119 results on '"Scalabrini A."'
Search Results
2. Assessing Mental Representation as an Indicator of Self and Interpersonal Functioning in Psychotherapy Patients
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Diana Diamond, Andrea Fossati, Serena Borroni, Andrea Scalabrini, Clara Mucci, Elisabetta Masci, Antonella Somma, Borroni, S., Scalabrini, A., Masci, E., Mucci, C., Diamond, D., Somma, A., and Fossati, A.
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Adult ,Male ,Personality Inventory ,media_common.quotation_subject ,Dysfunctional family ,Personality Disorders ,maladaptive personality ,mental representations ,Differentiation-Relatedness Scale ,personality functioning ,DSM-5 ,Settore M-PSI/08 - Psicologia Clinica ,Settore M-PSI/07 - Psicologia Dinamica ,medicine ,Humans ,Personality ,Big Five personality traits ,media_common ,Multilevel model ,Reproducibility of Results ,medicine.disease ,Personality disorders ,Diagnostic and Statistical Manual of Mental Disorders ,Psychotherapy ,Inter-rater reliability ,Convergent validity ,Female ,Personality Assessment Inventory ,Psychology ,Clinical psychology - Abstract
The goal of this study was to test in a clinical sample the interrater reliability and convergent validity of the Differentiation-Relatedness Scale (D-RS), a measure that evaluates mental representations based on open-ended descriptions of self and significant others. The study also investigated the ability of the D-RS to predict personality disorders (PDs) from Section II of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and the dysfunctional trait domains presented in the Alternative DSM-5 Model for Personality Disorders Criterion B in Section III of the DSM-5. We also evaluated if the D-RS predicts observed Section II PDs over and above Criterion B of the Alternative DSM-5 Model for Personality Disorders. We found that the interrater reliability of the D-RS was good on the basis of the mean scores of 6 independent raters and that it showed moderate convergent validity. Results of dominance analyses indicated that the D-RS is a significant predictor of Section II borderline PD and of the overall number of DSM-5 PDs. When we considered the Section III Criterion B for PDs, the D-RS was not able to predict any of the Personality Inventory for DSM-5 domains, suggesting that the D-RS may be more related to personality functioning behind mental representations than to maladaptive personality traits. Finally, results of hierarchical regression analyses suggested that the D-RS produced a significant but modest increase in the prediction of borderline PD traits and the overall number of PDs traits even when the effect of the Personality Inventory for DSM-5 domains were controlled for.
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- 2020
3. All roads lead to the default-mode network—global source of DMN abnormalities in major depressive disorder
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Sara Poletti, Georg Northoff, Francesco Benedetti, Raffaella Zanardi, Benedetta Vai, Stefano Damiani, Clara Mucci, Andrea Scalabrini, Cristina Colombo, Scalabrini, A., Vai, B., Poletti, S., Damiani, S., Mucci, C., Colombo, C., Zanardi, R., Benedetti, F., and Northoff, G.
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Article ,Brain ,Brain Mapping ,Default Mode Network ,Humans ,Magnetic Resonance Imaging ,Neural Pathways ,Depressive Disorder, Major ,03 medical and health sciences ,0302 clinical medicine ,Settore M-PSI/07 - Psicologia Dinamica ,medicine ,Signal correlation ,Lead (electronics) ,Settore MED/25 - Psichiatria ,Default mode network ,Pharmacology ,Depressive Disorder ,Resting state fMRI ,Functional connectivity ,Healthy subjects ,Major ,medicine.disease ,030227 psychiatry ,Psychiatry and Mental health ,Settore M-PSI/02 - Psicobiologia e Psicologia Fisiologica ,Major depressive disorder ,Psychology ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Major depressive disorder (MDD) is a psychiatric disorder characterized by abnormal resting state functional connectivity (rsFC) in various neural networks and especially in default-mode network (DMN). However, inconsistent findings, i.e., increased and decreased DMN rsFC, have been reported, which raise the question for the source of DMN changes in MDD. Testing whether the DMN abnormalities in MDD can be traced to either a local, i.e., intra-network, or a global, i.e., inter-network, source, we conducted a novel sequence of rsFC analyses, i.e., global FC, intra-network FC, and inter-network FC. Moreover, all analyses were conducted without global signal regression (non-GSR) and with GSR in order to identify the impact of specifically the global component of functional connectivity on within-network functional connectivity within specifically the DMN. In MDD our findings demonstrate (i) increased representation of global signal correlation (GSCORR) in DMN regions, as confirmed independently by degree of centrality (DC) and by an independent DMN template, (ii) increased within-network DMN rsFC, (iii) highly increased inter-network rsFC of both lower- and higher order non-DMN networks with DMN, (iv) high accuracy in classifying MDD vs. healthy subjects by using GSCORR as predictor. Further supporting the global, i.e., non-DMN source of within-network rsFC of the DMN, all results were obtained only when including the global signal, i.e., non-GSR, but not when conducting GSR. Together, we show for the first time increased global signal representation within rsFC of DMN as stemming from inter-network sources as distinguished from local sources, i.e., within- or intra-DMN.
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- 2020
4. Use of CentriMag for refractory cardiogenic shock in a puerperal woman: case report
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Paulo Manuel Pêgo-Fernandes, Augusto Scalabrini Neto, Ludhmila Abrahão Hajjar, Priscila Berenice da Costa, Roberto Kalil Filho, and Fabio Biscegli Jatene
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medicine.medical_specialty ,Myocarditis ,medicine.medical_treatment ,Heart failure ,Context (language use) ,Balloon ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Extracorporeal membrane oxygenation ,Refractory cardiogenic shock ,030212 general & internal medicine ,CentriMag ,business.industry ,Cardiogenic shock ,General Medicine ,medicine.disease ,Surgery ,Medicine ,Dobutamine ,Heart-assist devices ,Puerperal ,Implant ,ECMO ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
CONTEXT: Heart failure in Brazil is a major public health problem and, even with advances in treatment, it still presents high morbidity and mortality. As a treatment option, mechanical circulatory assist devices (MCADs) have greatly increased in importance over the last decade. CASE REPORT: This report concerns a case of refractory cardiogenic shock due to acute myocarditis in a 35-year-old puerperal female patient who presented with retrosternal pain, fatigue and dyspnea. At the hospital, she was diagnosed with myocarditis. There was no improvement in perfusion even after receiving dobutamine, intra-aortic balloon passage (IAB) and venoarterial extracorporeal membrane oxygenation (VA-ECMO). Therefore, it was decided to implant a MCAD (CentriMag). During hospitalization, recovery from the bi-ventricular dysfunction was achieved. The CentriMag device was removed 10 days after it had been implanted, and the patient was discharged after another 8 days. The myocarditis was proven to be due to the Coxsackie virus. CONCLUSIONS: The decision to implant a MCAD should be individualized, as patient profiles do not always match the indications in the guidelines and protocols. In this study, clinical discussion of the case among the medical and multi-professional teams was essential in order to be able to successfully reverse the patient’s severe clinical condition without sequelae, through using a CentriMag implant.
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- 2021
5. Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial
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Francesca Gay, Pellegrino Musto, Delia Rota-Scalabrini, Luca Bertamini, Angelo Belotti, Monica Galli, Massimo Offidani, Elena Zamagni, Antonio Ledda, Mariella Grasso, Stelvio Ballanti, Antonio Spadano, Michele Cea, Francesca Patriarca, Mattia D'Agostino, Andrea Capra, Nicola Giuliani, Paolo de Fabritiis, Sara Aquino, Angelo Palmas, Barbara Gamberi, Renato Zambello, Maria Teresa Petrucci, Paolo Corradini, Michele Cavo, Mario Boccadoro, Gay F., Musto P., Rota-Scalabrini D., Bertamini L., Belotti A., Galli M., Offidani M., Zamagni E., Ledda A., Grasso M., Ballanti S., Spadano A., Cea M., Patriarca F., D'Agostino M., Capra A., Giuliani N., de Fabritiis P., Aquino S., Palmas A., Gamberi B., Zambello R., Petrucci M.T., Corradini P., Cavo M., and Boccadoro M.
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Male ,Antibodies, Monoclonal ,Antineoplastic Combined Chemotherapy Protocols ,Bortezomib ,Combined Modality Therapy ,Cyclophosphamide ,Dexamethasone ,Female ,Follow-Up Studies ,Hematopoietic Stem Cell Transplantation ,Humans ,Lenalidomide ,Melphalan ,Middle Aged ,Multiple Myeloma ,Oligopeptides ,Prognosis ,Survival Rate ,Thalidomide ,Transplantation, Autologous ,chemistry.chemical_compound ,Maintenance therapy ,Monoclonal ,Medicine ,multiple myeloma, newly diagnosed, carfilzomib, cyclophosphamide, lenalidomide, dexamethasone, induction treatment, autologous stem-cell transplantation, maintenance treatment, phase 2, trial ,Multiple myeloma ,carfilzomib ,trial ,induction treatment ,Oncology ,Oligopeptide ,newly diagnosed ,Autologous ,Human ,medicine.drug ,medicine.medical_specialty ,Prognosi ,autologous stem-cell transplantation ,Antibodies ,Follow-Up Studie ,Internal medicine ,Autologous transplantation ,Transplantation ,Antineoplastic Combined Chemotherapy Protocol ,maintenance treatment ,business.industry ,medicine.disease ,Settore MED/15 ,Carfilzomib ,chemistry ,phase 2 ,business - Abstract
Background: Bortezomib-based induction followed by high-dose melphalan (200 mg/m2) and autologous stem-cell transplantation (MEL200-ASCT) and maintenance treatment with lenalidomide alone is the current standard of care for young and fit patients with newly diagnosed multiple myeloma. We aimed to evaluate the efficacy and safety of different carfilzomib-based induction and consolidation approaches with or without transplantation and of maintenance treatment with carfilzomib plus lenalidomide versus lenalidomide alone in newly diagnosed multiple myeloma. Methods: UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done in 42 Italian academic and community practice centres. We enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 65 years or younger with a Karnofsky Performance Status of 60% or higher. Patients were stratified according to International Staging System stage (I vs II/III) and age (
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- 2021
6. Time is of essence - Abnormal time perspectives mediate the impact of childhood trauma on depression severity
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Zhiguo Hu, Georg Northoff, Andrea Scalabrini, Jin-Fang Han, Zhonglin Tan, Ying Ying Wang, Xiwen Hu, Jianfeng Zhang, and Yuting Hu
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Mediation (statistics) ,Poison control ,Major depressive disorder ,Diagnosis and therapy ,Suicide prevention ,Childhood trauma ,03 medical and health sciences ,0302 clinical medicine ,Settore M-PSI/08 - Psicologia Clinica ,Surveys and Questionnaires ,Settore M-PSI/07 - Psicologia Dinamica ,Injury prevention ,medicine ,Humans ,Early childhood ,Settore MED/25 - Psichiatria ,Biological Psychiatry ,Depression (differential diagnoses) ,Depressive Disorder ,Depressive Disorder, Major ,Mediation model ,Depression ,Negotiating ,business.industry ,Time perspective ,Major ,medicine.disease ,030227 psychiatry ,Psychiatry and Mental health ,Settore M-PSI/02 - Psicobiologia e Psicologia Fisiologica ,Beck Hopelessness Scale ,business ,030217 neurology & neurosurgery ,Clinical psychology - Abstract
Background Major depressive disorder (MDD) is a multifaceted mental disorder where participants, in addition to various symptoms, often suffer from increased focus on past time perspective and higher incidence of childhood trauma. Whether the abnormal time perspective is a result of the depressive symptoms or, alternatively, mediates between childhood trauma and depression remains unclear. Aims To examine the triangular relationship between early life trauma, time perspective, and depressive symptoms. Method We investigated a large-scale MDD sample (n = 93) and healthy subject sample (n = 69) with Beck depression inventory-II (BDI-II), Beck hopelessness scale (BHS), childhood traumatic questionnaire-Short Form (CTQ-SF), and the Zimbardo time perspective inventory (ZTPI). Results The MDD patients reported more childhood trauma experiences, and were featured by abnormal time perspectives on past and future when compared to healthy control. By applying two alternative mediation models, we observed that the time perspective acted as a mediator between childhood trauma and depressive symptom severity, rather than as a consequence of depressive symptom. Furthermore, this abnormal time perspective was a risk factor to MDD, as the childhood trauma only mediated the time perspective in MDD. Finally, we showed that time perspective was a long-term personal trait and unchanged after the remission of depression symptoms under five-day transcranial magnetic stimulation. Conclusions Abnormal time perspective mediates the impact of early childhood trauma on depressive symptomatology. Besides better understanding of the temporal basis of depressive symptoms, we highlight the importance of preventive time perspective therapy in subjects with childhood trauma.
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- 2021
7. Antibody Therapies for Large B-Cell Lymphoma
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Umberto Vitolo, Mattia Novo, Elisa Santambrogio, Pio Manlio Mirko Frascione, and Delia Rota-Scalabrini
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medicine.drug_class ,medicine.medical_treatment ,diffuse large B-cell lymphoma ,Review ,Monoclonal antibody ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Antigen ,medicine ,Immunology and Allergy ,Pharmacology (medical) ,B-cell lymphoma ,business.industry ,Gastroenterology ,Immunotherapy ,medicine.disease ,targeted therapy ,Lymphoma ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Rituximab ,immunotherapy ,monoclonal antibodies ,bispecific antibodies ,business ,Diffuse large B-cell lymphoma ,checkpoint inhibitors ,030215 immunology ,medicine.drug - Abstract
Large B-cell lymphomas (LBCLs) constitute a subgroup of aggressive but highly curable lymphoproliferative diseases. Treatment of relapsed/refractory (R/R) patients still represents an unmet clinical need, and novel drugs and combinations are in continuous development. The pan–B cell panel of surface antigens that characterizes LBCL leads to a large umbrella of druggable targets. Monoclonal antibodies (mAbs) express their activity against lymphoma by targeting multiple tumor-specific antigens. This category consists of a number of molecules with different mechanisms of action, including naked mAbs, radioimmunoconjugates, antibody-drug conjugates, checkpoint inhibitors, and bispecific antibodies. In the last decade, apart from the well-known role of the anti-CD20 mAb rituximab, novel mAbs have led to remarkable steps forward in the treatment of R/R LBCL in monotherapy and combined with chemotherapy. Multiple studies are in development trying to bring these novel compounds into the frontline setting to empower the RCHOP effect or as alternative chemotherapy-free options for elderly/unfit patients. This review provides insight into antilymphoma mAbs, focused on the efficacy and safety of the main molecules approved or in development for LBCL andperspectives on the treatment of this disease.
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- 2021
8. Chemotherapy combinations for B-cell lymphoma and chemo-free approach in elderly patients: an update on best practice
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Umberto Vitolo, Delia Rota-Scalabrini, Elisa Santambrogio, and Mattia Novo
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Oncology ,medicine.medical_specialty ,Lymphoma, B-Cell ,Clinical Decision-Making ,Follicular lymphoma ,Risk Assessment ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,B-cell lymphoma ,B cell ,Aged ,Aged, 80 and over ,business.industry ,Age Factors ,Disease Management ,food and beverages ,Hematology ,Prognosis ,medicine.disease ,Combined Modality Therapy ,Chemotherapy combinations ,Lymphoma ,Treatment Outcome ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Retreatment ,Mantle cell lymphoma ,Disease Susceptibility ,business ,Diffuse large B-cell lymphoma ,030215 immunology - Abstract
Elderly patients represent a consistent portion of new diagnoses of B cell Non-Hodgkin Lymphoma (B-NHL). The treatment approach in this setting can be challenging for clinicians due to treatment toxicities and patients' comorbidities to deal with. Immunochemotherapy still represents the main option in the front-line setting for diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL), with different options to choose depending on patient characteristics. In the last decade, a number of new drugs and combinations have been investigated, demonstrating efficacy and safety even in the older population and extending the spectrum of treatment choices for this setting.This article reviews the majority data in literature on immunochemotherapy regimens and chemo-free approaches available for DLBCL, FL, and MCL in the elderly, both in front-line and relapse/refractory setting, the incoming drugs and how to identify the best option for each patient.The therapeutic approach for elderly B-NHL is challenging and a tailored approach guided by a geriatric assessment is mandatory, in order to optimize efficacy and minimize treatment-related toxicities. The more extended use of biological drugs may potentially lead to prolonged survival with reduction of toxicities and improved quality of life.
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- 2020
9. Prolonged survival in the absence of disease-recurrence in advanced-stage follicular lymphoma following chemo-immunotherapy: 13-year update of the prospective, multicenter randomized GITMO-IIL trial
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Alessandro Rambaldi, Carola Boccomini, Atto Billio, Francesco Angrilli, Roberto Passera, Marco Ladetto, Francesco Zallio, Gianpietro Semenzato, Liliana Devizzi, Fabio Ciceri, Barbara Mantoan, Fausto Rossini, Alessandra Dondi, Alessandra Tucci, Fabio Benedetti, Caterina Stelitano, Delia Rota-Scalabrini, Valerio Zoli, Paolo Corradini, Riccardo Bruna, Corrado Tarella, Maurizio Musso, Franco Narni, Caterina Patti, Guido Gini, Claudia Castellino, Tommasina Perrone, Anna Maria Barbui, Francesco Lanza, Anna Marina Liberati, Guido Parvis, Francesco Di Raimondo, Alessandro Massimo Gianni, Alessandro Pulsoni, Angela Gueli, Bruna R., Benedetti F., Boccomini C., Patti C., Barbui A. M., Pulsoni A., Musso M., Liberati A. M., Gini G., Castellino C., Rossini F., Ciceri F., Rota-Scalabrini D., Stelitano C., Di Raimondo F., Tucci A., Devizzi L., Zoli V., Zallio F., Narni F., Dondi A., Parvis G., Semenzato G., Lanza F., Perrone T., Angrilli F., Billio A., Gueli A., Mantoan B., Rambaldi A., Massimo Gianni A., Corradini P., Passera R., Ladetto M., Tarella C., Bruna, R., Benedetti, F., Boccomini, C., Patti, C., Barbui, A. M., Pulsoni, A., Musso, M., Liberati, A. M., Gini, G., Castellino, C., Rossini, F., Ciceri, F., Rota-Scalabrini, D., Stelitano, C., Di Raimondo, F., Tucci, A., Devizzi, L., Zoli, V., Zallio, F., Narni, F., Dondi, A., Parvis, G., Semenzato, G., Lanza, F., Perrone, T., Angrilli, F., Billio, A., Gueli, A., Mantoan, B., Rambaldi, A., Massimo Gianni, A., Corradini, P., Passera, R., Ladetto, M., and Tarella, C.
