,Time Factors ,Adolescent ,Combination therapy ,medicine.medical_treatment ,Retinoic acid ,Salvage therapy ,Tretinoin ,Gastroenterology ,chemistry.chemical_compound ,Leukemia, Promyelocytic, Acute ,Recurrence ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Salvage Therapy ,Chemotherapy ,Hematology ,business.industry ,Remission Induction ,General Medicine ,medicine.disease ,Leukemia ,chemistry ,Immunology ,Idarubicin ,Late Relapse ,business - Abstract
Two patients with acute promyelocytic leukemia (APL) relapsed at 111 and 84 months after achievement of complete remission (CR) induced by a combination of all- trans retinoic acid and chemotherapy. In both patients molecular remission, obtained after consolidation, had been confirmed at 60 months from CR achievement. At relapse, morphological, immunophenotypic, cytogenetic, and molecular analyses showed findings identical to those at diagnosis. Hematological and molecular remission was induced with the identical treatment applied at diagnosis. We conclude that, although infrequently, patients with APL treated with modern combination therapy can experience very late relapse and can be rescued with treatment similar to that administered at diagnosis.
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- 2004
77. Involvement of nitric oxide in farnesyltransferase inhibitor-mediated apoptosis in chronic myeloid leukemia cells
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Bianca Serio, Valeria Visconte, Bruno Rotoli, Jaroslaw P. Maciejewski, Nunzia Montuori, Luigiana Luciano, Patrizia Ricci, Carmine Selleri, Selleri, C., Maciejewski, J. P., Montuori, Nunzia, Ricci, P., Visconte, V., Serio, B., Luciano, L., Rotoli, Bruno, Selleri, Carmine, J. P., Maciejewski, P., Ricci, V., Visconte, B., Serio, L., Luciano, and B. R. o. t. o. l., I.
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Farnesyltransferase ,Immunology ,Nitric Oxide Synthase Type II ,Antigens, CD34 ,Apoptosis ,Bone Marrow Cells ,Biology ,Protein Serine-Threonine Kinases ,Nitric Oxide ,Biochemistry ,Fas ligand ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,RhoB GTP-Binding Protein ,Cytotoxic T cell ,Farnesyltranstransferase ,Humans ,RNA, Messenger ,fas Receptor ,Enzyme Inhibitors ,rhoB GTP-Binding Protein ,Alkyl and Aryl Transferases ,Caspase 3 ,Farnesyltransferase inhibitor ,Myeloid leukemia ,Cell Biology ,Hematology ,Caspase Inhibitors ,Enzyme Activation ,Proto-Oncogene Proteins c-bcl-2 ,Caspases ,Cancer research ,biology.protein ,Neoplastic Stem Cells ,Nitric Oxide Synthase ,K562 Cells ,rhoA GTP-Binding Protein ,K562 cells - Abstract
The mechanism of action of farnesyltransferase inhibitors (FTIs) has not been fully clarified. We investigated the cytotoxic effects of various FTIs in chronic myeloid leukemia (CML), using LAMA cells and marrow cells from 40 CML patients in chronic phase. FTI-mediated cytotoxic effect was observed in LAMA cells and in 65% of primary CML cells, whereas marrow cells from controls were only weakly affected. Cytotoxic effects were partially related to enhanced apoptosis; however, Fas-receptor (FasR) and Fas-ligand (FasL) expression were not modified by FTIs. Susceptibility to FTI-mediated inhibition did not correlate with FasR/FasL expression in CD34+ CML cells. Moreover, intra-cellular activation of caspase-1 and -8 were not altered by FTIs, and their blockade did not reverse FTI toxicity. However, we observed FTI-induced activation of caspase-3, and its inhibition partially reverted FTI-induced apoptosis. FTIs did not modulate bcl2, bclxL, and bclxS expression, whereas they increased inducible nitric oxide (iNOS) mRNA and protein levels, resulting in higher NO production. Furthermore, C3 exoenzyme, a Rho inhibitor, significantly increased iNOS expression in CML cells, suggesting that FTIs may up-regulate NO formation at least partially through FTI-mediated inhibition of Rho. We conclude that FTIs induce selective apoptosis in CML cells via activation of iNOS and caspase-3.
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- 2003
78. Induction Therapy With Continuous Alternate-Day Low Dose Lenalidomide Combined With Low-Dose Prednisone In Octogenarian Multiple Myeloma Patients
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Bianca Serio, M Rocco, Mariarosaria Sessa, G Villani, Idalucia Ferrara, Valentina Giudice, Carmine Selleri, R Fontana, and L Pezzullo
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medicine.medical_specialty ,Aspirin ,Performance status ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Discontinuation ,Surgery ,Zoledronic acid ,Prednisone ,Internal medicine ,Medicine ,business ,Adverse effect ,Multiple myeloma ,Lenalidomide ,medicine.drug - Abstract
About 30% of patients with newly diagnosed multiple myeloma (NDMM) are older than 75 years. Immunomodulatory drugs (IMIDs) have improved response rates and outcomes of NDMM, except for patients older than 75 years more vulnerable to side effects of IMIDs because of their frailty and comorbidities. We evaluated efficacy, toxicity and health-related quality of life (HRQOL) associated with continuous alternate-day low dose lenalidomide (LD-R, 10 mg on alternate days) and low dose prednisone (15 mg/day) (LD-RP) in 7 octogenarian NDMM patients (5 males and 2 females) with a median age of 82 years (range 80-87). All octogenarian patients had IgG MM, except 1 oligosecretory lambda chain MM; all were in Durie-Salmon stage III, except 1 in stage II, and had poor WHO performance status (median: 2, range 1-3). Patients were evaluated at baseline and every 6 months for HRQOL according to MM-specific questionnaire QLQ-MY20 of European Organisation for Research and Treatment of Cancer (EORTC). All patients received aspirin thromboprophylaxis, 57% of them requiring from diagnosis erythropoietin and zoledronic acid treatment. In these 7 octogenarian NDMM patients completing at least three months of therapy, the overall response rate (ORR) was 86%, including 1 complete remission (CR), 2 very good partial remission (VgPR) and 3 PR. After a median follow-up of 12 months (range 3-24), the quality of response improved with continuous LD-RP treatment with a cumulative median reduction in monoclonal protein levels of 85% (range 20-100%); none of the patients required discontinuation of treatment secondary to specific hematologic and/or extra-hematologic toxicity. In addition, QLQ MY-20 questionnaires revealed that 70% of patients treated with continuous LD-RP reported improvements of QOL scores. Two out of 7 octogenarian patients died (1 for progression after 12 months and 1 for sepsis no treatment-related), and 2-year overall survival and progression-free survival estimates were 41% and 75%, respectively. Noteworthy, all patients treated with continuous alternate-day LD-RP showed a progressive increase in the percentage of CD3+ CD56+ NK cells during the first 6 months of LD-RP therapy reaching a plateau maintained until +12 months after initiation of therapy: the median percentage of NK cells was 4% before LD-RP treatment versus 10%, 13%, 30%, 31%, and 27% at +1, +3, +6, +9 and +12 months, respectively. Mean fold increase of NK cells during LD-RP therapy was 1.5, 2.5, and 6.5 at +1, +3 and +6 months, respectively. Progressive increase of NK cells was concomitantly associated with reduction in tumor-linked monoclonal immunoglobulin in all patients and increased circulating NK cells further support that this drug may mediate its anti-MM effect, at least in part by modulating NK-cell number and function. Our data provide evidence that continuous alternate-day low dose lenalidomide is a manageable and effective frontline treatment for octogenarian NDMM patients and increases circulating NK cells. These preliminary results require further validation in prospective larger studies. Disclosures: No relevant conflicts of interest to declare.
