80 results on '"L. Vinti"'
Search Results
2. P359: IMPROVED OVERALL SURVIVAL AND MRD CLEARANCE WITH BLINATUMOMAB VS CHEMOTHERAPY AS PRE-TRANSPLANT CONSOLIDATION IN PEDIATRIC HIGH-RISK FIRST-RELAPSE B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL)
- Author
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F. Locatelli, G. Zugmaier, C. Rizzari, J. Morris, B. Gruhn, T. Klingebiel, R. Parasole, C. Linderkamp, C. Flotho, A. Petit, C. Micalizzi, Y. Zeng, R. Desai, W. Kormany, C. Eckert, A. Möricke, M. Sartor, O. Hrusak, C. Peters, V. Saha, L. Vinti, and A. von Stackelberg
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
- Full Text
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3. P521: TREATMENT OF BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM IN PEDIATRIC PATIENTS WITH TAGRAXOFUSP, A CD123-TARGETED THERAPY
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N. Pemmaraju, B. Cuglievan, J. Lasky, A. Kheradpour, N. Hijiya, A. S. Stein, S. Meshinchi, C. Mullen, E. Angelucci, L. Vinti, T. I. Mughal, and A. Pawlowska
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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- View/download PDF
4. Bone marrow failure may be caused by chromosome anomalies exerting effects on RUNX1T1 gene
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R. Valli, L. Vinti, A. Frattini, M. Fabbri, G. Montalbano, C. Olivieri, A. Minelli, F. Locatelli, F. Pasquali, and E. Maserati
- Subjects
Severe aplastic anaemia ,Pancytopenia ,Chromosome structural anomalies ,Chromosome 8 ,Chromosome 2 ,RUNX1T1 gene ,Genetics ,QH426-470 - Abstract
Abstract Background The majority of the cases of bone marrow failure syndromes/aplastic anaemias (BMFS/AA) are non-hereditary and considered idiopathic (80–85%). The peripheral blood picture is variable, with anaemia, neutropenia and/or thrombocytopenia, and the patients with idiopathic BMFS/AA may have a risk of transformation into a myelodysplastic syndrome (MDS) and/or an acute myeloid leukaemia (AML), as ascertained for all inherited BMFS. We already reported four patients with different forms of BMFS/AA with chromosome anomalies as primary etiologic event: the chromosome changes exerted an effect on specific genes, namely RUNX1, MPL, and FLI1, leading to the disease. Results We report two further patients with non-hereditary BM failure, with diagnosis of severe aplastic anaemia and pancytopenia caused by two different constitutional structural anomalies involving chromosome 8, and possibly leading to the disorder due to effects on the RUNX1T1 gene, which was hypo-expressed and hyper-expressed, respectively, in the two patients. The chromosome change was unbalanced in one patient, and balanced in the other one. Conclusions We analyzed the sequence of events in the pathogenesis of the disease in the two patients, including a number of non-haematological signs present in the one with the unbalanced anomaly. We demonstrated that in these two patients the primary event causing BMFS/AA was the constitutional chromosome anomaly. If we take into account the cohort of 219 patients with a similar diagnosis in whom we made cytogenetic studies in the years 2003–2017, we conclude that cytogenetic investigations were instrumental to reach a diagnosis in 52 of them. We postulate that a chromosome change is the primary cause of BMFS/AA in a not negligible proportion of cases, as it was ascertained in 6 of these patients.
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- 2018
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5. T.10.10 IMPACT OF SMOKING HABIT ON THE OUTCOMES OF ENDOSCOPIC SLEEVE GASTROPLASTY
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G. Carlino, I. Boskoski, V. Bove, M. De Siena, V. Pontecorvi, G. Giannetti, G. Polidori, L. Vinti, C. Massari, N. Antonini, G. Palumbo, G. Costamagna, C. Spada, and M.V. Matteo
- Subjects
Hepatology ,Gastroenterology - Published
- 2023
6. OC.05.4 REDO ENDOSCOPIC SLEEVE GASTROPLASTY (RE-ESG): THE EXPERIENCE OF A SINGLE TERTIARY CENTER
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M.V. Matteo, V. Bove, M. De Siena, V. Pontecorvi, G. Polidori, L. Vinti, G. Palumbo, G. Giannetti, N. Antonini, C. Massari, C. Spada, G. Costamagna, I. Boskoski, and G. Carlino
- Subjects
Hepatology ,Gastroenterology - Published
- 2023
7. T.12.5 2 YEARS OUTCOMES OF TRANSORAL OUTLET REDUCTION FOR DUMPING SYNDROME AND WEIGHT REGAIN AFTER ROUX-EN-Y GASTRIC BYPASS
- Author
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V. Pontecorvi, M.V. Matteo, V. Bove, M. De Siena, N. Antonini, C. Massari, G. Carlino, L. Vinti, G. Polidori, L. Ficuccilli, G. Costamagna, C. Spada, and I. Boskoski
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Hepatology ,Gastroenterology - Published
- 2023
8. T.10.7 REDO TRANSORAL OUTLET REDUCTION (RE-TORE): TECHNICAL FEASIBILITY AND MEDIUM-TERM OUTCOMES
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M.V. Matteo, V. Pontecorvi, V. Bove, M. De Siena, G. Polidori, L. Vinti, G. Giannetti, C. Massari, N. Antonini, G. Palumbo, G. Costamagna, C. Spada, I. Boskoski, and G. Carlino
- Subjects
Hepatology ,Gastroenterology - Published
- 2023
9. PHASE 2 KEYNOTE-667 STUDY OF PEMBROLIZUMAB (PEMBRO) IN CHILDREN AND YOUNG ADULTS WITH NEWLY DIAGNOSED CLASSICAL HODGKIN LYMPHOMA (Chl) AND SLOW EARLY RESPONSE (SER) TO FRONTLINE CHEMOTHERAPY (CHEMO)
- Author
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L. Vinti, Stephen Daw, C. Alvarez, F. Fagioli, A. Beishuizen, G. Michel, M. Moleti, M. Cepelova, A. Thorwarth, C. Rigaud, D. de Sabando, J. Parker, Y. Zhu, P. Pillai, A. Nahar, and C. Mauz-Koerholz
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2022
10. BRENTUXIMAB-BENDAMUSTINE IN CHILDREN, ADOLESCENT AND YOUNG ADULTS WITH RELAPSED/REFRACTORY ANAPLASTIC LARGE CELL LYMPHOMA
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L. Vinti, B. Lucarelli, R. De Vito, F. Tangari, L. Mussolin, K. Girardi, R. Carta, and F. Locatelli
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Cancer Research ,Oncology ,Hematology - Published
- 2022
11. RNA-seq analysis of plasmatic exosomal miRNAs in pediatric Hodgkin Lymphoma
- Author
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L Vinti, Stefania Bortoluzzi, Alessandra Sala, Marta Pillon, M Mascarin, Carlotta C. Damanti, C Elia, Zorzi M De, Federica Lovisa, Elisa Carraro, Lara Mussolin, Enrico Gaffo, O Repetto, Re V De, Salvatore Buffardi, L Caggiari, Ilaria Gallingani, and Anna Garbin
- Subjects
Cancer research ,Hodgkin lymphoma ,RNA-Seq ,Exosomal mirnas ,Biology - Published
- 2020
12. Are event-free survival and freedom-from progression compromised by reduced radiation doses fields? Comparison between the results of the AIEOP (Italian Association of Pediatric Hematology and Oncology) LH-2004 & MH96 Protocols
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F Rossi, Maurizio Mascarin, Paola Muggeo, M Bianchi, S Bernasconi, M Provenzi, Salvatore Buffardi, L Vinti, Elena Facchini, R Rondelli, Alessandra Sala, Roberta Burnelli, S D’Amico, Alberto Garaventa, Marta Pillon, and P. Farruggia
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Freedom from progression ,Event free survival ,medicine ,Pediatric hematology ,business - Published
- 2020
13. Bone marrow failure may be caused by chromosome anomalies exerting effects on
- Author
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R, Valli, L, Vinti, A, Frattini, M, Fabbri, G, Montalbano, C, Olivieri, A, Minelli, F, Locatelli, F, Pasquali, and E, Maserati
- Subjects
Chromosome 8 ,Pancytopenia ,Chromosome structural anomalies ,hemic and lymphatic diseases ,Research ,RUNX1T1 gene ,Chromosome 2 ,Severe aplastic anaemia - Abstract
Background The majority of the cases of bone marrow failure syndromes/aplastic anaemias (BMFS/AA) are non-hereditary and considered idiopathic (80–85%). The peripheral blood picture is variable, with anaemia, neutropenia and/or thrombocytopenia, and the patients with idiopathic BMFS/AA may have a risk of transformation into a myelodysplastic syndrome (MDS) and/or an acute myeloid leukaemia (AML), as ascertained for all inherited BMFS. We already reported four patients with different forms of BMFS/AA with chromosome anomalies as primary etiologic event: the chromosome changes exerted an effect on specific genes, namely RUNX1, MPL, and FLI1, leading to the disease. Results We report two further patients with non-hereditary BM failure, with diagnosis of severe aplastic anaemia and pancytopenia caused by two different constitutional structural anomalies involving chromosome 8, and possibly leading to the disorder due to effects on the RUNX1T1 gene, which was hypo-expressed and hyper-expressed, respectively, in the two patients. The chromosome change was unbalanced in one patient, and balanced in the other one. Conclusions We analyzed the sequence of events in the pathogenesis of the disease in the two patients, including a number of non-haematological signs present in the one with the unbalanced anomaly. We demonstrated that in these two patients the primary event causing BMFS/AA was the constitutional chromosome anomaly. If we take into account the cohort of 219 patients with a similar diagnosis in whom we made cytogenetic studies in the years 2003–2017, we conclude that cytogenetic investigations were instrumental to reach a diagnosis in 52 of them. We postulate that a chromosome change is the primary cause of BMFS/AA in a not negligible proportion of cases, as it was ascertained in 6 of these patients. Electronic supplementary material The online version of this article (10.1186/s13039-017-0352-2) contains supplementary material, which is available to authorized users.