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Male ,Oncology ,Lymphoma ,medicine.medical_treatment ,advanced-stage follicular lymphoma ,Follicular lymphoma ,Kaplan-Meier Estimate ,law.invention ,0302 clinical medicine ,Cancer immunotherapy ,Randomized controlled trial ,Recurrence ,immune system diseases ,law ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Prospective cohort study ,Lymphoma, Follicular ,non-Hodgkin lymphoma ,Remission Induction ,Hematology ,Middle Aged ,Prognosis ,Combined Modality Therapy ,Treatment Outcome ,Italy ,chemoimmunotherapy ,Female ,Rituximab ,Adult ,Follow-Up Studies ,Humans ,Neoplasm Staging ,Proportional Hazards Models ,Young Adult ,medicine.drug ,medicine.medical_specialty ,Sudden death ,Article ,NO ,03 medical and health sciences ,Lymphoma, therapy, clinical trial ,Internal medicine ,medicine ,Cancer staging ,Chemotherapy ,business.industry ,Follicular ,medicine.disease ,business ,030215 immunology - Abstract
A prospective trial conducted in the period 2000-2005 showed no survival advantage for high-dose chemotherapy with rituximab and autograft (R-HDS) versus conventional chemotherapy with rituximab (CHOP-R) as first-line therapy in 134 high-risk follicular lymphoma patients aged
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- 2019
10. Survival Analysis of Newly Diagnosed Transplant-Eligible Multiple Myeloma Patients in the Randomized Forte Trial
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Francesca Gay, Pellegrino Musto, Delia Rota Scalabrini, Monica Galli, Angelo Belotti, Elena Zamagni, Luca Bertamini, Renato Zambello, Micol Quaresima, Giovanni De Sabbata, Giuseppe Pietrantuono, Mattia D'Agostino, Daniela Oddolo, Andrea Capra, Anna Marina Liberati, Salvatore Palmieri, Franco Narni, Massimo Offidani, Michele Cavo, and Mario Boccadoro
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medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,medicine ,Cell Biology ,Hematology ,Newly diagnosed ,medicine.disease ,business ,Biochemistry ,Survival analysis ,Multiple myeloma - Abstract
Background. Proteasome inhibitor (PI)-based induction/consolidation proved to be effective in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for melphalan 200 mg/m2 plus autologous stem-cell transplantation (MEL200-ASCT). High response rates have been reported with carfilzomib (K) plus lenalidomide-dexamethasone (KRd) or cyclophosphamide-dexamethasone (KCd). Lenalidomide (R) alone is a standard of care for post-ASCT maintenance; K maintenance showed promising results in phase I/II studies, but no data on KR maintenance vs R are available. Aims. The aims of this analysis were to evaluate the progression-free survival (PFS) of KRd induction-ASCT-KRd consolidation (KRd_ASCT) vs 12 cycles of KRd (KRd12) vs KCd induction-ASCT-KCd consolidation (KCd_ASCT) and the PFS of KR vs R maintenance. Secondary aims were efficacy in different subgroups of pts and safety of the maintenance phase. Methods. NDMM pts ≤65 years were randomized [R1: 1:1:1, stratification International Staging System (ISS) and age] to: KRd_ASCT: 4 28-day cycles with KRd induction (K 20/36 mg/m2 IV days 1,2,8,9,15,16; R 25 mg days 1-21; dexamethasone [d] 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KRd consolidation cycles; KRd12: 12 KRd cycles; KCd_ASCT: 4 28-day induction cycles with KCd (K 20/36 mg/m2 IV days 1,2,8,9,15,16; cyclophosphamide 300 mg/m2 days 1,8,15; d 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KCd consolidation cycles. Thereafter, pts were randomized (R2) to maintenance with KR (K 36 mg/m2 days 1,2,15,16, subsequently amended to 70 mg/m2 days 1,15 for up to 2 years; plus R 10 mg days 1-21 every 28 days until progression) or R alone (10 mg days 1-21 every 28 days until progression). Centralized minimal residual disease (MRD) evaluation (8-color second-generation flow cytometry, sensitivity 10-5) was performed in pts achieving ≥very good partial response before maintenance and every 6 months (m) during maintenance. Data cut-off was June 30, 2020. Results. 474 NDMM pts were randomized (KRd_ASCT, n=158; KRd12, n=157; KCd_ASCT, n=159) and analyzed. Pt characteristics were well balanced. Intention-to-treat (ITT) data of pre-maintenance MRD (KRd_ASCT, 62%; KRd12 56%, KCd_ASCT 43%) and safety of the induction/consolidation phases in the 3 arms were already reported (F. Gay et al. ASH 2018; S. Oliva et al. ASH 2019). After a median follow-up from R1 of 45 m, median PFS was not reached with KRd_ASCT, 57 m with KRd12 and 53 m with KCd_ASCT (KRd_ASCT vs KCd_ASCT: HR 0.53, P During maintenance, a similar proportion of pts experienced ≥1 grade (G)3-4 hematologic adverse events (AEs)/serious AEs (SAEs) in the 2 arms (KR 22% vs R 23%); the most frequent were neutropenia (KR 18% vs R 21%) and thrombocytopenia (KR 3% vs R 3%). Rate of ≥1 G3-4 non-hematologic AEs/SAEs was higher with KR (27%) compared with R (15%), P=0.012; the most frequent were infections (KR 4% vs R 7%); all other events were reported in ≤5% of pts and included: gastrointestinal (KR 5% vs R 2%), cardiac (KR 4% vs R 1%), hypertension (KR 3% vs R 0%), and thrombotic microangiopathy (3% vs 0%). 4 pts developed a second primary malignancy in KR (breast 1 pt; thyroid 1 pt; myelodysplastic syndrome 1 pt; non-melanoma skin cancer 1pt) vs 1 pt in R (acute lymphoblastic leukemia). Dose reductions of R were reported in 23% of KR and 29% of R pts; dose reductions of K were reported in 20% of pts. The rate of discontinuation due to AEs was similar in the 2 arms (KR 10% vs R 9%). Conclusions. Treatment with KRd_ASCT significantly improved PFS compared with both KRd12 and KCd_ASCT. Maintenance with KR also improved PFS vs R. Figure Disclosures Gay: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto:Celgene: Honoraria; Amgen: Honoraria. Galli:BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Belotti:Jannsen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Zamagni:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. De Sabbata:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. D'Agostino:GSK: Membership on an entity's Board of Directors or advisory committees. Liberati:VERASTEM: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding; INCYTE: Honoraria; JANSSEN: Honoraria; CELGENE: Honoraria; AMGEN: Honoraria; BMS: Honoraria; BEIGENE: Honoraria; ARCHIGEN: Honoraria; BIOPHARMA: Honoraria; FIBROGEN: Honoraria. Offidani:Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau. Boccadoro:AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, lenalidomide and dexamethasone).
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- 2020
11. IKKβ targeting reduces KRAS-induced lung cancer angiogenesis in vitro and in vivo: A potential anti-angiogenic therapeutic target
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Felipe Silva Rodrigues, Laura Beatriz da Silva Cardeal, Ricardo J. Giordano, Albert S. Baldwin, Luiza Coimbra Scalabrini, Daniela S. Basseres, Leila da Silva Magalhães, Tatiana Correa Carneiro-Lobo, Edmilson Ozorio dos Santos, and Elena Levantini
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Male ,Vascular Endothelial Growth Factor A ,0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Pyridines ,Angiogenesis ,medicine.disease_cause ,anti-angiogenic therapy ,Mice ,0302 clinical medicine ,Piperidines ,Cell Movement ,Mice, Inbred NOD ,Medicine ,RNA, Small Interfering ,Ikk beta therapeutic targeting ,Tube formation ,Mice, Inbred BALB C ,Neovascularization, Pathologic ,NF-kappa B ,VEGF ,I-kappa B Kinase ,Endothelial stem cell ,Oncology ,030220 oncology & carcinogenesis ,growth factors signaling ,Human umbilical vein endothelial cell ,biological phenomena, cell phenomena, and immunity ,Pulmonary and Respiratory Medicine ,Article ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Cell Line, Tumor ,Oxazines ,Animals ,Humans ,Lung cancer ,Protein Kinase Inhibitors ,ANTINEOPLÁSICOS ,IL-8 ,business.industry ,Cell growth ,K-RAS-induced lung cancer ,Interleukin-8 ,Endothelial Cells ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,enzymes and coenzymes (carbohydrates) ,030104 developmental biology ,cytokine cascade ,Mutation ,Cancer research ,business ,Carcinogenesis - Abstract
Objectives The ability of tumor cells to drive angiogenesis is an important cancer hallmark that positively correlates with metastatic potential and poor prognosis. Therefore, targeting angiogenesis is a rational therapeutic approach and dissecting proangiogenic pathways is important, particularly for malignancies driven by oncogenic KRAS, which are widespread and lack effective targeted therapies. Based on published studies showing that oncogenic RAS promotes angiogenesis by upregulating the proangiogenic NF-κB target genes IL-8 and VEGF, that NF-κB activation by KRAS requires the IKKβ kinase, and that targeting IKKβ reduces KRAS-induced lung tumor growth in vivo, but has limited effects on cell growth in vitro, we hypothesized that IKKβ targeting would reduce lung tumor growth by inhibiting KRAS-induced angiogenesis. Materials and methods To test this hypothesis, we targeted IKKβ in KRAS-mutant lung cancer cell lines either by siRNA-mediated transfection or by treatment with Compound A (CmpdA), a highly specific IKKβ inhibitor, and used in vitro and in vivo assays to evaluate angiogenesis. Results and conclusions Both pharmacological and siRNA-mediated IKKβ targeting in lung cells reduced expression and secretion of NF-κB-regulated proangiogenic factors IL-8 and VEGF. Moreover, conditioned media from IKKβ-targeted lung cells reduced human umbilical vein endothelial cell (HUVEC) migration, invasion and tube formation in vitro. Furthermore, siRNA-mediated IKKβ inhibition reduced xenograft tumor growth and vascularity in vivo. Finally, IKKβ inhibition also affects endothelial cell function in a cancer-independent manner, as IKKβ inhibition reduced pathological retinal angiogenesis in a mouse model of oxygen-induced retinopathy. Taken together, these results provide a novel mechanistic understanding of how the IKKβ pathway affects human lung tumorigenesis, indicating that IKKβ promotes KRAS-induced angiogenesis both by cancer cell-intrinsic and cancer cell-independent mechanisms, which strongly suggests IKKβ inhibition as a promising antiangiogenic approach to be explored for KRAS-induced lung cancer therapy.
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- 2019
12. Dose/schedule-adjusted Rd-R vs continuous Rd for elderly, intermediate-fit patients with newly diagnosed multiple myeloma
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Monica Galli, Federico Monaco, Sara Bringhen, Roberto Marasca, Mario Boccadoro, Giulia Benevolo, Nicola Cascavilla, Francesca Patriarca, Claudia Cellini, Annalisa Bernardini, Elisabetta Antonioli, Alessandra Pompa, Gianluca Gaidano, Nicola Giuliani, Tommaso Caravita di Toritto, Delia Rota-Scalabrini, Andrea Capra, Massimo Offidani, Francesca Bonello, Patrizia Tosi, Mattia D'Agostino, Alessandra Larocca, Paola Tacchetti, and Paolo Corradini
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Male ,medicine.medical_specialty ,Immunology ,Phases of clinical research ,Neutropenia ,Biochemistry ,Gastroenterology ,Dexamethasone ,Disease-Free Survival ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Lenalidomide ,Aged ,Aged, 80 and over ,business.industry ,Standard treatment ,Hazard ratio ,Cell Biology ,Hematology ,medicine.disease ,Confidence interval ,Discontinuation ,Survival Rate ,Female ,business ,Multiple Myeloma ,medicine.drug ,Follow-Up Studies - Abstract
Lenalidomide-dexamethasone (Rd) is standard treatment for elderly patients with multiple myeloma (MM). In this randomized phase 3 study, we investigated efficacy and feasibility of dose/schedule-adjusted Rd followed by maintenance at 10 mg per day without dexamethasone (Rd-R) vs continuous Rd in elderly, intermediate-fit newly diagnosed patients with MM. Primary end point was event-free survival (EFS), defined as progression/death from any cause, lenalidomide discontinuation, or hematologic grade 4 or nonhematologic grade 3 to 4 adverse event (AE). Of 199 evaluable patients, 101 received Rd-R and 98 continuous Rd. Median follow-up was 37 months. EFS was 10.4 vs 6.9 months (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51-0.95; P = .02); median progression-free survival, 20.2 vs 18.3 months (HR, 0.78; 95% CI, 0.55-1.10; P = .16); and 3-year overall survival, 74% vs 63% (HR, 0.62; 95% CI, 0.37-1.03; P = .06) with Rd-R vs Rd, respectively. Rate of ≥1 nonhematologic grade ≥3 AE was 33% vs 43% (P = .14) in Rd-R vs Rd groups, with neutropenia (21% vs 18%), infections (10% vs 12%), and skin disorders (7% vs 3%) the most frequent; constitutional and central nervous system AEs mainly related to dexamethasone were more frequent with Rd. Lenalidomide was discontinued for AEs in 24% vs 30% and reduced in 45% vs 62% of patients receiving Rd-R vs Rd, respectively. In intermediate-fit patients, switching to reduced-dose lenalidomide maintenance without dexamethasone after 9 Rd cycles was feasible, with similar outcomes to standard continuous Rd. This trial was registered at www.clinicaltrials.gov as #NCT02215980.
- Published
- 2021
13. Application of the Euro Clonality next-generation sequencing-based marker screening approach to detect immunoglobulin heavy chain rearrangements in mantle cell lymphoma patients: first data from the Fondazione Italiana Linfomi MCL0208 trial
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Francesca Cordero, Greta Romano, Raffaele A. Calogero, Donato Mannina, Marco Beccuti, Elisa Genuardi, Beatrice Alessandria, Catello Califano, Marco Ladetto, Sergio Cortelazzo, Delia Rota Scalabrini, and Simone Ferrero
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Oncology ,medicine.medical_specialty ,immunoglobulin genes ,methodology ,minimal residual disease ,molecular biology ,non-Hodgkin lymphoma ,polymerase chain reaction ,Neoplasm, Residual ,Short Report ,Context (language use) ,Lymphoma, Mantle-Cell ,DNA sequencing ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Short Reports ,immune system diseases ,law ,Outcome predictor ,hemic and lymphatic diseases ,Internal medicine ,Molecular marker ,Biomarkers, Tumor ,medicine ,Humans ,non‐Hodgkin lymphoma ,Polymerase chain reaction ,Gene Rearrangement ,Genes, Immunoglobulin ,business.industry ,High-Throughput Nucleotide Sequencing ,Hematology ,medicine.disease ,Haematological malignancy – Clinical ,Minimal residual disease ,Italy ,chemistry ,030220 oncology & carcinogenesis ,Immunoglobulin heavy chain ,Mantle cell lymphoma ,Immunoglobulin Heavy Chains ,business ,030215 immunology - Abstract
Summary Minimal residual disease (MRD) determined by classic polymerase chain reaction (PCR) methods is a powerful outcome predictor in mantle cell lymphoma (MCL). Nevertheless, some technical pitfalls can reduce the rate of of molecular markers. Therefore, we applied the EuroClonality‐NGS IGH (next‐generation sequencing immunoglobulin heavy chain) method (previously published in acute lymphoblastic leukaemia) to 20 MCL patients enrolled in an Italian phase III trial sponsored by Fondazione Italiana Linfomi. Results from this preliminary investigation show that EuroClonality‐NGS IGH method is feasible in the MCL context, detecting a molecular IGH target in 19/20 investigated cases, allowing MRD monitoring also in those patients lacking a molecular marker for classical screening approaches.
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- 2021
14. Aurora A kinase and its activator TPX2 are potential therapeutic targets in KRAS-induced pancreatic cancer
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Vitor Heidrich, Luiza Coimbra Scalabrini, Ester Risério Matos Bertoldi, Elena Levantini, Bianca Dazzani, Eduardo M. Reis, Sandro M. Gomes-Filho, Daniela S. Basseres, and Edmilson Ozorio dos Santos
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0301 basic medicine ,Cancer Research ,endocrine system diseases ,Targeting Protein for Xklp2 ,Therapeutic target ,Aurora inhibitor ,Aurora A kinase ,Cell Cycle Proteins ,Kaplan-Meier Estimate ,Adenocarcinoma ,medicine.disease_cause ,AURKA or TPX2 as new targets ,BIOMARCADORES ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,0302 clinical medicine ,RNA interference ,Pancreatic cancer ,Cell Line, Tumor ,KRAS ,Medicine ,Humans ,Molecular Targeted Therapy ,RNA, Small Interfering ,Clonogenic assay ,neoplasms ,Protein Kinase Inhibitors ,Aurora Kinase A ,business.industry ,General Medicine ,Oncogenes ,medicine.disease ,Prognosis ,Phenotype ,digestive system diseases ,mechanisms of tumorigenesis ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Molecular Medicine ,business ,Microtubule-Associated Proteins - Abstract
Purpose Oncogenic KRAS mutations are found in over 90% of pancreatic ductal adenocarcinomas (PDACs). As yet, however, no effective therapies are available for KRAS-induced malignancies. Therefore, research aimed at the identification of KRAS targets with therapeutic potential is warranted. Our goal was to investigate Aurora A (AURKA) and targeting protein for Xklp2 (TPX2) as potential therapeutic targets in PDAC. Methods AURKA and TPX2 expression was assessed using RNAseq and qRT-PCR in PDAC patient samples and matched non-tumor pancreatic tissues. Publicly available PDAC datasets were used to investigate associations of AURKA and TPX2 expression levels with patient survival and the presence of KRAS mutations. Next, we used an Aurora kinase inhibitor, or KRAS, AURKA and TPX2 targeting using RNA interference in KRAS-mutant PDAC cells and, subsequently, analyzed their clonogenic and anchorage-independent growth and migration. Results We found that relative to matched non-tumor tissues, PDAC tumors displayed significantly higher expression levels of AURKA and TPX2. In addition, we found that AURKA and TPX2 were co-expressed in PDAC datasets, and that high expression levels of AURKA and TPX2 were associated with a shorter patient survival and with the presence of oncogenic KRAS mutations. In addition, we found that siRNA-mediated KRAS targeting in KRAS-mutant PDAC cells reduced AURKA and TPX2 expression. Furthermore, targeting AURKA or TPX2 in KRAS-mutant PDAC cells reduced their clonogenic and anchorage-independent growth, as well their migration. Conclusions From our data we conclude that AURKA and TPX2 may act as KRAS biomarkers in PDAC that can predict a worse prognosis, and that AURKA or TPX2 targeting in PDAC cells may reduce their transformed phenotype. These results indicate that AURKA and TPX2 may serve as promising targets to be explored for KRAS-mutant PDAC therapy.