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- 2013
79. Permissive Conditions for Evolution of PNH Clones Are Characterized by Overproduction of IFN-γ by Clonal CD4 and CD8 T Cells, Fas-L by CTLs, and Promoted by Immunogenetic Background
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Anna M. Jankowska, Jaroslaw P. Maciejewski, Heather Cazzolli, Ronald Paquette, Thomas P. Loughran, Susan B. Nyland, Alan F. List, Bianca Serio, Pearlie K. Epling-Burnette, Christine L. O'Keefe, Marcin W. Wlodarski, and Michael J. Clemente
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education.field_of_study ,T cell ,Immunology ,Population ,Clone (cell biology) ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Immune system ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Paroxysmal nocturnal hemoglobinuria ,medicine ,HLA-DR ,Cytotoxic T cell ,education ,CD8 - Abstract
The association between immune-mediated aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) has been well documented, yet the related immune pathophysiology remains ill-defined. Response of AA patients with PNH clones to immunosuppressive agents such as anti-thymocyte globulin (ATG) and cyclosporine A provides clinical evidence for the involvement of the immune system in the evolution of PNH. The similar immunobiology of PNH and AA is also exemplified by the overrepresentation of HLA-DR*15 in AA, AA/PNH and PNH. To discern the relationship between T cell responses and effector mechanisms we applied a battery of immune tests to patients with these rare diseases. First, using T cell receptor Vβ flow cytometry in a cohort of patients with AA (N=42), AA/PNH (N=15), or PNH (N=18), we identified cytotoxic CD8 T cell (CTL) clonal expansions in 28/42 (66.7%), 9/15 (60%), and 7/18 (38.8%) patients, respectively. CD4 T cell expansions were present in 6/42 of AA (14.3%), 2/15 (13.3%) of AA/PNH, and 2/18 (11.1%) of PNH patients. We then studied whether expanded clones were associated with production of inflammatory cytokines; across the entire cohort, patients with clonal CD8 Vβ expansions demonstrated a significantly increased proportion of IFN-γ producing T cells as well as elevated levels of circulating Fas-L when compared to patients without clonal skewing (p=.032 CD4+IFN-γ+, p=.008 CD8+IFN-γ+, p=.097 sFAS-L). Even more pronounced was the increase in the proportion of IFN-γ producing CD4 T cells in patients with clonal CD4 Vβ expansions (p=.010). Furthermore, while a strong trend toward increased sFAS-L as detected by ELISA was found in patients with CD8 Vβ skewing vs. those without, patients with pronounced CD4 expansions did not produce elevated Fas-L levels, consistent with different effector mechanisms employed by CD4 vs. CD8 T cells. Based on these results we hypothesized that the presence of PNH clones will be associated with activation of immune effector mechanisms. Linear regression analysis of the size of the PNH clone vs. proportion of IFN-γ CTLs displayed a positive correlation that nearly reached statistical significance at α=0.05 (p=.067). A high proportion of CD4 IFN-γ cells (defined by a value above 95% mean confidence intervals of controls) was also associated with the presence of PNH (p=.048). Genetic analysis revealed further clues as to the increased propensity of patients with AA and PNH clones to produce elevated levels of IFN-γ; the hypersecretor genotype T/T for IFN-γ was over-represented in AA (28% vs. 10% in controls, p=.02) and correlated with presence of a PNH clone (35% vs. 14%, p=.01). An essential role of T cells in generating permissive conditions for the evolution of PNH clones is also supported by the immunogenetic relationship of PNH to HLA-DR*15, a relationship which was confirmed in our population of patients: phenotype frequency of HLA DR*15 was 42.8% AA, 40% AA/PNH, 27.8% PNH vs. 17.2% in control group. When HLA DR*15 positive and DR15 negative patients were compared, those with DR*15 displayed a strong trend toward increased proportion of CD8+IFN-γ producing cells (p=.094), previously shown to be elevated in patients with PNH clones. Our results reveal insights into the nature of permissive conditions involving oligoclonal T cell responses, oversecretion of proinflammatory cytokines, and immunogenetic background which together may promote the expansion of PNH clones. Conversely, it remains possible that the cytotoxic milieu may be a result of an immune response directed against intrinsically abnormal PNH clones.
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- 2008
80. Subcutaneous Alemtuzumab Is a Safe and Effective Treatment for Global or Single-Lineage Immune-Mediated Marrow Failures: a Survey from the EBMT-WPSAA
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Giulia Scalia, Gérard Socié, Joerg Halter, Judith C. W. Marsh, Bruno Rotoli, Andrea Bacigalupo, Sébastien Maury, A. D. Kulagin, Antonio M. Risitano, Vikas Gupta, Elisa Seneca, Annapaola Iori, André Tichelli, Bianca Serio, Luigi Del Vecchio, Ludovica Marando, Hubert Schrezenmeier, Jakob Passweg, and Carmine Selleri
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medicine.medical_specialty ,business.industry ,Standard treatment ,medicine.medical_treatment ,Immunology ,Bone marrow failure ,Valganciclovir ,Immunosuppression ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Gastroenterology ,Regimen ,Internal medicine ,medicine ,Alemtuzumab ,Aplastic anemia ,business ,medicine.drug - Abstract
Acquired marrow failure syndromes may globally affect all hematopoietic lineages, as in aplastic anemia (AA), or may selectively involve single lineages, as in pure red cell (PRCA) or in pure white cell aplasias (PWCA). Because of their common cellular immune-mediated pathophysiology, standard treatment for these conditions includes immunosuppression (IS), which may differ according to the specific disease. We investigated an experimental IS regimen based on the anti-CD52 antibody alemtuzumab (MabCampath®, ALE); the study included a phase II/III prospective trial, as well as a collection of retrospective cases. A total of 32 patients have been treated by ALE (18 SAA, 10 PRCA and 4 PWCA), fourteen of them (mostly PRCA) having not received previous IS. The most utilized schedule (as defined in the prospective trial) was 3,10,30,30,30 mg (total dose 103), administered subcutaneously in consecutive days, with adequate premedication; the last dose was amended in PRCA and PWCA patients (total dose 73 mg). In the prospective trial, all patients also received oral low dose cyclosporine A (1 mg/kg) from day 7, and an intensive anti-infectious prophylaxis, which included oral valgancyclovir and cotrimoxazol. All patients completed the treatment with unrelevant injection-related side effect (fever and/or rash in some cases) and absence of laboratory abnormalities. Complete lympho-ablation was observed in all patients within 2–3 days, which persisted for several weeks; transient worsening of neutropenia and/or thrombocytopenia were observed in some cases. The median follow up was 12 months; there were 5 deaths, only one was possibly related to the treatment. In the prospective trial (n=23), infectious events were rare: a single FUO, associated with fatal complication of an underlying atrial fibrillation, other four viral infections (1 VZV with shingles, 2 HSV and 1 flu), all resolving quickly. No CMV or EBV disease was observed, even if 3 border-line CMV reactivations were documented (after discontinuation of the antiviral prophylaxis), promptly resolved by preemptive valganciclovir. One HBV reactivation without hepatitis required lamivudine. The response rate was globally 61% (42% CR and 19% PR), which raised to 73% (50% CR and 23% PR) when only patients with a follow up of at least 4 months were considered. In the more homogeneous cohort of the prospective trial, response rate was analyzed according to the underlying disease. Among 10 AA treated (5 as first line), 7 had an adequate follow up and showed 4 CR (57%) and 2 PR (29%). Response rate was even higher in 10 PRCA (8 as first line): 7 were evaluable for response, with 5 CR (71%) and 1 PR (14%); the 1 non responding patient subsequently showed evolution to MDS. Finally, 2 of 3 PWCA achieved a CR (66%), with the remaining showing early progression to MDS. Among the responding patients, relapses were quite frequent, even while on cyclosporine: 3/6 SAAs, 5/6 PRCAs and 1/2 PWCA. Relapses were successfully treated by additional ALE (as single shoots or complete courses). Immune reconstitution was delayed up to several months, especially affecting the CD4+ compartment; this was also due to additional ALE needed to treat or to prevent relapses. In conclusion, subcutaneous ALE is a feasible and safe IS regimen for patients suffering from immune-mediated marrow failure syndromes. Preliminary results suggest excellent efficacy, even if responses may be quite late (3–4 months); relapses often occur, but can be easily managed by ALE retreatment. ALE is an excellent alternative to standard IS regimen, and deserves systematic investigation in bone marrow failure patients.
