131 results on '"Girardi, A."'
Search Results
2. Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients
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Cyrenne, Benoit M., Lewis, Julia M., Weed, Jason G., Carlson, Kacie R., Mirza, Fatima N., Foss, Francine M., and Girardi, Michael
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- 2017
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3. The genetics and molecular biology of T-ALL
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Girardi, Tiziana, Vicente, Carmen, Cools, Jan, and De Keersmaecker, Kim
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- 2017
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4. Prospective and Retrospective Observational Study in Adult and Pediatric Patients with GATA2 Variants (GATA2 Deficiency)
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Samuele Roncareggi, Katia Girardi, Francesca Fioredda, Francesca Conti, Erika Borlenghi, Concetta Micalizzi, Gaia Mancuso, Fabiola Guerra, Emilia Cirillo, Antonio Marzollo, Piero Farruggia, Daniela Onofrillo, Riccardo Masetti, Raffaele Badolato, Luca Arcuri, Tiziana Angela Coliva, Francesca Vendemini, Claudio Pignata, Sonia Bonanomi, Andrea Biondi, and Francesco Saettini
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
5. Impact of Anti-Sars-Cov-2 Monoclonal Antibodies in the Management of Patients with Lymphoma and COVID19: A Retrospective Study
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Assanto, Giovanni Manfredi, primary, Di Rocco, Alice, additional, Malfona, Francesco, additional, Capriata, Marcello, additional, Del Giudice, Ilaria, additional, Petrucci, Luigi, additional, Girardi, Paola, additional, D'elia, Gianna Maria, additional, Martelli, Maurizio, additional, Gentile, Giuseppe, additional, Micozzi, Alessandra, additional, and Pulsoni, Alessandro, additional
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- 2022
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6. Prospective and Retrospective Observational Study in Adult and Pediatric Patients with GATA2 Variants (GATA2 Deficiency)
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Roncareggi, Samuele, primary, Girardi, Katia, additional, Fioredda, Francesca, additional, Conti, Francesca, additional, Borlenghi, Erika, additional, Micalizzi, Concetta, additional, Mancuso, Gaia, additional, Guerra, Fabiola, additional, Cirillo, Emilia, additional, Marzollo, Antonio, additional, Farruggia, Piero, additional, Onofrillo, Daniela, additional, Masetti, Riccardo, additional, Badolato, Raffaele, additional, Arcuri, Luca, additional, Coliva, Tiziana Angela, additional, Vendemini, Francesca, additional, Pignata, Claudio, additional, Bonanomi, Sonia, additional, Biondi, Andrea, additional, and Saettini, Francesco, additional
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- 2022
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7. Brentuximab in Children, Adolescent and Young Adults with Relapsed/Refractory Anaplastic Large Cell Lymphoma
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Vinti, Luciana, primary, Merli, Pietro, additional, Agolini, Emanuele, additional, Stocchi, Francesca, additional, Lucarelli, Barbarella, additional, Girardi, Katia, additional, Algeri, Mattia, additional, Boccieri, Emilia, additional, Lodi, Mariachiara, additional, Becilli, Marco, additional, and Cefalo, Maria Giuseppina, additional
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- 2022
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8. Brentuximab in Children, Adolescent and Young Adults with Relapsed/Refractory Anaplastic Large Cell Lymphoma
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Luciana Vinti, Pietro Merli, Emanuele Agolini, Francesca Stocchi, Barbarella Lucarelli, Katia Girardi, Mattia Algeri, Emilia Boccieri, Mariachiara Lodi, Marco Becilli, and Maria Giuseppina Cefalo
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
9. High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade
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Kießling, Michael K., Oberholzer, Patrick A., Mondal, Chandrani, Karpova, Maria B., Zipser, Marie C., Lin, William M., Girardi, Michael, MacConaill, Laura E., Kehoe, Sarah M., Hatton, Charlie, French, Lars E., Garraway, Levi A., Polier, Gernot, Süss, Dorothee, Klemke, Claus-Detlev, Krammer, Peter H., Gülow, Karsten, and Dummer, Reinhard
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- 2011
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10. Response to Extracorporeal Photopheresis in Patients with Cutaneous T-Cell Lymphoma: A Retrospective Medical Chart Review
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Girardi, Michael, primary, Johnson, Amy G, additional, Carlson, Kacie, additional, Huang, Xingyue, additional, Corman, Shelby, additional, Edmundson, Patrick, additional, Kale, Hrishikesh P, additional, Rusibamayila, Nifasha, additional, and Foss, Francine M., additional
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- 2021
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11. Rapid generation of maturationally synchronized human dendritic cells: contribution to the clinical efficacy of extracorporeal photochemotherapy
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Berger, Carole, Hoffmann, Kristin, Vasquez, Juan G., Mane, Shrikant, Lewis, Julia, Filler, Renata, Lin, Aiping, Zhao, Hongyu, Durazzo, Tyler, Baird, Abigail, Lin, William, Foss, Francine, Christensen, Inger, Girardi, Michael, Tigelaar, Robert, and Edelson, Richard
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- 2010
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12. Risk of Recurrent Venous Thromboembolism in Patients with Acute Isolated Subsegmental Pulmonary Embolism - a Single Center Chart Review
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Girardi, Laura, Ciuffini, Leonardo, Mai, Vicky, Carrier, Marc, and Le Gal, Gregoire
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- 2023
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13. Role of tissue factor in a mouse model of thrombotic microangiopathy induced by antiphospholipid antibodies
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Seshan, Surya V., Franzke, Claus-Werner, Redecha, Patricia, Monestier, Marc, Mackman, Nigel, and Girardi, Guillermina
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- 2009
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14. Pravastatin prevents miscarriages in mice: role of tissue factor in placental and fetal injury
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Redecha, Patricia, van Rooijen, Nico, Torry, Donald, and Girardi, Guillermina
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- 2009
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15. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody–induced fetal injury
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Redecha, Patricia, Tilley, Rachel, Tencati, Michael, Salmon, Jane E., Kirchhofer, Daniel, Mackman, Nigel, and Girardi, Guillermina
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- 2007
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16. Response to Extracorporeal Photopheresis in Patients with Cutaneous T-Cell Lymphoma: A Retrospective Medical Chart Review
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Nifasha Rusibamayila, Hrishikesh Kale, Amy G Johnson, Shelby Corman, Francine M. Foss, Kacie R. Carlson, Patrick Edmundson, Xingyue Huang, and Michael Girardi
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medicine.medical_specialty ,business.industry ,Medical record ,Immunology ,Cutaneous T-cell lymphoma ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Dermatology ,Extracorporeal Photopheresis ,medicine ,In patient ,business - Abstract
INTRODUCTION Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has been used in the treatment of cutaneous T-cell lymphoma (CTCL) for over 30 years. Clinical trials of newer agents for the treatment of CTCL have shown response rates of approximately 30% in heterogeneous patient populations. The objective of this study was to assess the effectiveness of ECP in the treatment of CTCL patients in real-world clinical practice. METHODS This is an interim analysis of a retrospective medical chart review study conducted at clinical sites in the United States, in which treating physicians were responsible for patient selection and data collection via structured case report forms. Patients with a confirmed diagnosis of CTCL who initiated ECP between January 1, 2017 and February 28, 2019 were included in the study. In addition, patients must have initiated ECP at age ≥18 years with no ECP treatment received within the year prior to data collection, have received at least 3 months of ECP treatment, and have response data available in the patient chart. Data collected included patient demographics, clinical characteristics, and treatments received prior to and concomitantly with ECP. Clinical outcomes were collected every 3 months during treatment for up to 18 months, and included the body surface area (BSA) affected, appearance of new skin lesions, and the physician-rated Clinical Global Impression-Improvement (CGI-I) scores. Response to ECP was defined as >50% reduction in BSA affected at any point during the follow-up period, consisting of the time from ECP initiation through the time of data collection. Data analysis was descriptive in nature. RESULTS Four clinical sites participated in the study and enrolled a total of 26 patients for the interim analysis. Patients were predominantly female (53.8%) and White (88.5%). Mean age at CTCL diagnosis was 68.4 years, and the majority patients were diagnosed with Sézary syndrome (57.5%) or mycosis fungoides (30.8%). Nearly half of patients (46.1%) had stage IV disease at diagnosis (IVA, 26.9%; IVB, 19.2%) and half of patients (50.0%) had lymph node involvement at diagnosis. Median BSA involvement with plaques/patches at diagnosis was 80% (interquartile range [IQR], 20% to 90%). Six patients (23.1%) achieved >50% reduction in BSA affected, and among those, median time to response was 6.0 months (IQR, 2.9 to 15.0 months). New skin lesions appeared in 5 patients (19.2%). Among those with available data, the percentage of patients rated as minimally improved, much improved, or very much improved on the CGI-I was 57.7% at 3 months (N=26), 50.0% at 6 months (N=18), and 60.0% at 9 months (N=15) after ECP initiation. CONCLUSIONS This retrospective observational study describes patient characteristics and clinical outcomes among CTCL-diagnosed patients initiating therapy with ECP. Despite the population treated with ECP in real-world practice being older and having more advanced-stage disease compared to recent clinical trials, response rate was comparable. Disclosures Girardi: Transimmune: Patents & Royalties: Inventor/IP; Helsinn: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Soligenix: Research Funding; Mallinckrodt Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Stradefy Biosciences Inc: Patents & Royalties: Inventor/IP; Actelion: Membership on an entity's Board of Directors or advisory committees, Research Funding. Huang: Mallinckrodt Pharmaceuticals: Current Employment. Corman: Mallinckrodt Pharmaceuticals: Consultancy. Edmundson: Mallinckrodt Pharmaceuticals: Consultancy. Kale: Mallinckrodt Pharmaceuticals: Consultancy. Rusibamayila: Mallinckrodt Pharmaceuticals: Consultancy. Foss: Kura: Honoraria; Daiichi Sankyo: Honoraria; Seattle Genetics: Honoraria, Speakers Bureau; Acrotech: Honoraria, Speakers Bureau; Mallinckrodt: Honoraria; Kyowa: Honoraria.