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- 2020
15. Beneath the surface: hyper-connectivity between caudate and salience regions in ADHD fMRI at rest
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Pierluigi Politi, Livio Tarchi, Matteo Rocchetti, Simone Marini, Stefano Damiani, Andrea Scalabrini, Francesco Oliva, and Umberto Provenzani
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Male ,Adolescent ,Functional dynamics ,Caudate nucleus ,behavioral disciplines and activities ,Amygdala ,Attention deficit hyperactivity disorder ,03 medical and health sciences ,0302 clinical medicine ,Reward ,Salience (neuroscience) ,Salience network ,fMRI ,mental disorders ,Settore M-PSI/07 - Psicologia Dinamica ,Developmental and Educational Psychology ,medicine ,Humans ,0501 psychology and cognitive sciences ,Child ,Settore MED/25 - Psichiatria ,Attention Deficit Disorder with Hyperactivity ,Brain ,Caudate Nucleus ,Female ,Magnetic Resonance Imaging ,Putamen ,05 social sciences ,Adhd group ,General Medicine ,medicine.disease ,030227 psychiatry ,Psychiatry and Mental health ,medicine.anatomical_structure ,Settore M-PSI/02 - Psicobiologia e Psicologia Fisiologica ,Pediatrics, Perinatology and Child Health ,Psychology ,Neuroscience ,Neurotypical ,050104 developmental & child psychology - Abstract
Attention-Deficit/Hyperactivity Disorder (ADHD) comprises disturbances in attention, emotional regulation, and reward-related processes. In spite of the active efforts in researching neurofunctional correlates of these symptoms, how the activity of subcortical regions—such as basal ganglia—is related to ADHD has yet to be clarified. More specifically, how age may influence the critical changes observed in functional dynamics from childhood to adulthood remains relatively unexplored. We hence selected five core subcortical regions (amygdala, caudate, putamen, pallidum and hippocampus) as regions of interest from the previous literature, measuring their whole-brain voxel-wise rsFC in a sample of 95 ADHD and 90 neurotypical children and adolescents aged from 7 to 18. The only subcortical structure showing significant differences in rsFC was the caudate nucleus. Specifically, we measured increased rsFC with anterior cingulate and right insula, two mesolimbic regions pertaining to the Salience Network. The degree of hyper-rsFC positively correlated with ADHD symptomatology, and showed different patterns of evolution in ADHD vs neurotypical subjects. Finally, the rsFC scores allowed a fair discrimination of the ADHD group (Area Under the Curve ≥ 0.7). These findings shed further light on the fundamental role covered by subcortical structures in ADHD pathogenesis and neurodevelopment, providing new evidence to fill the gap between neurofunctional and clinical expressions of ADHD.
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- 2020
16. Dissociation as a disorder of integration – On the footsteps of Pierre Janet
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Stefano Damiani, Rosy Esposito, Georg Northoff, Andrea Scalabrini, and Clara Mucci
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Consciousness ,Pierre Janet ,Altered state of consciousness ,Right anterior insula ,Psychology of self ,Integration ,Amnesia ,Dissociative Disorders ,Empirical Research ,Dissociation (psychology) ,03 medical and health sciences ,0302 clinical medicine ,Neuroimaging ,Settore M-PSI/08 - Psicologia Clinica ,Network level ,Settore M-PSI/07 - Psicologia Dinamica ,medicine ,Derealization ,Humans ,Biological Psychiatry ,Spontaneous activity of the brain ,Pharmacology ,Brain ,medicine.disease ,Magnetic Resonance Imaging ,030227 psychiatry ,Temporo-spatial dynamics ,Dissociation ,Settore M-PSI/02 - Psicobiologia e Psicologia Fisiologica ,nervous system ,medicine.symptom ,Nerve Net ,Psychology ,Neuroscience - Abstract
At the end of the 19th century Pierre Janet described dissociation as an altered state of consciousness manifested in disrupted integration of psychological functions. Clinically, such disruption comprises compartmentalization symptoms like amnesia, detachment symptoms like depersonalization/derealization, and structural dissociation of personality with changes in the sense of self. The exact neuronal mechanisms leading to these different symptoms remain unclear. We here suggest to put Janet's original account of dissociation as disrupted integration of psychological functions into a novel context, that is, a neuronal context as related to current brain imaging. This requires a combined theoretical and empirical approach on data supporting such neuronal reframing of Janet. For that, we here review (i) past and (ii) recent psychological and neuronal views on dissociation together with neuroscientific theories of integration, which (iii) are supported and complemented by preliminary fMRI data. We propose three neuronal mechanisms of dynamic integration operating at different levels of the brain's spontaneous activity - temporo-spatial binding on the regional level, temporo-spatial synchronization on the network level, and temporo-spatial globalization on the global level. These neuronal mechanisms, in turn, may be related to different symptomatic manifestation of dissociation operating at different levels, e.g., compartmentalization, detachment, and structural, which, as we suggest, can all be traced to disrupted integration of neuronal and psychological functions as originally envisioned by Janet.
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- 2020
17. IKKβ kinase promotes stemness, migration, and invasion in KRAS-driven lung adenocarcinoma cells
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Björn Kruspig, Elena Levantini, Luiza Coimbra Scalabrini, Daniela S. Basseres, Vanessa Silva Miranda, Tatiana Correa Carneiro-Lobo, Daniel J. Murphy, and Felipe Silva Rodrigues
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cancer stem cells ,Lung Neoplasms ,MMP2 ,endocrine system diseases ,NF-κB signalling ,migration ,medicine.disease_cause ,lcsh:Chemistry ,Cell Movement ,Cell Self Renewal ,RNA, Small Interfering ,lcsh:QH301-705.5 ,Spectroscopy ,Cell migration ,General Medicine ,invasion ,I-kappa B Kinase ,Computer Science Applications ,Gene Expression Regulation, Neoplastic ,Neoplastic Stem Cells ,Adenocarcinoma ,KRAS ,IKKβ kinase ,Adenocarcinoma of Lung ,Biology ,Article ,Catalysis ,Proto-Oncogene Proteins p21(ras) ,Inorganic Chemistry ,stemness ,Cancer stem cell ,Cell Line, Tumor ,Spheroids, Cellular ,medicine ,Humans ,Neoplasm Invasiveness ,Physical and Theoretical Chemistry ,Kinase activity ,Lung cancer ,neoplasms ,Molecular Biology ,Cell Proliferation ,Organic Chemistry ,Cancer ,ADENOCARCINOMA ,medicine.disease ,digestive system diseases ,respiratory tract diseases ,lung cancer ,lcsh:Biology (General) ,lcsh:QD1-999 ,Mutation ,Cancer research - Abstract
KRAS oncogenic mutations are widespread in lung cancer and, because direct targeting of KRAS has proven to be challenging, KRAS-driven cancers lack effective therapies. One alternative strategy for developing KRAS targeted therapies is to identify downstream targets involved in promoting important malignant features, such as the acquisition of a cancer stem-like and metastatic phenotype. Based on previous studies showing that KRAS activates nuclear factor kappa-B (NF-&kappa, B) through inhibitor of nuclear factor kappa-B kinase &beta, (IKK&beta, ) to promote lung tumourigenesis, we hypothesized that inhibition of IKK&beta, would reduce stemness, migration and invasion of KRAS-mutant human lung cancer cells. We show that KRAS-driven lung tumoursphere-derived cells exhibit stemness features and increased IKK&beta, kinase activity. IKK&beta, targeting by different approaches reduces the expression of stemness-associated genes, tumoursphere formation, and self-renewal, and preferentially impairs the proliferation of KRAS-driven lung tumoursphere-derived cells. Moreover, we show that IKK&beta, targeting reduces tumour cell migration and invasion, potentially by regulating both expression and activity of matrix metalloproteinase 2 (MMP2). In conclusion, our results indicate that IKK&beta, is an important mediator of KRAS-induced stemness and invasive features in lung cancer, and, therefore, might constitute a promising strategy to lower recurrence rates, reduce metastatic dissemination, and improve survival of lung cancer patients with KRAS-driven disease.
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- 2020
18. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial
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Vassiliki Karantza, Shparyk Yaroslav, Sumrall Bradley, Javier Cortes, Iwata Hiroji, Kolesnik Oleksii, Ahn Jin Hee, Harbeck Nadia, Prausova Jana, Song Xinni, Berzoy Oleksandr, Mena Raul, Osaki Akihiko, Kahan Zsuzsanna, Simon Michael, Ozguroglu Mustafa, Chmielowska Ewa, Tsugawa Koichiro, Tsao Chao-Jung, Ozyilkan Ozgur, Nowecki Zbigniew, Fadeeva Natalia, Kaen Diego, Garcia Saenz Jose, Porter David, Ngan Kai Cheong Roger, Sherene Loi, Bermejo de las Heras Begona, Turner Nicholas, David W. Cescon, Hope S. Rugo, Oliff Ira, Kelly Catherine, Barrios Carlos, Cole Scott, Shevnya Sergii, Seock-Ah Im, Hoskins Kent, Komisarenko Hanna, Yavuz Sinan, Chaudhry Madhu, Sagara Yasuaki, Brust Leandro, Chan Steve, Gomez Villanueva Angel, Gallardo Carlos, Watanabe Junichiro, Ishikawa Takashi, Schleider Michael, Salas Claudio, Hardy-Bessard Anne-Claire, Erhan Gokmen, Adamchuk Hryhoriy, Beelen Karin, Holeckova Petra, Szczylik Cezary, Fujii Takaaki, Nakamura Seigo, Aruga Tomoyuki, Gokmen Erhan, Jing Zhao, Hiroji Iwata, Molinas Mandel Nil, Gogineni Keerthi, Im Seock-Ah, Zifang Guo, Loi Sherene, Costa Fabiano, Forstmeyer Dirk, Kosaka Yoshimasa, Gomez Diaz Alvaro, Ponomarova Olga, Wimberger Pauline, DAlessio Antonietta, Suzuki Eiji, Blohmer Jens-Uwe, Kowalwszyn Ruben, Molina Matias, Clingan Philip, Yamamoto Yutaka, Sabanathan Dhanusha, Gursel Aktan, Vynnychenko Ihor, Ferrario Cristiano, Schumann Raquel Von, Trukhin Dmytro, Arkosy Peter, Tseng Ling-Ming, Moore Susan, Gunduz Seyda, Stampleman Laura, de Freitas Junior Ruffo, Acevedo Alejandro, Lipatov Oleg, Niikura Naoki, Norikazu Masuda, Rusyn Andrii, Kral Zdenek, Crown John, Yamamoto Naohito, Jakobsen Erik, Blau Sibel, Bustam Anita, Zamora Adelantado Esther, Nanda Rita, Omene Coral, Arslan Cagatay, Kwong Ava, Teixeira Luis, Jensen Jeanette, Ito Yoshinori, Siegel Robert, Mastura Md Yusof, Nowakowska-Zajdel Ewa, Miyoshi Yasuo, Yu Joanne, Tuthill Mark, Mukhametshina Guzel, Matsumoto Koji, Gion Maria, Melichar Bohuslav, Desmoulins Isabelle, Moiseyenko Vladimir, Zurawski Bogdan, Carlos Gallardo, Lorincz Tamas, Cruz Jurado Josefina, Bondarenko Igor, Kaczerowsky Flores de Sousa Anna, Yamauchi Teruo, Loutfi Randa, Esther Holgado, Holgado Esther, Twelves Christopher, Streb Joanna, Tanabe Yuko, Tarnawski Rafal, Morales-Vasquez Flavia, Park Kwong Hwa, Csoszi Tibor, Meshcheryakov Andrey, Scalabrini Neto Antonio Orlando, Oleg Lipatov, Iwasa Tsutomu, Ricevuto Enrico, Tamura Kenji, Patson Brian, Liu Mei-Ching, Cinieri Saverio, Loibl Sibylle, Tjan-Heijnen Vivianne, Glavicic Vesna, Panwalkar Amit, Hargis Jeffrey, Kryzhanivska Anna, Yusof Mastura, O'Reilly Seamus, Rubovszky Gabor, Irvin William, Takahashi Masato, Ohtani Shoichiro, Peter Schmid, Carlos H. Barrios, Sanchez Cesar, Zbigniew Nowecki, Arkhipov Alexander, Chung Michael, Liu Chien-Ting, Mukai Hirofumi, Marco Torregroza Otero, Charpentier Danielle, Park-Simon Tjoung-Won, Lee Keun Seok, Leshchenko Iurii, Huang Chiun-Sheng, Tsai Michaela, Panella Timothy, Petrakova Katarina, MacPherson Iain, Schmid Peter, Baron-Hay Sally, Ursol Grygorii, Lacerda Domicio Carvalho, Cobb Patrick, Sanchez Jesus, Park Yeon Hee, Reyes Contreras Jessica, Fein Luis, Hegg Roberto, Diamond Jennifer, Huober Jens, Rugo Hope, Rybalova Irina, de la Cruz Merino Luis, Linnet Soren, Inoue Kenichi, Wheatley Duncan, Cescon David, Cicin Irfan, Gombos Andrea, Bonnefoi Herve, Nasonova Alla, Taylor Donatienne, Martinez Rodriguez Jorge, Valdes-Albini Frances, Juarez Ramiro Alejandro, Cortes Javier, Lu Janice, Silva Felipe, Lueftner Diana, Landherr Laszlo, Gomez Abuin Gonzalo, Yanez Eduardo, Rocha Roberto Odebrecht, Chow Louis, Otchenash Natalya, Radecka Barbara, Kolesnik Olena, Basaran Gul, Kurbacher Christian, Mahr Karoly, Goncalves Anthony, Begbie Stephen, Graham Janine, Fasching Peter, Varela Mirta, and Lissa Fernando Cezar Toniazzi
- Subjects
Oncology ,double blind procedure ,pharmacist ,CD274 protein, human ,hazard ratio ,0302 clinical medicine ,middle aged ,Antineoplastic Combined Chemotherapy Protocols ,cancer survival ,comparative study ,education.field_of_study ,progression free survival ,adult ,drug effect ,gemcitabine ,clinical trial ,General Medicine ,nausea ,anemia ,Progression-Free Survival ,priority journal ,immunological antineoplastic agent ,thyroiditis ,pembrolizumab ,metastatic breast cancer ,neoadjuvant chemotherapy ,medicine.medical_specialty ,Antineoplastic Agents ,intention to treat analysis ,Article ,skin manifestation ,03 medical and health sciences ,Breast cancer ,cancer combination chemotherapy ,neutropenia ,Humans ,Progression-free survival ,human ,education ,protein expression ,cancer immunotherapy ,treatment response ,Interim analysis ,medicine.disease ,major clinical study ,tumor recurrence ,Carboplatin ,programmed death 1 ligand 1 ,drug efficacy ,multicenter study ,chemistry ,monoclonal antibody ,randomized controlled trial ,fatigue ,drug tolerability ,cancer patient ,age distribution ,drug safety ,colitis ,clinical outcome ,Triple Negative Breast Neoplasms ,Pembrolizumab ,030204 cardiovascular system & hematology ,B7-H1 Antigen ,Placebos ,chemistry.chemical_compound ,paclitaxel ,Antineoplastic Agents, Immunological ,Outcome Assessment, Health Care ,030212 general & internal medicine ,antineoplastic agent ,cancer adjuvant therapy ,Eastern Cooperative Oncology Group performance status ,female ,carboplatin ,sodium chloride ,immunohistochemistry ,medicine.drug ,interactive voice response system ,alanine aminotransferase ,overall survival ,Population ,Antibodies, Monoclonal, Humanized ,Double-Blind Method ,Internal medicine ,medicine ,follow up ,hyperthyroidism ,pneumonia ,controlled study ,Taxane ,phase 3 clinical trial ,business.industry ,hypertransaminasemia ,alopecia ,Gemcitabine ,human tissue ,cancer recurrence ,functional status assessment ,triple negative breast cancer ,placebo ,inoperable cancer ,pathology ,hypothyroidism ,Neoplasm Recurrence, Local ,business ,metabolism ,Follow-Up Studies - Abstract
Background: Pembrolizumab monotherapy showed durable antitumour activity and manageable safety in patients with metastatic triple-negative breast cancer. We aimed to examine whether the addition of pembrolizumab would enhance the antitumour activity of chemotherapy in patients with metastatic triple-negative breast cancer. Methods: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine–carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ?1 or, Breast Cancer Research Foundation, BCRF; Pfizer; AstraZeneca; Merck; Roche; Samsung; Merck Sharp and Dohme, MSD; Eisai, JC reports personal fees and research funding paid to his institution from Roche, AstraZeneca, Merck Sharp & Dohme, and Eisai; personal fees from Celgene, Cellestia, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, GlaxoSmithKline, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Kyowa Kirin, Novartis, Pfizer, Samsung Bioepis; research funding paid to his institution from Ariad Pharmaceuticals, Bayer Healthcare, F Hoffman-La Roche, Guardanth Health, Piqur Therapeutics, Puma C, and Queen Mary University of London, outside the submitted work. In addition, JC has a MedSIR patent pending. DWC reports research support from Merck during the conduct of the study; research support paid to his institution from Merck, Pfizer, and GlaxoSmithKline; personal fees from Merck, Roche–Genentech, AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Puma, Agenda, Exact Sciences, and Dynamo Therapeutics, outside the submitted work. In addition, DWC has a Biomarkers of TTK inhibitors patent pending. HSR reports funding for sponsored studies paid to the University of California San Francisco from Pfizer, Novartis, Lilly, Roche–Genentech, Macrogenics, OBI, Merck, Eisai, Immunomedics, Daiichi Sankyo, Seattle Genetics, and Odonate; travel support for educational meetings from Daiichi Sankyo, Mylan, Pfizer, Merck, AstraZeneca, Novartis, and Macrogenics; and consulting fees from Samsung and Puma, outside the submitted work. S-AI reports grants from AstraZeneca, Eisai, Pfizer, Roche, and Daewoong; an advisory role for AstraZeneca, Amgen, Eisai, Hanmi, Novartis, Lily, MedPacto, Pfizer, and Roche; and travel expenses for presentation from Novartis, outside the submitted work. CG reports Advisory Board fees from Merck Sharp & Dohme and Roche; and speaker's bureau fees from Bristol Myers Squibb and AstraZeneca, outside the submitted work. CHB reports grants and fees from Merck Sharp & Dohme for clinical research consulting during the conduct of the study; consulting–advisory role fees from Boehringer Ingelheim, GlaxoSmithKline, and Bayer; consulting–advisory role fees and grants for clinical research from Novartis, Pfizer, Roche–Genentech, Eisai, Merck Sharp & Dohme, and AstraZeneca; grants for clinical research from Abbvie, Amgen, Astellas Pharma, Bristol Myers Squibb, Celgene, Covance, Lilly, Medication, Merck Serono, and PharmaMar; grants for academic research projects from CPO, Pontificia Universidade Católica do Rio Grande do Sul, Latin American Cooperative Oncology Group, Grupo Brasileiro Estudos Câncer Mama, and Instituto Nacional de Câncer-Brazil, outside the submitted work. HI reports a grant from Merck Sharp & Dohme during the conduct of the study; honoraria and consulting fees from Novartis, AstraZeneca, Pfizer, Lilly, Daiichi Sankyo, Eisai, and Chugai; and a grant from Chugai, outside the submitted work. NM reports honoraria and research funding paid to his institution from Chugai, AstraZeneca, Pfizer, Eli-Lilly, Eisai, Takeda, Kyowa-Kirin, Merck Sharp & Dohme, Novartis, and Daiichi Sankyo, outside the submitted work. EG reports non-financial support from Merck Sharp & Dohme during the conduct of the study; honoraria, consulting–advisory fees and meeting support from Novartis, Roche, Bristol Myers Squibb, and Pfizer; and honoraria from AstraZeneca and Astellas, outside the submitted work. SL reports research funding or consulting fees paid to her institution from Bristol Myers Squibb, Roche–Genentech, Puma Biotechnology, Pfizer, Seattle Genetics, Novartis, Merck Sharp & Dohme, Eli Lilly, Aduro Biotech, GI Therapeutics, AstraZeneca, and GlaxoSmithKline; and non-remunerated consultancy for Bristol Myers Squibb, Roche–Genentech, Pfizer, Seattle Genetics, Novartis, Merck Sharp & Dohme, and AstraZeneca, outside the submitted work. In addition, SL is supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. ZG, JZ, GA, and VK are employees of Merck Sharp & Dohme and own stock or stock options in Merck. PS reports consultancy fees from Pfizer, AstraZeneca, Novartis, Roche, Merck Sharp & Dohme, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma; consultancy fees to his spouse from Genentech and Roche; and grants or funding to his institution from Roche, Genentech, Oncogenex, Novartis, Astellas, and AstraZeneca, outside the submitted work. All other authors declare no competing interests., The authors thank the patients, their families and caregivers for participating in this trial, all of the investigators and site personnel, and the following employees of Merck Sharp & Dohme: Wilbur Pan, Deborah Card, Eleanor Readinger, Shana Hamm, Roger Maxwell, and Krystal Bourdon, for collection of data, supervision of research, provision of study materials or patients or administrative or logistical support; Aline Galvao, for collection of data, supervision of research, administrative or logistical support, and review of imaging data related to the primary end point; Donna Letizia, for collection of data and imaging expertise; Jennifer Kimmel, for study management; Mercedes Bustamante, for data collection and management; Xuan Zhou and Madhusudhan Reddy Papasani, for statistical expertise; Christine McCrary Sisk, for medical writing and editorial assistance; and Joseph C Naggar and Michele McColgan, for administrative or logistical support.