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- 2008
81. C3-Mediated Extravascular Hemolysis as Additional Mechanism of Disease in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients Treated by the Complent Inhibitor Eculizumab
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Franco Iuliano, Antonio M. Risitano, Bianca Serio, Antonio Marino, Eros Di Bona, Francesco Pietrogrande, Carla Boschetti, Elisa Seneca, Silvana Bonfigli, Annapaola Iori, Stefano Pulini, Angelo Michele Carella, Elisabetta Antonioli, Angela Amendola, Filippo Barbano, Bruno Rotoli, Silvana Capalbo, Danilo Ranaldi, Giacomo Gianfaldoni, Filippo Milano, Wilma Barcellini, Rosario Notaro, Ludovica Marando, Lucio Luzzatto, Francesco Fabbiano, Alberto Zanella, and Francesco Rodeghiero
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education.field_of_study ,medicine.medical_specialty ,medicine.diagnostic_test ,Anemia ,business.industry ,Immunology ,Population ,Cell Biology ,Hematology ,Eculizumab ,medicine.disease ,Biochemistry ,Gastroenterology ,Hemolysis ,Coombs test ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Paroxysmal nocturnal hemoglobinuria ,Hemoglobin ,education ,business ,Complement membrane attack complex ,medicine.drug - Abstract
PNH is a hematological disorder characterized by complement-mediated intravascular hemolysis due to lack on RBCs of the complement regulators CD55 and CD59 and subsequent activation of the membrane attack complex (MAC). Eculizumab (EC) is an anti-complement fraction 5 antibody which abolishes intravascular hemolysis in PNH patients, leading to reduction of transfusion requirement and of anemia. Although the effector complement pathway is completely blocked by eculizumab in all patients, response to this agent in terms of transfusion requirement and hemoglobin level varies considerably. We have investigated the notion that patients with suboptimal hematological response may suffer from residual hemolysis mediated by mechanisms other than intravascular hemolysis via MAC. After the initial observation of a positive C3d Coombs test in some PNH patients on EC, we extensively studies C3 coating by flow cytometry in 56 PNH patients (41 of them while receiving EC). We found that in all cases on EC treatment a significant proportion of RBCs were coated with complement fraction 3 (C3); by converse, in 28 untreated PNH patients we found no evidence of C3 on red cells. C3 coating was strictly limited to CD59-neg RBCs, as CD59+/C3+ RBCs (as those seen in cold agglutinine disease patients, positive control) were never found. C3 coating was quite different among EC-treated patients, and correlated with the PNH RBC population. The percentage of C3+ cells within the PNH RBC population (the only subjected to C3 coating) was quite different in individual patients (0.5–61.3%, median 22.6%) and substantially preserved over time. We compared the level of C3 coating with the hematological response: all the 41 EC-treated patients showed marked LDH reduction with a substantial improvement of anemia, leading to transfusion independence in 34/41 patients (83%) and stable resolution of anemia in 14 (34%, defined optimal responders). The optimal responders showed a lower percentage of C3+ cells in comparison to suboptimal responders (20.9±19.0 vs 32.2±17.8; p=0.04). Indeed, patients with lower C3 coating (below the median value of 22.6%) showed a significantly higher rate of optimal response (51% in comparison to 15% of those with coating above the median, p=0.01). C3 coating also correlated with the absolute reticulocyte count (p=0.03), clearly suggesting that C3 coating was associated with ongoing residual extravascular hemolysis in vivo, and with pre-treatment LDH level (p=0.001). To confirm the presence of extravascular hemolysis, in 3 index patients with suboptimal response reduced RBC half-life was demonstrated in vivo by 51Cr RBC survival study, which showed reduced RBC half-life and excess uptake in liver and spleen. One of these patients underwent video-laparoscopic splenectomy, which led to transfusion independence and significant increase in Hb level. These data demonstrate that C3 coating of PNH RBCs is a common phenomenon in PNH patients on EC; in addition, we provide evidence that this leads to C3-mediated extravascular hemolysis through the reticulo-endothelial system. This novel mechanism of disease may account for residual hemolysis and suboptimal clinical benefit in some EC treated PNH, paving the way for additional therapeutic strategies to optimize the hematological response to this agent.
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- 2008
82. Analysis of Immunogenetic Factors in Paroxysmal Nocturnal Hemoglobinuria Reveal Increased Frequency of IL-10 Low Secretor Genotype and Correlates with Induced IL-10 Production.