- Published
- 2017
14. PS952 NELARABINE AS SALVAGE THERAPY FOR PEDIATRIC PATIENTS WITH RELAPSED T-ALL
- Author
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L. Vinti, F. Locatelli, L. Antonetti, L. Strocchio, and K. Girardi
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Nelarabine ,medicine ,Salvage therapy ,Hematology ,business ,medicine.drug - Published
- 2019
15. Current Relevant Knowledge on Dog Reproductive Physiology – a Review
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Ioana Hașegan, A. Șonea, Mioara Matei, L. Vintilă, Camelia Ion, and A. Bîrțoiu
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canine ,folliculogenesis ,in vivo oocyte maturation ,oogenesis ,physiology ,Agriculture ,Technology ,Science - Abstract
Successful in vitro techniques depend on the possibility to mimic in vivo conditions. For this reason, knowledge on reproductive physiology is necessary to define an efficient entirely in vitro system to produce embryos. A better understanding of the processes and the factors underlying in vivo fertilisation in the dog is necessar. In vitro oocyte maturation had been extensively studied, but we could wonder if in vivo processes are identical with what was observed during in vitro studies. Improving reproductive biotechnologies therefore requires the realization of fundamental studies to better describe and understand phenomena. This review presents a summary of current available knowledge about dog reproductive physiology and biology of the canine oocyte development and maturation, specifically those factors influencing in vitro developmental competence of the oocyte. An understanding of the mechanisms controlling oocyte maturation and development is a particularly important target because it would be helpful to developing assisted breeding in this species.
- Published
- 2023
16. Semen Collection, Assessment and Processing for in vitro Fertilization in Dog – a Review
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Ioana Hașegan, A. Șonea, Mioara Matei, L. Vintilă, Camelia Ion, and A. Bîrțoiu
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capacitation ,cryopreservation ,dog sperm ,evaluation ,prelevation ,Agriculture ,Technology ,Science - Abstract
The attainment of a feasible in vitro capacitation is clearly dependent on the maintenance of suitable energy levels of mammalian spermatozoa. This is because of the fact that all the sperm changes related to capacitation, such as the increase in tyrosine phosphorylation or changes in motility patterns, are energy-consuming. Canine semen can be capacitated and undergoes acrosome reaction in vitro and spermatozoa are able to fertilize homologous oocytes in in vitro culture conditions. The aim of this paper is to describe the recent research of the authors in the field. Recent and classical reviews and new trends regarding semen prelevation, evaluation and preparation for in vitro fertilization in dog.
- Published
- 2023
17. Outcomes of infants with very late relapse of acute lymphoblastic leukaemia initially treated in Interfant-06.
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Lecornec N, Fahd M, De Lorenzo P, Valsecchi MG, Micalizzi C, Diaz P, Pennella C, Locatelli F, Vinti L, Cavé H, Caye-Eude A, Stary J, Pieters R, Baruchel A, and Brethon B
- Published
- 2024
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18. Breast Relapse of Pediatric B-Cell Acute Lymphoblastic Leukemia After CAR-T Therapy Detected by 18 F-FDG PET/CT.
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Perrone E, Taralli S, Pagliara D, Larocca LM, Vinti L, and Leccisotti L
- Subjects
- Humans, Female, Child, Neoplasm Recurrence, Local diagnostic imaging, Neoplasm Recurrence, Local pathology, Breast Neoplasms diagnostic imaging, Breast Neoplasms therapy, Breast Neoplasms pathology, Radiopharmaceuticals, Fluorodeoxyglucose F18, Positron Emission Tomography Computed Tomography methods, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnostic imaging
- Abstract
Background: B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy. Medullary and extramedullary disease relapse is a well-known occurrence in B-ALL pediatric patients treated with standard chemo-immunotherapy and, more recently, with chimeric antigen receptor (CAR)-T cell therapy.
18 F-Fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) emerges as a sensitive imaging tool for detecting disease relapse at extra-medullary sites, with only limited literature evidence in the CAR-T therapy setting., Case Report: In a 12-year-old female treated with CAR-T therapy for B-ALL relapse,18 F-FDG PET/CT scan performed for surveillance, after disease remission, detected a solitary and clinically occult relapse in the breast parenchyma that was histologically confirmed., Conclusion: At our knowledge, this is the first report about a pediatric B-ALL patient with a solitary and occult breast relapse after CAR-T therapy, early discovered by18 F-FDG PET/CT during disease monitoring., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)- Published
- 2024
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19. Success Predictors of Endoscopic Sleeve Gastroplasty.
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Matteo MV, Bove V, Ciasca G, Carlino G, Di Santo R, Vinti L, Polidori G, Pontecorvi V, Papi M, Spada C, and Boškoski I
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- Humans, Female, Male, Obesity surgery, Retrospective Studies, Treatment Outcome, Weight Loss, Gastroplasty methods, Obesity, Morbid surgery
- Abstract
Objective: Endoscopic sleeve gastroplasty (ESG) is a minimally invasive procedure that proved to be safe and effective in obesity treatment. However, not all subjects respond to treatment in the same way, and, with a view to personalized care, it is essential to identify predictors of success or failure., Methods: A retrospective 2-year followed-up cohort of ESG subjects was analyzed to investigate the presence of any baseline or early indicators of long-term optimal or suboptimal ESG outcomes., Results: A total of 315 subjects (73% women) were included, with 73% of patients exhibiting an Excess weight loss percentage (%EWL) >25% at the 24 months. Neither demographic parameters (age and sex), smoking habits, and menopause in women nor the presence of comorbidities proved potential predictive value. Interestingly, the %EWL at 1 month after ESG was the strongest predictor of 24-month therapeutic success. Subsequently, we estimated an "early threshold for success" for 1 month-%EWL by employing Youden's index method., Conclusions: ESG is a safe and effective bariatric treatment that can be offered to a wide range of subjects. Early weight loss seems to impact long-term ESG results significantly and may allow proper early post-operative care optimization., (© 2024. The Author(s).)
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- 2024
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20. A case of T-cell acute lymphoblastic leukemia in retroviral gene therapy for ADA-SCID.
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Cesana D, Cicalese MP, Calabria A, Merli P, Caruso R, Volpin M, Rudilosso L, Migliavacca M, Barzaghi F, Fossati C, Gazzo F, Pizzi S, Ciolfi A, Bruselles A, Tucci F, Spinozzi G, Pais G, Benedicenti F, Barcella M, Merelli I, Gallina P, Giannelli S, Dionisio F, Scala S, Casiraghi M, Strocchio L, Vinti L, Pacillo L, Draghi E, Cesana M, Riccardo S, Colantuono C, Six E, Cavazzana M, Carlucci F, Schmidt M, Cancrini C, Ciceri F, Vago L, Cacchiarelli D, Gentner B, Naldini L, Tartaglia M, Montini E, Locatelli F, and Aiuti A
- Subjects
- Humans, Male, Retroviridae genetics, Adenosine Deaminase deficiency, Adenosine Deaminase genetics, Genetic Therapy methods, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Proto-Oncogene Mas, Severe Combined Immunodeficiency therapy, Severe Combined Immunodeficiency genetics, Genetic Vectors genetics, Hematopoietic Stem Cell Transplantation, Agammaglobulinemia therapy, Agammaglobulinemia genetics
- Abstract
Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. The patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low Adenosine Deaminase (ADA) activity resulting from methylation of viral promoter. The insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. Blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. Before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. The limited incidence of vector-related adverse events in ADA-deficiency compared to other γ-RV GT trials could be explained by differences in transgenes, background disease and patient's specific factors., (© 2024. The Author(s).)
- Published
- 2024
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21. Lymphomonocytic inflammatory infiltrate with numerous eosinophilic granulocytes in the interstitium in a surviving heart transplant recipient: a case report.
- Author
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Placidi S, Francalanci P, Adorisio R, Girardi K, Vinti L, Panebianco M, Rebonato M, Amodeo A, and Grutter G
- Abstract
Findings of eosinophilic and lymphomonocytic inflammatory infiltrates in endomyocardial biopsies (EMBs) may help in myocardial disease diagnosis identification. Eosinophilic myocarditis (EM), a rare condition, is fatal if left untreated and has rarely been described in heart transplant recipients. An extensive work up is necessary to achieve an early etiological diagnosis; however, the underlying cause remains unexplained in nearly one-third of the patients. The cornerstone of treatment is corticosteroids, comprehensive therapy and heart failure management (including advanced mechanical support for fulminant myocarditis). We have described the case of a 17-year-old heart transplant recipient who presented with a cardiogenic shock. He was admitted to our intensive care unit and treated with inotropic drugs, such as milrinone, adrenaline, vasopressin, and levosimendan; the doses of these drugs were in accordance with our internal protocol. The patient underwent cardiac catheterization, coronarography, and right ventricular EMB. EMB revealed inflammatory lymphomonocytic and eosinophil granulocyte infiltrates; thus, steroid therapy was initiated, with complete recovery achieved after 15 days. Performing an early differential diagnosis among eosinophilic infiltration, acute cellular rejection (ACR), and possible chemotherapeutic damage is emerging as an important challenge. To our knowledge, this is the first reported case of a lymphomonocytic inflammatory infiltration with numerous eosinophilic granulocytes in the interstitium in a surviving heart transplant recipient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Placidi, Francalanci, Adorisio, Girardi, Vinti, Panebianco, Rebonato, Amodeo and Grutter.)
- Published
- 2024
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22. Efficacy and manageable safety of tagraxofusp in blastic plasmacytoid dendritic cell neoplasm: a case series of pediatric and adolescent/young adult patients.