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- 2020
19. A Comprehensive and Systematic Analysis of Minimal Residual Disease (MRD) Monitoring in Follicular Lymphoma: Results from the Fondazione Italiana Linfomi (FIL) FOLL12 Trial
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Marzia Cavalli, Filippo Ballerini, Delia Rota Scalabrini, M. Ladetto, Valter Gattei, Francesca Guerrini, Massimo Degan, Pietro Maria Stefani, Lucia Anna De Novi, Tommasina Perrone, Martina Ferrante, Elisa Genuardi, Irene Della Starza, Ilaria Del Giudice, Brunangelo Falini, Simone Ferrero, Stefano Luminari, Riccardo Bomben, Barbara Mantoan, Mario Petrini, Sara Galimberti, Massimo Federico, Irene Dogliotti, Luigi Marcheselli, Sara Veronica Usai, Eva Zaina, Attilio Olivieri, Francesca Re, Susanna Grassi, Elena Ciabatti, Donato Mannina, and Beatrice Alessandria
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,medicine ,Follicular lymphoma ,Cell Biology ,Hematology ,medicine.disease ,business ,Biochemistry ,Minimal residual disease - Abstract
Background. Immunochemotherapy is effective in follicular lymphoma (FL), but most patients (pts) eventually relapse. MRD analysis, based on the detection of Bcl-2/IGH rearrangement by highly sensitive PCR-based tools, is effective in identifying pts at risk of relapse [Ladetto Blood 2012; Pott EHA23]. However, several issues are still unresolved, including: i) which is the best tissue source and the most reliable technique; ii) which are the most predictive time points; iii) which is the role of disease kinetics during the long natural history of FL. The FIL FOLL12 prospective, phase III randomized clinical trial (EudraCT: 2012-003170-60) included a systematic MRD analysis on both peripheral blood (PB) and bone marrow (BM) taken at eight different pre-planned time points, by both nested and real time quantitative (RQ)-PCR. Therefore, it allows addressing these unresolved issues. Methods. The FOLL12 compared conventional rituximab maintenance [Salles et al, Lancet 2010] vs a combined PET/MRD response-based post-induction approach in pts with advanced FL after first line chemo-immunotherapy. Clinical results have been already reported [Luminari et al, ICML16]. PB and BM samples were centralized at four Italian Euro-MRD certified laboratories. MRD was assessed with consensus primers on Bcl-2/IGH rearrangements (MBR, mcr and minor rearrangements) by both nested and RQ-PCR at eight time points: baseline, end of induction (EoI) and every six months thereafter till month 36. MRD data were treated as a time-varying covariate and analyzed by means of flexible parametric survival model (Parmar-Royston) with the log cumulative baseline hazard function. MRD data were modeled with restricted cubic spline as function of time. Effect of fixed covariates and landmark analysis were performed with the Cox PH regression. Any estimation was reported with its 95%CI. Results. Overall, 10,702 analytical results were generated, (3,000 for marker screening and 7,702 for MRD). 780 of 786 eligible pts (99%) were screened at baseline for the presence of a molecular marker. 443/780 (57%) had a detectable Bcl-2/IGH rearrangement, as expected. High rates of MRD negativity were observed at EoI, with similar results by both techniques (87% in BM and 95% in PB by nested-PCR, 90% in BM and 95% in PB with RQ-PCR). Overall, the presence of one MRD positive result was associated during the entire follow-up period with an increased risk of relapse in the subsequent six months interval (HR for PFS 2.82, 95% CI 1.84-4.34, p Conclusions. This comprehensive MRD study in FL clearly indicates that: i) punctual MRD analysis is predictive of poor outcome at multiple pre-planned time points taken over a 36 months period; ii) both nested and RQ-PCR performed adequately, the latter being preferable as broadly used and internationally standardized; iii) BM allows better prediction at the early time points but, starting from month 12 after EoI PB is superimposable to BM, allowing effective and reliable long-term non-invasive MRD monitoring; iv) the high predictive value of punctual time point analysis is further improved by a kinetic approach to the interpretation of MRD results. Figure 1 Figure 1. Disclosures Ladetto: AbbVie, Jazz, Gentili, Incyte, ADC Therapeutics, Acerta, Pfizer: Honoraria; Roche, J&J, Celgene, Novartis, Amgen, Gilead, Beigene, GSK: Honoraria. Ferrero: Servier: Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding, Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees. Del Giudice: Tolero: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees. Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Gattei: abbVie: Research Funding; Janssen: Research Funding; Menarini: Research Funding. Mannina: Janssen,Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Falini: Rasna Therapeutics: Honoraria. Luminari: Roche, Celgene, Teva Pharmaceuticals, Gilead Sciences, and Takeda Pharmaceuticals: Honoraria.
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- 2021
20. OAB-004: Carfilzomib-based induction/consolidation with or without autologous transplant and Lenalidomide (R) or Carfilzomib-Lenalidomide (KR) maintenance: efficacy in high-risk patients of the FORTE study
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Roberto Mina, Elena Zamagni, Delia Rota-Scalabrini, Paolo Corradini, Mariella Grasso, Stelvio Ballanti, Nicola Giuliani, Luca De Rosa, Claudia Cellini, Iolanda Donatella Vincelli, Cristina Velluti, Andrea Capra, Anna Maria Cafro, Alessandro Gozzetti, Massimo Gentile, Sara Aquino, Angelo Palmas, Antonio Ledda, Maria Teresa Petrucci, Pellegrino Musto, Mario Boccadoro, and Francesca Gay
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Cancer Research ,medicine.medical_specialty ,Double hit ,High risk patients ,MRD Negativity ,business.industry ,Hematology ,medicine.disease ,Carfilzomib ,Gastroenterology ,chemistry.chemical_compound ,Oncology ,chemistry ,Standard Risk ,Internal medicine ,medicine ,Autologous transplant ,business ,Multiple myeloma ,Lenalidomide ,medicine.drug - Abstract
Introduction Multiple myeloma (MM) patients (pts) with high-risk cytogenetic abnormalities (CA) have a shorter survival as compared to the standard-risk ones. In the FORTE study, carfilzomib-lenalidomide-dexamethasone induction/consolidation with ASCT (KRd-ASCT) significantly improved progression-free survival (PFS) vs KRd without ASCT (KRd12) or carfilzomib-cyclophosphamide-dexamethasone (KCd) plus ASCT (KCd-ASCT). KR maintenance also prolonged PFS vs R. The primary aim of this analysis was to evaluate the impact of treatment on PFS and 1-year sustained MRD negativity (1y-MRD neg) rates according to pt cytogenetic risk. Methods Pts were randomized to KRd-ASCT vs KCd-ASCT vs KRd12 and, thereafter, to KR vs R maintenance. High risk (HiR) was defined as the presence of ≥1 HiR CA [del17p, t(4;14), t(14;16), del1p and 1q gain (3 copies) or amp1q (≥4 copies)], double hit (DH) as the presence of ≥2 HiR CA, standard risk (SR) as the absence of all evaluated HiR CA. Results 396 out of 474 enrolled pts with complete fluorescence in situ hybridization (FISH) data were included in the analysis: 243 HiR, 105 DH and 153 SR pts. Among HiR pts, 60 had del17p, 65 t(4;14), 20 t(14;16), 44 del1p, 126 1q gain and 49 amp1q. SR pts benefited from intensification with KRd-ASCT vs KRd12 (HR 0.47, p=0.05) and KCd-ASCT (HR 0.38, p=0.01), with a 4-year PFS of 80%, 67% and 57%, respectively. In HiR pts, KRd-ASCT improved PFS vs KRd12 (HR 0.6, p=0.04) and KCd-ASCT (HR 0.57, p=0.01), with a 4-year PFS of 62%, 45% and 45%, respectively. The advantage with KRd-ASCT vs KRd12 (HR 0.53, p=0.07) and KCd-ASCT (HR 0.49; p=0.03) was also observed in DH pts (4-year PFS 55%, 31% and 33%, respectively). Despite the limited number of patients in each subgroup, a trend towards a PFS benefit from KRd-ASCT vs KRd12 was observed in pts with del17p (HR 0.61, p=0.3), t(4;14) (HR 0.59, p=0.2) and 1q gain (HR 0.45, p=0.02). In pts with del1p, KRd-ASCT (HR 0.24, p=0.06) and KRd12 (HR 0.33, p=0.09) showed superiority over KCd-ASCT, while amp1q pts had the worst outcome regardless of treatment (KRd-ASCT vs KCd-ASCT, HR 1.16, p=0.73; KRd12 vs KCd-ASCT, HR 1.34, p=0.45). KR improved PFS vs R in SR (3-year PFS 90% vs 73%, HR 0.42, p=0.06), HiR (3-year PFS 69% vs 56%, HR 0.6, p=0.04) and DH pts (3-year PFS 67% vs 42%, HR 0.53, p=0.1). Despite the small subgroups, a beneficial trend with KR vs R was observed in pts with del17p (HR 0.59, p=0.37), t(4;14) (HR 0.59, p=0.3), 1q gain (HR 0.54, p=0.07) and del1p (HR 0.23, p=0.08), while amp1q pts showed the worst outcome and no benefit from KR vs R (HR 0.83, p=0.7). Conclusion KRd-ASCT and KR maintenance are highly effective in SR and also in HiR and DH pts, with impressive 4-year PFS from diagnosis (KRd-ASCT: HiR 62%, DH 55%) and 3-year PFS from maintenance (KR: HiR 69%, DH 67%), thus providing an effective option in HiR pts, who still represent an unmet medical need.
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- 2021
21. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer
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Fizazi, Karim, Tran, Namphuong, Fein, Luis, Matsubara, Nobuaki, Rodriguez Antolin, Alfredo, Alekseev, Boris Y., Ãzgã¼roglu, Mustafa, Dingwei, Ye, Feyerabend, Susan, Protheroe, Andrew, De Porre, Peter, Kheoh, Thian, Park, Youn C., Todd, Mary B., Chi, Korbenfeld E, Kim N., Metrebian, S, Kaen, L, Staneloni, E, Batagelj, E, Tan, H, Hovey, E, Woo, H, Frydenberg, M, Chua, W, D’Hondt, L, Evaraert, E, Verschaeve, V, Wynendaele, W, Schrijvers, D, Waltregny, D, Whenham, N, Demey, W, Franke, F, Panhoca, R, Damião, R, Zucca, L, Da Rosa, V, Reis, R, Scalabrini, A, Nahas, W, Girotto, G, Nogueira, A, Gomes, A, Coradazzi, A, Kurteva, G, Siemens, R, Gingerich, J, Fleshner, N, Fradet, Y, Morgan, S, North, S, Saad, F, Shayegan, B, Zalewski, P, Pinochet, R, Orellana, N, Ding, Q, Ye, Z, Xie, L, Du, C, Chen, Z, Huang, Y, Sun, Z, Li, H, Jin, J, Li, C, Wan, B, Tian, Y, Zhou, F, Xie, K, Yao, X, Qiu, M, Zou, Q, Na, Y, Sun, Y, Xue, B, Ma, L, Martinez, C, Salazar, M, Larios, C, Solano, S, Pavlik, I, Brodak, M, Hora, M, Büchler, T, Borre, M, Johansen, J, Mejlholm, I, Poulsen, M, Wittendorf, He, Tammela, T, Vaarala, M, Theodore, C, Staudacher, L, Villers, A, Laplaige, P, Suttman, H, Steuber, T, Natale, S, Jones, R, Tran, A, Mazhar, D, Mills, J, Nyirady, P, Salamon, C, Torzsok, F, Feher, J, Géczi, L, Lakatos, A, Keizman, D, Sella, A, Frank, S, Peer, A, Rosenbaum, E, Berger, R, Mermershtain, W, Carteni, G, Tonini, G, De Giorgi, U, Facchini, G, Berruti, Alfredo, Bracarda, S, Basso, U, Galli, L, Tortora, G, Alietta, M, Fukasawa, S, Suzuki, H, Hasumi, H, Tsuchiya, T, Uemura, H, Kanayama, H, Hashine, K, Sato, F, Matsumoto, H, Oya, M, Lee, Jl, Park, S, Keam, B, Yun, H, Kim, Y, Kang, B, Lee, K, Kim, C, Saad, M, Sundram, M, Calvo, D, Moreno, R, Rodriquez, J, Hernandez, C, van den Berg, H, De La Rosett, J, Van Moorse, R, Hunting, J, Hendriks, M, Kueppers, F, Gilling, P, Beaven, A, Holmes, M, Jassem, J, Oszukowska, E, Niezabitowski, J, Jaxa Larecka, D, Chwalinski, M, Swiniarski, P, Silva, C, Conceicãoa, P, Fraga, A, Mauricio, J, Rodrigues, T, Pinheiro, L, Lima, E, Palma Dos Reis, J, Volovat, C, Jinga, V, Harza, M, Alyasova, A, Budnik, N, Bychkov, Y, Izmaylov, A, Khvorosten, D, Matveev, V, Novsov, A, Vladimirov, V, Tevs, D, Sheveleva, L, Bulanov, A, Semenov, A, Fadeeva, N, Kulikov, E, Emelyanov, S, Karyakin, O, Shirinkin, V, Shkolnik, M, Lykov, A, Skopin, P, Kopyltsov, E, Mincik, I, Mir, O, Kliment, J, Mikurcik, E, Gajdos, M, Milichovsky, I, Malan, J, Bahlmann, J, Moshokoa, E, Madlala, T, Coetzee, L, Ribal, M, Miñana, B, Martinez Breijo, S, Carballido, J, Olmos, D, Requena, M, Morote, J, Damber, Je, Haggman, M, Nyman, C, Ljungberg, B, Bjartell, A, Ozen, H, Beduk, Y, Sozen, S, Cetinkaya, M, Ozyurt, M, Tansug, Z, Mungan, A, Tanidir, Y, Toktas, M, Hotko, E, Stus, V, Lyulko, O, Vinnyk, Y, Shparyk, Y, Sakalo, V, Bondarenko, I, Paramonov, V, Khareba, G, Hodos, V., Lääketieteen ja biotieteiden tiedekunta - Faculty of Medicine and Life Sciences, Tampere University, UCL - SSS/IREC/MONT - Pôle Mont Godinne, and UCL - (MGD) Service d'oncologie médicale
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Adult ,Male ,medicine.medical_specialty ,Prednisolone ,Kirurgia, anestesiologia, tehohoito, radiologia - Surgery, anesthesiology, intensive care, radiology ,Abiraterone Acetate ,030232 urology & nephrology ,Urology ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Prednisone ,Antineoplastic Combined Chemotherapy Protocols ,80 and over ,medicine ,Humans ,Aged ,Aged, 80 and over ,Androgen Antagonists ,Middle Aged ,Neoplasm Metastasis ,Prostatic Neoplasms ,Steroid 17-alpha-Hydroxylase ,Survival Analysis ,Medicine (all) ,Gynecology ,business.industry ,Apalutamide ,Abiraterone acetate ,General Medicine ,medicine.disease ,Interim analysis ,Clinical trial ,Darolutamide ,chemistry ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P
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- 2017
22. Impact of Imaging FDG-PET/CT Minimal Residual Disease Assessment on Outcomes and Matching with Bone Marrow Techniques in Newly Diagnosed Transplant Eligible Multiple Myeloma (MM) Patients: Results of the Phase II Randomized Forte Trial
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Elena Zamagni, Cristina Nanni, Francesca Gay, Luca Dozza, Delia Rota Scalabrini, Mattia D'Agostino, Rossella Ribolla, Monica Galli, Manuela Racca, Renato Zambello, Elena Rivolti, Domenico Albano, Annibale Versari, Mariella Grasso, Rossella Troia, Antonio Spadano, Francesca Patriarca, Marina Ruggeri, Marco Rensi, Anna Pascarella, Pietro Zucchetta, Paola Tacchetti, Stefano Fanti, Mario Boccadoro, Michele Cavo, Pellegrino Musto, and Stefania Oliva
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medicine.medical_specialty ,Matching (statistics) ,business.industry ,Immunology ,Cell Biology ,Hematology ,Newly diagnosed ,medicine.disease ,Biochemistry ,Minimal residual disease ,medicine.anatomical_structure ,Medicine ,Fdg pet ct ,Radiology ,Bone marrow ,business ,Multiple myeloma - Abstract
Background: 18F-FDG-PET/CT is currently the standard technique to define imaging-minimal residual disease (MRD) in multiple myeloma (MM) patients. A joint analysis of 2 prospective randomized trials in newly diagnosed transplant-eligible MM (NDTEMM) patients applied for the first time the Deauville Scores (DS) to focal lesions (FS) and bone marrow uptake (BMS) showing the liver background (DS < 4) as the best cut-off to define PET/CT negativity after therapy and complete metabolic response (CMR) (Zamagni et al, ASH 2018). Validation of this new standardized criteria in an independent prospective series of NDTEMM patients is highly required. Imaging-PET/CT MRD also showed to be complementary to Multiparameter Flow Cytometry (MFC) in predicting patient's outcomes (Moreau P, JCO 2017). In this analysis, we aimed at confirming the applicability and validity of DS criteria to define PET/CT CMR and showing their impact on patient's outcomes in the multicenter phase II randomized FORTE trial for NDTEMM patients. We also looked at the complementarity with BM techniques, especially MFC. Methods: NDTEMM patients ≤ 65 years were randomized to receive carfilzomib, lenalidomide, dexamethasone (KRD) induction - autologous stem cell transplantation (ASCT) intensification-KRd consolidation (arm A); KRd12 (arm B) and carfilzomib, cyclophosphamide, dexamethasone (KCd) induction-ASCT intensification-KCd consolidation (arm C). Thereafter, patients were randomized to maintenance with lenalidomide alone or plus carfilzomib. PET/CT scans were performed locally at baseline (B) and prior to the start of maintenance (PM). DS were applied both in the BM and FLs, as previously described (Zamagni E, EHA 2020). CMR was defined as DS < 4 both in the FLs and BM. MRD evaluation was performed by 8-color second-generation flow cytometry (sensitivity 10-5) in patients who achieved at least VGPR before maintenance (Gay F, ASCO 2019). The impact of each parameter on outcomes was evaluated by landmark analyses at PM. A multivariable Cox regression analysis was adopted to identify independent predictors for PFS and OS. Results: 182 out of the 474 global patients enrolled in the trial had a pre- and post-treatment PET/CT evaluation available and were included in this analysis. Patients' baseline characteristics were: median age 57 years, ISS and R-ISS stage III 18% and 10%, respectively, high-risk cytogenetics (t(4;14) ± del(17p) ± t(14;16), detected by FISH) 26%, reflecting baseline clinical features of the entire FORTE population. At B, 93% of patients had FLs, with a median maximum standardized uptake value (SUVmax) of 5.7 [IQR: 4.1-8.1], 7% presented extra-medullary lesions and nearly all patients had increased BM uptake, with a median SUVmax of 3.4 [IQR: 2.8-4.3]. FS and BMS ≥ 4 were present in 87% and 57% of patients, respectively. At PM, PET/CT negativity according to DS < 4, was present in 80% in the FLs and 85% in the BM, respectively. 63% showed CMR. 92% and 61% of patients achieved ≥ VGPR and CR as best response, respectively, while 73% of them achieved MFC MRD negativity. The achievement of a best CR significantly correlated with BMS < 4 at PM (P= 0.003). In univariate analysis, at Landmark time PM, FS Conclusion: In conclusion, the present analysis confirms the applicability and validity of DS criteria to define PET/CT CMR in an independent prospective series of NDTEMM patients. CMR significantly and independently correlated in uni- and multivariable analysis with patient's outcomes in terms of PFS and OS and was complementary to the MFC MRD negativity. Figure Disclosures Zamagni: Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. Gay:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. D'Agostino:GSK: Membership on an entity's Board of Directors or advisory committees. Galli:Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; BMS: Honoraria. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Rivolti:Celgene: Membership on an entity's Board of Directors or advisory committees. Tacchetti:Bristol-Myers Squibb: Honoraria; AbbVie: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Oncopeptides: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Fanti:Bayer, Astellas, GE Healthcare, ANMI, Janssen: Membership on an entity's Board of Directors or advisory committees; Bayer, Astellas, GE Healthcare, Sanofi, AAA: Honoraria. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Cavo:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Oliva:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria.