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Ramsingh, Giridharan, primary, Nearman, Zachary, primary, Hung, Chris, primary, Bianca, Serio, primary, Risitano, Antonio, primary, and Maciejewski, Jaroslaw, primary
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- 2006
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83. Decreased Numbers of Tregs in Aplastic Anemia Is Detected by Immunohistochemistry and Flow Cytometry
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Jennifer Powers, Jaroslaw M.D. Maciejewski, Ziad Peerwani, Ramon V. Tiu, Erik Hsi, and Bianca Serio
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Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Immunology ,hemic and immune systems ,chemical and pharmacologic phenomena ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Pancytopenia ,Flow cytometry ,medicine ,Immunohistochemistry ,Aplastic anemia ,business - Abstract
Idiopathic aplastic anemia (AA) is characterized by immune-mediated destruction of hematopoietic stem cells, leading to peripheral pancytopenia. Immune pathogenesis in AA is supported by experimental data, as well as clinical observations and may be related to the breach of peripheral or central tolerance. Regulatory T cells (Treg) constitute one of the most important mechanisms of central tolerance engaged in the down-modulation of autoreactive T cells. Tregs have been found to be reduced in several autoimmune diseases and decreased frequencies of Tregs were also reported in AA and MDS. Overexpression of the high affinity IL-2 receptor alpha chain (CD25) and the forkhead family transcription factor P3 (FoxP3), required for the development and function of Tregs, serve as phenotypic markers for Tregs. We investigated Treg levels in a cohort of AA patients (N=21) and healthy individuals (N=15); flow cytometric quantification of Treg was carried out after surface/intracellular staining of whole blood for Treg markers (CD3, CD4, CD25, FoxP3). After proper gating (light scatter properties, CD3, CD4, CD25), CD4+ T cells were subdivided into CD25−, CD25int and CD25hi populations, and the co-expression of CD25hi and Foxp3 was analyzed. In comparison to controls, AA patients (N=12) show not only lower frequencies of CD4+CD25hi+ T cells within the total lymphocyte population (median 0.07% vs. 0.21%; p=.03), but also absolute lower absolute numbers (1.31/uL vs. 5.78/uL, p=.0002). Similarly, CD4+CD25hi+FoxP3+ T cells were found to be depressed in untreated AA patients in comparison to controls (median 0.07% vs. 0.21% and 1.06/uL vs. 4.76/uL; p=.03 and p=.003). While Tregs were lower in patients with active disease unresponsive to immunosuppressive treatment (responder 0.1% vs non responder 0.07%, CD4+CD25hi Tcells, p=.02), serial testing performed in 6 patients treated with ATG/CsA did not reveal correlation between hematologic improvement and recovery of Treg numbers. When double immunohistochemical staining for CD3 and Foxp3 was performed in pre-treatment bone marrow core biopsies of AA patients (N=3) and controls (N=2) a mean of 3 CD3+Foxp3+ cells/10 high power fields (hpf) were counted (vs. mean 28/10 hpf, p
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- 2007
84. Analysis of Immunogenetic Factors in Myelodysplastic Syndromes (MDS) Reveals Potential Pathogenic Role Cytokine Genotypes Such as TGF-β
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Ramon V. Tiu, Zach Nearman, Mikkael A. Sekeres, Bianca Serio, Ania Jankowska, Jaroslaw M.D. Maciejewski, and Christine O’Keefe
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education.field_of_study ,Immunology ,Population ,Haplotype ,Single-nucleotide polymorphism ,Cell Biology ,Hematology ,Human leukocyte antigen ,Immunogenetics ,Biology ,Biochemistry ,Molecular biology ,Genotype frequency ,hemic and lymphatic diseases ,Genotype ,Genetic predisposition ,education - Abstract
Pathophysiologic and clinical features of MDS are related to the phenotype of the dysplastic hematopoietic clone. The immunogenetic background resulting from complex genetic predisposition traits may influence the quality of the immune response and shape the clinical features of MDS, including the severity of cytopenias and speed of malignant evolution. To test this hypothesis we selected the following immunogenetic factors: KIR and KIR-ligand (KIR-L) genotype, as well as cytokine/receptor single nucleotide polymorphisms (SNP). We genotyped a cohort of 90 patients with MDS/sAML (30 RA/RCMD, 30 RARS/ RCMD-RS, 30 RAEB/sAML); 60 healthy donors matched for ethnicity were analyzed as a control. A group of 66 patients with aplastic anemia (AA) was used as a reference. HLA type, KIR, KIR-L haplotypes, and the following SNPs were analyzed: IL-1α (−889 T/C),IL2 (−330 T/G +166 G/T), IL4 (−1098 T/G -590 T/C -33 T/C, IL-1R (−1970 C/T), IL-1RA (mspa 111100 T/C), IL-4RA (+ 190 G/A), IL-1 β (−511 C/T, +3962 T/C), IL-6 (−174 C/G, nt565 G/A), IL-10 (−1082 G/A, -819 C/T), IL-12 (−1188 C/A), TGF-β (+10 C/T, +25 G/C), INF- γ (+874 A/T), TNF- α (−308 G/A, -238 G/A), CTLA-4 (exon 1, +49 A/G), FcgIIIR (+559 G/T) as well as SNPs in the CD45 gene (exon 4 +77 C/G, +138 A/G). In the MDS cohort, no difference in the frequency of KIR genotype constellations was identified. However, a higher frequency of 2DS5 (66% vs. 26%, p=.01) and a decreased frequency of 2DL3 (62% vs. 87% p=.02) was found when patients with hypocellular MDS (N=10) were analyzed separately. No significant difference in KIR-L C1/C2 genotype frequency between the group was found. However, an increased incidence of C2/C2 was found in high grade MDS/sAML (RAEB/sAML 44% vs. 13%, p=.02). In MDS, there was a decreased frequency of stimulatory 2DS1/C2 mismatch consistent with potentially enhanced cytotoxicity (17% vs. 44%, p=.01). No significant difference in the MDS cohort compared to control and when MDS subgroup were compared to each other, was found for the SNPs in IL-4RA, IL-12, IL-1α, IFN-γ, IL-2, IL-1 α, IL-1R, and IL4. However, when we examined the frequency of TGF- β genotypes, the MDS population showed a higher rate of TT codon 10 variant (59% vs. 32% in controls, p=.002) and of GG codon 25 variant (71% vs. 35% in controls, p=.0001), consistent with a “high secretor phenotype”. Of note is that, when AA was examined and compared to controls, a higher frequency of TGF-β high secretor genotype was found (GG codon 25 variant; 61% vs 35% in controls, p=.03). We also found a higher incidence of A/A genotype for CTLA-4 in MDS (47 vs 27, p=.001). This relationship was even more pronounced in hypocellular MDS. Moreover, hypocellular MDS was characterized by a higher prevalence of IL10 -819 T/T and -592 A/A phenotypes (40% vs 12% p=.03), which are functionally associated with a lower secretion. In sum, our findings demonstrate that various immunogenetic factors may be demonstrated in MDS patients, which may likely influence the quality of immune response and shape clinical features of MDS. Certain genotypic constellations (e.g., TGF gene variants) resemble, in particular in hypocellular MDS, a constellation seen in AA.