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Pemmaraju N, Cuglievan B, Lasky J, Kheradpour A, Hijiya N, Stein AS, Meshinchi S, Mullen CA, Angelucci E, Vinti L, Mughal TI, and Pawlowska AB
- Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) predominantly occurs in adults ≥60 years old; 10-20% of cases are pediatric or adolescent/young adult (AYA) patients. Tagraxofusp (TAG, Elzonris
® ) is the only approved treatment for BPDCN; in the United States it is approved for patients aged ≥2 years. Data on treating pediatric and AYA BPDCN patients are limited. We present a case series of pediatric and AYA patients with BPDCN treated with TAG. Eight patients (five newly diagnosed; three relapsed/refractory [R/R]), aged 2-21 years, received 12 mcg/kg TAG. Seven patients were female; most had skin ( n = 6) and/or bone marrow ( n = 4) involvement. No new safety signals were identified. Grade 3 adverse events were headache ( n = 1) and transaminitis ( n = 2). Three patients with newly diagnosed BPDCN achieved complete response, one achieved partial response, and one had stable disease (SD). One patient with R/R BPDCN achieved a minor response; one had SD. Seven patients (88%) were bridged to stem cell transplant: 80% of newly diagnosed patients and 100% of R/R patients. Five patients remained alive at last follow-up. These cases highlight the efficacy and safety of TAG in pediatric and AYA patients for whom there is no other approved BPDCN therapy., Competing Interests: Naveen Pemmaraju: Consultancy: Pacylex Pharmaceuticals, ImmunoGen, Inc, Bristol‐Myers Squibb Co., Blueprint Medicines, ClearView Healthcare Partners, Protagonist Therapeutics, Inc., Affymetrix, Incyte, Novartis Pharmaceuticals, LFB Biotechnologies, Stemline Therapeutics, Inc., Celgene Corporation, AbbVie Pharmaceuticals, MustangBio, Roche Diagnostics, DAVA Oncology, Aptitude Health, CareDx, Inc.; Other: Research Support and Research Funding: Novartis Pharmaceuticals; Research Funding: Affymetrix; Membership on an entity's Board of Directors or advisory committees: Stemline Therapeutics, Inc., AbbVie Pharmaceuticals, ASH Communications Committee, ASCO Leukemia Advisory Panel, HemOnc Times/Oncology Times, Dan's House of Hope; Other and Research Funding: Stemline Therapeutics, Inc., AbbVie Pharmaceuticals, Cellectis S.A. ADR, Daiichi Sankyo, Inc., Plexxikon, Samus; Other: MustangBio, Springer Science+Business Media, SagerStrong Foundation. Branko Cuglievan: Nothing to disclose. Joseph Lasky: Nothing to disclose. Albert Kheradpour: Nothing to disclose. Nobuko Hijiya: Consultancy: Stemline Therapeutics, Inc., Novartis; DSMB: Novartis, Incyte. Research Support (to institution): Novartis, Pfizer. Anthony S. Stein: Advisory Board: Sanofi; Speaker's Bureau: Amgen. Soheil Meshinchi: Nothing to disclose. Craig A. Mullen: Nothing to disclose. Emanuele Angelucci: Honoraria: Menarini/Stemline, Novartis; Board of Directors or advisory committees: bluebird bio, Glaxo, Gilead, Roche; Participation DMC: Vifor Pharma, BMS, Vertex Inc. Luciana Vinti: Advisory and Consultancy: Amgen, Clinigen; Speaker's Bureau: Amgen, Takeda; Research grant or Funding: Merck Sharp and Dohme. Tariq I. Mughal: Consultant to Stemline Therapeutics Inc, New York, NY, USA; Other: Oxford University Press, Informa (financial benefit and/or patents). Anna B. Pawlowska: Nothing to disclose., (© 2024 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2024
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23. Impact of Mercaptopurine Metabolites on Disease Outcome in the AIEOP-BFM ALL 2009 Protocol for Acute Lymphoblastic Leukemia.
- Author
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Franca R, Stocco G, Kiren V, Tessitore A, Fagioli F, Quarello P, Bertorello N, Rizzari C, Colombini A, Bettini LR, Locatelli F, Vinti L, Girardi K, Silvestri D, Valsecchi MG, Decorti G, and Rabusin M
- Abstract
In the maintenance phase of Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP)- Berlin-Frankfurt-Muenster (BFM) acute lymphoblastic leukemia (ALL) 2009 protocol, mercaptopurine (MP) is given at the planned dose of 50 mg/m
2 /day; however, dose adjustments are routinely performed to target patients' white blood cells to the optimal range of 2,000-3,000 cells/μL. Pediatric patients with ALL (n = 290, age: median (1st-3rd quartile): 4.8 (3.0-8.1) years; boys: 56.9%) were enrolled mainly in 4 medium-large Italian pediatric hospitals; 14.1% of patients relapsed after a median (1st-3rd quartile) follow-up time of 4.43 (3.82-5.46) years from maintenance beginning. MP metabolites (thionucleotide (TGN) and methyl-derivatives (MMPN)) were measured in the erythrocytes of 387 blood samples of 200 patients by high performance liquid chromatography with ultraviolet detection. Single-nucleotide polymorphisms (SNPs; (rs1800462, rs1800460, and rs1142345 in TPMT gene, rs116855232 in NUDT15, rs1127354, rs7270101, rs6051702 in ITPA, and rs2413739 in PACSIN2) were characterized by Taqman SNP genotyping assays. Cox proportional hazard models did not show an impact of TGN levels and variability on relapse. In contrast, after multivariate analysis, relapse hazard ratio (HR) increased in children with ALL of the intermediate risk arm compared with those in standard risk arm (3.44, 95% confidence interval (CI), 1.31-9.05, P = 0.012), and in carriers of the PACSIN2 rs2413739 T allele compared with those with the CC genotype (heterozygotes CT: HR, 2.32, 95% CI, 0.90-5.97, P = 0.081; and homozygous TT: HR, 4.14, 95% CI, 1.54-11.11, P = 0.005). Future studies are needed to confirm the lack of impact of TGN levels and variability on relapse in the AIEOP-BFM ALL trials, and to clarify the mechanism of PACSIN2 rs2413739 on outcome., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)- Published
- 2023
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24. Impact of Pregnancy on Weight Loss After Endoscopic Sleeve Gastroplasty.
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Carlino G, Benson AA, Bove V, Pontecorvi V, De Siena M, Matteo MV, Farina A, Polidori G, Vinti L, Giannetti G, Costamagna G, Spada C, and Boškoski I
- Subjects
- Humans, Female, Retrospective Studies, Quality of Life, Treatment Outcome, Obesity surgery, Weight Loss, Gastroplasty, Obesity, Morbid surgery
- Abstract
Purpose: Obesity and pregnancy are strictly related: on the one hand, obesity-one of the most common comorbidities in women of reproductive age-contributes to infertility and obesity-related pregnancy complications, whereas pregnancy is a condition in which, physiologically, the pregnant woman undergoes weight gain. Endoscopic sleeve gastroplasty (ESG) may be used for the treatment of obesity in women of childbearing age., Materials and Methods: A retrospective analysis was conducted to evaluate weight trajectories, the evolution of obesity-related comorbidities, and lifestyle modification in women who became pregnant after ESG. A comparison was made between childbearing-age women who became pregnant after ESG and non-pregnant women., Results: A total of 150 childbearing-age women underwent ESG at a large tertiary medical center. Of these, 11 patients (33.4 ± 6.2 years) became pregnant after the procedure, following a mean time interval of 5.5 ± 3.9 months. Three women (two affected by polycystic ovary syndrome) reported difficulty getting pregnant before undergoing ESG. The mean preconception BMI was 31.9±4.0 kg/m
2 (-7.24 ± 4.0 kg/m2 after ESG). Total body weight loss (TBWL, %) was 18.08 ± 8.00, 11.00 ± 11.08, and 12.08 ± 8.49, at the beginning of pregnancy, at the delivery, and at the first follow-up (19.6 ± 7.8 months after ESG). TBWL of at least 5% was achieved before pregnancy in all patients (73% reached a TBWL ≥ 10%). No significant differences in weight loss and QoL were found between the pregnancy and non-pregnancy groups up to 24 months after ESG., Conclusions: Endoscopic sleeve gastroplasty allows for adequate weight loss before and after pregnancy in patients with obesity., (© 2023. The Author(s).)- Published
- 2023
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25. MiR-146a-5p enrichment in small-extracellular vesicles of relapsed pediatric ALCL patients promotes macrophages infiltration and differentiation.
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Garbin A, Contarini G, Damanti CC, Tosato A, Bortoluzzi S, Gaffo E, Pizzi M, Carraro E, Lo Nigro L, Vinti L, Pillon M, Biffi A, Lovisa F, and Mussolin L
- Subjects
- Humans, Child, Neoplasm Recurrence, Local genetics, Macrophages, Cell Differentiation, Receptor Protein-Tyrosine Kinases, Lymphoma, Large-Cell, Anaplastic genetics, MicroRNAs genetics, Extracellular Vesicles genetics
- Abstract
Anaplastic large cell lymphoma (ALCL) is a CD30-positive lymphoma accounting for 20% of all pediatric T-cell lymphomas. Current first line treatment can cure most of ALCL patients but 10-30% of them are resistant or relapse. In this context, liquid biopsy has the potential to help clinicians in disease screening and treatment response monitoring. Small-RNA-sequencing analysis performed on plasma small-extracellular vesicles (s-EVs) from 20 pediatric anaplastic lymphoma kinase positive (ALK + ) ALCL patients at diagnosis revealed a specific miRNAs cargo in relapsed patients compared to non-relapsed, with seven miRNAs enriched in s-EVs of relapsed patients. MiR-146a-5p and miR-378a-3p showed a negative prognostic impact both in univariate and multivariate analysis, possibly representing, together with let-7 g-5p, a miRNA panel for the early identification of high-risk patients. Among them, miR-146a-5p is known to modulate tumor supporting-M2 macrophages differentiation, but the role of these cells in pediatric ALK + ALCL is still unknown. To elucidate the role of miR-146a-5p and M2 macrophages in pediatric ALCL disease, THP-1-derived macrophages were treated with s-EVs from ALK + ALCL cell lines, showing increased miR-146a-5p intracellular expression, migrating capability and M2-markers CD163 and Arginase-1 upregulation. In turn, conditioned media from M2 macrophages or miR-146a-5p-transfected THP-1 increased ALCL cells' aggressive features and were enriched in interleukin-8. Overall, these data suggest a role of miR-146a-5p in promoting macrophage infiltration and M2-like polarization in ALCL. Our findings incite further investigation on the role of M2 macrophages in ALCL aggressiveness and dissemination, also considering the novel treatment options targeting tumor associated macrophages., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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26. Achievement of operational tolerance in a pediatric liver transplant recipient following successful hematopoietic stem cell transplantation from a different donor.