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- 2020
23. Ixazomib-Based Induction Followed By Single-Agent Ixazomib Maintenance in Transplant Ineligible, Newly Diagnosed Multiple Myeloma Patients: Updated Results of the EMN10-Unito Trial
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Anna Baraldi, Giovannino Ciccone, Renato Zambello, Angelo Belotti, Michele Cea, Delia Rota Scalabrini, Norbert Pescosta, Francesca Patriarca, Roberto Mina, Annalisa Bernardini, Mario Boccadoro, Sara Bringhen, Nicola Cascavilla, Anna Marina Liberati, Francesca Fazio, Alessandra Larocca, Paolo Corradini, and Andrea Capra
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Newly diagnosed ,medicine.disease ,Biochemistry ,Transplant ineligible ,Ixazomib ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Medicine ,Single agent ,business ,Multiple myeloma - Abstract
INTRODUCTION. The proteasome inhibitor (PI) Ixazomib, approved for the treatment of relapsed/refractory multiple myeloma (MM), represents an appealing option for the management of elderly patients, due to its oral administration and the lack of peripheral neuropathy. We previously presented preliminary results of the phase II EMN10-Unito study investigating Ixazomib in combination with dexamethasone (Id), Cyclophosphamide-dexamethasone (ICd), Thalidomide-dexamethasone (ITd) or Bendamustine-dexamethasone (IBd) as induction therapy followed by single-agent Ixazomib maintenance in transplant-ineligible newly diagnosed (ND) MM patients. Here we present updated results of the study with a longer follow-up. METHODS. Transplant-ineligible NDMM patients ≥65 years were enrolled. Treatment consisted of 9 28-day induction cycles of Ixazomib 4 mg on days 1,8,15 and dexamethasone 40 mg on days 1,8,15,22 or Id plus either Cyclophosphamide 300 mg/m2 orally on days 1,8,15 or Thalidomide 100 mg/day or Bendamustine 75 mg/m2 iv on days 1,8; followed by Ixazomib maintenance (4 mg on days 1,8,15) for up to 2 years. The primary endpoint was the selection of the most effective induction regimen considering a 2-year progression-free survival (PFS) ≥65% as satisfactory; secondary endpoints were very good partial response (VGPR), PFS2, overall survival (OS) and adverse events (AEs) during induction and maintenance. RESULTS. 171 patients (Id 41, ICd 59, ITd 60 and IBd 11) with a median age of 74 years were enrolled and started treatment. Two of the four investigational arms were prematurely closed due to low-enrollment (IBd arm, 11 patients enrolled) and high risk of inefficacy (Id, 41 patients enrolled). Median follow-up was 27 months. After the induction phase, ICd and ITd resulted in higher ≥ PR (75%-84% vs. 57%; p Overall, 102 patients (60%) completed the induction phase and proceeded to ixazomib maintenance (median follow-up from start of maintenance: 18 months). The best response during maintenance was PR in 26%, VGPR in 29%, and complete response (CR) in 26% of patients; 18% of patients improved the response obtained during induction by at least one IMWG category. The median PFS from start of maintenance was 15 months. The median duration of maintenance was 12 months. All grades AEs occurred in 39% of patients during maintenance, while grade 3-4 AEs occurred in 10% of patients. Grade 1-2 peripheral neuropathy (PN) was reported in 15% of patients, without grade 3-4 events. Overall, 15% required at least one dose reduction of ixazomib and 12% discontinued ixazomib maintenance due to AEs. CONCLUSIONS. Safety and efficacy data suggest that Id combined with cyclophosphamide was the most promising induction strategy compared to the other investigated combinations. Continuous treatment with single-agent Ixazomib confirmed its efficacy and tolerability in elderly NDMM patients. Disclosures Mina: Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larocca:GSK: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Corradini:KiowaKirin: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Incyte: Consultancy; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria. Liberati:CELGENE: Honoraria; BIOPHARMA: Honoraria; ARCHIGEN: Honoraria; BEIGENE: Honoraria; BMS: Honoraria; AMGEN: Honoraria; FIBROGEN: Honoraria; INCYTE: Honoraria; VERASTEM: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding; JANSSEN: Honoraria. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees. Bringhen:Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including ixazomib, dexamethasone, cyclophosphamide, thalidomide and bendamustine).
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- 2020
24. On-Demand Plerixafor with Cyclophosphamide and G-CSF for Hematopoietic Stem-Cell Mobilization in Multiple Myeloma Patients: Preliminary Results of a Prospective Observational Study (MOZOBL06877)
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Giusy Cetani, Mario Boccadoro, Daniele Derudas, Andrea Capra, Delia Rota Scalabrini, Maria Teresa Petrucci, Alessandra Malfitano, Paolo Corradini, Michele Cavo, Roberto Mina, Pellegrino Musto, Massimo Offidani, Velia Bongarzoni, Giuseppe Milone, Francesco Pisani, Chiara Nozzoli, Tommaso Caravita di Toritto, Roberto M. Lemoli, Francesca Bonello, Alessandra Larocca, Stelvio Ballanti, and Patrizia Tosi
- Subjects
Oncology ,medicine.medical_specialty ,Cyclophosphamide ,business.industry ,Plerixafor ,education ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Internal medicine ,On demand ,Medicine ,Observational study ,business ,health care economics and organizations ,Hematopoietic Stem Cell Mobilization ,Multiple myeloma ,medicine.drug - Abstract
Background. High-dose melphalan followed by autologous stem cell transplantation is a standard of care in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients and is also an option at relapse. Therefore, since the minimum number of CD34+ cells required to ensure adequate bone marrow recovery after myeloablative chemotherapy is 2x10^6/kg, an adequate upfront stem-cell collection is necessary in MM patients. Approximately 5-15% of MM patients mobilized with granulocyte colony-stimulating factor (G-CSF) or G-CSF+cyclophosphamide (G-CSF/CY) fail stem-cell collection ( Methods. NDMM patients undergoing stem-cell mobilization with cyclophosphamide (2-4 g/m2) and G-CSF (5-10 mcg/kg/day), with on-demand plerixafor according to clinical practice ( Results. At the data cut-off (09 June 2020), a total of 252 patients had been enrolled: of these, 192 patients (59, 29-72 years) were available for the analysis. The median number of induction cycles before mobilization was 4 (range 1-7); median time from diagnosis to mobilization was 6 months (IQR 5-8). Induction therapy consisted of a bortezomib-based regimen in 171 (90%), carfilzomib/lenalidomide-based regimen in 14 (7%), lenalidomide-based regimen in 3 patients (2%). 187/192 (97%) patients successfully collected ≥2 x 10^6/Kg CD34: of these, 153/192 (80%) collected with G-CSF/CY, 29/192 (15%) required the administration of plerixafor. The PM rate was 5/192 (2.5%): of these, 3/5 did not receive plerixafor in addition to G-CSF/CY, while 2/5 failed stem-cell collection despite the use of plerixafor. The median number of CD34 collected was 9.8x10^6/Kg (6.7-14.2). The median number of CD34/Kg collected with or without plerixafor was 5.1 (4.3-9.1) and 10.6 (8.1-14.4), respectively. The median number of apheresis days was 1 (IQR 1-2), with a stem-cell collection efficiency (CD34 number collected/ days of apheresis) equal to 7.7 x10^6 CD34/kg/day. The median number of apheresis days was 1 without plerixafor and 2 with plerixafor, with a stem-cell collection efficiency (CD34 number collected/ days of apheresis) equal to 8.8 without plerixafor and 3 with plerixafor. In patients who received plerixafor, the median number of CD34/ul pre-apheresis was 16 (10-19.5); after the administration of plerixafor, the median number of CD34/ul pre-apheresis increased to 46 (21-81). Non hematological AEs within 30 days after mobilization occurred in 8% of patients (grade 3-4: 2%); all grade and grade 3-4 infections occurred in 2% of patients each. In a multivariate analysis, main factors predicting the use of plerixafor were ISS 3 (vs. 1, OR 4.43; p=0.008), bone marrow plasma cells at diagnosis >60% (OR 3.85; p=0.006), white blood cell (WBC) count pre-mobilization (OR 6.66; p Conclusion. "On-demand" plerixafor combined with G-CSF/CY is a safe and effective rescue strategy for stem-cell collection in MM, reducing the PM rate to 2.5%. Extensive bone marrow plasmacytosis, ISS 3 disease at diagnosis, use of lenalidomide during induction and a low WBC count pre-mobilization predicted the use of plerixafor. Thus, pre-emptive administration of plerixafor in patients presenting one or more risk factors for poor mobilization might help in further reducing the PM rate. Disclosures Mina: Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Petrucci:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lemoli:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio ASA: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Offidani:BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Corradini:F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Incyte: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; KiowaKirin: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Sanofi: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Kite: Consultancy, Honoraria. Cavo:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Honoraria. Boccadoro:GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Larocca:Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of patients with multiple myeloma (including cyclophosphamide, G-CSF and plerixafor).
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- 2020
25. Safe Use of Carfilzomib in a Patient with Multiple Myeloma and Intermittent Type 1 Brugada ECG Pattern: A Case Report
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Eleonora Ghisoni, Laura Marandino, Pasquale Lombardi, Alessandro Bonzano, Paolo Becco, Massimo Aglietta, Marco Fizzotti, Francesca Gay, and Delia Rota Scalabrini
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medicine.medical_specialty ,medicine.medical_treatment ,Myeloma ,Brugada phenocopies ,Brugada syndrome ,Carfilzomib ,Sepsis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacotherapy ,Internal medicine ,medicine ,cardiovascular diseases ,Adverse effect ,Multiple myeloma ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Hematology ,General Medicine ,medicine.disease ,chemistry ,030220 oncology & carcinogenesis ,Cardiology ,business ,Electrocardiography ,030215 immunology - Abstract
Cardiovascular adverse events (CVAEs) are of considerable importance in patients with multiple myeloma (MM), given the significant prevalence of coexisting cardiovascular risk factors and the potential treatment-induced toxicity. Brugada syndrome is a rare cardiological disease responsible for arrhythmia and potentially fatal cardiac arrest. Brugada phenocopies (BrP) are clinical entities which show an identical ECG patterns, but prompt resolution after treatment of the trigger event. A 65-year-old female newly diagnosed MM patient treated with a carfilzomib-based chemotherapy developed a type 1 Brugada ECG pattern during a hospitalization course for sepsis. As fever and the septic event resolved, further ECGs showed no abnormalities and carfilzomib-based treatment could be resumed with no further CVAEs. Though fever-induced BrP is a universally known phenomenon, to our knowledge this is the first case of BrP in a patient with MM during active treatment with carfilzomib.
- Published
- 2019
26. Carfilzomib-based induction/consolidation with or without autologous transplant (ASCT) followed by lenalidomide (R) or carfilzomib-lenalidomide (KR) maintenance: Efficacy in high-risk patients
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Francesca Gay, Roberto Mina, Delia Rota-Scalabrini, Monica Galli, Angelo Belotti, Elena Zamagni, Luca Bertamini, Renato Zambello, Barbara Gamberi, Giovanni De Sabbata, Giuseppe Pietrantuono, Andrea Capra, Anna Pascarella, Anna Marina Liberati, Salvatore Palmieri, Angela Cuoghi, Massimo Offidani, Michele Cavo, Pellegrino Musto, and Mario Boccadoro
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Oncology ,Cancer Research ,medicine.medical_specialty ,High risk patients ,business.industry ,medicine.disease ,Carfilzomib ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,Autologous transplant ,business ,Multiple myeloma ,Lenalidomide ,medicine.drug - Abstract
8002 Background: Cytogenetic abnormalities (CA) are one of the most powerful prognostic factors in multiple myeloma (MM). In the FORTE study, carfilzomib-lenalidomide-dexamethasone induction/consolidation with ASCT (KRd_ASCT) significantly improved progression-free survival (PFS) vs KRd without ASCT (KRd12, HR 0.64) or carfilzomib-cyclophosphamide-dexamethasone (KCd) plus ASCT (KCd_ASCT, HR 0.53). KR maintenance significantly improved PFS vs R (HR 0.63). Methods: MM patients (pts) were randomized to KRd_ASCT vs KCd_ASCT vs KRd12 and, thereafter, to KR vs R maintenance. Subgroup analyses according to FISH evaluated the impact of each single high-risk (HiR) CA [del17p, t(4;14), t(14;16), del1p and 1q gain (3 copies) or amp1q (≥4 copies)] and that of combined CA, defining HiR by the presence of ≥1 HiR CA and double-hit (DH) by the presence of ≥2 HiR CA. Pts negative for all the HiR CA were considered at standard risk (SR). The primary objective was the impact of treatment on PFS according to pt risk. Results: 396 out of 474 enrolled pts were included in the analysis with complete FISH data: 243 HiR, 105 DH and 153 SR. Among HiR pts, 60 had del17p, 65 t(4;14), 20 t(14;16), 44 del1p, 126 1q gain and 49 amp1q. SR pts benefited from intensification with KRd_ASCT vs KRd12 (HR 0.47, p = 0.05) and KCd_ASCT (HR 0.38, p = 0.01), with a 4-year PFS of 80%, 67% and 57%, respectively. In HiR pts, KRd_ASCT improved PFS vs KRd12 (HR 0.6, p = 0.04) and KCd_ASCT (HR 0.57, p = 0.01), with a 4-year PFS of 62%, 45% and 45%, respectively. The advantage with KRd_ASCT vs KRd12 (HR 0.53, p = 0.07) and KCd_ASCT (HR 0.49; p = 0.03) was also observed in DH pts (4-year PFS 55%, 31% and 33%, respectively). Analyses by single CA were limited by the small number of pts in each subgroup, but a trend towards a PFS benefit from KRd_ASCT vs KRd12 was seen in pts with del17p (HR 0.61, p = 0.3), t(4;14) (HR 0.59, p = 0.2) and 1q gain (HR 0.45, p = 0.02). In pts with del1p, KRd_ASCT (HR 0.24, p = 0.06) and KRd12 (HR 0.33, p = 0.09) showed superiority over KCd_ASCT, while amp1q pts had the worst outcome regardless of treatment (KRd_ASCT vs KCd_ASCT, HR 1.16, p = 0.73; KRd12 vs KCd_ASCT, HR 1.34, p = 0.45). KR improved PFS vs R in SR (3-year PFS 90% vs 73%, HR 0.42, p = 0.06), HiR (3-year PFS 69% vs 56%, HR 0.6, p = 0.04) and DH pts (3-year PFS 67% vs 42%, HR 0.53, p = 0.1). Despite the small subgroups, a beneficial trend with KR vs R was observed in pts with del17p (HR 0.59, p = 0.37), t(4;14) (HR 0.59, p = 0.3), 1q gain (HR 0.54, p = 0.07) and del1p (HR 0.23, p = 0.08), while amp1q pts showed the worst outcome and no benefit from KR vs R (HR 0.83, p = 0.7). Conclusions: KRd_ASCT and KR maintenance are highly effective in SR and also in HiR and DH pts, with impressive 4-year PFS from diagnosis (KRd_ASCT: HiR 62%, DH 55%) and 3-year PFS from maintenance (KR: HiR 69%, DH 67%), thus supporting their use in HiR pts, who represent an unmet medical need. Clinical trial information: NCT02203643.