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- 2021
17. Weekly Dosing Schedule of Brentuximab Vedotin in Mycosis Fungoides/Sezary Syndrome and Aggressive T Cell Lymphomas
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Lee, Megan, primary, Schiffer, Molly, additional, Isufi, Iris, additional, Huntington, Scott F., additional, Xu, Mina L., additional, Seropian, Stuart, additional, Gowda, Lohith, additional, Kothari, Shalin K., additional, Girardi, Michael, additional, and Foss, Francine M., additional
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- 2020
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18. Weekly Dosing Schedule of Brentuximab Vedotin in Mycosis Fungoides/Sezary Syndrome and Aggressive T Cell Lymphomas
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Francine M. Foss, Michael Girardi, Scott F. Huntington, Stuart Seropian, Shalin Kothari, Lohith Gowda, Iris Isufi, Megan Lee, Molly Schiffer, and Mina L. Xu
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Mycosis fungoides ,medicine.medical_specialty ,CD30 ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Peripheral T-cell lymphoma ,Lymphoma ,Tolerability ,Internal medicine ,medicine ,Dosing ,Brentuximab vedotin ,business ,Anaplastic large-cell lymphoma ,medicine.drug - Abstract
Introduction While the approved dose of brentuximab in T cell lymphomas has been every 3 weeks on a 1.8 mg/kg schedule, earlier studies exploring weekly dosing showed that a dose of 1.2 mg/kg on a weekly dosing (every 3 out of 4 weeks) in pts with Hodgkin's lymphoma and hematologic malignancies may improve cancer response rates while still having manageable side effects3. We explored the weekly dosing schedule in 37 pts (pts) with mycosis fungoides/Sezary syndrome (MF/SS) and aggressive T cell lymphomas and compared to our experience with every 3 week dosing in 36 pts to evaluate tolerability and efficacy of the weekly schedule.. Methods We reviewed charts of 67 pts, 36 received dosing q 3 weeks and 37 received a dose weekly for 3 consecutive weeks on a 4-week schedule. Pts included MF/SS (n=35), gamma delta T cell lymphoma (n=2), anaplastic large cell lymphoma (n=12), Peripheral T cell Lymphoma (n=10), angioimmunoblastic T cell lymphoma (n=4), adult T cell leukemia (n=2), and NK-T cell lymphoma. Pts were treated with brentuximab vedotin at a dose of either 1.8 mg/kg every 3 weeks or 1.2 mg/kg weekly x 3 every 4 weeks. CD30 expression was scored by the pathologist in tumor biopsies as high (10%-49%). Toxicity data was recorded from the medical records and data analyzed descriptively. Results Of 67 pts in this study, the average age was 61. Doses were 1.8 mg/kg for the q 3 week schedule and 0.75 to 1.2 mg/kg for the weekly x 3 schedule. Cycles were 3-47 for q 3 weeks and 1-9.7 for weekly dosing. CD30 expression was high in 13% of pts, low in 43%, and absent in 6% with equal distribution between the weekly and q 3 week cohorts, as shown in Table 1. Dose adjustments were made in 67% of q 3 week and 61% of weekly pts for neurotoxicity (n=28), with a higher incidence in the q 3 week pts compared to those with weekly dosing (75% vs 53%, p=0.01) . Discontinuation for progression (25% vs 30%) was similar for both groups. In the weekly group, 8 pts had a stem cell transplant, including allogeneic transplantation in 3. Conclusion In the Phase II registration trial of brentuximab vedotin 1.8 mg/kg q3 weeks, 41% of pts had neuropathy (severe in 12%). 1 Forty two percent of discontinuations were for neuropathy. In our weekly schedule, incidence of neuropathy was lower and led to fewer treatment discontinuations. Our retrospective data shows that Brentuximab vedotin is well tolerated on a weekly dosing schedule and has activity in pts with MF/SS and aggressive T cell lymphomas. As in prior studies, responses were seen with low CD30 expression4, 5. Prospective clinical trials with a self-reported neurotoxicity scale and quality of life instruments should be performed address the impact of more frequent, lower doses of brentuximab vedotin on patient outcomes. 1 Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T et al.J Clin Oncol 2012; 30(18): 2190-2196. doi: 10.1200/JCO.2011.38.0402 2 Prince HM, Kim YH, Horwitz SM, Dummer R, Scarisbrick J, Quaglino P et al.Lancet 2017; 390(10094): 555-566. doi: 10.1016/S0140-6736(17)31266-7 3 Fanale MA, Forero-Torres A, Rosenblatt JD, Advani RH, Franklin AR, Kennedy DA et al.Clin Cancer Res 2012; 18(1): 248-255. doi: 10.1158/1078-0432.CCR-11-1425 4 Duvic M, Tetzlaff MT, Gangar P, Clos AL, Sui D, Talpur R. J Clin Oncol 2015; 33(32): 3759-3765. doi: 10.1200/JCO.2014.60.3787 5 Kim YH, Tavallaee M, Sundram U, Salva KA, Wood GS, Li S et al.J Clin Oncol 2015; 33(32): 3750-3758. doi: 10.1200/JCO.2014.60.3969 Figure Disclosures Huntington: Pharmacyclics: Honoraria; DTRM: Research Funding; Genentech: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Bayer: Consultancy, Honoraria; AbbVie: Consultancy; Astrazeneca: Honoraria. Xu:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.
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- 2020
19. SLC20A1 at the Interface between Macrophages and Red Blood Cells
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Quattrone, Federica, primary, Gawish, Riem, primary, Martins, Rui, primary, Gorki, Anna-Dorothea, primary, Watzenboeck, Martin, primary, Hladik, Anastasiya, primary, Lakovits, Karin, primary, Rebsamen, Manuele, primary, Girardi, Enrico, primary, Superti-Furga, Giulio, primary, and Knapp, Sylvia, primary
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- 2019
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20. A New Promising Third Generation CAR-CD30 T-Cell Therapy for CD30+ Lymphoma
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De Angelis, Biagio, primary, Guercio, Marika, additional, Orlando, Domenico, additional, Di Cecca, Stefano, additional, Sinibaldi, Matilde, additional, Boffa, Iolanda, additional, Caruso, Simona, additional, Abbaszadeh, Zeinab, additional, Camera, Antonio, additional, Biancamaria, Cembrola, additional, Bovetti, Katia, additional, Caruana, Ignazio, additional, Del Bufalo, Francesca, additional, Merli, Pietro, additional, Vinti, Luciana, additional, Girardi, Katia, additional, Ruggeri, Annalisa, additional, De Vito, Rita, additional, Quintarelli, Concetta, additional, and Locatelli, Franco, additional
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- 2019
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21. Two Different Platelet Thresholds for Bleeding Prophylaxis in Children with Malignancies or Non-Malignant Disorders: The Bambino Gesù Children's Hospital Experience
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Berti, Pierpaolo, primary, Trua, Guglielmo, additional, Lamura, Francesco, additional, Costantino, Laila, additional, Damico, Costantino, additional, Paoloni, Alessandra, additional, Romano, Maria Teresa, additional, Girardi, Katia, additional, Strocchio, Luisa, additional, Cicchetti, Elisabetta, additional, Bernardi, Alessandra, additional, De Nava, Valentina, additional, Cappelli, Antonio, additional, Onetti Muda, Andrea, additional, and Montanari, Mauro, additional
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- 2019
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22. The genetics and molecular biology of T-ALL
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Tiziana Girardi, Kim De Keersmaecker, Carmen Vicente, and Jan Cools
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0301 basic medicine ,medicine.medical_treatment ,Immunology ,Biology ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Bioinformatics ,medicine.disease_cause ,Biochemistry ,Article ,Targeted therapy ,Pathogenesis ,03 medical and health sciences ,CDKN2A ,hemic and lymphatic diseases ,medicine ,Humans ,Epigenetics ,Transcription factor ,Genetics ,Mutation ,Cell Biology ,Hematology ,medicine.disease ,Leukemia ,030104 developmental biology ,Signal transduction - Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy caused by the accumulation of genomic lesions that affect the development of T-cells. Since many years, it has been established that deregulated expression of transcription factors, impairment of the CDKN2A/2B cell cycle regulators and hyperactive NOTCH1 signaling play prominent roles in the pathogenesis of this leukemia. In the past decade, systematic screening of T-ALL genomes by high resolution copy number arrays and next- generation sequencing technologies has revealed that T-cell progenitors accumulate additional mutations affecting JAK/STAT signaling, protein translation and epigenetic control, providing novel attractive targets for therapy. In this review, we provide an update on our knowledge on T-ALL pathogenesis, on the opportunities for the introduction of targeted therapy and on the challenges that are still ahead. ispartof: Blood vol:129 issue:9 pages:1113-1123 ispartof: location:United States status: published
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- 2017
23. Prospective and Retrospective Observational Study in Adult and Pediatric Patients with GATA2Variants (GATA2 Deficiency)
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Roncareggi, Samuele, Girardi, Katia, Fioredda, Francesca, Conti, Francesca, Borlenghi, Erika, Micalizzi, Concetta, Mancuso, Gaia, Guerra, Fabiola, Cirillo, Emilia, Marzollo, Antonio, Farruggia, Piero, Onofrillo, Daniela, Masetti, Riccardo, Badolato, Raffaele, Arcuri, Luca, Coliva, Tiziana Angela, Vendemini, Francesca, Pignata, Claudio, Bonanomi, Sonia, Biondi, Andrea, and Saettini, Francesco
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- 2022
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24. Two Different Platelet Thresholds for Bleeding Prophylaxis in Children with Malignancies or Non-Malignant Disorders: The Bambino Gesù Children's Hospital Experience
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Alessandra Paoloni, Mauro Montanari, Valentina De Nava, Andrea Onetti Muda, Guglielmo Trua, Luisa Strocchio, Costantino Damico, Antonio Cappelli, Francesco Lamura, Alessandra Bernardi, Elisabetta Cicchetti, Maria Teresa Romano, Pierpaolo Berti, Katia Girardi, and Laila Costantino
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Pediatrics ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Non malignant ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Hospital experience ,Transplantation ,Platelet transfusion ,Acute lymphocytic leukemia ,medicine ,Platelet ,business - Abstract