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- 2007
85. Subcutaneous Alemtuzumab Is Safe and Effective for Treatment of Global or Single-Lineage Immune-Mediated Marrow Failure: A Pilot Study
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Lucio Catalano, Antonio M. Risitano, Bruno Rotoli, Bianca Serio, Andrea Camera, Ludovica Marando, Luigi Del Vecchio, Giulia Scalia, and Carmine Selleri
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Pure red cell aplasia ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Neutropenia ,medicine.disease ,Biochemistry ,Gastroenterology ,Surgery ,Transplantation ,Regimen ,Internal medicine ,Injection site reaction ,medicine ,Alemtuzumab ,Chills ,medicine.symptom ,business ,medicine.drug - Abstract
Acquired marrow failure syndromes may globally affect all hematopoietic lineages, as in severe aplastic anemia (SAA), or may selectively involve single lineages, as in pure red cell aplasia (PRCA) or in agranulocytosis (AGR). All these conditions share a cellular immune-mediated pathophysiology, which is supported by many experimental data; thus, various immunosuppressive (IS) strategies have been exploited. Alemtuzumab (MabCampath®) (ALE) is a lympholytic MoAb with strong and prolonged IS activity, more reliable than ATG or ALG as for activity, dosing and commercial availability. Here we report a phase II/III pilot study with ALE followed by low-dose cyclosporine A (CsA) on 11 patients suffering from SAA (n=4), PRCA (n=5) or AGR (n=2). All patients received ALE as s.c. injection premedicated by betamethasone, clorpheniramine and paracetamol, with a dose escalating schedule of 3-10-30-30-(30) mg in consecutive days; the total dose was 103 mg for SAA, and 73 for PRCA and AGR. Six patients received one or more additional courses as a result of relapse, so a total of 18 courses were administered. All patients on day 7 started oral low dose CsA (1 mg/kg). Valgancyclovir 450 mg bi-daily and trimethoprim-sulphamethoxazole bi-daily thrice a week were administered as anti-CMV and anti-Pneumocystis Carinii prophylaxis, respectively. All patients completed the treatment, with severe or moderate infusion-related side effect (fever, chills and/or injection site reaction) occurring in 1 (not premedicated) and 3 cases, respectively. No significant abnormality of routine biochemical testing, nor other medically significant adverse events were reported. A complete lympho-ablation was observed in all patients within 2–3 days, which persisted for several weeks; in addition, transient worsening of neutropenia (managed by occasional G-CSF support) and of thrombocytopenia were observed in some patients. At a median follow-up of 6 months, infectious events were irrelevant: in cumulative 75 patient-months, 1 HSV and 1 flu have been recorded (globally 1 day of fever), all resolving quickly. No CMV reactivation was demonstrated. Immune reconstitution was delayed up to several months, with absolute lymphocyte count ranging between 30–200/uL, 100–400/uL, 250–800/uL and 500–2000/uL at months +1, +3, +6 and +12 from the treatment. The CD4+ compartment was significantly more affected than the CD8+, with a persistent inversion of the CD4/CD8 ratio. As for efficacy, the 4 SAA patients showed 1 CR, 1 PR (both relapsing at 6 months and re-treated with additional ALE courses), 1 NR at 3 months (addressed to early stem cell transplantation due to life-threatening hemorrhages); 1 is not evaluable yet. In the 5 PRCAs, there were 4 CR and 1 NR (at 3 months); 3 responding patients relapsed and were successfully managed by further courses of ALE. The 2 AGRs showed both CR, followed by late relapse (at 18 months) in one case (now receiving a second course). In conclusion, ALE administered as subcutaneous injection is a feasible and safe IS regimen for patients suffering from immune-mediated marrow failure syndromes. Infectious complications were unremarkable, and preliminary results suggest good efficacy, especially in lineage-restricted forms; as with other IS regimens, the hematological response is late (3–4 months) and relapses may occur, which are sensitive to further ALE courses. Such favorable risk-to-benefit ratio predicts for this regimen a leading position in the future IS strategies.
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- 2007
86. Immunogenetic Analysis Reveals the Association of INF-γ (+874 A/T) Hypersecretor Genotype in AA and a Low Frequency of KIR-2DL3/C1 Mismatch in Responders to Immunosuppression
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Ramon V. Tiu, Giridharan Ramsingh, Antonio M. Risitano, Mikkael A. Sekeres, Bianca Serio, and Jaroslaw M.D. Maciejewski
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Genetics ,Immunology ,Haplotype ,Cell Biology ,Hematology ,Human leukocyte antigen ,Biology ,Biochemistry ,Molecular biology ,Interleukin 10 ,Immune system ,Aldesleukin ,Genotype ,Interleukin 12 ,Cytotoxic T cell - Abstract
Clinical and laboratory evidence support an immune pathogenesis in most cases of idiopathic aplastic anemia (AA) and closely related disorders such as paroxysmal nocturnal hemoglobinuria (PNH). While external triggers are likely necessary, a complex constellation of immunogenetic factors may determine disease susceptibility. Many immunogenetic factors can influence the quality of immune response and affect the propensity to immune-mediated attack on hematopoietic stem cells in AA. Here we investigated whether KIR and KIR-L (HLA-A) genotype and cytokine/receptor gene variants are over-represented in AA and PNH. We studied a cohort of 77 patients with AA (23 AA, 20 AA/PNH and 34 PNH), 10 with hypocellular MDS and 175 healthy controls. The following SNPs in immunoregulatory genes were analyzed: IL-1α (−889 T/C), IL-2 (−330 T/G +166 G/T), IL-4 (−1098 T/G −590 T/C −33 T/C), IL-1R (−1970 C/T), IL-1Rα (mspa111100 T/C), IL-4RA (+ 190 G/A), IL-1β (−511 C/T, +3962 T/C), IL-6 (−174 C/G, nt565 G/A), IL-10 (−1082 G/A, −819 C/T, −592 C/A), IL-12 (−1188 C/A), TGF-β (+10 C/T, +25 G/C), INF-γ (+874 A/T), TNF-α (−308 G/A, −238 G/A) and immunomodulatory receptor genes including CTLA-4 exon 6 (+49 G/A), FcRIIIa (158 F/V) and CD45-exons 6 (+138 A/G), and 4 (+54 A/G, +77 C/G). As binding of KIR to the appropriate HLA ligand (KIR-L) can modulate activation of NK and cytotoxic T cells, we examined the combined impact of KIR/KIR-L genotypes on the risk of AA and PNH syndrome. In AA we found a decreased frequency of inhibitory KIR-2DL3 genes (68% vs. 89%, p=.0002); analysis of the KIR genotype in correlation with the corresponding KIR-L profile, revealed a decreased frequency of stimulatory 2DS1/C2 mismatch resulting in a potentially enhanced cytotoxic activity (14% vs.44%, p=.003). No association was found for most of the SNPs tested. However, when we examined the frequency TGF-β genotypes, increased frequency of GG variant in codon 25 (61% vs. 35% in controls, p=.03), associated with the “high secretor” phenotype, was found in AA. This relationship was also present in hypocellular MDS (82% vs. 32%, p=.007). Additionally, we found a lower incidence of TT genotypes for the IL-1Rα gene (33% vs. 62% p=.02). We confirm that the hypersecretor genotype T/T of INF-γ was over-represented in AA (28% vs. 10% in controls, p=.02). Subgroup analysis revealed that the T/T genotype of IFN-γ (35% vs. 14% p=.01) correlated with presence of a PNH clone. Previously, we have shown the association of HLA-DR15 with responsiveness to immunosuppression. When AA patients were subgrouped according to response to ATG/CsA, therapy refractoriness correlated with the presence of the C2/C2 haplotype (30% vs. 0% p=.02) and inhibitory KIR-2DL3/C1 mismatch (70% vs. 0%, p=.01) which may result in a greater propensity to breach of self-tolerance. In comparison, in the total AA group, C2/C2 haplotype and KIR-2DL3/C1 mismatch were present in 17% vs. 24% and 8% vs. 16% of controls, respectively. An increase in the frequency of 2DL3 and a decrease in 2DS1 mismatch may result in imbalance between cytotoxicity and KIR inhibition. In sum, our findings demonstrate that complex inherited traits involving immunogenetic factors may genetically determine propensity to bone marrow failure syndromes.