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- 2021
27. Post-Transplant Cyclophosphamide and Tacrolimus—Mycophenolate Mofetil Combination Governs GVHD and Immunosuppression Need, Reducing Late Toxicities in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors
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Dario Sangiolo, Ivana Ferrero, Daniela Gottardi, Andrea Saglietto, Luca Paruzzo, Franca Fagioli, E. Vassallo, Alessandro Cignetti, Valentina Gaidano, Loretta Gammaitoni, Daniela Caravelli, Lorenzo D'Ambrosio, Stefano Poletto, Delia Rota-Scalabrini, Alessandra Polo, Massimo Aglietta, Massimo Berger, Susanna Gallo, Rosanna Pessolano, Francesco Saglio, Paolo Becco, Pio Manlio Mirko Frascione, Fabrizio Carnevale-Schianca, Marco Fizzotti, Monica Mangioni, Giovanni Grignani, and Milena Salierno
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medicine.medical_specialty ,Cyclophosphamide ,post-transplant cyclophosphamide ,Lymphocyte ,medicine.medical_treatment ,lcsh:Medicine ,long term outcomes ,Gastroenterology ,Article ,allogeneic hematopoietic cell transplantation ,graft-versus-host disease ,immunosuppression modulation ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,business.industry ,lcsh:R ,Immunosuppression ,General Medicine ,medicine.disease ,Tacrolimus ,Discontinuation ,Transplantation ,surgical procedures, operative ,medicine.anatomical_structure ,Graft-versus-host disease ,030220 oncology & carcinogenesis ,Toxicity ,business ,030215 immunology ,medicine.drug - Abstract
Combined direct antineoplastic activity and the long-lasting immunological effects of allogeneic hematopoietic cell transplant (HCT) can cure many hematological malignancies, but broad adoption requires non-relapse mortality (NRM) rates and graft-versus-host disease (GVHD) control. Recently, posttransplant cyclophosphamide (PTCy) given after a bone marrow transplant significantly reduced GVHD-incidence, while PTCy given with tacrolimus/mofetil mycophenolate (T/MMF) showed activity following allogeneic peripheral blood stem cell transplantation (alloPBSCT). Here, we report the experience of a larger cohort (85 consecutive patients) and expanded follow-up period (03/2011–12/2019) with high-risk hematological malignancies who received alloPBSCT from Human-Leukocyte-Antigens HLA-matched unrelated/related donors. GVHD-prophylaxis was PTCy 50 mg/kg (days+3 and +4) combined with T/MMF (day+5 forward). All patients stopped MMF on day+28 with day+110 = median tacrolimus discontinuation. Cumulative incidences were 12% for acute and 7% for chronic GVHD- and no GVHD-attributed deaths. For surviving patients, the 12, 24, and 36-month probabilities of being off immunosuppression were 92, 96, and 96%, respectively. After a 36-month median follow-up, NRM was 4%, median event-free survival (EFS) and overall survival (OS) had yet to occur. One- and two-year chronic GVHD-EFS results were 57% (95% CI, 46–68%) and 53% (95% CI, 45–61%), respectively, with limited late infections and long-term organ toxicities. Disease relapse caused the most treatment failures (38% at 2 years), but low transplant toxicity allowed many patients (14/37, 38%) to receive donor lymphocyte infusions as a post-relapse strategy. We confirmed that PTCy+T/MMF treatment effectively prevented acute and chronic GVHD and limited NRM to unprecedented low rates without loss of disease control efficacy in an expanded patient cohort. This trial is registered at U.S. National Library of Medicine as #NCT02300571.
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- 2021
28. The extent of dissociation in borderline personality disorder: A meta-analytic review
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Andrea Scalabrini, Marco Cavicchioli, Cesare Maffei, Andrea Fossati, Scalabrini, Andrea, Cavicchioli, Marco, Fossati, Andrea, and Maffei, Cesare
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050103 clinical psychology ,medicine.medical_specialty ,medicine.drug_class ,Population ,Comorbidity ,Dissociative Disorders ,dissociation ,Dissociative ,Dissociation (psychology) ,psychiatric disorder ,03 medical and health sciences ,0302 clinical medicine ,Borderline Personality Disorder ,Settore M-PSI/08 - Psicologia Clinica ,mental disorders ,Settore M-PSI/07 - Psicologia Dinamica ,medicine ,Humans ,0501 psychology and cognitive sciences ,Dissociative disorders ,education ,Psychiatry ,Borderline personality disorder ,education.field_of_study ,dissociative spectrum ,psychiatric disorders ,05 social sciences ,medicine.disease ,Personality disorders ,030227 psychiatry ,Psychiatry and Mental health ,Clinical Psychology ,Psychiatry and Mental Health ,medicine.symptom ,Psychology ,Psychopathology ,Clinical psychology - Abstract
Several authors have studied dissociation within the borderline personality disorder (BPD) population and postulated 3 dissociative subgroups. Conversely, other authors suggest that dissociation may play a central role in the development of trauma-related disorders and specifically in BPD. Nevertheless, the role of dissociation in BPD seems to be controversial. Our aim is to perform a meta-analytic review of the literature to evaluate the extent of dissociation in BPD compared to other psychopathological disorders to clarify its role in this specific condition. Ten eligible studies resulted in a total of 2,035 subjects. Results show that levels of dissociation are higher in BPD than in other psychiatric disorders in general, although this difference is moderate and the heterogeneity of effect sizes is large. In particular, individuals with BPD seem to show higher levels of dissociation than those with several psychiatric and personality disorders but not dissociative disorders or posttraumatic stress disorder. These findings support the fact that dissociation is not specifically a core feature of BPD and, in addition, sustain the existence of a continuum of severity within the psychiatric population. Nevertheless, the current work has several limitations related to the paucity of studies included, the heterogeneity of control groups, their clear definition, and the statistical robustness of the results. In addition, our conclusions require future research in order to explain the role of different forms of dissociation and their etiological factors among the psychiatric population. Eventually, we invite clinicians and researchers to systematically evaluate dissociation in order to reach a better diagnosis for a more specific treatment indication.
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- 2017
29. Personality and Personality Disorders
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Andrea Scalabrini, Georg Northoff, and Clara Mucci
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Subjectivity ,Psychoanalysis ,media_common.quotation_subject ,External reality ,Psychodynamics ,medicine.disease ,Personality disorders ,Settore M-PSI/08 - Psicologia Clinica ,Settore M-PSI/07 - Psicologia Dinamica ,medicine ,Personality ,Construct (philosophy) ,Psychology ,media_common - Abstract
Personality is a complex construct that is closely related to the subjective experiences between internal world and external reality, a sense of subjectivity that is referred to the concept of self in psychiatry and psychodynamic literature.
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- 2018
30. Persistence of minimal residual disease in bone marrow predicts outcome in follicular lymphomas treated with a rituximab-intensive program
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Ladetto, M., Lobetti-Bodoni, C., Mantoan, B., Ceccarelli, M., Boccomini, C., Genuardi, E., Chiappella, A., Baldini, L., Rossi, G., Pulsoni, A., Di Raimondo, F., Rigacci, L., Pinto, A., Galimberti, S., Bari, A., Rota-Scalabrini, D., Ferrari, A., Zaja, F., Gallamini, A., Specchia, G., Musto, P., Rossi, F. G., Gamba, E., Evangelista, A., Vitolo, U., Fondazione Italiana Linfomi: Chiara Lobetti-Bodoni, Barbara, Mantoan, Elisa, Genuardi, Mario, Boccadoro, Marco, Ladetto, Giovannino, Ciccone, Andrea, Evangelista, Manuela, Ceccarelli, Carola, Boccomini, Annalisa, Chiappella, Barbara, Botto, Lorella, Orsucci, Umberto, Vitolo, Maria, Goldaniga, Francesca Gaia Rossi, Luca, Baldini, Chiara, Bottelli, Alessandra, Tucci, Giuseppe, Rossi, Alessandro, Pulsoni, Federico De Angelis, Eleonora, Russo, Maurizio, Martelli, Robin, Foà, Francesco Di Raimondo, Annalisa, Chiarenza, Luigi, Rigacci, Benedetta, Puccini, Alberto, Bosi, Antonello, Pinto, Mario, Petrini, Sara, Galimberti, Alessia, Bari, Stefano, Sacchi, Massimo, Federico, Delia, Rota-Scalabrini, Massimo, Aglietta, Angela, Ferrari, Isabel Alvarez De Celis, Francesco, Merli, Francesco, Zaja, Renato, Fanin, Claudia, Castellino, Andrea, Gallamini, Guido, Parvis, Giuseppe, Saglio, Tommasina, Perrone, Giorgina, Specchia, Pellegrino, Musto, Enrica, Gamba, Paolo, Corradini, Enrico Maria Pogliani, Anna Marina Liberati, Giuseppe, Leone, Caterina, Patti, Giuseppe, Fioritoni, Chiara, Rusconi, Enrica, Morra, Anna, Tonso, Giuseppina, Cabras, Emanuele, Angelucci, Andrea, Rossi, Alessandro, Rambaldi, Sergio, Cortelazzo, Sergio, Morandi, Lanza, Francesco, Giovanni, Pizzolo, Sergio, Amadori, Pier Luigi Zinzani, Caterina, Stelitano, Francesco, Nobile, Ladetto M, Lobetti-Bodoni C, Mantoan B, Ceccarelli M, Boccomini C, Genuardi E, Chiappella A, Baldini L, Rossi G, Pulsoni A, Di Raimondo F, Rigacci L, Pinto A, Galimberti S, Bari A, Rota-Scalabrini D, Ferrari A, Zaja F, Gallamini A, Specchia G, Musto P, Rossi FG, Gamba E, Evangelista A, Vitolo U, Fondazione Italiana Linfomi, [Zinzani PL], Ladetto, M, Lobetti Bodoni, C, Mantoan, B, Ceccarelli, M, Boccomini, C, Genuardi, E, Chiappella, A, Baldini, L, Rossi, G, Pulsoni, A, Di Raimondo, F, Rigacci, L, Pinto, A, Galimberti, S, Bari, A, Rota Scalabrini, D, Ferrari, A, Zaja, Francesco, Gallamini, A, Specchia, G, Musto, P, Rossi, Fg, Gamba, E, Evangelista, A, and Vitolo, U.
- Subjects
Aged ,Antibodies, Monoclonal, Murine-Derived ,Antineoplastic Combined Chemotherapy Protocols ,Combined Modality Therapy ,Consolidation Chemotherapy ,Disease-Free Survival ,Female ,Humans ,Lymphoma, Follicular ,Male ,Middle Aged ,Neoplasm, Residual ,Oncogene Proteins, Fusion ,Prognosis ,Rituximab ,Pathology ,Lymphoma ,Follicular lymphoma ,Gastroenterology ,Biochemistry ,hemic and lymphatic diseases ,Monoclonal ,minimal resdual disease ,bone marrow ,follicular lymphomas ,Oncogene Proteins ,Hematology ,Hazard ratio ,medicine.anatomical_structure ,Residual ,Immunology ,Cell Biology ,medicine.drug ,Murine-Derived ,medicine.medical_specialty ,Antibodies ,NO ,follicular lymphoma ,Chemoimmunotherapy ,Internal medicine ,medicine ,Fusion ,business.industry ,Follicular ,medicine.disease ,Minimal residual disease ,Neoplasm ,Bone marrow ,business - Abstract
We assessed the prognostic value of minimal residual disease (MRD) within the ML17638 phase 3 trial from the Fondazione Italiana Linfomi, investigating the role of rituximab maintenance in elderly follicular lymphoma (FL) patients after a brief first-line chemoimmunotherapy. MRD for the bcl-2/IgH translocation was determined on bone marrow cells in a centralized laboratory belonging to the Euro-MRD consortium, using qualitative and quantitative polymerase chain reactions (PCRs). Of 234 enrolled patients, 227 (97%) were screened at diagnosis. A molecular marker (MM) was found in 51%. Patients with an MM were monitored at 8 subsequent times. Of the 675 expected follow-up samples, 83% were analyzed. Conversion to PCR negativity predicted better progression-free survival (PFS) at all post-treatment times (eg, end of therapy: 3-year PFS, 72% vs 39%; P < .007). MRD was predictive in both maintenance (83% vs 60%; P < .007) and observation (71% vs 50%; P < .001) groups. PCR positivity at the end of induction was an independent adverse predictor (hazard ratio, 3.1; 95% confidence interval, 1.36-7.07). MRD is a powerful independent outcome predictor in FL patients who receive rituximab-intensive programs, suggesting a need to investigate its value for decision-making. This trial was registered at www.clinicaltrial.gov as #NCT01144364.
- Published
- 2013
31. Prevalence of neuropathic component of pain in a cohort of patients admitted to an Internal Medicine Department for chronic pain
- Author
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Francesca Franco, Fabio Gilioli, Giuseppe Chesi, Giovanni Scanelli, Claudio Giumelli, and Erio Scalabrini
- Subjects
education.field_of_study ,medicine.medical_specialty ,Referred pain ,Visual analogue scale ,business.industry ,Population ,lcsh:R ,Chronic pain ,lcsh:Medicine ,General Medicine ,medicine.disease ,Internal medicine ,Neuropathic pain ,Cohort ,Etiology ,medicine ,Physical therapy ,Cancer pain ,education ,business ,chronic pain, neuropathic pain, neuropathic pain diagnostic questionnaire - Abstract
Due to the increasing age of the population the number of people suffering from chronic pain has significantly increased. People with chronic pain suffer from various diseases. Often this pain is not adequately controlled and is refractory, while its neuropathic component, which requires a different treatment, is perhaps underestimated compared to more properly nociceptive pain. The purpose of this study was to evaluate the presence of a neuropathic component in a cohort of 105 patients consecutively admitted to three Internal Medicine Units in Emilia Romagna. For the identification of the component of neuropathic pain diagnostic (DN4) questionnaire, previously validated, has been used. The average age of the patients studied was 64.4 years. The group of subjects with chronic non-cancer pain (78%) was numerically higher than the group of patients suffering from cancer pain (22%). All patients had pain and, according to the visual analogue scale (VAS), pain ranged from moderate to severe (median 7). Although without reaching statistically significant data, according to the VAS scale, cancer pain had an average higher value than non-cancer pain (7 vs 6.5). The prevalence of neuropathic component of pain was higher in patients with non-cancer pain (66% vs 57%). Instead, the recorded pain intensity in patients with neuropathic component was statistically much higher than the group in which the neuropathic component was absent (6.9 vs 6.1; P
- Published
- 2015
32. Post-Transplant Cyclophosphamide and Tacrolimus–Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors
- Author
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Alessandra Polo, Marco Fizzotti, Luisa Gioeni, Massimo Berger, Francesca Nesi, E. Vassallo, Antonino Sottile, Dario Sangiolo, Loretta Gammaitoni, Giovanni Grignani, Daniela Caravelli, Lorenzo D'Ambrosio, Paolo Becco, Delia Rota Scalabrini, Valentina Coha, Massimo Aglietta, Susanna Gallo, Franca Fagioli, Monica Mangioni, Fabrizio Carnevale-Schianca, and Lidia Giraudo
- Subjects
Adult ,Male ,medicine.medical_specialty ,Allogeneic bone marrow transplantation ,Graft-versus-host disease ,Post-transplant cyclophosphamide ,Hematology ,Transplantation ,Cyclophosphamide ,medicine.medical_treatment ,Graft vs Host Disease ,Gastroenterology ,Tacrolimus ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,immune system diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Transplantation, Homologous ,Cumulative incidence ,Aged ,Peripheral Blood Stem Cell Transplantation ,business.industry ,Immunosuppression ,Middle Aged ,Mycophenolic Acid ,medicine.disease ,Survival Analysis ,Tissue Donors ,Regimen ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Hematologic Neoplasms ,Histocompatibility ,Immunology ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571.
- Published
- 2017
33. Resveratrol Reverses the Impaired Vasodilation Observed in 2K-1C Hypertension through Endothelial Function Improvement
- Author
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C. R. K. Antonietto, A. C. Scalabrini, B. F. M. Pereira, C. B. A. Restini, and T. S. Marinho
- Subjects
medicine.medical_specialty ,Vascular smooth muscle ,biology ,Endothelium ,Vasodilation ,biology.organism_classification ,medicine.disease ,Nitric oxide ,chemistry.chemical_compound ,Blood pressure ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Enos ,Internal medicine ,medicine ,medicine.symptom ,Endothelial dysfunction ,Vasoconstriction - Abstract
Background: The production of endothelial-derived factors induces either vasoconstriction or vasodilation; nitric oxide (NO) is the most distinguished relaxing factor. Endothelial dysfunction is associated with hypertension. The partial loss in the NO-promoted vasodilation is due to its decreased bioavailability and/or to an activity reduction of endothelium NO synthase (eNOS). Reactive oxygen species (ROS), present in oxidative stress, seize NO and diminish its bioavailability. Transresveratrol (RESV) has been proved to increase NO and eNOS levels. Thus, RESV could be capable of improving NO dependent vascular relaxation on aortic rings isolated from treated 2K-1C animals through ROS damage reduction. Aim: Evaluate the effects of RESV treatment on the relaxation of aortic rings isolated from treated 2K-1C rats while focusing on the effects of the treatment on systolic blood pressure. Methods: Male Wistar rats (180 g) were grouped: two 2K-1C and two Sham groups, one of each was treated with RESV (20 mg/kg, gavage) dissolved in Tween 80 and one of each was treated with water plus Tween 80 (control) for six weeks. The rats had their systolic blood pressure (SBP) measured before and after the treatments. Vascular reactivity studies were conducted in order to observe and compare acetylcholine (ACh)-induced relaxations in the presence and absence of the NOS inhibitor L-NAME (10-4 mol/L). Results: SBP for 2K-1C was significantly reduced in the treated group (179.13 ± 4.90 mmHg, n = 23) when compared to the untreated group (196.66 ± 6.06 mmHg, n = 15, p
- Published
- 2014
34. Intrathecal levels of IL-6, IL-11 and LIF in Alzheimer's disease and frontotemporal lobar degeneration
- Author
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Chiara Fenoglio, Eliana Venturelli, Nereo Bresolin, Diego Scalabrini, Ilaria Guidi, Luigi Bergamaschini, Chiara Villa, Pierluigi Baron, Daniela Galimberti, Francesca Cortini, Elio Scarpini, Carlo Vergani, Galimberti, D, Venturelli, E, Fenoglio, C, Guidi, I, Villa, C, Bergamaschini, L, Cortini, F, Scalabrini, D, Baron, P, Vergani, C, Bresolin, N, and Scarpini, E
- Subjects
Male ,medicine.medical_specialty ,Pathology ,Amyloid beta ,tau Proteins ,Leukemia Inhibitory Factor ,Central nervous system disease ,Cerebrospinal fluid ,Alzheimer Disease ,Predictive Value of Tests ,Internal medicine ,mental disorders ,medicine ,Humans ,Interleukin 6 ,Aged ,Amyloid beta-Peptides ,biology ,Interleukin-6 ,business.industry ,Interleukins ,Alzheimer's disease (AD), Cerebrospinal fluid (CSF), Cytokines, Frontotemporal lobar degeneration (FTLD), Interleukin-11 (IL-11) ,Neurodegeneration ,Interleukin ,Frontotemporal lobar degeneration ,Middle Aged ,Interleukin-11 ,medicine.disease ,Peptide Fragments ,Up-Regulation ,Endocrinology ,Neurology ,biology.protein ,Dementia ,Female ,Neurology (clinical) ,Alzheimer's disease ,business ,Biomarkers - Abstract
Cerebrospinal fluid (CSF) levels of interleukin (IL)-6, IL-11 and leukaemia inhibitory factor (LIF) were evaluated in 43 patients with Alzheimer's disease (AD) and 24 patients with frontotemporal lobar degeneration (FTLD) as compared with 30 agematched controls (CON), and correlated with clinical and demographic data and with CSF biomarkers amyloid beta (Aβ)42, total tau and tau phosphorylated at position 181 (P-tau). CSF IL-11 mean levels were significantly increased in AD and FTLD as compared with CON (6.5 ± 4.6 and 6.6 ± 5.1 versus 3.1 ± 3.3 pg/ml, P = 0.009). IL-6 mean levels did not differ between patients and CON (P > 0.05),whereas LIF levels were not detectable in patients or in CON. In AD patients, a significantly positive correlation between MMSE scores and IL-11 CSF concentration was observed (r = 0.344, P = 0.028). No correlations with CSF Aβ42, total tau and P-tau were found. IL-11, but not IL-6 levels are increased in AD and FTLD, and the highest peaks were observed in patients with a less severe degree of cognitive deterioration, therefore suggesting a role of this cytokine in early phases of neurodegeneration. © 2008 Steinkopff-Verlag.