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Algeri M, Velardi E, Spada M, Galaverna F, Carta R, Vinti L, Palumbo G, Gaspari S, Pietrobattista A, Boccieri E, Becilli M, Francalanci P, Bertaina V, Merli P, and Locatelli F
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- Male, Humans, Child, Tissue Donors, Immune Tolerance, Transplantation, Homologous adverse effects, Liver Transplantation adverse effects, Hematopoietic Stem Cell Transplantation adverse effects, Anemia, Aplastic etiology, Graft vs Host Disease etiology
- Abstract
Hematopoietic stem cell transplantation (HSCT)-based approaches are increasingly investigated strategies to induce tolerance in recipients of solid allografts. However, in the majority of cases, these approaches rely on the infusion of hematopoietic stem cells recovered from the same solid organ donor. In this report, we describe the case of a boy who received liver transplantation from a deceased donor, who had successfully underwent allogeneic HSCT from an unrelated donor for hepatitis-associated aplastic anemia. In this patient, it was possible to permanently withdraw post-HSCT immune suppression without causing any sign of liver graft dysfunction. To the best of our knowledge, this is the first case of operational tolerance documented in a patient who received combined liver transplantation and HSCT from different donors., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)
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- 2023
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27. Incidence and Characteristics of Hypersensitivity Reactions to PEG-asparaginase Observed in 6136 Children With Acute Lymphoblastic Leukemia Enrolled in the AIEOP-BFM ALL 2009 Study Protocol.
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Rizzari C, Möricke A, Valsecchi MG, Conter V, Zimmermann M, Silvestri D, Attarbaschi A, Niggli F, Barbaric D, Stary J, Elitzur S, Cario G, Vinti L, Boos J, Zucchetti M, Lanvers-Kaminsky C, von Stackelberg A, Biondi A, and Schrappe M
- Abstract
The incidence of hypersensitivity reactions (HSRs) to PEG-asparaginase (PEG-ASNase) was evaluated in 6136 children with ALL enrolled in the AIEOP-BFM ALL 2009 study. Patients with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL) were stratified as standard-risk/medium-risk (MR)/high-risk (HR) and those with T-ALL as non-High/HR. PEG-ASNase was administered intravenously at 2500 IU/sqm/dose. All patients received 2 PEG-ASNase doses in induction; thereafter non-HR versus HR patients received 1 versus 6 PEG-ASNase doses, respectively. After the single regular dose of PEG-ASNase at the beginning of delayed intensification, BCP-ALL-MR patients were randomized to receive 9 additional PEG-ASNase doses every 2 weeks (experimental arm [EA]) versus none (standard arm [SA]); HR patients were randomized to receive, in consolidation, 4 weekly PEG-ASNase doses (EA) versus none (SA). The HSR cumulative incidence (CI) was estimated adjusting for competing risks. An HSR occurred in 472 of 6136 (7.7%) patients. T-non- HR/BCP-Standard-Risk, BCP-MR-SA, BCP-MR-EA, HR-SA and HR-EA patients had 1-year-CI-HSR (±SE) rates of 5.2% (0.5), 5.2% (0.5), 4.0% (0.8), 20.2% (1.2), and 6.4% (1.3), respectively. The randomized intensification of PEG-ASNase did not significantly impact on HSR incidence in BCP-MR patients (1-y-CI-HSR 3.8% [0.8] versus 3.2% [0.6] in MR-EA versus MR-SA; P = 0.55), while impacted significantly in HR patients (1-y-CI-HSR 6.4% [1.3] versus 17.9% [1.8] in HR-EA and HR-SA, respectively; P < 0.001). The CI-HSR was comparable among non-HR groups and was not increased by a substantial intensification of PEG-ASNase in the BCP-MR-EA group whilst it was markedly higher in HR-SA than in HR-EA patients, suggesting that, in such a chemotherapy context, a continuous exposure to PEG-ASNase reduces the risk of developing an HSR., Competing Interests: CR: Jazz Pharmaceuticals, Servier, Clinigen, Amgen: honoraria. AM: Clinigen and BTG: consultancy honoraria. JB: institutional and personal consultation fees, advisory board memberships, invited lectures and travel and research grants from asparaginase suppliers Medac, Shire, Sigma-Tau, Baxalta, Servier, Opi, Eusapharma, Jazz in the last decade(s). Focusing on the last years restricted to institutional grants from JAZZ (research) and Servier (Consulting, research, invited lecture). MS and/or study group have received research support from SHIRE, Jazz Pharma, Servier, SigmaTau, and Novartis. Honoraria from Servier, Novartis, and Jazz Pharma. VC: Medac, Sigma-Tau and Shire: research funds; Sigma-Tau and Shire: consultancy honoraria. AA: honoraria for lectures, consultancy or advisory board participation from Jazz Pharmaceuticals, Amgen, Novartis, MSD, Amgen, Novartis, MSD, and Gilead. He has received compensation for travel expenses from Jazz Pharmaceuticals. CL-K: Clinigen: Honoraria; Servier: Travel Grants. All the other authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)
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- 2023
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28. Long-term Outcomes of Transoral Outlet Reduction (TORe) for Dumping Syndrome and Weight Regain After Roux-en-Y Gastric Bypass.
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Pontecorvi V, Matteo MV, Bove V, De Siena M, Giannetti G, Carlino G, Polidori G, Vinti L, Angelini G, Iaconelli A, Familiari P, Raffaelli M, Costamagna G, and Boškoski I
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- Humans, Female, Middle Aged, Male, Dumping Syndrome etiology, Dumping Syndrome surgery, Retrospective Studies, Weight Gain, Suture Techniques, Reoperation methods, Weight Loss, Treatment Outcome, Gastric Bypass adverse effects, Gastric Bypass methods, Obesity, Morbid surgery
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Background: Both weight regain and dumping syndrome (DS) after Roux-en-Y gastric bypass (RYGB) have been related to the dilation of gastro-jejunal anastomosis. The aim of this study is to assess the safety and long-term efficacy of endoscopic transoral outlet reduction (TORe) for DS and/or weight regain after RYBG., Materials and Methods: A retrospective analysis was performed on a prospective database. Sigstad's score, early and late Arts Dumping Score (ADS) questionnaires, absolute weight loss (AWL), percentage of total body weight loss (%TBWL), and percentage of excess weight loss (%EWL) were assessed at baseline and at 6, 12, and 24 months after TORe., Results: Eighty-seven patients (median age 46 years, 79% female) underwent TORe. The median baseline BMI was 36.2 kg/m
2 . Out of 87 patients, 58 were classified as "dumpers" due to Sigstad's score ≥ 7. The resolution rate of DS (Sigstad's score < 7) was 68.9%, 66.7%, and 57.2% at 6, 12, and 24 months after TORe, respectively. A significant decrease in Sigstad's score as well as in early and late ADS questionnaires was observed (p < 0.001). The median Sigstad's score dropped from 15 (11-8.5) pre-operatively to 2 (0-12) at 24 months. The %TBWL was 10.5%, 9.9%, and 8.1% at 6, 12, and 24 months, respectively. Further, "dumpers" with resolution of DS showed better weight loss results compared with those with persistent DS (p < 0.001). The only adverse event observed was a perigastric fluid collection successfully managed conservatively., Conclusion: TORe is a minimally invasive treatment for DS and/or weight regain after RYGB, with evidence of long-term efficacy., (© 2023. The Author(s).)- Published
- 2023
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29. Ibrutinib plus RICE or RVICI for relapsed/refractory mature B-cell non-Hodgkin lymphoma in children and young adults: SPARKLE trial.
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Burke GAA, Vinti L, Kabickova E, Beishuizen A, Tacyildiz N, Uyttebroeck A, Kang HJ, Luisi F, Minard-Colin V, Burkhardt B, Tamegnon M, Sun S, Curtis M, Deshpande S, Nottage K, Howes A, Srinivasan S, Bhojwani D, Norris R, and Cairo M
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- Humans, Young Adult, Child, Adolescent, Rituximab, Etoposide, Carboplatin, Ifosfamide, Lymphoma, Large B-Cell, Diffuse
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Part 1 results of the open-label, randomized, global phase 3 SPARKLE trial supported continued assessment of ibrutinib with either modified rituximab, ifosfamide, carboplatin, and etoposide (RICE) or rituximab, vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone (RVICI) in pediatric patients with relapsed/refractory (R/R) mature B-cell non-Hodgkin lymphoma (B-NHL). We report final results of Part 2 evaluating the efficacy of ibrutinib plus RICE or RVICI vs RICE/RVICI alone. Patients aged 1 to 30 years (initial diagnosis <18 years) were randomized 2:1 to receive ibrutinib with or without RICE/RVICI. Primary endpoint was event-free survival (EFS) based on independent committee-confirmed events. Fifty-one patients were enrolled. Median age was 15 years; Burkitt lymphoma, Burkitt leukemia, and Burkitt-like lymphoma (total: 45%) and diffuse large B-cell lymphoma/primary mediastinal B-cell lymphoma (51%) were the most common subtypes. At the preplanned interim analysis, median EFS was 6.1 vs 7.0 months with ibrutinib plus RICE/RVICI vs RICE/RVICI, respectively (hazard ratio, 0.9; 90% confidence interval, 0.5-1.6; P = .387); further enrollment was ceased. With ibrutinib plus RICE/RVICI vs RICE/RVICI, median overall survival was 14.1 vs 11.1 months, overall response rate was 69% vs 81%, and 46% vs 44% proceeded to stem cell transplantation. In both treatment arms, 100% of patients experienced grade ≥3 treatment-emergent adverse events. No EFS benefit was seen with ibrutinib. Salvage was generally poor in patients who received prior rituximab, regardless of treatment arm. No new safety signals were observed. Ibrutinib exposure in pediatric patients fell within the target range of exposure in adults. Trial is registered on www.clinicaltrials.gov (NCT02703272)., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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30. Development and Initial Validation of the ONCOREUM Score to Differentiate Childhood Cancer with Arthropathy from Juvenile Idiopathic Arthritis.