Background: Prophylactic platelet transfusion is commonly used to prevent life-threatening bleeding events in patients with severe thrombocytopenia associated with chemotherapy courses or hematopoietic stem cells transplantation (HSCT). In adults, the transfusion threshold for prophylaxis is usually set at 10x109plts/L, but in pediatric setting, it is still a matter of debate. Moreover, evidences from the PLADO trial (Slichter SJ et al. N Engl J Med. 2010) and recommendations form international guidelines (ICTMG, Nahirniak S et al. Transfus Med Rev. 2015) suggest two different platelet doses in Inpatients and Outpatients, but clinical experiences in children are still lacking. Aims: In order to confirm the safety of the recommended transfusion threshold, to test two different platelet doses in hospitalized patients and Outpatient setting and to optimize platelet clinical use, as a Children's Hospital, we applied, starting from January 2018, a new prophylactic platelet transfusion policy. Methods: Platelet dose was calculated based on body-surface area (BSA) of each patient (from age-standardized weight). As suggested by ICTMG, different platelets doses were given to Inpatients and Outpatients: (low-dose) 1.1x1011platelets per square meter (plts/m2) and (medium-dose) 2.2x1011plts/m2, respectively. The transfusion threshold for prophylaxis was set at 10x109plts/L, but higher threshold could be considered as per clinical decision (in presence of bleeding signs or risk factors for major bleeding). Patients with platelets refractoriness and newborns, were excluded from our study. Only major bleeding events (grade 3 or higher according to World Health Organization criteria) were collected during the study period. Results: From January 2018 to June 2019, 15278 platelet pediatric aliquots were transfused in our Hospital. Of all the aliquots, 8876 (58.1%) were obtained from apheresis procedures and 6402 (41.9%) from buffy-coat-derived pooled platelet concentrates. Almost 77% (11751) of the all aliquots were transfused in patients with onco-hematologic diseases. Among these, 9771 (64.0%) in the Inpatient group (N=547) and 1980 (13.0%) in the Outpatient group (N=385). Between Inpatients, 6794 (44.5%) aliquots were transfused in Onco-Hematology Ward and 2977 (19.5%) in the HSCT unit. During the study period, only 10 major bleeding events were observed. No fatal hemorrhagic episode was recorded and all of the bleedings occurred in hospitalized patients, and accounted for almost 2% of this population. Intracranial bleeding accounted for five out of six grade 4 bleeding episodes, and occurred in two patients with acute myelogenous leukemia, in one patient with Hodgkin lymphoma and in two patients with advance neuroblastoma. The other grade 4 bleeding event was a massive peritoneal and pleuric hemorrhage with a life-threatening haemodinamic instability in a patient with acute lymphoblastic leukemia (the main characteristics of these patients are reported in the table). Conclusions: our results show that a platelet transfusion policy based on recommendation mainly developed in adults may be safely applied also to pediatric patients with cancer or receiving HSCT. In fact, the lower dose used in Inpatient group resulted in a grade 4 bleeding rate similar to that observed in the PLADO trial (1.0% vs 0.7%). The double dose transfused in Oupatients was effective in preventing major bleeding events. Table. Disclosures No relevant conflicts of interest to declare.
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- 2019
25. A New Promising Third Generation CAR-CD30 T-Cell Therapy for CD30+ Lymphoma
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Annalisa Ruggeri, Cembrola Biancamaria, Luciana Vinti, Marika Guercio, Stefano Di Cecca, Domenico Orlando, Pietro Merli, Simona Caruso, Concetta Quintarelli, Franco Locatelli, Ignazio Caruana, Zeinab Abbaszadeh, Rita De Vito, Katia Bovetti, Antonio Camera, Iolanda Boffa, Katia Girardi, Biagio De Angelis, Francesca Del Bufalo, and Matilde Sinibaldi
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CD30 ,business.industry ,medicine.medical_treatment ,T cell ,Immunology ,CD34 ,Cell Biology ,Hematology ,Suicide gene ,Biochemistry ,Cytokine ,medicine.anatomical_structure ,Antigen ,NSG mouse ,medicine ,Cancer research ,Cytotoxic T cell ,business - Abstract
Prognosis of a significant proportion of patients with chemotherapy-refractory or multiply-relapsed CD30+ Non-Hodgkin's Lymphoma (NHL) or Hodgkin lymphoma (HL) still remain poor. Targeting CD30 with monoclonal antibodies in HL and anaplastic large cell lymphoma was shown to induce remarkable clinical activity; however, occurrence of adverse events (mainly neuropathy) may result into treatment discontinuation in many patients. Immunotherapeutic approaches targeting CD30 by chimeric antigen receptor (CAR) has been demonstrated to be of value in two independent clinical trials, although clinical benefit was sub-optimal. We designed a new CAR construct characterized by an anti-CD30 single-chain variable-fragment cassette (AC10), linked to CD3ζ by the signaling domains of two costimulatory molecules, namely either CD28.4-1BB or CD28.OX40. The inducible Caspase-9 (iCasp9) safety switch was included in both constructs with the goal of promptly controlling undue toxicity. As a selectable marker, we added in frame the CD34 antigen. The in vitro anti-tumor efficacy was evaluated by using either the NHL cell line: Karpas299, or the HL cell lines: L428, in both short-term cytotoxic assay (51Cr release assays) and long-term co-cultures for 6 days. Supernatant from co-culture experiments was analyzed by Elisa. We assessed the antitumor effect of CAR.CD30 T cells in a in vivo NSG mouse model engrafted i.v. with lymphoma FF-luciferase cell lines Karpas299 or L428, and monitored tumor growth by IVIS Imaging system. For tumor re-challenging, mice of the NHL model surviving until day +140, were i.v. infused with 0.2x106 Karpas299 cells, and subsequently followed for additional 110 days. Persistence of CAR.CD30 T cells was evaluated, together with a deep characterization of memory profile of T cells. Independently from the costimulatory domains CD28.OX40 or CD28.4-1BB, the generated retroviral vectors showed similar transduction efficiency of T cells (86.5±5.1% and 79.3±5.3%, respectively). Nevertheless, CD28.OX40 costimulatory domains was associated with more stable expression of the CAR over time, during extensive in vitro culture (84.72±5.30% vs 63.98±11.51% CD28.4-1BB CAR T cells at 30 days after transduction; p=0.002). For both CAR constructs, we did not observe any significant difference in the suicide gene iCasp9 activity, both in vitro and in vivo. In short-term cytotoxic assay, both CAR.CD30 T cells significantly and specifically lysed CD30+ NHL and HL tumor cell lines. In long-term co-culture, CD28.OX40 showed a superior anti-lymphoma in vitro activity as compared to CD28.41BB T cells, when challenged at very high tumor/effector ratio (8:1) (for Karpas 299; p=0.03). Moreover, the antigen stimulation was associated to higher levels of Th1 cytokine production, with CD28.OX40 T cells secreting a significantly higher amount of IFNγ, IL2 and TNFα as compared to CD28.41BB T cells (p= 0.040; p=0.008; p=0.02; respectively). Bioluminescence in HL (L428) tumor-bearing mice, treated with NT T cells, rapidly increased up to 5 log in less than 50 days and mice either died or were sacrificed due to morbidity. The best outcome was observed in mice treated with CD28.OX40, as three out of five mice were still alive at the experimental end-point of day+165, as compared with mice treated with CD28.4-1BB (60% vs 0%, p=0.0021). In NHL (Karpas 299) mouse models, CD28.OX40 had an extensive anti-tumor control superior to that of CD28.41BB T cells, leading to a significant reduction of tumor bioluminescence at day 45 (3.32x10 vs 2.29x10, p=0.04). The median survival of mice treated with NT and CD28.4-1BB CAR T cells was 45.5 and 58 days respectively, but undetermined for mice treated with CD28.OX40 CAR T cells (p=0.0002). After 140 days, cured mice were re-challenged with Karpas 299; mice were followed for other 100 days. Bioluminescence analysis showed rapid progression of the tumor in the control mice cohort, as well as in CD28.4-1BB treated mice. In contrast, in CD28.OX40 treated mice, at day+240 days, 4 out of 6 mice were tumor-free, resulting into a statistically significant survival benefit (p=0.0014). Only in mice treated with 28.OX40 T cells, we observed a long-lasting persistence of circulating CAR-T cells up to day +221. In summary, we have developed a novel CAR.CD30 construct displaying features that make it a particularly suitable candidate for a clinical trial in patients suffering from CD30+ tumors. Disclosures Merli: Novartis: Honoraria; Sobi: Consultancy; Amgen: Honoraria; Bellicum: Consultancy. Locatelli:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BluebirdBio: Consultancy; Miltenyi: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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- 2019
26. SLC20A1 at the Interface between Macrophages and Red Blood Cells
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Anna-Dorothea Gorki, Karin Lakovits, Federica Quattrone, Rui Martins, Giulio Superti-Furga, Sylvia Knapp, Martin L. Watzenboeck, Anastasiya Hladik, Riem Gawish, Enrico Girardi, and Manuele Rebsamen
- Subjects
Chemistry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Heme transport ,Hemolysis ,Cell biology ,chemistry.chemical_compound ,Nursing care ,medicine.anatomical_structure ,Erythropoietin ,medicine ,Red pulp ,Erythropoiesis ,Hemoglobin ,Heme ,medicine.drug - Abstract
Red blood cells (RBCs) comprise 84% of our body's cells and have the essential function of transporting oxygen from the lungs to all organs. The daily production rate of RBCs is enormous and the pathways mediating this process are quite complex. One important aspect hereby is the synthesis of hemoglobin and heme, the iron-containing prosthetic group that enables hemoglobin to bind oxygen.RBCs differentiate within the erythropoietic niche, which consists of erythroid precursors and specialized macrophages. These so-called nursing macrophages provide nutrients and iron, a fundamental component of heme. The precise mechanisms of heme transport within a cell and the potential of heme transfer between cells is not completely understood. To get insights into heme transport we took advantage of the cytotoxic capacity of heme and performed a CRISPR-Cas9 loss of function screen by focusing on SLC transporters. We identified SLC20A1 as an essential protein mediating heme toxicity and verified that intracellular heme levels as well as heme-induced downstream gene inductions were reduced in the absence of Slc20a1. Based on these evidences we hypothesized that SLC20A1 might be involved in the trafficking of heme, possibly important during erythropoiesis, since mice lacking Slc20a1 exhibit embryonic lethality due to liver apoptosis and anemia (Beck L. et al., PLoS One 2013). To test the biological role of Slc20a1 in adult mice, we conditionally deleted Slc20a1 using tamoxifen in ERT2-Cre Slc20a1fl animals and observed the spontaneous development of severe anemia and splenomegaly within 2 weeks after tamoxifen administration. We further discovered that the anemia-related expansion of red pulp macrophages (RPM) consisted predominantly of non-recombined wild type cells, whereas successfully recombined (Slc20a1 deficient) cells seemed stuck in the monocytic stage. These data suggest that Slc20a1 might be involved in the differentiation and maturation of monocytes to RPMs. When we performed a specific Slc20a1 deletion in nursing macrophages (CD169 Cre), mice neither showed signs of anemia, nor experienced impaired recovery upon anemia induction following phlebotomy or induction of hemolysis. However, deleting Sc20a1 specifically in the erythroid compartment using Slc20a1fl mice crossed to erythropoietin receptor-cre (EpoR-Cre) animals, resulted in embryonic lethality. Mice died around E12.5 due to severe anemia. Analysis of E11.5 animals disclosed erythroid precursors to be arrested in the pro-erythroblast stage.These data suggest that SLC20A1 is a protein involved in heme-mediated toxicity and possibly in the trafficking of heme with strong impact on fetal and adult erythropoiesis. Disclosures No relevant conflicts of interest to declare.