- Published
- 2008
35. Bendamustine with or without rituximab for the treatment of heavily pretreated non-Hodgkin's lymphoma patients : A multicenter retrospective study on behalf of the Italian Lymphoma Foundation (FIL)
- Author
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Enrico Orciuolo, Emilio Iannitto, Pier Luigi Zinzani, Monica Balzarotti, Benedetta Puccini, Caterina Patti, Luigi Rigacci, Andrea Piccin, Gianluca Gaidano, Marco De Gobbi, Velia Bongarzoni, Delia Rota-Scalabrini, Sergio Storti, Roberto Freilone, Alberto Bosi, Francesco Zaja, Anna Marina Liberati, Sergio Cortelazzo, Alfonso Maria D'Arco, Andrea Carpaneto, Rigacci L, Puccini B, Cortelazzo S, Gaidano G, Piccin A, D'Arco A, Freilone R, Storti S, Orciuolo E, Zinzani P.L., Zaja F, Bongarzoni V, Balzarotti M, Rota-Scalabrini D, Patti C, Gobbi M, Carpaneto A, Liberati AM, Bosi A, Iannitto E., Rigacci, L, Puccini, B, Cortelazzo, S, Gaidano, G, Piccin, A, D'Arco, A, Freilone, R, Storti, S, Orciuolo, E, Zinzani, Pl, Zaja, Francesco, Bongarzoni, V, Balzarotti, M, Rota Scalabrini, D, Patti, C, Gobbi, M, Carpaneto, A, Liberati, Am, Bosi, A, and Iannitto, E.
- Subjects
Oncology ,Male ,medicine.medical_treatment ,Medical Oncology ,chemistry.chemical_compound ,Antibodies, Monoclonal, Murine-Derived ,Recurrence ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Antineoplastic agents ,Bendamustine Hydrochloride ,Multicenter Studies as Topic ,Treatment Failure ,Relapsed lymphoma ,Societies, Medical ,Aged, 80 and over ,Lymphoma, Non-Hodgkin ,Hematology ,General Medicine ,Middle Aged ,Nitrogen mustard ,Italy ,Chemotherapy, Adjuvant ,Nitrogen Mustard Compounds ,Bendamustine ,Rituximab ,Female ,medicine.drug ,Foundations ,Adult ,medicine.medical_specialty ,lymphoma ,Internal medicine ,medicine ,Humans ,RITUXIMAB ,Aged ,Retrospective Studies ,Chemotherapy ,business.industry ,medicine.disease ,Survival Analysis ,Surgery ,Lymphoma ,Non-Hodgkin's lymphoma ,Bendamustine Rituximab Relapsed lymphoma Antineoplastic agents ,Regimen ,Settore MED/15 - MALATTIE DEL SANGUE ,chemistry ,business ,Progressive disease - Abstract
Bendamustine is an alkylating agent with a nitrogen mustard group and a purine-like benzimidazole group. The aim of this study was to collect all the Italian experiences with this drug in order to evaluate the results in term of response to therapy and toxicities. We analyzed lymphoma patients treated in 24 Italian haematological centres with bendamustine alone or in combination with anti-CD20 antibody. One hundred seventy-five relapsed or refractory lymphoma patients were enrolled. The median age was 69 years (range 26-87). Seventy-nine patients were relapsed, 35 were refractory and 61 presented a progressive disease after partial response. The diagnoses were 60 indolent non-follicular lymphomas, 34 diffuse large B-cell lymphomas, 48 follicular lymphomas, 30 mantle cell lymphomas and three peripheral T-cell lymphomas. All patients were evaluable for response: 52 (29%) with complete remission, 72 (43%) with partial response with an overall response rate of 71%, and 51 non-responders. With a median observation period of 10 months (1-43), 70% of patients are alive. In summary, this retrospective study shows that treatment with bendamustine alone or in combination with rituximab is a safe and effective regimen in a subset of multi-resistant patients.
- Published
- 2012
36. ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned
- Author
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Viviani S., Rambaldi A., Brusamolino E., Levis A., Bonfante V., Vitolo U., Pulsoni A., Liberati A. M., Specchia G., Valagussa P., Rossi A., Zaja F., Pogliani E. M., Pregno P., Gotti M., Gallamini A., Rota Scalabrini D., Bonadonna G., Gianni A. M., Michelangelo Foundation, Gruppo Italiano di Terapie Innovative nei Linfomi, Intergruppo Italiano Linfomi, ZINZANI, PIER LUIGI, Viviani, S, Zinzani, P, Rambaldi, A, Brusamolino, E, Levis, A, Bonfante, V, Vitolo, U, Pulsoni, A, Liberati, A, Specchia, G, Valagussa, P, Rossi, A, Zaja, F, Pogliani, E, Pregno, P, Gotti, M, Gallamini, A, Rota Scalabrini, D, Bonadonna, G, Gianni, A, Viviani S., Zinzani P.L., Rambaldi A., Brusamolino E., Levis A., Bonfante V., Vitolo U., Pulsoni A., Liberati A.M., Specchia G., Valagussa P., Rossi A., Zaja F., Pogliani E.M., Pregno P., Gotti M., Gallamini A., Rota Scalabrini D., Bonadonna G., Gianni A.M., Michelangelo Foundation, Gruppo Italiano di Terapie Innovative nei Linfomi, Intergruppo Italiano Linfomi, Zinzani, Pl, Liberati, Am, Zaja, Francesco, Pogliani, Em, Gianni, Am, Michelangelo, Foundation, Gruppo Italiano di Terapie Innovative nei, Linfomi, and Intergruppo Italiano, Linfomi
- Subjects
BEACOPP ,Male ,drug megadose ,medicine.medical_treatment ,hematologic disease ,Salvage therapy ,Kaplan-Meier Estimate ,cancer risk ,chemotherapy ,law.invention ,sepsis ,Randomized controlled trial ,law ,cancer control ,MED/15 - MALATTIE DEL SANGUE ,Antineoplastic Combined Chemotherapy Protocols ,advanced cancer ,event free survival ,cell transplant ,disease ,fertility ,hybrid ,ifosfamide ,mopp ,regimen ,standard ,vinorelbine ,Etoposide ,Remission Induction ,article ,leukemia ,Hematopoietic Stem Cell Transplantation ,General Medicine ,Middle Aged ,acute granulocytic leukemia ,Hodgkin Disease ,Combined Modality Therapy ,Dacarbazine ,priority journal ,Vincristine ,Female ,radiation dose ,medicine.drug ,Human ,survival rate ,Adult ,medicine.medical_specialty ,Adolescent ,overall survival ,disease classification ,Vinblastine ,cancer growth ,Disease-Free Survival ,cardiopulmonary insufficiency ,Bleomycin ,Young Adult ,cancer combination chemotherapy ,medicine ,cancer radiotherapy ,follow up ,Humans ,controlled study ,Hodgkin's Lymphoma ,Cyclophosphamide ,Proportional Hazards Models ,Neoplasm Staging ,Salvage Therapy ,treatment duration ,Antineoplastic Combined Chemotherapy Protocol ,business.industry ,Proportional hazards model ,cancer staging ,adolescent ,adult ,clinical protocol ,Hodgkin disease ,human ,liver failure ,major clinical study ,salvage therapy ,treatment outcome ,ABVD ,medicine.disease ,Hodgkin's lymphoma ,Surgery ,Doxorubicin ,Procarbazine ,Proportional Hazards Model ,Prednisone ,business ,Progressive disease - Abstract
BACKGROUND: BEACOPP, an intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, has been advocated as the new standard of treatment for advanced Hodgkin's lymphoma, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS: We randomly assigned 331 patients with previously untreated and unfavorable Hodgkin's lymphoma (stage IIB, III, or IV, or an international prognostic score of ≥3 on a scale of 0 to 7, with higher scores indicating increased risk), to receive either BEACOPP or ABVD, each followed by local radiotherapy when indicated. Patients with residual or progressive disease after the initial therapy were to be treated according to a state-of-the-art high-dose salvage program. The median follow-up period was 61 months. RESULTS: The 7-year rate of freedom from first progression was 85% among patients who had received initial treatment with BEACOPP and 73% among those who had received initial treatment with ABVD (P=0.004), and the 7-year rate of event-free survival was 78% and 71%, respectively (P=0.15). A total of 65 patients (20 in the BEACOPP group, and 45 in the ABVD group) went on to receive the intended high-dose salvage regimen. As of the cutoff date, 3 of the 20 patients in the BEACOPP group and 15 of the 45 in the ABVD group who had had progressive disease or relapse after the initial therapy were alive and free of disease. After completion of the overall planned treatment, including salvage therapy, the 7-year rate of freedom from a second progression was 88% in the BEACOPP group and 82% in the ABVD group (P=0.12), and the 7-year rate of overall survival was 89% and 84%, respectively (P=0.39). Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group. CONCLUSIONS: Treatment with BEACOPP, as compared with ABVD, resulted in better initial tumor control, but the long-term clinical outcome did not differ significantly between the two regimens. (Funded by Fondazione Michelangelo; ClinicalTrials.gov number, NCT01251107.).
- Published
- 2011
37. Patients with cirrhosis in the ED: early predictors of infection and mortality
- Author
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Augusto Scalabrini Neto, Rafael Oliveira Ximenes, Roger D. Dias, Mauricio Menezes Aben Athar Ivo, Gabriel Taricani Kubota, Marcio A. Diniz, Caroline Colacique, Luiz Augusto Carneiro D'Albuquerque, and Alberto Queiroz Farias
- Subjects
Liver Cirrhosis ,Male ,medicine.medical_specialty ,Cirrhosis ,Acute Lung Injury ,Severity of Illness Index ,Hospitals, University ,03 medical and health sciences ,Liver disease ,0302 clinical medicine ,Liver Cirrhosis, Alcoholic ,Internal medicine ,Lymphopenia ,Severity of illness ,medicine ,Humans ,Decompensation ,Hospital Mortality ,Aged ,Retrospective Studies ,biology ,business.industry ,C-reactive protein ,030208 emergency & critical care medicine ,Retrospective cohort study ,General Medicine ,Emergency department ,Odds ratio ,Bacterial Infections ,Middle Aged ,medicine.disease ,MORTALIDADE ,Surgery ,C-Reactive Protein ,Emergency Medicine ,biology.protein ,030211 gastroenterology & hepatology ,Female ,business ,Emergency Service, Hospital ,Brazil - Abstract
Background Patients with cirrhosis have high risk of bacterial infections and cirrhosis decompensation, resulting in admission to emergency department (ED). However, there are no criteria developed in the ED to identify patients with cirrhosis with bacterial infection and with high mortality risk. Study objective The objective of the study is to identify variables from ED arrival associated with bacterial infections and inhospital mortality. Methods This is a retrospective single-center study using a tertiary hospital's database to identify consecutive ED patients with decompensated cirrhosis. Clinical variables and laboratory results were obtained by chart review. Logistic regression models were built to determine variables independently associated with bacterial infection and mortality. Scores using these variables were designed. Results One hundred forty-nine patients were enrolled, most of them males (77.9%) with alcoholic cirrhosis (53%) and advanced liver disease (Child-Pugh C, 47.2%). Bacterial infections were diagnosed in 72 patients (48.3%), and 36 (24.2%) died during hospital stay. Variables independently associated with bacterial infection were lymphocytes less than or equal to 900/mm 3 (odds ratio [OR], 3.85 [95% confidence interval {CI}, 1.47-10]; P = .006) and C-reactive protein greater than 59.4 mg/L (OR, 5.05 [95% CI, 1.93-13.2]; P = .001). Variables independently associated with mortality were creatinine greater than 1.5 mg/dL (OR, 4.35 [95% CI, 1.87-10.1]; P = .001) and international normalized ratio greater than 1.65 (OR, 3.71 [95% CI, 1.6-8.61]; P = .002). Scores designed to predict bacterial infection and mortality (Mortality in Cirrhosis Emergency Department Score) had an area under the receiver operating characteristic curve of 0.82 and 0.801, respectively. The Mortality in Cirrhosis Emergency Department Score performed better than Model for End-Stage Liver Disease score. Conclusions In this cohort of ED patients with decompensated cirrhosis, lymphopenia and elevated C-reactive protein were related to bacterial infections, and elevated creatinine and international normalized ratio were related to mortality. Scores built with these variables should be prospectively validated.
- Published
- 2016
38. Bendamustine with or without rituximab in the treatment of relapsed chronic lymphocytic leukaemia: an Italian retrospective study
- Author
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Maurizio Musso, Nicola Di Renzo, Fortunato Morabito, Antonino Mulè, Emilio Iannitto, Andrea Piccin, Giovanni Franco, Elsa Pennese, Massimo Gentile, Giuseppe Visani, Salvatrice Mancuso, Roberto Marasca, Luigi Rigacci, Rita Fazzi, Pellegrino Musto, Velia Bongarzoni, Alfonso Maria D'Arco, A Augello, Delia Rota-Scalabrini, and Antonella Montanini
- Subjects
Bendamustine ,medicine.medical_specialty ,Hematology ,business.industry ,Chronic lymphocytic leukemia ,Retrospective cohort study ,medicine.disease ,Gastroenterology ,Nitrogen mustard ,Surgery ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Toxicity ,Cohort ,Medicine ,Rituximab ,business ,medicine.drug - Abstract
To retrospectively assess the efficacy of bendamustine alone and with rituximab (R-B), 109 patients with relapsed chronic lymphocytic leukaemia (CLL) were enrolled in 24 Italian centres. The median age was 66 years (range 39-85). Forty-three percent of patients had relapsed and 57% were resistant (median previous therapies = 3; range 1-8). Twenty-two patients received bendamustine alone and 87 patients received R-B (median B dosage: 100 mg/m(2) per day, range 90-130 mg/m(2) per day). The overall response rate was 69·6% (complete response 28·6%; partial response 41%), and was significantly higher in patients treated with R-B (P = 0·014) and in those responsive to the previous treatment (P=0·04). After a median follow-up of 7·9 months (range 1-148), the median progression-free survival was 16 months and the median duration of response was 13 months. Median overall survival (OS) was 16·8 months for the whole cohort; patients not responding to the treatment had a significantly worse outcome than those who attained a response (P = 0·0001). In multivariate analysis, only resistant disease status at start of bendamustine treatment (HR 3·2, 95% CI 1·4-7·3, P = 0·006) had an independent prognostic value for OS. Toxicity was manageable and mostly haematological. In conclusion, in our experience R-B was an effective and well-tolerated treatment for relapsed/refractory CLL patients, producing a remarkable high CR rate and mild toxicity.