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Civino A, Bovis F, Ponzano M, Alighieri G, Prete E, Sorrentino S, Magni-Manzoni S, Vinti L, Romano M, Santoro N, Filocamo G, Belotti T, Santarelli F, Gorio C, Cattalini M, Stabile G, Conter V, Rondelli R, Pession A, and Ravelli A
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- Child, Humans, Bayes Theorem, Cross-Sectional Studies, Arthritis, Juvenile complications, Arthritis, Juvenile diagnosis, Neoplasms complications, Neoplasms diagnosis, Joint Diseases diagnosis, Joint Diseases etiology
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Objective: To develop and validate a weighted score, the ONCOREUM score, that aids physicians in differentiation of cancer with arthropathy from juvenile idiopathic arthritis (JIA)., Study Design: Data were extracted from the ONCOREUM Study, a multicenter, cross-sectional investigation aimed at comparing children with cancer and arthropathy to children with JIA. Three statistical approaches were applied to develop the ONCOREUM score and assess the role of each variable in the diagnosis of cancer with arthropathy, including 2 approaches based on multivariable stepwise selection (models 1 and 2) and 1 approach on a Bayesian model averaging method (model 3). The β coefficients estimated in the models were used to assign score points. Considering that not missing a child with cancer is a mandatory clinical objective, discriminating performance was assessed by fixing sensitivity at 100%. Score performance was evaluated in both developmental and validation samples (representing 80% and 20% of the study population, respectively)., Results: Patients with cancer and arthropathy (49 with solid tumors and 46 with hematologic malignancies without peripheral blasts) and 677 patients with JIA were included. The highest area under the receiver operating characteristic (ROC) curve (AUC) in the validation data set was yielded by model 1, which was selected to constitute the ONCOREUM score. The score ranged from -18 to 21.8, and the optimal cutoff obtained through ROC analysis was -6. The sensitivity, specificity, and AUC of the cutoff in the validation sample were 100%, 70%, and 0.85, respectively., Conclusions: The ONCOREUM score is a powerful and easily applicable tool that may facilitate early differentiation of malignancies with articular complaints from JIA., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2023
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31. Case report: Primary ovarian Burkitt's lymphoma: A puzzling scenario in pediatric population.
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Persano G, Crocoli A, Martucci C, Vinti L, Cassanelli G, Stracuzzi A, Cardoni A, and Inserra A
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Burkitt's lymphoma (BL) is defined as a highly invasive B-cell lymphoma, usually characterized by an excellent prognosis, more than 90% of children and adolescents being cured with highly dose-intensive multiagent chemotherapy. Primary ovarian localization without involvement of other organs is a rare manifestation of BL, especially in pediatric population. Symptoms at diagnosis are similar to other ovarian lesions and differential diagnosis may be challenging for clinicians. A 12-year-old girl was referred to our institution for abdominal pain and palpable mass observed by the pediatrician. Diagnostic work-up demonstrated a large mass arising from the right ovary, causing compression on abdominal aorta, inferior vena cava, ureters and bowel, with a second smaller lesion on the left ovary. At surgery, a 15 cm-large, ruptured mass arising from the right ovary was found, associated with a second lesion originating from the left ovary (8 cm) and multiple nodules of the greater omentum. Right salpingo-oophorectomy was performed, incisional biopsies were taken from the left ovary and omental nodules and peritoneal fluid samples were collected for cytology. Pathology revealed a Burkitt lymphoma and the patient underwent chemotherapy according to AIEOP LNH-97 Protocol, group R3 with Rituximab . Preoperative diagnosis of primary ovarian lymphoma is extremely difficult. Surgical exploration is often necessary in patients presenting with acute abdominal or pelvic pain; when the suspicion of primary ovarian lymphoma arises intraoperatively, every effort should be made to minimize invasive procedure in order to enhance post-operative recovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Persano, Crocoli, Martucci, Vinti, Cassanelli, Stracuzzi, Cardoni and Inserra.)
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- 2023
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32. Improved survival and MRD remission with blinatumomab vs. chemotherapy in children with first high-risk relapse B-ALL.
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Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Zeng Y, Desai R, Kormany WN, Eckert C, Möricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, and von Stackelberg A
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- Humans, Child, Neoplasm Recurrence, Local drug therapy, Disease-Free Survival, Recurrence, Neoplasm, Residual drug therapy, Remission Induction, Antibodies, Bispecific therapeutic use, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
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- 2023
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33. Prospective Evaluation of Different Methods for Volumetric Analysis on [ 18 F]FDG PET/CT in Pediatric Hodgkin Lymphoma.
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Lopci E, Elia C, Catalfamo B, Burnelli R, De Re V, Mussolin L, Piccardo A, Cistaro A, Borsatti E, Zucchetta P, Bianchi M, Buffardi S, Farruggia P, Garaventa A, Sala A, Vinti L, Mauz-Koerholz C, and Mascarin M
- Abstract
Rationale: Therapy response evaluation by 18F-fluorodeoxyglucose PET/CT (FDG PET) has become a powerful tool for the discrimination of responders from non-responders in pediatric Hodgkin lymphoma (HL). Recently, volumetric analyses have been regarded as a valuable tool for disease prognostication and biological characterization in cancer. Given the multitude of methods available for volumetric analysis in HL, the AIEOP Hodgkin Lymphoma Study Group has designed a prospective analysis of the Italian cohort enrolled in the EuroNet-PHL-C2 trial. Methods: Primarily, the study aimed to compare the different segmentation techniques used for volumetric assessment in HL patients at baseline (PET1) and during therapy: early (PET2) and late assessment (PET3). Overall, 50 patients and 150 scans were investigated for the current analysis. A dedicated software was used to semi-automatically delineate contours of the lesions by using different threshold methods. More specifically, four methods were applied: (1) fixed 41% threshold of the maximum standardized uptake value (SUVmax) within the respective lymphoma site (V41%), (2) fixed absolute SUV threshold of 2.5 (V2.5); (3) SUVmax(lesion)/SUVmean liver >1.5 (Vliver); (4) adaptive method (AM). All parameters obtained from the different methods were analyzed with respect to response. Results: Among the different methods investigated, the strongest correlation was observed between AM and Vliver (rho > 0.9; p < 0.001 for SUVmean, MTV and TLG at all scan timing), along with V2.5 and AM or Vliver (rho 0.98, p < 0.001 for TLG at baseline; rho > 0.9; p < 0.001 for SUVmean, MTV and TLG at PET2 and PET3, respectively). To determine the best segmentation method, we applied logistic regression and correlated different results with Deauville scores at late evaluation. Logistic regression demonstrated that MTV (metabolic tumor volume) and TLG (total lesion glycolysis) computation according to V2.5 and Vliver significantly correlated to response to treatment (p = 0.01 and 0.04 for MTV and 0.03 and 0.04 for TLG, respectively). SUVmean also resulted in significant correlation as absolute value or variation. Conclusions: The best correlation for volumetric analysis was documented for AM and Vliver, followed by V2.5. The volumetric analyses obtained from V2.5 and Vliver significantly correlated to response to therapy, proving to be preferred thresholds in our pediatric HL cohort.
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- 2022
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34. Brentuximab vedotin in the treatment of paediatric patients with relapsed or refractory Hodgkin's lymphoma: Results of a real-life study.
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Massano D, Carraro E, Mussolin L, Buffardi S, Barat V, Zama D, Muggeo P, Vendemini F, Sau A, Moleti ML, Verzegnassi F, D'Amico S, Casini T, Garaventa A, Schiavello E, Cellini M, Vinti L, Farruggia P, Perruccio K, Cesaro S, De Santis R, Marinoni M, D'Alba I, Mura RM, Burnelli R, Mascarin M, and Pillon M
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- Adult, Brentuximab Vedotin, Child, Humans, Neoplasm Recurrence, Local drug therapy, Retrospective Studies, Treatment Outcome, Hodgkin Disease therapy, Immunoconjugates adverse effects
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Background: Brentuximab vedotin (BV) is an antibody drug-conjugated anti-CD30 approved for the treatment of adult classical Hodgkin's lymphoma (HL), whereas it is considered as off-label indication in paediatrics. The aim of the study was to evaluate the safety and efficacy of BV to treat patients aged less than 18 years with refractory/relapsed HL., Materials and Methods: In this multicentre, retrospective study, 68 paediatric patients who received at least one dose of BV between November 2011 and August 2020 were enrolled. A median of nine doses of BV were administered as monotherapy (n = 31) or combined with other therapies (n = 37). BV was administrated alone as consolidation therapy after stem cell transplantation (SCT) in 12 patients, before SCT in 18 patients, whereas in 15 patients it was used before and after SCT as consolidation therapy. Median follow-up was 2.8 years (range: 0.6-8.9 years)., Results: The best response was observed in the 86% of patients; the overall response rate was 66%. The 3-year progression-free survival was 58%, whereas the overall survival was 75%. No statistically significant differences between patients treated with BV monotherapy or combination were highlighted. In multivariate analysis, patients with non-nodular sclerosis HL and not transplanted had an increased risk of failure. Overall, 46% of patients had grade 3-4 adverse events that led to BV discontinuation in five of them., Conclusion: In conclusion, our study confirms that BV was a safe and effective drug, able to induce complete remission, either as monotherapy or in association with standard therapy., (© 2022 Wiley Periodicals LLC.)
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- 2022
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35. Inotuzumab ozogamicin as single agent in pediatric patients with relapsed and refractory acute lymphoblastic leukemia: results from a phase II trial.