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- 2007
87. Non Synonymous SNP-Array-Based Disease Association Analysis in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria
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Bianca Serio, Aaron D. Viny, Alan E. Lichtin, Ramon V. Tiu, Bartlomej Przychodzen, Christine L. O'Keefe, and Jaroslaw M.D. Maciejewski
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Genetics ,Immunology ,Clone (cell biology) ,Single-nucleotide polymorphism ,Cell Biology ,Hematology ,Human leukocyte antigen ,Biology ,Biochemistry ,Genotype ,SNP ,TAP1 ,Genotyping ,SNP array - Abstract
The pathogenesis of aplastic anemia (AA) includes external triggers that induce an immune-mediated attack in susceptible individuals. A complex genetic background is likely the basis for AA predisposition; various genetic factors, including HLA, KIR and SNPs in immune response genes, were studied in AA. However, such an empiric approach, despite the rational target selection, is inefficient. SNP array (SNP-A) genotyping technology allows for investigation of complex genetic traits and is a suitable hypothesis-generating technology. We stipulated that application of SNP-A in AA will allow for identification of SNPs in pathogenic loci. We applied the Illumina 12K non-synonymous SNP-A to study 77 AA and ethnically matched controls (ctr; N=60; +170 historical ctr). The power of this technique is demonstrated by our ability to obtain >2.6 million genotypes with a fidelity (against PCR) of 98%. The training set included 64 AA patients and 56 controls. Initially, Exemplar automated analysis was used; due the Bonferroni correction this study underpowered. However, our strategy included ranking SNPs based on their P value, low frequencies of pathogenic genotypes in ctr, and high case/ctr ratio narrowing the selection of potentially informative SNPs to be tested in a validation set. We also applied Random Forests, a nonparametric tree method, whereby all SNP were used multivariately to predict disease association; this method does not relay on Bonferroni correction and more closely reflects complex polygenic traits. Results pointed towards many SNPs recognized by both approaches and a number of SNP was chosen for further analysis. E.g., rs8022805 (GA) in telomerase-associated protein-1 (TEP1) was found in 19% of AA patients but only in 2.7% of controls (N=220, p
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- 2007
88. Phospho-IkappaB Is Abnormally Expressed in Bone Marrow of CMML Patients
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Jaroslaw P. Maciejewski, Ziad Peerwani, Eric D. Hsi, Bianca Serio, Ramon V. Tiu, and Andrew E. Schade
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Pathology ,medicine.medical_specialty ,Myeloid ,biology ,Immunology ,Cell ,Chronic myelomonocytic leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Pathogenesis ,medicine.anatomical_structure ,Fibrosis ,hemic and lymphatic diseases ,medicine ,biology.protein ,Immunohistochemistry ,Bone marrow ,Antibody - Abstract
Introduction: Chronic myelomonocytic leukemia (CMML) is a heterogeneous group of bone marrow disorders currently grouped into the MDS/MPD overlap by WHO classification. Its clinical and laboratory features includes the presence of up to 20% blast in the bone marrow and the peripheral blood, a PB monocyte count >1000/mL, splenomegaly, variable reticulin fibrosis in the bone marrow and cytopenias. The exact pathogenesis remains in question and there are no effective therapies. Recent studies in certain myeloid disorders suggest that the nuclear transcription factor NFkB regulates cell survival, proliferation, and differentiation. It has been found to be highly expressed in AML and may serve as an important therapeutic target. Little is known about NFkB in other hematologic disorders, including CMML. Examination of NFkB activation in situ has been technically difficult due to lack of quality antibody reagents suitable for fixed tissues. Recently, phosphospecific antibodies have become available, which reflect the functional status of proteins. IkB regulates NFkB subunits by sequestering them in the cytoplasm. Phosphorylation of IkB by IKK results in release of NFkB and translocation to the nucleus. Thus, phospho-IkB (pIkB) is an indicator of NFkB activation. We studied the pattern of pIkB expression in CMML as a surrogate of NFkB activation. Methods: We identified a cohort of 24 CMML (CMML1=17; CMML2=7) patients and 9 healthy controls. Cases were characterized clinically and pathologically. Immunohistochemistry (IHC) for pIkB was performed in trephine biopsies using a phosphor-specific antibody (Cell Signaling). The staining pattern was compared to normal bone marrow. We utilized JMP 5.1.2 statistical software to compare a variety of clinical and laboratory parameters. Results: The mean age of patients at diagnosis was 61 (range:38–72). Median WBC, Hgb, PLT, absolute monocytes were 18.6K/ul, 10.2g/dL, 93K/ul, 4K/ul respectively. As expected, the overall survival (OS) was short (mean OS = 11.1 months). Compared to normal bone marrow, pIkB was found to be abnormally activated in maturing granulocytic cells and was found to be present in cytoplasmic as well as nuclear locations. The mean % neutrophils that expressed pIkB was 36.6 compared to 14.9 for normal bone marrow (P Conclusions: An abnormal in situ pIkB expression pattern is present in CMML compared to normal bone marrow, suggesting abnormal activation of NFkB. Interestingly, maturing myeloid cell expression of pIKB was associated with higher WBC and absolute monocyte count. Further studies are warranted in examining the role of NFkB activation in CMML and potential therapeutic intervention in this pathway, such as with proteasome inhibitors.
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- 2007
89. Hemochromatois-Associated Gene Mutations in Patients with Myelodysplastic Syndromes with Refractory Anemia and Ringed Sideroblasts
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Hadrian Szpurka, Bianca Serio, Mikkael A. Sekeres, Alan E. Lichtin, Jaroslaw P. Maciejewski, Ilka Warshawsky, and Zachary P. Nearman
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Thrombocytosis ,Myelodysplastic syndromes ,Immunology ,Cell Biology ,Hematology ,Gene mutation ,Biology ,Refractory anemia with ringed sideroblasts ,medicine.disease ,Biochemistry ,hemic and lymphatic diseases ,Genotype ,medicine ,Restriction fragment length polymorphism ,Allele ,Hemochromatosis - Abstract
Complex interaction between a multitude of genetic variants may be responsible for differential susceptibility to specific diseases, and be responsible for phenotypic variability and heterogeneity of clinical presentations. Such a variability in clinical features confounded for many years investigations into the pathogenesis of myelodysplastic syndromes (MDS). We made a curious observation of increased ferritin levels in some newly diagnosed patients with MDS RARS (refractory anemia with ringed sideroblasts) in whom transfusional iron-overload was unlikely due to very low transfusion burden. Hence, we hypothesized that RARS patients may harbor hemochromatosis-related mutations, which could contribute to the pathophysiology of this particular subset of MDS. We studied a cohort of 109 MDS patients; 42 with RARS, and 67 with other forms of MDS (18 RA, 12 RAEB, 7 RAEB-T, 1 CMML, and 29 MDS/MPD overlap). All patients were genotyped using restriction fragment length polymorphism (RFLP) method, designed to detect presence of C282Y and H63D mutations of the HFE gene. We found significantly higher frequency of heterozygozity for the C282Y mutation in 21% of RARS patients (vs 9% in control population, n=2016, p= 0.017) while H63D genotype was not increased. The possible pathogenic role of this finding in RARS was supported by the normal distribution of mutant HFE alleles in patients with other forms of MDS (5% vs. 9%, p =0.35). Interestingly, 3/7 patients with RA not fulfilling the RARS criteria, but having increased numbers of ringed sideroblasts (
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- 2006
90. Impact of Genetic Polymorphisms on Immune Response and Clinical Features in MDS
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Anna M. Jankowska, Ramon V. Tiu, Giridharan Ramsingh, Bianca Serio, Jaroslaw P. Maciejewski, Mikkael A. Sekeres, Christine O’Keefe, Hadrian Szpurka, and Zach Nearman