- Published
- 2019
27. Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients
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Fatima N. Mirza, Julia M. Lewis, Michael Girardi, Francine M. Foss, Benoit M. Cyrenne, Jason G. Weed, and Kacie R. Carlson
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0301 basic medicine ,Male ,T cell ,Immunology ,Pharmacology ,Hydroxamic Acids ,Biochemistry ,Romidepsin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Cell Line, Tumor ,Depsipeptides ,medicine ,Humans ,Vorinostat ,neoplasms ,Sulfonamides ,Lymphoid Neoplasia ,Venetoclax ,business.industry ,Cutaneous T-cell lymphoma ,Cell Biology ,Hematology ,medicine.disease ,Bridged Bicyclo Compounds, Heterocyclic ,Lymphoma ,Lymphoma, T-Cell, Cutaneous ,Gene Expression Regulation, Neoplastic ,Histone Deacetylase Inhibitors ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Proto-Oncogene Proteins c-bcl-2 ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Histone deacetylase ,biological phenomena, cell phenomena, and immunity ,Drug Screening Assays, Antitumor ,business ,Ex vivo ,medicine.drug - Abstract
The presence and degree of peripheral blood involvement in patients with cutaneous T-cell lymphoma (CTCL) portend a worse clinical outcome. Available systemic therapies for CTCL may variably decrease tumor burden and improve quality of life, but offer limited effects on survival; thus, novel approaches to the treatment of advanced stages of this non-Hodgkin lymphoma are clearly warranted. Mutational analyses of CTCL patient peripheral blood malignant cell samples suggested the antiapoptotic mediator B-cell lymphoma 2 (BCL2) as a potential therapeutic target. To test this, we developed a screening assay for evaluating the sensitivity of CTCL cells to targeted molecular agents, and compared a novel BCL2 inhibitor, venetoclax, alone and in combination with a histone deacetylase (HDAC) inhibitor, vorinostat or romidepsin. Peripheral blood CTCL malignant cells were isolated from 25 patients and exposed ex vivo to the 3 drugs alone and in combination, and comparisons were made to 4 CTCL cell lines (Hut78, Sez4, HH, MyLa). The majority of CTCL patient samples were sensitive to venetoclax, and BCL2 expression levels were negatively correlated (r = -0.52; P =018) to 50% inhibitory concentration values. Furthermore, this anti-BCL2 effect was markedly potentiated by concurrent HDAC inhibition with 93% of samples treated with venetoclax and vorinostat and 73% of samples treated with venetoclax and romidepsin showing synergistic effects. These data strongly suggest that concurrent BCL2 and HDAC inhibition may offer synergy in the treatment of patients with advanced CTCL. By using combination therapies and correlating response to gene expression in this way, we hope to achieve more effective and personalized treatments for CTCL.
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- 2017
28. Role of tissue factor in a mouse model of thrombotic microangiopathy induced by antiphospholipid antibodies
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Marc Monestier, Patricia Redecha, Surya V. Seshan, Claus Werner Franzke, Guillermina Girardi, and Nigel Mackman
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Adult ,Male ,medicine.medical_specialty ,Thrombotic microangiopathy ,Kidney Glomerulus ,Immunology ,Renal function ,urologic and male genital diseases ,Biochemistry ,Immunoglobulin G ,Thromboplastin ,Thrombosis and Hemostasis ,Antigen-Antibody Reactions ,Mice ,Tissue factor ,immune system diseases ,Internal medicine ,Animals ,Humans ,Medicine ,Platelet ,Renal Insufficiency ,neoplasms ,Hematology ,biology ,business.industry ,Antibodies, Monoclonal ,Thrombosis ,Cell Biology ,Middle Aged ,medicine.disease ,female genital diseases and pregnancy complications ,Mice, Inbred C57BL ,Disease Models, Animal ,Microvessels ,Monoclonal ,Antibodies, Antiphospholipid ,biology.protein ,Female ,business - Abstract
Using different mouse monoclonal and human antiphospholipid (aPL) antibodies, we developed a new animal model of renal injury that shares many features with thrombotic microangiopathy (TMA). We found that more than 1 mechanism/signaling pathway is involved in glomerular injury induced by aPL antibodies in this model. Both complement-dependent and complement-independent pathways were identified that lead to glomerular endothelial cell damage and renal function impairment. We also found that C5a-C5aR interaction is a crucial step for the activation of the coagulation cascade and glomerular injury induced by complement-activating antibodies. In addition, our studies demonstrated complement-independent mechanisms in which reactivity with β2 glycoprotein I (β2GPI) plays an important role in aPL-induced glomerular damage and renal failure. Independently of the mechanism responsible for aPL-induced TMA, mice that express low levels of tissue factor (TF) were protected from glomerular injury. That genetic reduction of TF prevents renal injury induced by different aPL antibodies indicates that TF is a common mediator of glomerular damage and a possible target for selective pharmacologic intervention. Treatment with pravastatin, which down-regulates glomerular TF synthesis, prevents aPL-induced TMA in this mouse model, thus emphasizing that targeting TF might be a good therapeutic intervention in patients with TMA.
- Published
- 2009
29. Tissue factor: a link between C5a and neutrophil activation in antiphospholipid antibody–induced fetal injury
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Nigel Mackman, Rachel E. Tilley, Patricia Redecha, Guillermina Girardi, Daniel Kirchhofer, Michael Tencati, and Jane E. Salmon
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Neutrophils ,Immunology ,Complement C5a ,Inflammation ,Hemostasis, Thrombosis, and Vascular Biology ,Biochemistry ,Neutrophil Activation ,Thromboplastin ,Mice ,Tissue factor ,Pregnancy ,immune system diseases ,Antiphospholipid syndrome ,medicine ,Animals ,Humans ,Receptor, Anaphylatoxin C5a ,neoplasms ,Fetus ,biology ,Trophoblast ,Cell Biology ,Hematology ,medicine.disease ,Respiratory burst ,Oxidative Stress ,medicine.anatomical_structure ,Prenatal Injuries ,embryonic structures ,Antibodies, Antiphospholipid ,Embryo Loss ,biology.protein ,Female ,Antibody ,medicine.symptom ,Signal Transduction - Abstract
Fetal loss in patients with antiphospholipid (aPL) antibodies has been ascribed to thrombosis of placental vessels. However, we have shown that inflammation, specifically activation of complement with generation of the anaphylotoxin C5a, is an essential trigger of fetal injury. In this study, we analyzed the role of the procoagulant molecule tissue factor (TF) in a mouse model of aPL antibody–induced pregnancy loss. We found that either blockade of TF with a monoclonal antibody in wild-type mice or a genetic reduction of TF prevented aPL antibody–induced inflammation and pregnancy loss. In response to aPL antibody–generated C5a, neutrophils express TF potentiating inflammation in the deciduas and leading to miscarriages. Importantly, we showed that TF in myeloid cells but not fetal-derived cells (trophoblasts) was associated with fetal injury, suggesting that the site for pathologic TF expression is neutrophils. We found that TF expression in neutrophils contributes to respiratory burst and subsequent trophoblast injury and pregnancy loss induced by aPL antibodies. The identification of TF as an important mediator of C5a-induced oxidative burst in neutrophils in aPL-induced fetal injury provides a new target for therapy to prevent pregnancy loss in the antiphospholipid syndrome.
- Published
- 2007
30. Efficacy and Safety of Extended Duration Postoperative Thromboprophylaxis with Low-Molecular-Weight-Heparin Among Subgroups of Patients Undergoing Surgical Resection of Colorectal Cancer: A Post-Hoc Analysis of the Periop-01 Trial
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Girardi, Laura, Auer, Rebecca, Mallick, Ranjeeta, Wang, Tzu-Fei, and Carrier, Marc
- Abstract
Background: Clinical practice guidelines suggest the use of extended duration of postoperative thromboprophylaxis to prevent venous thromboembolic (VTE) complications after any cancer-related major abdominal or pelvic surgeries. However, recent trials including patients undergoing surgical resection of colorectal cancer have reported relatively low rates of symptomatic VTE. Hence, the risk and benefits of extended postoperative thromboprophylaxis need to be carefully assessed in this patient population. We sought to determine the impact of extended duration thromboprophylaxis with low-molecular-weight-heparin on VTE and bleeding events among different subgroups of patients undergoing surgical resection of localized colorectal cancer.