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Pennesi E, Michels N, Brivio E, van der Velden VHJ, Jiang Y, Thano A, Ammerlaan AJC, Boer JM, Beverloo HB, Sleight B, Chen Y, Vormoor-Bürger B, Rives S, Bielorai B, Rössig C, Petit A, Rizzari C, Engstler G, Starý J, Bautista Sirvent FJ, Chen-Santel C, Bruno B, Bertrand Y, Rialland F, Plat G, Reinhardt D, Vinti L, Von Stackelberg A, Locatelli F, and Zwaan CM
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- Acute Disease, Adolescent, Child, Child, Preschool, Humans, Infant, Inotuzumab Ozogamicin, Progression-Free Survival, Calicheamicins, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Inotuzumab Ozogamicin is a CD22-directed antibody conjugated to calicheamicin, approved in adults with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (BCP-ALL). Patients aged 1-18 years, with R/R CD22 + BCP-ALL were treated at the RP2D of 1.8 mg/m
2 . Using a single-stage design, with an overall response rate (ORR) ≤ 30% defined as not promissing and ORR > 55% as expected, 25 patients needed to be recruited to achieve 80% power at 0.05 significance level. Thirty-two patients were enrolled, 28 were treated, 27 were evaluable for response. The estimated ORR was 81.5% (95%CI: 61.9-93.7%), and 81.8% (18/22) of the responding subjects were minimal residual disease (MRD) negative. The study met its primary endpoint. Median follow up of survivors was 16 months (IQR: 14.49-20.07). One year Event Free Survival was 36.7% (95% CI: 22.2-60.4%), and Overall Survival was 55.1% (95% CI: 39.1-77.7%). Eighteen patients received consolidation (with HSCT and/or CAR T-cells therapy). Sinusoidal obstructive syndrome (SOS) occurred in seven patients. MRD negativity seemed correlated to calicheamicin sensitivity in vitro, but not to CD22 surface expression, saturation, or internalization. InO was effective in this population. The most relevant risk was the occurrence of SOS, particularly when InO treatment was followed by HSCT., (© 2022. The Author(s).)- Published
- 2022
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36. Brentuximab vedotin in combination with bendamustine in pediatric patients or young adults with relapsed or refractory Hodgkin lymphoma.
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Vinti L, Pagliara D, Buffardi S, Di Ruscio V, Stocchi F, Mariggiò E, Parasole R, Di Matteo A, Petruzziello F, Paganelli V, De Vito R, Del Bufalo F, Strocchio L, and Locatelli F
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- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bendamustine Hydrochloride adverse effects, Brentuximab Vedotin, Child, Humans, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local etiology, Retrospective Studies, Treatment Outcome, Young Adult, Hodgkin Disease pathology, Immunoconjugates therapeutic use
- Abstract
Although children and young adults with Hodgkin's lymphoma usually have a favorable prognosis, patients with primary refractory disease and some subsets of relapsed patients still have a dismal outcome. Brentuximab vedotin (BV) in combination with bendamustine may represent a suitable salvage therapy; data on 32 patients aged less than 25 years were retrospectively analyzed. Patients received up to six cycles of treatment of BV 1.8 mg/kg on day 1 and bendamustine 90-120 mg/m
2 on days 2 and 3. At the end of treatment, the overall response rate was 81%. The 3-year overall and progression-free survivals are 78.1% and 67%, respectively., (© 2022 Wiley Periodicals LLC.)- Published
- 2022
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37. Quantification of Minimal Disease by Digital PCR in ALK-Positive Anaplastic Large Cell Lymphoma: A Step towards Risk Stratification in International Trials?
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Damm-Welk C, Lovisa F, Contarini G, Lüdersen J, Carraro E, Knörr F, Förster J, Zimmermann M, Sala A, Vinti L, Tondo A, Pillon M, Woessmann W, and Mussolin L
- Abstract
Minimal disseminated and residual disease (MDD/MRD) analyzed by qualitative PCR for NPM-ALK fusion transcripts are validated prognostic factors in pediatric ALK-positive anaplastic large cell lymphoma (ALCL). Although potentially promising, MDD quantification by quantitative real-time PCR in international trials is technically challenging. Quantification of early MRD might further improve risk stratification. We aimed to assess droplet digital PCR for quantification of minimal disease in an inter-laboratory setting in a large cohort of 208 uniformly treated ALCL patients. Inter-laboratory quality control showed high concordance. Using a previously described cut-off of 30 copies NPM-ALK/104 copies ABL1 (NCN) in bone marrow and peripheral blood, MDD quantification allowed identification of very high-risk patients (5-year PFS% 34 ± 5 for patients with ≥30 NCN compared to 74 ± 6 and 76 ± 5 for patients with negative or <30 NCN, respectively, p < 0.0001). While MRD positivity was confirmed as a prognostic marker for the detection of very high-risk patients in this large study, quantification of MRD fusion transcripts did not improve stratification. PFS% was 80 ± 5 and 73 ± 6 for MDD- and MRD-negative patients, respectively, versus 35 ± 10 and 16 ± 8 for MRD-positive patients with <30 and ≥30 NCN, p < 0.0001. Our results suggest that MDD quantification by dPCR enables improved patient stratification in international clinical studies and patient selection for early clinical trials already at diagnosis.
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- 2022
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38. Short and Long-Term Toxicity in Pediatric Cancer Treatment: Central Nervous System Damage.
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Alessi I, Caroleo AM, de Palma L, Mastronuzzi A, Pro S, Colafati GS, Boni A, Della Vecchia N, Velardi M, Evangelisti M, Carboni A, Carai A, Vinti L, Valeriani M, Reale A, Parisi P, and Raucci U
- Abstract
Neurotoxicity caused by traditional chemotherapy and radiotherapy is well known and widely described. New therapies, such as biologic therapy and immunotherapy, are associated with better outcomes in pediatric patients but are also associated with central and peripheral nervous system side effects. Nevertheless, central nervous system (CNS) toxicity is a significant source of morbidity in the treatment of cancer patients. Some CNS complications appear during treatment while others present months or even years later. Radiation, traditional cytotoxic chemotherapy, and novel biologic and targeted therapies have all been recognized to cause CNS side effects; additionally, the risks of neurotoxicity can increase with combination therapy. Symptoms and complications can be varied such as edema, seizures, fatigue, psychiatric disorders, and venous thromboembolism, all of which can seriously influence the quality of life. Neurologic complications were seen in 33% of children with non-CNS solid malign tumors. The effects on the CNS are disabling and often permanent with limited treatments, thus it is important that clinicians recognize the effects of cancer therapy on the CNS. Knowledge of these conditions can help the practitioner be more vigilant for signs and symptoms of potential neurological complications during the management of pediatric cancers. As early detection and more effective anticancer therapies extend the survival of cancer patients, treatment-related CNS toxicity becomes increasingly vital. This review highlights major neurotoxicities due to pediatric cancer treatments and new therapeutic strategies; CNS primary tumors, the most frequent solid tumors in childhood, are excluded because of their intrinsic neurological morbidity.
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- 2022
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39. Outcome of Children and Adolescents with Recurrent Classical Hodgkin Lymphoma: The Italian Experience.
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Garaventa A, Parodi S, Guerrini G, Farruggia P, Sala A, Pillon M, Buffardi S, Rossi F, Bianchi M, Zecca M, Vinti L, Facchini E, Casini T, Bernasconi S, Amoroso L, D'Amico S, Provenzi M, De Santis R, Sau A, Muggeo P, Mura RM, Haupt R, Mascarin M, and Burnelli R
- Abstract
The objective of this study was to identify prognostic factors for children and adolescents with relapsed or progressive classical Hodgkin’s lymphoma (cHL) to design salvage therapy tailored to them. We analyzed a homogeneous pediatric population, diagnosed with progressive/relapsed cHL previously enrolled in two subsequent protocols of the Italian Association of Pediatric Hematology and Oncology in the period 1996−2016. There were 272 eligible patients, 17.5% of treated patients with cHL. Overall survival (OS) and event-free survival (EFS) after a 10-year follow-up were 65.3% and 53.3%, respectively. Patients with progressive disease (PD), advanced stage at recurrence, and ≥5 involved sites showed a significantly worse OS. PD, advanced stage, and extra-nodal involvement at recurrence were significantly associated with a poorer EFS. Multivariable analysis identified three categories for OS based on the type of recurrence and number of localizations: PD and ≥5 sites: OS 34%; PD and <5 sites: OS 56.5%; relapses: OS 73.6%. Four categories were obtained for EFS based on the type of recurrence and stage: PD and stage 3−4: EFS 25.5%; PD and stage 1−2: EFS 43%; relapse and stage 3−4: EFS 55.4%; relapse and stage 1−2: EFS 72.1%. Patients with PD, in advanced stage, or with ≥5 involved sites had a very poor survival and they should be considered refractory to first- and second-line standard chemotherapy. Probably, they should be considered for more innovative approaches since the first progression. Conversely, patients who relapsed later with localized disease had a better prognosis, and they could be considered for a conservative approach.
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- 2022
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40. Poor prognosis of B-cell acute lymphoblastic leukemia with TCF/PBX1 fusion gene and ovarian involvement at diagnosis: Two case reports and review of the literature.
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Vinti L, Del Baldo G, Lodi M, Stocchi F, Cefalo MG, and Pagliara D
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- Child, Gene Fusion, Homeodomain Proteins genetics, Humans, Prognosis, Translocation, Genetic, Basic Helix-Loop-Helix Transcription Factors, Oncogene Proteins, Fusion genetics, Pre-B-Cell Leukemia Transcription Factor 1 genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
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- 2022
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41. Prognostic Role of Minimal Disseminated Disease and NOTCH1/FBXW7 Mutational Status in Children with Lymphoblastic Lymphoma: The AIEOP Experience.
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Lovisa F, Gallingani I, Varotto E, Pasin C, Carraro E, Michielotto B, Garbin A, Damanti CC, Pizzi M, d'Amore ESG, Piglione M, Muggeo P, Buffardi S, Vinti L, Folsi VM, Onofrillo D, Biffi A, Buldini B, Pillon M, and Mussolin L
- Abstract
NOTCH1/FBXW7 (N/F) mutational status at diagnosis is employed for T-cell lymphoblastic lymphoma (T-LBL) patients' stratification in the international protocol LBL 2018. Our aim was to validate the prognostic role of Minimal Disseminated Disease (MDD) alone and in combination with N/F mutational status in a large retrospective series of LBL pediatric patients. MDD was analyzed in 132 bone marrow and/or peripheral blood samples by flow cytometry. Mutations in N/F genes were analyzed on 58 T-LBL tumor biopsies. Using the previously established cut-off of 3%, the four-year progression-free survival (PFS) was 57% for stage I-III patients with MDD ≥ 3% versus 80% for patients with MDD inferior to cut-off ( p = 0.068). We found a significant worsening in the four-year PFS for nonmutated (51 ± 12%) compared to mutated patients (100%, p = 0.0013). Combining MDD and N/F mutational status in a subgroup of available cases, we found a statistically significant difference in the four-year PFS for different risk groups ( p = 0.0012). Overall, our results demonstrate that N/F mutational status has a more relevant prognostic value than MDD at diagnosis. However, the combination of N/F mutations with MDD analysis could identify patients with very aggressive disease, which might benefit from a more intensive treatment.