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Genetics ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Haplotype ,Single-nucleotide polymorphism ,Cell Biology ,Hematology ,Human leukocyte antigen ,Biology ,Biochemistry ,Gastroenterology ,Pathogenesis ,Interleukin 10 ,Immune system ,Cytokine ,hemic and lymphatic diseases ,Internal medicine ,Genotype ,medicine - Abstract
The pathogenesis of cytopenias in myelodysplastic syndrome (MDS) is not fully explained by evolution of the clonal displacement of normal hematopoiesis. The quality of immune surveillance may contribute to generalized hematopoietic inhibition. E.g., certain cases may present with hypocellular marrow reminiscent of idiopathic aplastic anemia (AA). Immunogenetic background resulting from predisposing complex traits can influence the quality of immune response and shape clinical features of MDS. Immunogenetic factors include: KIR and KIR-ligand (KIR-L) genotype, as well as cytokine/receptor single nucleotide polymorphisms (SNP). We genotyped 130 patients with MDS (32 RA/RAMCD, 24 RARS/ RAMCD-RS, 51 RAEB/sAML, 23 MDS/MPD and CMML). Controls included current (n=87) and historical controls. We studied HLA type, KIR, KIR-L genotypes, and immunomodulatory SNPs, including: IL-1α (−889 T/C), IL-1R (−1970 C/T), IL-1RA (mspa111100 T/C), IL-4RA (+ 190 G/A), IL-1β (−511 C/T, +3962 T/C), IL-6 (−174 C/G, nt565 G/A), IL-10 (−1082 G/A, −819 C/T), IL-12 (−1188 C/A), TGF-β (+10 C/T, +25 G/C), TGF-βR2 (+358 A), INF-γ (+874 A/T), TNF-α (−308 G/A, −238 G/A), CTLA-4 (exon 1, +49 A/G), FcγIIIR (+559 G/T) as well as SNPs in CD45 gene (exon 4 +77 C/G, +138 A/G). In all MDS, no difference in the frequency of KIR genotype constellations was identified. However, higher frequency of stimulatory KIR2DS2 in low grade MDS (72% vs 48% in controls, p=.01) and 2DS5 in hypocellular MDS (62% vs 26%, p=.02) was found. When KIR-L C1/C2 genotype was studied, no significant difference in haplotype frequency was observed compared to controls. However, an increased incidence of C2/C2 was found in high grade MDS (70% vs 24%, p=.003). Analysis of the resulting KIR/KIR-L combination demonstrated increased frequency of inhibitory KIR2DL3/C1 mismatch (34% vs 16%, p=.04) in the MDS cohort consistent with higher cytotoxicity. A similar observation was made when we compared advanced and low-grade MDS (70% vs 23%, p=.02). A higher proportion of 2DS2/C1 mismatches (50% vs 10%, p=.006) in advanced MDS could reflect lesser degree of immune surveillance facilitating clonal expansion. No significant difference in MDS cohort, nor in any of subgroups compared to control and each other, was found for the SNPs in IL-4Rα, IL-12, IL-1β, IL-6, TGF-βR2, IL-10, IL-12, IL-1α, IL-1R, FcγIIIR, and CD45. However, when we examined the frequency of INF-γ and TGF-β genotypes, increased frequency of INF-γ AT variant (62% vs 33% in controls, p=.015) and a decrease frequency of TGF-β genotype T/T-G/G or T/C-G/G (53% vs 74%, p=.04) were found, consistent with high secretor phenotype. In addition, higher incidence of G/G phenotype for the CTLA-4 gene (p=.0001) was found in the MDS cohort and in low grade MDS (p=.003). Heightened immune response could result in similar hematopoietic suppression as observed in AA, and lead to hypoplasia. Consequently, we subdivided all MDS patients according to marrow cellularity and found that hypoplastic variant of MDS (n=10) was characterized by higher prevalence of A/T phenotype of INF-γ gene (70% vs 33%, p=.02), similar to a cohort of AA patients (n=26, 50% vs 33%, p=.05). An analogous observation was also made for G/A genotype of TNF-α. In sum, our findings demonstrate that a large number of immunogenetic predisposition factors associated with more risk immune response may exist in MDS, which may influence certain clinical features and phenotype.
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- 2006
91. Avascular necrosis in long-term survivors after allogeneic or autologous stem cell transplantation.
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Libuse Tauchmanovà, Gennaro De Rosa, Bianca Serio, Flavio Fazioli, Ciro Mainolfi, Gaetano Lombardi, Annamaria Colao, Marco Salvatore, Bruno Rotoli, and Carmine Selleri
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- 2003
- Full Text
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92. Successful management of pulmonary mucormycosis with liposomal amphotericin B and surgery treatment: a case report
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Bianca, Serio, Rosa, Rosamilio, Giudice, Valentina, Zeppa, Pio, Esposito, Silvano, Raffaele, Fontana, Silvana, Annunziata, Ida Lucia Ferrara, and Selleri, Carmine
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Adult ,Male ,Antifungal Agents ,Lung Diseases, Fungal ,Amphotericin B ,Remission Induction ,Humans ,Mucormycosis ,Combined Modality Therapy - Abstract
Mucormycosis is an increasingly recognized invasive fungal infection (IFI) in patients with acute myeloid leukemia (AML) and after allogeneic (allo) stem cell transplantation (HSCT); it is mainly due to the severe and prolonged neutropenia related to high-dose chemotherapy. In such patients, the lung is the most frequently involved site in mucormycosis. Since rapidly progressive dissemination may occur after pulmonary mucormycosis in hematologic malignancies, early diagnosis and prompt initiation of an effective antifungal therapy is mandatory for a successful outcome. We report the case of a young AML patient who developed, early after the onset of neutropenia in the first induction phase of chemotherapy, a rapidly progressive pulmonary IFI, successfully treated with liposomal Amphotericin-B (LAmB) and then with a limited open toracothomy biopsy, clearly establishing diagnosis of mucormycosis and removing lung infiltrate. Secondary prophylaxis with LamB, applied during both consolidation therapy and myeloablative sibling allogeneic HSCT, was effective to prevent IFI recurrence despite the development of grade I acute graft-versus-host disease (GVHD) and limited chronic GVHD requiring immunosuppressive treatment. Our case report further provide evidence that the combined surgical and LAmB therapy is an effective and safe choice for the management of pulmonary mucormycosis in hematological immunocompromised patients.
93. Accelerated bone mass senescence after hematopoietic stem cell transplantation
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Bianca, Serio, Luca, Pezzullo, Raffaele, Fontana, Silvana, Annunziata, Rosa, Rosamilio, Maria Rosaria Sessa, Valentina Giudice, Idalucia, Ferrara, Monia, Rocco, Gennaro De Rosa, Patrizia, Ricci, Libuse, Tauchmanovà, Nunzia, Montuori, Carmine Selleri, Serio, B, Pezzullo, L, Fontana, R, Annunziata, S, Rosamilio, R, Sessa, M, Giudice, V, Ferrara, I, Rocco, M, DE ROSA, Gennaro, Ricci, P, Tauchmanovà, L, Montuori, Nunzia, and Selleri, C.
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bone mass ,surgical procedures, operative ,immune system diseases ,hemopoietic stem cell transplantation ,Articles ,osteoporosis ,bisphosphonates ,allogeneic bone marrow transplantation - Abstract
Osteoporosis and avascular necrosis (AVN) are long-lasting and debilitating complications of hematopoietic stem cell transplantation (HSCT). We describe the magnitude of bone loss, AVN and impairment in osteogenic cell compartment following autologous (auto) and allogeneic (allo) HSCT, through the retrospective bone damage revaluation of 100 (50 auto- and 50 allo-HSCT) long-term survivors up to 15 years after transplant. Current treatment options for the management of these complications are also outlined. We found that auto- and allo-HSCT recipients show accelerated bone mineral loss and micro-architectural deterioration during the first years after transplant. Bone mass density (BMD) at the lumbar spine, but not at the femur neck, may improve in some patients after HSCT, suggesting more prolonged bone damage in cortical bone. Phalangeal BMD values remained low for even more years, suggesting persistent bone micro-architectural alterations after transplant. The incidence of AVN was higher in allo-HSCT recipients compared to auto-HSCT recipients. Steroid treatment length, but not its cumulative dose was associated with a higher incidence of bone loss. Allo-HSCT recipients affected by chronic graft versus host disease seem to be at greater risk of continuous bone loss and AVN development. Reduced BMD and higher incidence of AVN was partly related to a reduced regenerating capacity of the normal marrow osteogenic cell compartment. Our results suggest that all patients after auto-HSCT and allo-HSCT should be evaluated for their bone status and treated with anti-resorptive therapy as soon as abnormalities are detected.