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- 2023
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31. Machine Learning-Based Survival Analysis Reveals Prognostic Clinical and Genetic Insights for Patients with Cutaneous T-Cell Lymphoma
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Schreidah, Celine M., DeStephano, David M., Pan, Samuel S., Wang, Shikun, Shen, Haoyang, Ta, Casey N., Reynolds, George Bingham, Fahmy, Lauren M., Gordon, Emily R., Adeuyan, Oluwaseyi, Kwinta, Bradley D., Stonesifer, Connor J., Chan, Warren H., Choi, Jaehyuk, Duvic, Madeleine, Gallardo, Fernando, Girardi, Michael, Guitart, Joan, Kim, Youn H., Khodadoust, Michael S., Najidh, Safa, Ni, Xiao, Pujol, Ramon M., Tensen, Cornelis P., Vermeer, Maarten H., Whittaker, Sean, Tatonetti, Nicholas P., Chase, Herbert S., Pe'er, Itsik, and Geskin, Larisa J.
- Abstract
Introduction:Cutaneous T-cell lymphomas (CTCL) are heterogeneous lymphoproliferative disorders on a spectrum of disease presentation and severity. Around two-thirds of cutaneous T-cell lymphomas can be classified as mycosis fungoides (MF) or Sézary syndrome (SS). While advanced stages of MF and SS are associated with decreased survival and worse outcomes, even early-stage patients can possess a variable course. Numerous deep sequencing studies have fallen short in identifying genetic abnormalities that drive disease pathogenesis and predict prognosis. Large-cell transformation and elevated lactate dehydrogenase levels are associated with worse prognosis in SS; however, such features cannot accurately prognosticate patient survival. There is a need for investigation that may assist in the prognostication of survival in patients with CTCL. Machine learning methods may help to elucidate correlations between clinical and genetic factors to predict disease progression and outcomes.
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- 2023
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32. Synergistic Targeting of Protein Translation and Inhibition of NOTCH Signaling in T-ALL
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Sanchez-Martin, Marta, primary, Ambesi-Impiombato, Alberto, additional, Xu, Luyao, additional, Qin, Yue, additional, Herranz, Daniel, additional, Bansal, Mukesh, additional, Girardi, Tiziana, additional, De Keersmaecker, Kim, additional, Califano, Andrea, additional, and Ferrando, Adolfo A., additional
- Published
- 2015
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33. High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade
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Sarah M. Kehoe, Lars E. French, Patrick A. Oberholzer, William M. Lin, Marie C. Zipser, Chandrani Mondal, Peter H. Krammer, Karsten Gülow, Michael K. Kießling, Laura E. MacConaill, Michael Girardi, Reinhard Dummer, Levi A. Garraway, Claus Detlev Klemke, Dorothee Süss, Charlie Hatton, Gernot Polier, and Maria B. Karpova
- Subjects
Neuroblastoma RAS viral oncogene homolog ,medicine.medical_specialty ,CD30 ,T cell ,Biopsy ,Immunology ,Biology ,medicine.disease_cause ,Biochemistry ,Proto-Oncogene Proteins p21(ras) ,Mycosis Fungoides ,Internal medicine ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,medicine ,Humans ,Sezary Syndrome ,Protein Kinase Inhibitors ,Neoplasm Staging ,Mitogen-Activated Protein Kinase Kinases ,Mutation ,Mycosis fungoides ,Hematology ,Lymphoid Neoplasia ,Cell Biology ,medicine.disease ,Molecular biology ,Lymphoma ,High-Throughput Screening Assays ,Lymphoma, T-Cell, Cutaneous ,medicine.anatomical_structure ,Cancer research ,ras Proteins ,raf Kinases ,KRAS ,Signal Transduction - Abstract
Cutaneous T-cell lymphomas (CTCLs) are malignancies of skin-homing lymphoid cells, which have so far not been investigated thoroughly for common oncogenic mutations. We screened 90 biopsy specimens from CTCL patients (41 mycosis fungoides, 36 Sézary syndrome, and 13 non–mycosis fungoides/Sézary syndrome CTCL) for somatic mutations using OncoMap technology. We detected oncogenic mutations for the RAS pathway in 4 of 90 samples. One mycosis fungoides and one pleomorphic CTCL harbored a KRASG13D mutation; one Sézary syndrome and one CD30+ CTCL harbored a NRASQ61K amino acid change. All mutations were found in stage IV patients (4 of 42) who showed significantly decreased overall survival compared with stage IV patients without mutations (P = .04). In addition, we detected a NRASQ61K mutation in the CTCL cell line Hut78. Knockdown of NRAS by siRNA induced apoptosis in mutant Hut78 cells but not in CTCL cell lines lacking RAS mutations. The NRASQ61K mutation sensitized Hut78 cells toward growth inhibition by the MEK inhibitors U0126, AZD6244, and PD0325901. Furthermore, we found that MEK inhibitors exclusively induce apoptosis in Hut78 cells. Taken together, we conclude that RAS mutations are rare events at a late stage of CTCL, and our preclinical results suggest that such late-stage patients profit from MEK inhibitors.
- Published
- 2011
34. Rapid generation of maturationally synchronized human dendritic cells: contribution to the clinical efficacy of extracorporeal photochemotherapy
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Inger Christensen, Carole L. Berger, Juan Gabriel Vasquez, Michael Girardi, Tyler S. Durazzo, Hongyu Zhao, Julia M. Lewis, Renata B. Filler, Richard L. Edelson, Francine M. Foss, Robert E. Tigelaar, Abigail Baird, Shrikant Mane, William M. Lin, Aiping Lin, and Kristin Hoffmann
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Cellular differentiation ,medicine.medical_treatment ,T cell ,education ,Immunology ,Antigen presentation ,Gene Expression ,Graft vs Host Disease ,Cell Separation ,Biology ,Biochemistry ,Monocytes ,Immunophenotyping ,Transcriptome ,fluids and secretions ,Cancer immunotherapy ,medicine ,Humans ,Antigen-presenting cell ,In Situ Hybridization ,Immunobiology ,Oligonucleotide Array Sequence Analysis ,Antigen Presentation ,Reverse Transcriptase Polymerase Chain Reaction ,Monocyte ,Cell Differentiation ,Cell Biology ,Hematology ,Dendritic cell ,Dendritic Cells ,Flow Cytometry ,Lymphoma, T-Cell, Cutaneous ,medicine.anatomical_structure ,Photopheresis - Abstract
Extracorporeal photochemotherapy (ECP) is widely used to treat cutaneous T-cell lymphoma, graft-versus-host disease, and allografted organ rejection. Its clinical and experimental efficacy in cancer immunotherapy and autoreactive disorders suggests a novel mechanism. This study reveals that ECP induces a high percentage of processed monocytes to enter the antigen-presenting dendritic cell (DC) differentiation pathway, within a single day, without added cytokines, as determined by enhanced expression of relevant genes. The resulting DCs are capable of processing and presentation of exogenous and endogenous antigen and are largely maturationally synchronized, as assessed by the level of expression of costimulatory surface molecules. Principal component analysis of the ECP-induced monocyte transcriptome reveals that activation or suppression of more than 1100 genes produces a reproducible distinctive molecular signature, common to ECP-processed monocytes from normal subjects, and those from patients. Because ECP induces normal monocytes to enter the DC differentiation pathway, this phenomenon is independent of disease state. The efficiency with which ECP stimulates new functional DCs supports the possibility that these cells participate prominently in the clinical successes of the treatment. Appropriately modified by future advances, ECP may potentially offer a general source of therapeutic DCs.
- Published
- 2010
35. Association Between Immunoparesis and a Skewed Free Light Chain (FLC) Ratio: A New Prognostic Factor Of Progression from MGUS To Multiple Myeloma?