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- 2021
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42. Peripheral Nervous System Involvement in Non-Primary Pediatric Cancer: From Neurotoxicity to Possible Etiologies.
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Pro S, Vinti L, Boni A, Mastronuzzi A, Scilipoti M, Velardi M, Caroleo AM, Farina E, Badolato F, Alessi I, Di Nardo G, Carai A, Valeriani M, Reale A, Parisi P, and Raucci U
- Abstract
Peripheral neuropathy is a well described complication in children with cancer. Oncologists are generally well aware of the toxicity of the main agents, but fear the side effects of new drugs. As chemotherapeutic agents have been correlated with the activation of the immune system such as in Chemotherapy Induced Peripheral Neuropathy (CIPN), an abnormal response can lead to Autoimmune Peripheral Neuropathy (APN). Although less frequent but more severe, Radiation Induced Peripheral Neuropathy may be related to irreversible peripheral nervous system (PNS). Pediatric cancer patients also have a higher risk of entering a Pediatric Intensive Care Unit for complications related to therapy and disease. Injury to peripheral nerves is cumulative, and frequently, the additional stress of a malignancy and its therapy can unmask a subclinical neuropathy. Emerging risk factors for CIPN include treatment factors such as dose, duration and concurrent medication along with patient factors, namely age and inherited susceptibilities. The recent identification of individual genetic variations has advanced the understanding of physiopathological mechanisms and may direct future treatment approaches. More research is needed on pharmacological agents for the prevention or treatment of the condition as well as rehabilitation interventions, in order to allow for the simultaneous delivery of optimal cancer therapy and the mitigation of toxicity associated with pain and functional impairment. The aim of this paper is to review literature data regarding PNS complications in non-primary pediatric cancer.
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- 2021
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43. Musculoskeletal manifestations of childhood cancer and differential diagnosis with juvenile idiopathic arthritis (ONCOREUM): a multicentre, cross-sectional study.
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Civino A, Alighieri G, Prete E, Caroleo AM, Magni-Manzoni S, Vinti L, Romano M, Santoro N, Filocamo G, Belotti T, Santarelli F, Gorio C, Ricci F, Colombini A, Pastore S, Cesaro S, Barone P, Verzegnassi F, Olivieri AN, Ficara M, Miniaci A, Russo G, Gallizzi R, Pericoli R, Breda L, Mura R, Podda RA, Onofrillo D, Lattanzi B, Tirtei E, Maggio MC, De Santis R, Consolini R, Arlotta A, La Torre F, Mainardi C, Pelagatti MA, Coassin E, Capolsini I, Burnelli R, Tornesello A, Soscia F, De Fanti A, Rigante D, Pizzato C, De Fusco C, Abate ME, Roncadori A, Rossi E, Stabile G, Biondi A, Lepore L, Conter V, Rondelli R, Pession A, and Ravelli A
- Abstract
Background: Presenting symptoms of childhood cancers might mimic those of rheumatic diseases. However, the evidence available to guide differential diagnosis remains scarce. Preventing wrong or delayed diagnosis is therefore important to avoid incorrect administration of glucocorticoid or immunosuppressive therapy and worsening of prognosis. As such, we aimed to assess the prevalence and characteristics of presenting musculoskeletal manifestations in patients at cancer onset and to identify the factors that differentiate childhood malignancies with arthropathy from juvenile idiopathic arthritis., Methods: We did a multicentre, cross-sectional study at 25 paediatric haemato-oncology centres and 22 paediatric rheumatology centres in Italy. We prospectively recruited patients who were younger than 16 years that were newly diagnosed with cancer or juvenile idiopathic arthritis. We excluded patients with glucocorticoid pre-treatment (>1 mg/kg per day of oral prednisone or equivalent for ≥2 consecutive weeks). We collected data for patients with a new diagnosis of cancer or juvenile idiopathic arthritis using an electronic case report form on a web-based platform powered by the Cineca Interuniversity Consortium. The primary outcome was to describe the frequency and characteristics of musculoskeletal manifestations at cancer onset; and the secondary outcome was to identify factors that could discriminate malignancies presenting with arthropathy, with or without other musculoskeletal symptoms, from juvenile idiopathic arthritis using multivariable logistic regression analysis., Findings: Between May 1, 2015, and May 31, 2018, 1957 patients were eligible, of which 1277 (65%) had cancer and 680 (35%) had juvenile idiopathic arthritis. Musculoskeletal symptoms occurred in 324 (25% [95% CI 23·0-27·8]) of 1277 patients with cancer, of whom 207 had arthropathy. Patients with malignant bone tumours had the highest frequency of musculoskeletal symptoms (53 [80%] of 66), followed by patients with Langerhans histiocytosis (16 [47%] of 34), leukaemia (189 [32%] of 582), soft-tissue sarcomas (16 [24%] of 68), and neuroblastoma (21 [19%] of 109). In the 324 patients with cancer and musculoskeletal symptoms, the most common complaints were joint pain (199 [61%]), followed by limb bone pain (112 [35%]). Joint involvement had a prevalent monoarticular pattern (100 [48%] of 207) and oligoarticular pattern (86 [42%] had 2-4 joints involved and 20 [10%] had >4 joints involved), with the most frequently involved joints being the hip (88 [43%] of 207) and knee (81 [39%]). On multivariable analysis, limb bone pain was the independent variable most strongly associated with cancer (odds ratio [OR] 87·80 [95% CI 18·89-408·12]), followed by weight loss (59·88 [6·34-565·53]), thrombocytopenia (12·67 [2·40-66·92]), monoarticular involvement (11·30 [4·09-31·19]), hip involvement (3·30 [1·13-9·61]), and male sex (2·40 [1·03-5·58]). Factors independently associated with juvenile idiopathic arthritis were morning stiffness (OR 0·04 [95% CI 0·01-0·20]), joint swelling (0·03 [0·01-0·09]), and involvement of the small hand joints (0·02 [0-1·05])., Interpretation: Our study provides detailed information about presenting musculoskeletal manifestations of childhood cancers and highlights the clinical and laboratory features that are most helpful in the differential diagnosis with juvenile idiopathic arthritis., Funding: Associazione Lorenzo Risolo., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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44. Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts.
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Quintarelli C, Guercio M, Manni S, Boffa I, Sinibaldi M, Di Cecca S, Caruso S, Abbaszadeh Z, Camera A, Cembrola B, Ciccone R, Orfao A, Martin-Martin L, Gutierrez-Herrero S, Herrero-Garcia M, Cazzaniga G, Nunes V, Songia S, Marcatili P, Marin FI, Ruella M, Bertaina V, Vinti L, Del Bufalo F, Algeri M, Merli P, De Angelis B, and Locatelli F
- Subjects
- Animals, Cell Line, Tumor, Disease Models, Animal, Humans, Mice, Epitopes immunology, Leukemia, B-Cell immunology, Receptors, Chimeric Antigen immunology
- Abstract
Chimeric antigen receptor T-cells (CAR T-cells) for the treatment of relapsing/refractory B-cell precursor acute lymphoblastic leukemia have led to exciting clinical results. However, CAR T-cell approaches revealed a potential risk of CD19-/CAR+ leukemic relapse due to inadvertent transduction of leukemia cells., Background: METHODS: We evaluated the impact of a high percentage of leukemia blast contamination in patient-derived starting material (SM) on CAR T-cell drug product (DP) manufacturing. In vitro as well as in vivo models were employed to identify characteristics of the construct associated with better profile of safety in case of inadvertent B-cell leukemia transduction during CAR T-cell manufacturing., Results: The presence of large amounts of CD19+ cells in SM did not affect the transduction level of DPs, as well as the CAR T-cell rate of expansion at the end of standard production of 14 days. DPs were deeply characterized by flow cytometry and molecular biology for Ig-rearrangements, showing that the level of B-cell contamination in DPs did not correlate with the percentage of CD19+ cells in SM, in the studied patient cohort. Moreover, we investigated whether CAR design may affect the control of CAR+ leukemia cells. We provided evidences that CAR.CD19 short linker (SL) prevents complete epitope masking in CD19+CAR+ leukemia cells and we demonstrated in vitro and in vivo that CD19 +CAR(SL)+leukemic cells are killed by CAR.CD19 T-cells., Conclusions: Taken together, these data suggest that a VL-VH SL may result in a safe CAR-T product, even when manufacturing starts from biological materials characterized by heavy contamination of leukemia blasts., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2021
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45. Recurrent genetic fusions redefine MLL germ line acute lymphoblastic leukemia in infants.
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Fazio G, Bardini M, De Lorenzo P, Grioni A, Quadri M, Pedace L, Corral Abascal L, Palamini S, Palmi C, Buldini B, Vinti L, Parasole R, Barisone E, Zecca M, Favre C, Locatelli F, Conter V, Rizzari C, Valsecchi MG, Biondi A, and Cazzaniga G
- Subjects
- Female, Gene Rearrangement, Germ Cells pathology, Humans, Infant, Male, Oncogene Proteins, Fusion genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma therapy, Retrospective Studies, Histone-Lysine N-Methyltransferase genetics, Myeloid-Lymphoid Leukemia Protein genetics, Oncogene Fusion, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
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- 2021
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46. CD28.OX40 co-stimulatory combination is associated with long in vivo persistence and high activity of CAR.CD30 T-cells.