94. Host genetics and COVID-19 severity: increasing the accuracy of latest severity scores by Boolean quantum features
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Gabriele Martelloni, Alessio Turchi, Chiara Fallerini, Andrea Degl’Innocenti, Margherita Baldassarri, Simona Olmi, Simone Furini, Alessandra Renieri, GEN-COVID Multicenter study, Francesca Mari, Sergio Daga, Ilaria Meloni, Mirella Bruttini, Susanna Croci, Mirjam Lista, Debora Maffeo, Elena Pasquinelli, Giulia Brunelli, Kristina Zguro, Viola Bianca Serio, Enrica Antolini, Simona Letizia Basso, Samantha Minetto, Giulia Rollo, Martina Rozza, Angela Rina, Rossella Tita, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Anna Maria Pinto, Francesca Ariani, Francesca Montagnani, Mario Tumbarello, Ilaria Rancan, Massimiliano Fabbiani, Elena Bargagli, Laura Bergantini, Miriana d’Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli Raffaelli, Arianna Emiliozzi, Marco Feri, Alice Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Gian Piero Caldarelli, Davide Romani, Paolo Piacentini, Maria Bandini, Elena Desanctis, Silvia Cappelli, Anna Canaccini, Agnese Verzuri, Valentina Anemoli, Manola Pisani, Agostino Ognibene, Maria Lorubbio, Alessandro Pancrazzi, Massimo Vaghi, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Mario U. Mondelli, Stefania Mantovani, Raffaele Bruno, Marco Vecchia, Marcello Maffezzoni, Enrico Martinelli, Massimo Girardis, Stefano Busani, Sophie Venturelli, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Carlo Pallotto, Saverio Giuseppe Parisi, Monica Basso, Sandro Panese, Stefano Baratti, Pier Giorgio Scotton, Francesca Andretta, Mario Giobbia, Renzo Scaggiante, Francesca Gatti, Francesco Castelli, Eugenia Quiros-Roldan, Melania Degli Antoni, Isabella Zanella, Matteo della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Gabriella Maria Squeo, Filippo Aucella, Pamela Raggi, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Alessandra Guarnaccia, Serafina Valente, Alex Di Florio, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Gianluca Lacerenza, Cristina Mussini, Luisa Tavecchia, Lia Crotti, Gianfranco Parati, Roberto Menè, Maurizio Sanarico, Marco Gori, Francesco Raimondi, Alessandra Stella, Filippo Biscarini, Tiziana Bachetti, Maria Teresa La Rovere, Maurizio Bussotti, Serena Ludovisi, Katia Capitani, Simona Dei, Sabrina Ravaglia, Annarita Giliberti, Giulia Gori, Rosangela Artuso, Elena Andreucci, Angelica Pagliazzi, Erika Fiorentini, Antonio Perrella, Francesco Bianchi, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Sauro Luchi, Giovanna Morelli, Paola Petrocelli, Sarah Iacopini, Sara Modica, Silvia Baroni, Giulia Micheli, Marco Falcone, Donato Urso, Giusy Tiseo, Tommaso Matucci, Davide Grassi, Claudio Ferri, Franco Marinangeli, Francesco Brancati, Antonella Vincenti, Valentina Borgo, Stefania Lombardi, Mirco Lenzi, Massimo Antonio Di Pietro, Francesca Vichi, Benedetta Romanin, Letizia Attala, Cecilia Costa, Andrea Gabbuti, Alessio Bellucci, Marta Colaneri, Patrizia Casprini, Cristoforo Pomara, Massimiliano Esposito, Roberto Leoncini, Michele Cirianni, Lucrezia Galasso, Marco Antonio Bellini, Chiara Gabbi, and Nicola Picchiotti
- Subjects
COVID-19 ,host genetics ,integrated polygenic score ,genetic algorithm ,logistic regression ,genetic science modeling ,Genetics ,QH426-470 - Abstract
The impact of common and rare variants in COVID-19 host genetics has been widely studied. In particular, in Fallerini et al. (Human genetics, 2022, 141, 147–173), common and rare variants were used to define an interpretable machine learning model for predicting COVID-19 severity. First, variants were converted into sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. After that, the Boolean features, selected by these logistic models, were combined into an Integrated PolyGenic Score (IPGS), which offers a very simple description of the contribution of host genetics in COVID-19 severity.. IPGS leads to an accuracy of 55%–60% on different cohorts, and, after a logistic regression with both IPGS and age as inputs, it leads to an accuracy of 75%. The goal of this paper is to improve the previous results, using not only the most informative Boolean features with respect to the genetic bases of severity but also the information on host organs involved in the disease. In this study, we generalize the IPGS adding a statistical weight for each organ, through the transformation of Boolean features into “Boolean quantum features,” inspired by quantum mechanics. The organ coefficients were set via the application of the genetic algorithm PyGAD, and, after that, we defined two new integrated polygenic scores (IPGSph1 and IPGSph2). By applying a logistic regression with both IPGS, (IPGSph2 (or indifferently IPGSph1) and age as inputs, we reached an accuracy of 84%–86%, thus improving the results previously shown in Fallerini et al. (Human genetics, 2022, 141, 147–173) by a factor of 10%.
- Published
- 2024
- Full Text
- View/download PDF
95. Case report: PIK3CA somatic mutation leading to Klippel Trenaunay Syndrome and multiple tumors
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Viola Bianca Serio, Maria Palmieri, Simona Innamorato, Lorenzo Loberti, Chiara Fallerini, Francesca Ariani, Enrica Antolini, Jasmine Covarelli, Massimo Vaghi, Elisa Frullanti, Alessandra Renieri, and Anna Maria Pinto
- Subjects
NGS-liquid biopsy ,Klippel-Trenaunay Syndrome ,squamous cell carcinoma adenocarcinoma ,tailored therapy ,case report ,Genetics ,QH426-470 - Abstract
We report a case of Klippel Trenaunay Syndrome that was monitored both clinically and molecularly over a period of 9 years. A somatic mosaic mutation of PIK3CA (p(E545G)) was identified using both cfDNA NGS liquid biopsy and tissue biopsy. At the age of 56, due to intervening clonal mutations in PIK3CA background, she developed a squamous cell carcinoma in the right affected leg which was treated surgically. Nine years later, lung bilateral adenocarcinoma arose on PIK3CA mutated tissues supported by different clonal mutations. One year later, the patient died from metastases led by a new FGFR3 clone unresponsive to standard-of-care, immunotherapy-based. Our results highlight the presence of a molecular hallmark underlying neoplastic transformation that occurs upon an angiodysplastic process and support the view that PIK3CA mutated tissues must be treated as precancerous lesions. Importantly, they remark the effectiveness of combining cfDNA NGS liquid and tissue biopsies to monitor disease evolution as well as to identify aggressive clones targetable by tailored therapy, which is more efficient than conventional protocols.
- Published
- 2023
- Full Text
- View/download PDF
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