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Pizzuti, Michele, primary, Santagostino, Alberto, additional, Smaldore, Giuseppina, additional, Chitarrelli, Ida, additional, Vertone, Domenico, additional, Pascale, Sara Pasquina, additional, Matturro, Angela, additional, Attolico, Immacolata, additional, Amendola, Angela, additional, Cimminiello, Michele, additional, Filardi, Nunzio, additional, Girardi, Antonella, additional, Penitente, Romina, additional, Nuccorini, Roberta, additional, Coluzzi, Sabrina, additional, and Scavone, Enza, additional
- Published
- 2013
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36. Risk of Infection Among Patients with Non-Metastatic Solid Tumors or Non-Hodgkin’s Lymphoma Receiving Myelosuppressive Chemotherapy and Antimicrobial Prophylaxis in US Clinical Practice
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Weycker, Derek, primary, Chandler, David, additional, Barron, Rich, additional, Xu, Hairong, additional, Wu, Hongsheng, additional, Girardi, Vincent, additional, Edelsberg, John, additional, and Lyman, Gary H., additional
- Published
- 2013
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37. RP6530, a Dual PI3Kδ/γ Inhibitor, Attenutates AKT Phosphorylation and Induces Apoptosis In Primary Cutaneous T Cell Lymphoma (CTCL) Cells
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Lewis, Julia, primary, Girardi, Michael, additional, Vakkalanka, Swaroop, additional, Viswanadha, Srikant, additional, and Bertoni, Francesco, additional
- Published
- 2013
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38. Risk and Consequences of Neutropenic Complications Among Patients with Metastatic Solid Tumors Receiving Myelosuppressive Chemotherapy
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Weycker, Derek, primary, Li, Xiaoyan, additional, Kartashov, Alex, additional, Barron, Rich, additional, Edelsberg, John, additional, Xu, Hairong, additional, Girardi, Vincent, additional, and Lyman, Gary H., additional
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- 2013
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39. Risk and Consequences of Neutropenic Complications Among Patients with Metastatic Solid Tumors Receiving Myelosuppressive Chemotherapy
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Derek Weycker, Alex Kartashov, Gary H. Lyman, Xiaoyan Li, Hairong Xu, Vincent Girardi, John Edelsberg, and Rich Barron
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medicine.medical_specialty ,business.industry ,Immunology ,Retrospective cohort study ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Carboplatin ,Surgery ,Regimen ,chemistry.chemical_compound ,chemistry ,Docetaxel ,Internal medicine ,medicine ,Cumulative incidence ,business ,Febrile neutropenia ,medicine.drug - Abstract
Background While several studies have evaluated the risk and consequences of febrile neutropenia (FN) among patients receiving cancer chemotherapy in US clinical practice, none have focused on a broad group of patients with metastatic disease. Methods A retrospective cohort design and US healthcare claims data (2007-2011) were utilized. Study population included adult patients who underwent myelosuppressive chemotherapy for metastatic cancer of the breast (MBC), colon/rectum (MCC), lung (MLC), ovaries (MOC), or prostate (MPC). For each subject, the first qualifying chemotherapy course and each chemotherapy cycle therein, and each episode of chemotherapy-induced neutropenic complications (CINC) during the course, were identified; use of prophylaxis with colony-stimulating factors (CSF) and oral antimicrobial (AMB) agents also was identified. CINC was ascertained using broad (diagnosis of neutropenia, fever, and/or infection) and narrow (diagnosis of neutropenia) definitions, and was stratified by care setting. (Our outcome was CINC, rather than FN, because clinical data were not available and there is no specific diagnosis code for FN. In a validation study, FN risk was reported to be between risk of CINC based alternatively on aforementioned broad and narrow criteria [Weycker, BMC Health Services Research 2013].) Risk (i.e., incidence proportion) of CINC was estimated by tumor type and regimen; consequences of CINC-hospital length of stay (LOS) and mortality, CINC-related healthcare costs-were estimated by tumor type. Results CINC risk is reported herein only for the most frequently observed regimen for each tumor type: paclitaxel for MBC (17.8% of 15,309 patients), 5-fluorouracil + leucovorin + oxaliplatin for MCC (23.4% of 16,934), carboplatin + paclitaxel for MLC (22.9% of 21,994), carboplatin + paclitaxel for MOC (49.2% of 7,435), and docetaxel for MPC (68.4% of 4,668). Across these 5 regimens, use of CSF prophylaxis in cycle 1 ranged from 4.6-24.6% (Table 1). Risk of CINC (broad definition) during the course ranged from 11.6-20.5%; among subjects with CINC, 87.7-95.3% had CINC in the inpatient setting and 16.8-33.8% had CINC in cycle 1. For CINC requiring inpatient care (broad definition), hospital mortality ranged from 4.4-9.8%, hospital LOS (mean) from 6.9-7.3 days, and healthcare costs (mean) from $12,831-$16,003 across tumor types (Table 2). CINC risks based on narrow definition are in Table 1; CINC consequences based on narrow definition were similar to those for broad definition. Conclusion Among patients receiving common myelosuppressive chemotherapy regimens for metastatic disease in solid tumors in US clinical practice, 4.6-24.6% were administered CSF prophylaxis in cycle 1, while 11.6-20.5% experienced CINC (broad definition), treated most often in the inpatient setting. Disclosures: Weycker: Amgen Inc.: Research Funding. Li:Amgen Inc.: Employment, Equity Ownership. Kartashov:Amgen Inc.: Research Funding. Barron:Amgen Inc.: Employment, Equity Ownership. Edelsberg:Amgen Inc.: Research Funding. Xu:Amgen Inc.: Employment, Equity Ownership. Girardi:Amgen Inc.: Employment, Equity Ownership. Lyman:Amgen Inc.: PI on a research grant to Duke University Other.
- Published
- 2013
40. RP6530, a Dual PI3Kδ/γ Inhibitor, Attenutates AKT Phosphorylation and Induces Apoptosis In Primary Cutaneous T Cell Lymphoma (CTCL) Cells
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Swaroop Vakkalanka, Srikant Viswanadha, Francesco Bertoni, Michael Girardi, and Julia M. Lewis
- Subjects
medicine.medical_treatment ,T cell ,Immunology ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Molecular biology ,CD19 ,chemistry.chemical_compound ,Cytokine ,medicine.anatomical_structure ,chemistry ,Annexin ,medicine ,biology.protein ,Propidium iodide ,Annexin A5 ,Protein kinase B ,PI3K/AKT/mTOR pathway - Abstract
Background Mycosis fungoides (MF) is the most common form of CTCL. The peripheral blood of MF patients is variably involved with malignant skin-homing T cells, with Sézary syndrome representing an advanced form characterized by erythroderma and frank leukemic expansion of the cells. The Class 1A phosphoinositide-3-kinase (PI3K) signaling cascade is involved in control of a variety of cellular responses including cell-cycle and anti-apoptotic pathways. Inappropriate activation / phosphorylation of the downstream effector, Akt, via dysregulated PI3K signaling has been detected in a variety of cancers including CTCL, and may contribute to proliferation and survival of malignant cells. While the α and β isoforms of PI3K are ubiquitous in their distribution, expression of δ and γ is majorly associated with immune cells including T-lymphocytes. Selective pharmacologic targeting of PI3K δ/γ may therefore have therapeutic potential. RP6530 is a novel, potent, and selective PI3K δ/γ inhibitor. RP6530 demonstrates high potency against PI3Kδ (IC50=25 nM) and γ (IC50=33 nM) enzymes with selectivity over α (>300-fold) and β (>100-fold) isoforms. Cellular potency has been confirmed in target-specific assays, namely anti-FcεR1-(EC50=38 nM) or fMLP (EC50=39 nM) induced CD63 expression in human whole blood basophils, LPS-induced CD19+ cell proliferation in human whole blood (EC50=250 nM), and LPS-induced CD45R+ cell proliferation in mouse whole blood (EC50=101 nM). In this study, we examined the effects of RP6530 on Akt phosphorylation in CTCL cell lines HH and Sez4 and in purified malignant T cells from six CTCL patients exhibiting Sézary Syndrome. Methods Activity and selectivity of RP6530 for PI3Kδ and γ isoforms and subsequent downstream activity was determined in enzyme and cell-based assays. Malignant T cells were isolated by negative selection using an antibody plus magnetic bead kit (Miltenyi Biotec) designed for CD4+ T cell isolation supplemented with patient-specific anti-CD7 and/or CD26 antibodies. Purity of isolated cells as tested by flow cytometry was >96%. Purified malignant T cells were cultured in RPMI+1% BSA overnight then treated ± inhibitor for 1.5 hr, with serum plus a cytokine mix (IL2+7+15) added for the final 30 minutes to maximize Akt phosphorylation. The ratio of phosphorylated, pSer473-Akt to total Akt was then measured by phospho-flow cytometry. Results RP6530 caused dose-dependent inhibition of Akt Ser473 phosphorylation, with significant inhibition detectable even at the lowest concentration tested (10 nM, P = 0.035) and reaching 39.29% at 1000 nM. Inhibition observed was significantly greater (P = 0.0133) than that seen with the potent PI3K control inhibitor LY294002 (27.50%) at the same concentration. Non-linear regression analysis (Prism 5.0) of the mean pSer473-Akt:total-Akt ratio indicated the IC50 for RP6530 (198.2 nM) at ∼4-fold lower than for LY (939.7 nM). In addition, apoptosis induction as measured by Annexin V binding, was tested in purified malignant T cells from four Sezary Syndrome patients. Following a 48hr incubation with RP6530, a dose-dependent increase in late apoptotic, Annexin V+ Propidium Iodide (PI)+, cells was seen. The compound was effective even at lower concentrations, with 60.15% more Annexin V+ PI+ cells seen in cultures treated with 100 nM inhibitor than untreated cultures (P= 0.027), and with a 120.43% increase seen at the highest concentration tested (10 μM). Conclusion Results from in vitro studies suggest the therapeutic potential of RP6530 in the treatment of CTCL with peripheral blood involvement. Findings provide a rationale for future clinical trials in T-cell malignancies. Disclosures: Girardi: Rhizen Pharmaceuticals S.A.: Research Funding. Vakkalanka:Rhizen Pharmaceuticals, S.A.: Employment, Equity Ownership; Incozen Therapeutics Pvt. Ltd.: Employment, Equity Ownership. Viswanadha:Incozen Therapeutics Pvt. Ltd.: Employment. Bertoni:Rhizen Pharmaceuticals SA: Research Funding.