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Guercio M, Orlando D, Di Cecca S, Sinibaldi M, Boffa I, Caruso S, Abbaszadeh Z, Camera A, Cembrola B, Bovetti K, Manni S, Caruana I, Ciccone R, Del Bufalo F, Merli P, Vinti L, Girardi K, Ruggeri A, De Stefanis C, Pezzullo M, Giorda E, Scarsella M, De Vito R, Barresi S, Ciolfi A, Tartaglia M, Moretta L, Locatelli F, Quintarelli C, and De Angelis B
- Subjects
- Animals, Humans, Immunotherapy, Adoptive, Mice, Receptors, Antigen, T-Cell, T-Lymphocytes, CD28 Antigens, Receptors, Chimeric Antigen
- Abstract
The prognosis of many patients with chemotherapy-refractory or multiply relapsed CD30+ non-Hodgkin Lymphoma (NHL) or Hodgkin lymphoma (HL) still remains poor, and novel therapeutic approaches are warranted to address this unmet clinical need. In light of this consideration, we designed and pre-clinically validated a Chimeric Antigen Receptor (CAR) construct characterized by a novel anti-CD30 single-chain variable-fragment cassette, linked to CD3ζ by the signaling domains of two costimulatory molecules, namely either CD28.4-1BB or CD28.OX40. We found that CAR.CD30 T-cells exhibit remarkable cytolytic activity in vitro against HL and NHL cell lines, with sustained proliferation and pro-inflammatory cytokine production, even after multiple and sequential lymphoma cell challenges. CAR.CD30 T-cells also demonstrated anti-lymphoma activity in two in vivo xenograft immune-deficient mouse models of metastatic HL and NHL. We observed that administration of CAR.CD30 T-cells, incorporating the CD28.OX40 costimulatory domains and manufactured in the presence of IL7 and IL15, were associated with the best overall survival in the treated mice, along with the establishment of a long-term immunological memory, able to protect mice from further tumor re-challenge. Our data indicate that, in the context of in vivo systemic metastatic xenograft mouse models, the costimulatory machinery of CD28.OX40 is crucial for improving persistence, in vivo expansion and proliferation of CAR.CD30 T-cells upon tumor encounter. CD28.OX40 costimulatory combination is ultimately responsible for the antitumor efficacy of the approach, paving the way to translate this therapeutic strategy in patients with CD30+ HL and NHL.
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- 2021
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47. A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study).
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Brivio E, Locatelli F, Lopez-Yurda M, Malone A, Díaz-de-Heredia C, Bielorai B, Rossig C, van der Velden VHJ, Ammerlaan ACJ, Thano A, van der Sluis IM, den Boer ML, Chen Y, Sleight B, Brethon B, Nysom K, Sramkova L, Øra I, Vinti L, Chen-Santel C, and Zwaan CM
- Subjects
- Antineoplastic Agents, Immunological adverse effects, Child, Child, Preschool, Female, Humans, Infant, Inotuzumab Ozogamicin adverse effects, Male, Neoplasm Recurrence, Local drug therapy, Treatment Outcome, Antineoplastic Agents, Immunological therapeutic use, Inotuzumab Ozogamicin therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
This phase 1 study investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple relapsed/refractory (R/R) CD22+ acute lymphoblastic leukemia (ALL). Patients (age ≥1 year or <18 years) received 3 doses of InO (days 1, 8, and 15) per course. Dose escalation was based on dose-limiting toxicities (DLTs) during course 1. Dose level 1 (DL1) was 1.4 mg/m2 (0.6, 0.4, 0.4 mg/m2) and DL2 was 1.8 mg/m2 (0.8, 0.5, 0.5 mg/m2). Secondary end points included safety, antileukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLTs) were enrolled. In course 1, the first cohort had 1 of 6 (DL1) and 2 of 5 (DL2) patients who experienced DLTs; subsequent review considered DL2 DLTs to be non-dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, in which 0 of 6 (DL1) and 1 of 6 (DL2) patients had a DLT. Twenty-three patients experienced grade 3 to 4 adverse events; hepatic sinusoidal obstruction syndrome was reported in 2 patients after subsequent chemotherapy. Overall response rate after course 1 was 80% (95% confidence interval [CI], 59% to 93%) (20 of 25 patients; DL1: 75% [95% CI, 43% to 95%], DL2: 85% [95% CI, 55% to 98%]). Of the responders, 84% (95% CI, 60% to 97%) achieved minimal residual disease (MRD)-negative complete response, and 12-month overall survival was 40% (95% CI, 25% to 66%). Nine patients received hematopoietic stem cell transplantation or chimeric antigen receptor T cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating antileukemic activity in heavily pretreated children with CD22+ R/R ALL. RP2D was established as 1.8 mg/m2 per course, as in adults. This trial was registered at https://www.clinicaltrialsregister.eu as EUDRA-CT 2016-000227-71., (© 2021 by The American Society of Hematology.)
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- 2021
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48. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.
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Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Mergen N, Mohammad A, Kormany WN, Eckert C, Möricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, and von Stackelberg A
- Subjects
- Adolescent, Antibodies, Bispecific adverse effects, Antineoplastic Agents adverse effects, Child, Child, Preschool, Combined Modality Therapy, Consolidation Chemotherapy adverse effects, Disease-Free Survival, Female, Follow-Up Studies, Humans, Infant, Kaplan-Meier Estimate, Leukemia, B-Cell mortality, Male, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Recurrence, Risk Factors, Survival Rate, Antibodies, Bispecific therapeutic use, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation, Immunotherapy, Leukemia, B-Cell drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Importance: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL)., Objective: To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant., Design, Setting, and Participants: In this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts ≥5% and <25%) at randomization., Intervention: Patients were randomized to receive 1 cycle of blinatumomab (n = 54; 15 μg/m2/d for 4 weeks, continuous intravenous infusion) or chemotherapy (n = 54) for the third consolidation., Main Outcomes and Measures: The primary end point was event-free survival (events: relapse, death, second malignancy, or failure to achieve complete remission). The key secondary efficacy end point was overall survival. Other secondary end points included minimal residual disease remission and incidence of adverse events., Results: A total of 108 patients were randomized (median age, 5.0 years [interquartile range {IQR}, 4.0-10.5]; 51.9% girls; 97.2% M1 marrow) and all patients were included in the analysis. Enrollment was terminated early for benefit of blinatumomab in accordance with a prespecified stopping rule. After a median of 22.4 months of follow-up (IQR, 8.1-34.2), the incidence of events in the blinatumomab vs consolidation chemotherapy groups was 31% vs 57% (log-rank P < .001; hazard ratio [HR], 0.33 [95% CI, 0.18-0.61]). Deaths occurred in 8 patients (14.8%) in the blinatumomab group and 16 (29.6%) in the consolidation chemotherapy group. The overall survival HR was 0.43 (95% CI, 0.18-1.01). Minimal residual disease remission was observed in more patients in the blinatumomab vs consolidation chemotherapy group (90% [44/49] vs 54% [26/48]; difference, 35.6% [95% CI, 15.6%-52.5%]). No fatal adverse events were reported. In the blinatumomab vs consolidation chemotherapy group, the incidence of serious adverse events was 24.1% vs 43.1%, respectively, and the incidence of adverse events greater than or equal to grade 3 was 57.4% vs 82.4%. Adverse events leading to treatment discontinuation were reported in 2 patients in the blinatumomab group., Conclusions and Relevance: Among children with high-risk first-relapse B-ALL, treatment with 1 cycle of blinatumomab compared with standard intensive multidrug chemotherapy before allogeneic hematopoietic stem cell transplant resulted in an improved event-free survival at a median of 22.4 months of follow-up., Trial Registration: ClinicalTrials.gov Identifier: NCT02393859.
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- 2021
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49. Blinatumomab versus historical standard therapy in pediatric patients with relapsed/refractory Ph-negative B-cell precursor acute lymphoblastic leukemia.
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Locatelli F, Whitlock JA, Peters C, Chen-Santel C, Chia V, Dennis RM, Heym KM, Katz AJ, Kelsh MA, Sposto R, Tu H, Tuglus CA, Verma A, Vinti L, Wilkes JJ, Zubarovskaja N, Zugmaier G, von Stackelberg A, and Sun W
- Subjects
- Adolescent, Child, Child, Preschool, Female, Humans, Male, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Recurrence, Antibodies, Bispecific therapeutic use, Antineoplastic Agents therapeutic use, Philadelphia Chromosome, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy
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- 2020
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50. Repurposing anthelmintic agents to eradicate resistant leukemia.
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Mezzatesta C, Abduli L, Guinot A, Eckert C, Schewe D, Zaliova M, Vinti L, Marovca B, Tsai YC, Jenni S, Aguade-Gorgorio J, von Stackelberg A, Schrappe M, Locatelli F, Stanulla M, Cario G, Bourquin JP, and Bornhauser BC
- Subjects
- Animals, Anthelmintics therapeutic use, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Drug Resistance, Neoplasm, Humans, Mice, SCID, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Tumor Cells, Cultured, Tumor Microenvironment drug effects, Anthelmintics pharmacology, Antineoplastic Agents pharmacology, Drug Repositioning, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Abstract
Despite rapid progress in genomic profiling in acute lymphoblastic leukemia (ALL), identification of actionable targets and prediction of response to drugs remains challenging. To identify specific vulnerabilities in ALL, we performed a drug screen using primary human ALL samples cultured in a model of the bone marrow microenvironment combined with high content image analysis. Among the 2487 FDA-approved compounds tested, anthelmintic agents of the class of macrocyclic lactones exhibited potent anti-leukemia activity, similar to the already known anti-leukemia agents currently used in induction chemotherapy. Ex vivo validation in 55 primary ALL samples of both precursor B cell and T-ALL including refractory relapse cases confirmed strong anti-leukemia activity with IC
50 values in the low micromolar range. Anthelmintic agents increased intracellular chloride levels in primary leukemia cells, inducing mitochondrial outer membrane depolarization and cell death. Supporting the notion that simultaneously targeting cell death machineries at different angles may enhance the cell death response, combination of anthelmintic agents with the BCL-2 antagonist navitoclax or with the chemotherapeutic agent dexamethasone showed synergistic activity in primary ALL. These data reveal anti-leukemia activity of anthelmintic agents and support exploiting drug repurposing strategies to identify so far unrecognized anti-cancer agents with potential to eradicate even refractory leukemia.- Published
- 2020
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