- Published
- 2013
41. Risk of Infection Among Patients with Non-Metastatic Solid Tumors or Non-Hodgkin’s Lymphoma Receiving Myelosuppressive Chemotherapy and Antimicrobial Prophylaxis in US Clinical Practice
- Author
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Derek Weycker, John Edelsberg, Rich Barron, David Chandler, Vincent Girardi, Hairong Xu, Hongsheng Wu, and Gary H. Lyman
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Myelosuppressive Chemotherapy ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Chemotherapy regimen ,Oxaliplatin ,Folinic acid ,Regimen ,FOLFOX ,Docetaxel ,Internal medicine ,medicine ,Antibiotic prophylaxis ,business ,medicine.drug - Abstract
Background Clinical practice guidelines recommend oral antimicrobials (AMB)—principally, the fluoroquinolones—for prophylaxis against chemotherapy-related infections (CRI) in intermediate- and high-risk patients undergoing myelosuppressive chemotherapy. Available evidence on the risk of CRI among patients with non-metastatic solid tumors or non-Hodgkin's lymphoma (NHL) receiving myelosuppressive chemotherapy and AMB prophylaxis in US clinical practice is currently limited. Methods A retrospective cohort design and data from two US private healthcare claims repositories (2008-2011) were employed. The study population included adult patients who received myelosuppressive chemotherapy for non-metastatic cancer of the breast, colon/rectum, or lung, or for NHL. For each study subject, the first qualifying chemotherapy course, and each chemotherapy cycle and episode of CRI within the course, were identified. Use of prophylaxis with oral AMB agents—including antibacterial, antifungal, and antiviral drugs—as well as colony-stimulating factors (CSF) in each cycle also was identified. CRI was ascertained based on admission to an acute-care inpatient facility with a corresponding diagnosis (1⁰ or 2⁰) or an ambulatory encounter with a corresponding diagnosis and evidence of AMB therapy. Risk of CRI was evaluated during chemotherapy cycles in which patients received AMB prophylaxis; only results for the most frequently observed regimen for each tumor type are reported herein. Results The most common regimens—by tumor—were: breast cancer, docetaxel + cyclophosphamide (“TC”, 29% of 34,876); colorectal cancer, folinic acid (leucovorin) + fluorouracil + oxaliplatin (“FOLFOX”, 34% of 14,334); lung cancer, paclitaxel + carboplatin (“PC”, 25% of 17,334); and NHL, cyclophosphamide + doxorubicin + vincristine + prednisone with Rituxan (“CHOP-R”, 45% of 9,612). Across these four regimens, use of AMB prophylaxis in cycle 1 ranged from 3.5-8.6%; fluoroquinolones were the most common agents administered (range, 27.1-43.5%) (Table 1). Use of CSF prophylaxis in cycle 1 ranged from 10.4-61.2%. Among subjects who received first-cycle AMB prophylaxis, risk of CRI in that cycle ranged from 1.2-7.5%; among these subjects, 45-68% had CRI in the inpatient setting (Table 2). CRI risks in subsequent cycles with AMB prophylaxis were generally comparable. Conclusion Among patients with non-metastatic solid tumors or NHL receiving common myelosuppressive chemotherapy and AMB prophylaxis in US clinical practice, risk of CRI ranged from 1.2-8.6% in cycles in which AMB prophylaxis was administered. Disclosures: Weycker: Amgen Inc.: Research Funding. Chandler:Amgen Inc.: Employment, Equity Ownership. Barron:Amgen Inc.: Employment, Equity Ownership. Xu:Amgen Inc.: Employment, Equity Ownership. Wu:Amgen Inc.: Research Funding. Girardi:Amgen Inc.: Employment, Equity Ownership. Edelsberg:Amgen Inc.: Research Funding. Lyman:Amgen Inc.: PI on a research grant to Duke University Other.
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- 2013
42. Association Between Immunoparesis and a Skewed Free Light Chain (FLC) Ratio: A New Prognostic Factor Of Progression from MGUS To Multiple Myeloma?
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Roberta Nuccorini, Immacolata Attolico, Romina Penitente, Giuseppina Smaldore, Ida Chitarrelli, Michele Pizzuti, Sara Pasquina Pascale, Michele Cimminiello, Antonella Girardi, Sabrina Coluzzi, Angela Amendola, Enza Scavone, Angela Matturro, Nunzio Filardi, Domenico Vertone, and Alberto Santagostino
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medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Immunology ,Context (language use) ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Immunophenotyping ,Gammopathy ,Internal medicine ,Cohort ,medicine ,business ,Kappa ,Monoclonal gammopathy of undetermined significance ,Multiple myeloma - Abstract
Monoclonal gammopathy of undetermined significance (MGUS) occurs in 3% of people older than 50 years and up to 10% in those older than 70; it is associated with a 1%/year risk of progression to Multiple Myeloma (MM). In recent years there have been improvements in risk stratification models (involving molecular markers) of this disorder, which have led to better understanding of the biology and probability of progression of MGUS. In the context of numerous molecular events and heterogeneous risk of progression, developing individualized risk profiles for patients with MGUS represents an ongoing challenge that has to be addressed by prospective clinical monitoring and extensive correlative science. Free Lights Chains (FLC) ratio, plasma cells immunophenotype and DNA aneuplody are now important parameters of progression, in addition to the already known prognostic factors (immunoparesis, type and amount of the monoclonal component (MC). Recent data report immunoparesis and a skewed FLC ratio in 25% and 30%, respectively, of patients (pts) at diagnosis. In this study we evaluated the incidence of these two parameters in a cohort of 114 pts with MGUS, if they are associated and if their incidence is influenced by other parameters (time from diagnosis, type of Immunoglobulin (Ig) and/or light chains). The patients screened were 56 males and 58 females with a median age of 67 years (45-91). Median time from diagnosis to the time of observation was 3 years (0-21). The MC was IgA in 13 pts, IgG in 88, IgM in 13; 74 had a clonal Kappa (K) and 40 a lambda (L) light chain. K/L ratio was abnormal in 57 pts (50%). Immunoparesis was present in 60 pts (52,6%): 22 with a normal K/L ratio (38,5%) and 38 with an abnormal K/L ratio (66,6%) (p-0.004). In 18 pts two classes of Ig were involved. An association between the two parameters occurred in 39 pts (34,2%); it was more frequent in IgA MGUS (61,5%) than in IgG (31,8%) and IgM (23%); we did not observe any differences about immunoparesis between K MGUS (33,7%) and L MGUS (32,5%). The association between a skewed K/L ratio and immunoparesis was present in 25.4% of pts with time from diagnosis of less than 3 years and in 48,8% of pts with a longer time from diagnosis (p-0.04). Our new data confirm that immunoparesis is more frequent in pts with an abnormal K/L ratio. The association seems to be more frequent in case of IgA gammopathy; there are no differences between the two types of light chain. Our data also confirm that the longer is the time elapsed from diagnosis, the higher are the frequency of an abnormal K/L ratio and the incidence of immunoparesis, with a greater probability of association. We need still a larger number of pts with an adequate follow up to evaluate if the association between immunoparesis and abnormal K/L ratio has a prognostic value, although the higher frequency of association in the subset of pts with a longer time from diagnosis seems to contradict this hypothesis. Disclosures: No relevant conflicts of interest to declare.
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- 2013
43. Negative Depletion of B Cells and T Cells Expressing the αβ Chain of the T-Cell Receptor (TCR) for Haploidentical Stem Cell Transplantation
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Pira, Giuseppina Li, primary, Landi, Fabiola, additional, Filippini, Perla, additional, Giustiniani, Paola, additional, Bertaina, Alice, additional, Pagliara, Daria, additional, Pinto, Rita M, additional, Girardi, Katia, additional, Del Principe, Giovanna, additional, Ceccarelli, Stefano, additional, Locatelli, Franco, additional, and Rutella, Sergio, additional
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- 2012
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44. Cutaneous Toxicity Associated with Pralatrexate in Cutaneous and Peripheral T-Cell Lymphoma
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Parker, Terri L., primary, Barbarotta, Lisa, additional, Girardi, Michael, additional, and Foss, Francine M., additional
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- 2012
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45. Cutaneous Toxicity Associated with Pralatrexate in Cutaneous and Peripheral T-Cell Lymphoma
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Francine M. Foss, Lisa Barbarotta, Michael Girardi, and Terri L. Parker
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Chemotherapy ,medicine.medical_specialty ,Erythema ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Immunology ,Pralatrexate ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Dermatology ,Peripheral T-cell lymphoma ,Surgery ,Moist desquamation ,Toxicity ,Skin biopsy ,medicine ,Mucositis ,medicine.symptom ,business ,medicine.drug - Abstract
Abstract 3660 Background: Pralatrexate is a folate analogue metabolic inhibitor that is approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) (O'Connor, O.A. et al. JCO. 2011 29: 1181–1189). More recently, pralatrexate has been investigated for the treatment of relapsed or refractory cutaneous T-cell lymphoma (CTCL) (Horowitz, S.M. et al. Blood. 2012 119: 4115–4122). The most common adverse event (AE) observed with pralatrexate has been mucositis with other reported AEs consisting of fatigue, nausea, and cutaneous toxicity. Methods: We retrospectively analyzed the data of 22 patients who had received pralatrexate for a diagnosis of either PTCL or CTCL at our institution since 2010 in order to determine the incidence of cutaneous toxicity. Results: Of the 22 patients, 4 had a diagnosis of PTCL, 18 had CTCL. In the PTCL cohort, the median age was 66.5 with the median number of prior treatments (nonsystemic and systemic) being 2.75. One patient (25%) developed cutaneous toxicity which resulted in death. A skin biopsy revealed toxic erythema of chemotherapy and the skin lesions progressed to bullae and moist desquamation. In the CTCL cohort, the median age was 60 with the median number of treatments being 5. A total of 14 patients (78%) developed cutaneous toxicity. The toxicity included worsening erythema, skin breakdown, ulceration, and pain at the CTCL lesion sites. The majority of patients (n= 10; 71%) developed the toxicity following cycle 1 week 1 of treatment. The development of cutaneous toxicity was seen in 8 patients at a dose of 15mg/m2, in 3 patients at a dose of 10mg/m2, and in 2 patients who underwent dose escalations to 17.5mg/m2 and 20mg/m2respectively. Of those patients who developed cutaneous toxicity, 8 (57%) required the pralatrexate to be held and 2 patients (14%) required hospitalization and treatment with intravenous antibiotics for superimposed skin infection. The cutaneous toxicity observed was not associated with any other adverse event. Seven patients (39%) in the entire CTCL cohort developed grade I/II mucositis and 3 (17%) developed grade I diarrhea. In 7 patients (50%) the pralatrexate was restarted at a lower dose, 3 patients were changed to an every other week dosing schedule, and 2 patients continued on pralatrexate with no change following resolution of their symptoms. Only 2 patients were not continued on pralatrexate following the cutaneous toxicity. In all 12 patients who were retreated with pralatrexate, cutaneous toxicity did not reoccur and the dose was able to be escalated. At the time of data analysis, 7 patients remained on treatment with pralatrexate while the remainder had discontinued therapy secondary to disease progression. Conclusions: In this retrospective review, a high incidence of cutaneous toxicity was seen in CTCL patients who were treated with pralatrexate. The cutaneous toxicity might be interpreted as a “skin flare” since it may be concentrated at sites of CTCL lesions. The majority of patients developed the toxicity with the first dose and were able to continue on pralatrexate at a lower dose with eventual dose escalation. Based on data analysis, the “skin flare” is not dose dependent or associated with disease response. Disclosures: Off Label Use: Pralatrexate is FDA approved for the treatment of relapsed or refractory peripheral T-cell lymphoma. Our abstract discusses its use, specifically the cutaneous toxicity observed, in both peripheral and cutaneous T-cell lymphoma. The use of pralatrexate in relapsed or refractory cutaneous T-cell lymphoma is off-label. Barbarotta:Genentech: Speakers Bureau; Allos: Speakers Bureau. Foss:Seattle Genetics: Consultancy; Celgene: Consultancy; Eisai: Consultancy; Celgene: Study Grant, Study Grant Other; Merck: Study Grant, Study Grant Other; Allos: Consultancy.
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- 2012
46. Negative Depletion of B Cells and T Cells Expressing the αβ Chain of the T-Cell Receptor (TCR) for Haploidentical Stem Cell Transplantation
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Sergio Rutella, Franco Locatelli, Katia Girardi, Giovanna Del Principe, Fabiola Landi, Stefano Ceccarelli, Giuseppina Li Pira, Alice Bertaina, Rita Maria Pinto, Perla Filippini, Daria Pagliara, and Paola Giustiniani
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biology ,medicine.medical_treatment ,CD3 ,Immunology ,CD34 ,Cell Biology ,Hematology ,Leukapheresis ,Hematopoietic stem cell transplantation ,Dendritic cell ,Natural killer T cell ,Biochemistry ,CD19 ,medicine ,biology.protein ,Stem cell - Abstract
Abstract 343 Introduction. Allogeneic hematopoietic stem cell transplantation (HSCT) from a HLA-haploidentical relative is a suitable option for patients (pts) lacking a compatible donor, either related or unrelated. The two main approaches for overcoming the obstacles of HLA barriers are based either on the infusion of large numbers of T-cell-depleted HSC or on intensive pharmacological prevention of graft-versus-host disease (GVHD). While for many years T-cell depletion (TCD) of the graft has been based on either immunomagnetic positive selection of CD34+ cells or on physical removal of all subsets of T cells by virtue of mAb, we and other groups have recently developed a novel method of ex vivo TCD based on the selective elimination of αβ+ T cells through labeling with a biotinylated anti-TCRαβ Ab, followed by incubation with an anti-biotin Ab conjugated to paramagnetic beads (Miltenyi Biotec, Germany). This approach also allows the removal of B cells to prevent post-transplant EBV-associated lymphoproliferative disease (PTLD). Here, we report the results of graft manipulation using this approach. Methods. Twenty-two children entered the study, 15 with hematological malignancies and 7 with non-malignant disorders. No post-transplant GvHD prophylaxis was employed. HLA-haploidentical family donors received G-CSF (12–16 μg/kg of body weight) to mobilize HSC prior to large-volume leukapheresis, which was commenced when circulating CD34+ HSC were >20 cells/μl. Cell therapy products containing up to 60×109 white blood cells (WBC) were processed according to the manufacturer's protocol. In some cases, leukapheresis bags were stored overnight at 4°C in appropriate media at a WBC concentration Results. Median recovery of CD34+ HSC and median number of infused CD34+ HSC were 99.3% (range 55.4–100) and 14.7×106/kg (range 7.9–37), respectively. The graft contained 3.9×106 CD3+ T cells/kg (range 0.9–30.9) and 0.08×106 B cells/kg (range 0.002–0.32). The log-depletion of αβ+ T cells was 4.5 (range 3.2–6.1), with a median number of transplanted αβ+ T cells equal to 36×103/kg (range 1–139.9). Patients received 36×106 CD56+ NK cells/kg (range 1.6–80.3) and 4.1×106 γδ+ T cells/kg (range 0.9–30.8). A median of 40.8% NK cells (range 30.3–60.2) co-expressed Tim-3, an activating co-receptor promoting IFN-γ production and being scarcely expressed on NK cells that reconstitute after allogeneic HSCT. The αβ/CD19-depleted grafts also contained DC1 and DC2 precursors, which were identified based on BDCA-1 (0.23% of all nucleated cells, range 0.02–2.4), BDCA-3 (0.93%, range 0.57–9.4) and BDCA-2 (0.66%, range 0.49–1.28) or BDCA-4 expression (0.69%, range 0.02–1.5), respectively. Invariant NKT cells were enumerated using mAb reacting against the TCR Vα24-Jα18 chain and were detected in minute percentages ( Conclusions. The immunomagnetic removal of αβ+ T cells and B cells was effective and gave reproducible results. In all cases, a remarkable depletion of unwanted T and B cells was attained. The depleted graft contained high numbers of CD34+ HSC, as well as of immune effector cells implicated in the control of leukemia growth and GVHD, such as γδ+ T cells, NK cells, DC1, DC2 and non-classical CD14+CD16+ monocytes. From a clinical standpoint, the infusion of αβ/CD19-depleted grafts from HLA-haploidentical family donors was safe, resulting into sustained donor engraftment without life-threatening complications. Disclosures: No relevant conflicts of interest to declare.
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- 2012
47. Response: validity of evidence demonstrating efficacy of extracorporeal photochemotherapy
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Berger, Carole, primary, Lewis, Julia, additional, Girardi, Michael, additional, Tigelaar, Robert, additional, and Edelson, Richard, additional
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- 2011
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48. Response: validity of evidence demonstrating efficacy of extracorporeal photochemotherapy
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Richard L. Edelson, Robert E. Tigelaar, Michael Girardi, Carole L. Berger, and Julia M. Lewis
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medicine.medical_specialty ,business.industry ,Mechanism (biology) ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Photopheresis ,Correspondence ,Extracorporeal photochemotherapy ,Medicine ,business ,Intensive care medicine - Abstract
We appreciate the opportunity that the letter of Drs George and Roederer offers us to clarify and highlight our findings relevant to the mechanism(s) underlying the immunotherapeutic efficacy of extracorporeal photochemotherapy (ECP). Specifically, we reported several lines of convergent evidence
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- 2011
49. Antiphospholipid Antibodies Promote Leukocyte-Endothelial Cell Adhesion by Antagonizing Endothelial NO Synthase Via b2GPI and ApoER2.
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Tarango, Cristina, primary, Ramesh, Sangeetha, additional, Morrell, Craig N., additional, Thomas, Gail D., additional, Girardi, Guillermina, additional, Salmon, Jane, additional, Yuhanna, Ivan S., additional, Herz, Joachim, additional, Thorpe, Philip, additional, Shaul, Philip, additional, and Mineo, Chieko, additional
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- 2009
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50. Antiphospholipid Antibodies Promote Leukocyte-Endothelial Cell Adhesion by Antagonizing Endothelial NO Synthase Via b2GPI and ApoER2
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Jane E. Salmon, Joachim Herz, Philip E. Thorpe, Chieko Mineo, Craig N. Morrell, Cristina Tarango, Guillermina Girardi, Sangeetha Ramesh, Gail D. Thomas, Ivan S. Yuhanna, and Philip W. Shaul
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medicine.medical_specialty ,biology ,Endothelium ,Cell adhesion molecule ,Immunology ,Cell Biology ,Hematology ,Pharmacology ,biology.organism_classification ,Biochemistry ,Endothelial stem cell ,Vascular endothelial growth factor A ,medicine.anatomical_structure ,Endocrinology ,Downregulation and upregulation ,immune system diseases ,Enos ,Internal medicine ,LDL receptor ,medicine ,neoplasms ,Fibrinolytic agent - Abstract
Abstract 3039 Poster Board II-1015 The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies (aPL), with pathogenic aPL directed primarily against the cell surface protein β2 glycoprotein I (β2GPI), increased risk for thrombosis and cardiovascular events, and pregnancy morbidity. The endothelium is a critical direct target of aPL, which upregulate adhesion molecule expression and procoagulant activity. However, the molecular basis for aPL actions on endothelium is unknown. Nitric oxide (NO) generated by endothelial NO synthase (eNOS) has potent antiadhesive and antithrombotic properties. In this study we determined if aPL-induced alterations in endothelial cell phenotype are mediated by aPL actions on eNOS. Normal human IgG (NHIgG) and polyclonal aPL were obtained from healthy adults and APS patients, respectively. We found that aPL prevented acetylcholine (Ach)- or VEGF-mediated attenuation of monocyte adhesion to cultured endothelial cells and this was reversed by an NO donor, indicating a role for eNOS antagonism. In contrast, NHIgG did not affect adhesion. Whereas NHIgG did not alter eNOS activation, stimulation of eNOS by VEGF and other agonists was fully antagonized by aPL. In mice, NO-dependent, Ach-induced increases in carotid vascular conductance were unaffected by NHIgG but impaired by aPL, indicating that these processes are operative in vivo. Additional studies in culture showed that aPL attenuates eNOS activation by inhibiting Ser1179 phosphorylation, deprivation of β2GPI prevented aPL inhibition of eNOS, and monoclonal antibody against β2GPI mimicked the effects of aPL. Furthermore, receptor-associated protein (RAP) antagonism of LDL receptors, which are known to bind dimerized β2GPI, prevented aPL inhibition of eNOS in culture, and mice null for the LDL receptor apolipoprotein receptor 2 (apoER2) were protected from aPL inhibition of eNOS in vivo. Moreover, aPL-stimulated increases in leukocyte-endothelial adhesion were absent in both eNOS-/- and apoER2-/- mice. Thus, aPL-induced increases in leukocyte-endothelial adhesion are caused by eNOS antagonism, which is due to impaired S1179 phosphorylation mediated by β2GPI and apoER2. Novel therapies for APS can now be developed targeting these mechanisms. Disclosures Thomas: NIcox Research Institute: Research Funding. Thorpe:Peregrine Pharm.: Consultancy, sponsored research agreement.
- Published
- 2009
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