- Published
- 2011
39. Primary retroperitoneal mucinous cystadenoma - case report
- Author
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Marco Aurelio Santo-Filho, Ricardo Artigiani, David Carlos Shigueoka, Milton Scalabrini, Gaspar de Jesus Lopes-Filho, Ramiro Colleoni, and Universidade Federal de São Paulo (UNIFESP)
- Subjects
medicine.medical_specialty ,RD1-811 ,business.industry ,Medicine ,Surgery ,General Medicine ,Radiology ,RC799-869 ,Diseases of the digestive system. Gastroenterology ,business ,medicine.disease ,Letter to the Editor ,Mucinous cystadenoma - Abstract
Universidade Federal de São Paulo (UNIFESP), Escola Paulista de Medicina (EPM) UNIFESP, EPM SciELO
- Published
- 2014
40. Carfilzomib-Lenalidomide-Dexamethasone (KRd) Induction-Autologous Transplant (ASCT)-Krd Consolidation Vs KRd 12 Cycles Vs Carfilzomib-Cyclophosphamide-Dexamethasone (KCd) Induction-ASCT-KCd Consolidation: Analysis of the Randomized Forte Trial in Newly Diagnosed Multiple Myeloma (NDMM)
- Author
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Francesca Gay, Chiara Cerrato, Delia Rota Scalabrini, Monica Galli, Angelo Belotti, Elena Zamagni, Antonio Ledda, Mariella Grasso, Emanuele Angelucci, Anna Marina Liberati, Patrizia Tosi, Francesco Pisani, Stefano Spada, Ombretta Annibali, Anna Baraldi, Paola Omedé, Piero Galieni, Rita Rizzi, Norbert Pescosta, Sonia Ronconi, Donatella Vincelli, Anna Maria Cafro, Massimo Offidani, Antonio Palumbo, Pellegrino Musto, Michele Cavo, and Mario Boccadoro
- Subjects
medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Newly diagnosed ,medicine.disease ,Biochemistry ,Carfilzomib ,Transplantation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,Internal medicine ,Partial response ,medicine ,Cyclophosphamide/Dexamethasone ,Autologous transplant ,business ,Multiple myeloma ,030215 immunology ,Lenalidomide ,medicine.drug - Abstract
Background: Proteasome inhibitor (PI)-based induction and consolidation proved to be effective in newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for melphalan 200 mg/m2-autologous stem cell transplant (MEL200-ASCT). High response rates have been reported with the second-generation PI Carfilzomib in combination with Lenalidomide-dexamethasone (KRd) or Cyclophosphamide-dexamethasone (KCd). Aims: The primary aim was to evaluate the efficacy and safety of KRd induction-ASCT-KRd consolidation (KRd-ASCT-KRd) vs 12 cycles of KRd (KRd12) vs KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd). Methods: NDMM pts ≤65 years were randomized (1:1:1; stratification ISS and age) to: KRd-ASCT-KRd: 4 28-day cycles with KRd induction (Carfilzomib 20/36 mg/m2 IV days 1,2,8,9,15,16; Lenalidomide 25 mg days 1-21; dexamethasone 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KRd consolidation cycles; KRd12: 12 KRd cycles; KCd-ASCT-KCd: 4 28-day induction cycles with KCd (Carfilzomib 20/36 mg/m2 IV days 1,2,8,9,15,16; Cyclophosphamide 300 mg/m2 days 1,8,15; dexamethasone 20 mg days 1,2,8,9,15,16) followed by MEL200-ASCT and 4 KCd consolidation cycles. Thereafter, pts were randomized to maintenance with Lenalidomide alone or plus Carfilzomib. Centralized minimal residual disease (MRD) evaluation - 8-color second generation flow cytometry, sensitivity 10-5 - was performed in pts achieving ≥very good partial response (VGPR). Endpoints were pre-maintenance stringent complete response (sCR) and MRD negativity in intention-to-treat (ITT) analysis. Data cut-off was May 30, 2018. Results: 474 NDMM pts were randomized (KRd-ASCT-KRd, n=158; KRd12, n=157; KCd-ASCT-KCd, n=159) and analyzed. Pts characteristics were well balanced. Median follow-up was 20 months. Depth of response improved during treatment (Figure). By ITT analysis, rates of pre-maintenance sCR was similar between KRd-ASCT-KRd (41%) and KRd12 (42%), and significantly higher than with KCd-ASCT-KCd (30%; P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.047; P value KRd12 vs KCd-ASCT-KCd=0.028). Similarly, rate of ≥CR was 49% with KRd-ASCT-KRd, 52% with KRd12 and 38% with KCd-ASCT-KCd (P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.041; P value KRd12 vs KCd-ASCT-KCd=0.014) and rate of ≥CR+unconfirmed CR (missing immunofixation confirmation) raised to 60% vs 63% vs 46% in the 3 groups, respectively; rate of ≥VGPR was 88% with KRd-ASCT-KRd, 86% with KRd12 and 74% with KCd-ASCT-KCd (P value KRd-ASCT-KRd vs KCd-ASCT-KCd=0.002; P value KRd12 vs KCd-ASCT-KCd=0.008). In multivariate analysis, the main factor affecting probability of achieving ≥VGPR, ≥CR or sCR was treatment with KRd-ASCT-KRd or KRd12 vs KCd, with no significant impact of ISS Stage or FISH abnormalities. In ITT analysis (MRD missing [31/395 VGPR pts, 8%] and Conclusions: Rates of MRD negativity, sCR, ≥CR, ≥VGPR were significantly higher with KRd-ASCT-KRd and KRd12 vs KCd. At present, no differences in MRD and overall best response (sCR, ≥CR, ≥VGPR) were noticed between KRd-ASCT-KRd and KRd12; longer follow-up is needed to evaluate survival. Treatment was well tolerated. Updated data will be presented at the meeting. Figure. Figure. Disclosures Gay: Roche: Other: Advisory Board; Seattle Genetics: Other: Advisory Board; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Other: Advisory Board; Amgen: Honoraria; Takeda: Honoraria, Other: Advisory Board. Galli:Sigma-Tau: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Belotti:Celgene: Other: Advisory Board; Amgen: Other: Advisory Board. Zamagni:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Angelucci:Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol in MDS; Celgene: Honoraria, Other: Chair DMC proptocol BELIEVE 1 and BELIVE 2 in Thalassemia; Vertex Pharmaceuticals Incorporated (MA) and CRISPR Therapeutics AG (CH): Other: Chair DMC CRISPR CAS9 in Hemoglobinopathies; Jazz Pharmaceuticals Italy: Other: Local (national) advisory board on AML; Roche Italia: Other: Local (national) advisory board on biosimilars. Annibali:Celgene; Takeda; Amgen, Janssen Cilag: Honoraria. Offidani:Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board. Palumbo:Takeda: Employment. Musto:Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Cavo:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria.
- Published
- 2018
41. Abstract B09: Exploring IKKβ as an antiangiogenic therapeutic target in KRAS-induced lung cancer
- Author
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Daniela S. Basseres, Laura Beatriz da Silva Cardeal, Albert S. Baldwin, Luiza Coimbra Scalabrini, Ricardo J. Giordano, Tatiana Correa Carneiro-Lobo, and Edmilson Ozorio dos Santos
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Tube formation ,Cancer Research ,business.industry ,Cell growth ,Angiogenesis ,medicine.medical_treatment ,Cancer ,medicine.disease ,medicine.disease_cause ,Cytokine ,Oncology ,Cancer cell ,medicine ,Cancer research ,KRAS ,Lung cancer ,business - Abstract
Activating mutations in KRAS are prevalent in cancer, but therapies targeted to oncogenic RAS have so far failed. An alternative route for blocking RAS-driven oncogenic pathways is to target downstream effectors of RAS involved in promoting the oncogenic phenotype. One of the critical characteristics required for tumors to grow and progress is the ability of tumor cells to drive angiogenesis. Interestingly, oncogenic RAS promotes angiogenesis by upregulating the proangiogenic IL-8 cytokine, an NF-κB target gene, and we have shown that NF-κB activation by KRAS requires the IKKβ kinase. Interestingly, IKKβ targeting only minimally affects KRAS-mutant cell growth in vitro, nonetheless it significantly reduces KRAS-induced lung tumor growth in situ. Therefore, we hypothesized that IKKβ inhibition would reduce KRAS-induced lung tumor growth by impairing angiogenesis. To test this hypothesis, we targeted IKKβ in KRAS-mutant lung cancer cell lines A549 and H358, both by RNAi and by treatment with Compound A (CmpdA), a highly specific IKKβ inhibitor. Both approaches reduced expression and secretion of IL-8 and VEGF, another NF-κB-regulated proangiogenic growth factor. Moreover, conditioned media from IKKβ-targeted lung cells reduced endothelial cell migration and tube formation in vitro. Furthermore, siRNA-mediated IKKβ inhibition reduced xenograft tumor growth and angiogenesis in vivo. Finally, we determined that IKKβ inhibition can affect endothelial cell function independently of cancer cells as well, as CmpdA treatment directly reduced endothelial cell migration and reduced pathologic retinal angiogenesis in a mouse model of neonatal retinopathy. Taken together, these results suggest that IKKβ inhibition therapy may be an important general antiangiogenic therapy and may reduce KRAS-induced lung tumor angiogenesis, thereby providing a clinical therapeutic benefit for lung cancer patients harboring KRAS mutations. Citation Format: Tatiana C. Carneiro-Lobo, Edmilson Ozorio dos Santos, Luiza Coimbra Scalabrini, Laura B. Cardeal, Albert S. Baldwin, Ricardo José Giordano, Daniela S. Basseres. Exploring IKKβ as an antiangiogenic therapeutic target in KRAS-induced lung cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B09.
- Published
- 2018
42. Lack of replication ofKIF1Bgene in an Italian primary progressive multiple sclerosis cohort
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Vittorio Martinelli, F. Martinelli-Boneschi, Diego Scalabrini, Giancarlo Comi, Daniela Galimberti, Federica Esposito, Bruno Colombo, Chiara Fenoglio, M. De Riz, L. Collimedaglia, Paolo Brambilla, Elio Scarpini, Angelo Ghezzi, Maria Serpente, Gabriella Coniglio, Mariaemma Rodegher, Ruggero Capra, and Claudia Cantoni
- Subjects
Oncology ,medicine.medical_specialty ,Pathology ,business.industry ,Multiple sclerosis ,Single-nucleotide polymorphism ,Disease ,Odds ratio ,medicine.disease ,Confidence interval ,Neurology ,Internal medicine ,Epidemiology ,Cohort ,Medicine ,Neurology (clinical) ,Risk factor ,business - Abstract
Background: KIF1B gene represents the first non-inflammatory gene with a putative role on axonal loss and neurodegeneration found to be associated with multiple sclerosis (MS). The objective of this study is to test the association of the rs10492972 C allelic variant of KIF1B gene in a large Italian cohort of patients with primary progressive and progressive relapsing MS (PPMS and PRMS), which represents a subtype of MS mainly driven by neurodegenerative phenomena. Methods: rs10492972 has been genotyped in an outbred sample of 222 primary PPMS and PRMS and 221 healthy controls of unique northern Italian origin using the TaqMan assay. Results: A non-significant age- and sex-adjusted odds ratio of 0.96 [95% confidence interval (CI) 0.71–1.31] has been found in C carriers, and a non-significant risk of 0.99 [95% CI 0.77–1.63] in C carriers according to a dominant model. Stratification by sex, age at onset younger than 35 years and symptoms at the onset of the disease did not reveal any significant findings. No influence on disability progression, measured with the multiple sclerosis severity score, was found in C carriers. Conclusions: These results suggest that there is no effect in carrying the rs10492972 C variant on the risk of disease as well as on the rate of disability progression in a cohort of Italian patients with PPMS and patients with PRMS. These data need to be confirmed in an independent sample of patients with progressive MS.
- Published
- 2010
43. Novel exon 1 progranulin gene variant in Alzheimer’s disease
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Stefano F. Cappa, Simone Pomati, E. Dalla Valle, Chiara Villa, Francesca Cortini, Claudio Mariani, Francesca Clerici, Daniela Galimberti, Diego Scalabrini, Ilaria Guidi, Elio Scarpini, Alessandra Marcone, Chiara Fenoglio, Eliana Venturelli, and Nereo Bresolin
- Subjects
Silent mutation ,Genetics ,Mutation ,business.industry ,Frontotemporal lobar degeneration ,medicine.disease ,medicine.disease_cause ,Peripheral blood mononuclear cell ,Exon ,Neurology ,Polymorphism (computer science) ,RNA splicing ,Medicine ,Neurology (clinical) ,Allele ,business - Abstract
Background and purpose: Progranulin (PGRN) expression is increased in activated microglia in Alzheimer's disease (AD) brain, suggesting a potential role in this pathology. Methods: A mutation scanning of exons and flanking regions of PGRN was carried out in 120 patients with sporadic frontotemporal lobar degeneration and 145 with sporadic AD. Results: Amongst variants not yet deposited, a novel allelic variant was identified in Exon 1 (g100169G > A). It leads to an amino acidic change (p.Gly35Arg) and was observed in a patient with late onset AD. In silico analysis predicted that this mutation is possibly damaging. A second variant (g.100165C > T), resulting in a silent mutation (pAsp33Asp), was found in a patient with semantic dementia and in another with early onset AD. Both variants were absent in 226 controls. In addition, two rare non-pathogenic variants lying very close to PGRN splice-site regions (IVS2 + 7G > A and IVS7 + 7G > A) were observed. Transcriptional analysis in peripheral blood mononuclear cells from patients demonstrated they do not affect exon splicing. Conclusions: A novel putative PGRN mutation leading to an amino acidic substitution was identified in a patient with clinical AD.
- Published
- 2008
44. Gastric Bypass and Cardiac Autonomic Activity: Influence of Gender and Age
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Marcos Borges Machado, Augusto Scalabrini-Neto, and Irineu Tadeu Velasco
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Adult ,Male ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Gastric Bypass ,Autonomic Nervous System ,Body Mass Index ,Cohort Studies ,Young Adult ,Sex Factors ,Heart Rate ,Weight loss ,Weight Loss ,Heart rate ,medicine ,Humans ,Heart rate variability ,Young adult ,Sinoatrial Node ,Nutrition and Dietetics ,business.industry ,Age Factors ,Middle Aged ,medicine.disease ,Obesity ,Obesity, Morbid ,Autonomic nervous system ,Anesthesia ,Female ,Surgery ,Waist Circumference ,medicine.symptom ,business ,Body mass index ,circulatory and respiratory physiology ,Cohort study - Abstract
Background Obesity is associated with increased sympathetic activity and higher mortality. Treatment of this condition is often frustrating. Roux-en-Y gastric bypass is the most effective technique nowadays for treatment of obesity. The aim of the present study is to assess the effects of this surgery on the cardiac autonomic activity, including the influence of gender and age, through heart rate variability (HRV) analysis. Methods The study group consisted of 71 obese patients undergoing gastric bypass. Time domain measures of HRV, obtained from 24-h Holter recordings, were evaluated before and 6 months after surgery, and the results were compared. Percentage of interval differences of successive normal sinus beats greater than 50 ms (pNN50) and square root of the mean squared differences of successive normal sinus beat intervals (rMSSD) was used to estimate the short-term components of HRV, related to the parasympathetic activity. Standard deviation of intervals between all normal sinus beats (SDNN) was related to overall HRV. Results SDNN, pNN50, and rMSSD showed significant increase 6 months after surgery (p
- Published
- 2008
45. Incorrect Application Technique of Metered Dose Inhalers by Internal Medicine Residents: Impact of Exposure to a Practical Situation
- Author
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Marcos Ribeiro, Júlio César de Oliveira, Rafael Stelmach, Alberto Cukier, Augusto Scalabrini, and Priscila Games Robles-Ribeiro
- Subjects
Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Cross-sectional study ,MEDLINE ,Observation ,Internal Medicine ,medicine ,Humans ,Immunology and Allergy ,Anti-Asthmatic Agents ,Metered Dose Inhalers ,Intensive care medicine ,Asthma ,business.industry ,Internship and Residency ,medicine.disease ,Metered-dose inhaler ,Inhalation technique ,Cross-Sectional Studies ,Pediatrics, Perinatology and Child Health ,Clinical Competence ,Clinical competence ,Persistent asthma ,business ,Brazil - Abstract
We evaluated residents regarding maintenance treatment of asthma and the technique for using metered dose inhalers. Methods. Residents were asked to prescribe a treatment for a patient with poorly controlled persistent asthma and to demonstrate the use of metered dose inhaler (MDI) medication. Results. 76% of 239 residents correctly identified the medication indicated for the case; only 30% of them adequately performed the inhalation technique (49% from HCFMUSP vs. 19% from other institutions; p < 0.001). Conclusions. The results demonstrate that, when seeing a typical patient with uncontrolled persistent asthma, most residents are able to correctly identify the drugs indicated for treatment but not adequately instruct the MDI technique use.
- Published
- 2007
46. SELPLG and SELP single-nucleotide polymorphisms in multiple sclerosis
- Author
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Tai Wai Yeo, Elio Scarpini, An Goris, Laura Piccio, Stephen Sawcer, Eliana Venturelli, Diego Scalabrini, Maria Ban, Alastair Compston, Daniela Galimberti, Chiara Fenoglio, Milena De Riz, Mel Maranian, Julia Gray, and Nereo Bresolin
- Subjects
Adult ,Male ,Multiple Sclerosis ,Genotype ,P-selectin ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Gene Frequency ,Genetic variation ,medicine ,Humans ,SNP ,Allele frequency ,Aged ,Genetics ,Membrane Glycoproteins ,General Neuroscience ,Multiple sclerosis ,Case-control study ,Middle Aged ,Blotting, Northern ,medicine.disease ,P-Selectin ,Case-Control Studies ,Immunology ,Female - Abstract
P-Selectin (SELP) and P-selectin glycoprotein ligand-1 (SELPLG) constitute a receptor/ligand complex involved in the recruitment of activated lymphocytes, a critical event in the pathogenesis of multiple sclerosis (MS). In order to determine whether genetic variation in these pivotal molecules influences susceptibility to MS, we genotyped 214 Italian patients compared with 220 Italian controls for three single-nucleotide polymorphisms (SNPs): SELPLG Met62Ile, SELP C-2123G and SELP Thr715Pro. No significant differences in both SELP SNPs were found between patients and controls, whereas a decreased frequency of the Met62Ile SNP was found in patients versus controls in the Italian population (P = 0.025). To confirm these preliminary findings, the Met62Ile SNP was analysed in 938 UK trio families. This SNP did not show evidence for association with susceptibility to MS in the larger UK cohort. Therefore, none of the SNPs investigated is associated with MS, although this analysis does not conclusively exclude SELPLG and SELP as genetic risk factors for MS as much variation remains untested.
- Published
- 2006
47. P-selectin glycoprotein ligand-1 variable number of tandem repeats (VNTR) polymorphism in patients with multiple sclerosis
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Diego Scalabrini, Chiara Fenoglio, Cristoforo Comi, Marco Ronzoni, Carlo Lovati, Milena De Riz, Eliana Venturelli, Francesco Monaco, Laura Piccio, Nereo Bresolin, Luca Castelli, Elio Scarpini, Claudio Mariani, and Daniela Galimberti
- Subjects
Adult ,Central Nervous System ,Male ,Heterozygote ,Multiple Sclerosis ,Genotype ,P-selectin ,Lymphocyte ,DNA Mutational Analysis ,Minisatellite Repeats ,Biology ,Lymphocyte Activation ,Pathogenesis ,Gene Frequency ,Cell Adhesion ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Age of Onset ,Allele ,Gene ,Membrane Glycoproteins ,Polymorphism, Genetic ,General Neuroscience ,Multiple sclerosis ,medicine.disease ,Variable number tandem repeat ,medicine.anatomical_structure ,Immunology ,Female ,P-selectin glycoprotein ligand-1 - Abstract
P-selectin glycoprotein ligand-1 (PSGL-1) is an important adhesion molecule involved in lymphocyte recruitment into the brain, which represents a crucial step in the pathogenesis of multiple sclerosis (MS). Three hundred twenty-one MS patients and 342 controls were genotyped for the presence of a polymorphism in the PSGL-1 gene, consisting of a variable number of tandem repeats (VNTR) originating three possible alleles: A , B and C , in order to test whether they influence the susceptibility and the course of the disease. No significant differences among allelic frequencies of A , B and C alleles in MS as compared with controls were observed. Stratifying patients according to the course of the disease, a significantly increased frequency of the shortest C allele in PP-MS was found (7.1%), either in comparison with controls ( P = 0.011) or with all other MS patients, who had acute inflammatory attacks at onset and an initial RR form ( P = 0.036). Besides, none of SP-MS patients was a carrier of the C allele and B carriers converted later from RR to SP course as compared with A/A subjects (after 15.8 rather than 8.8 years, P = 0.01). In conclusion, the C allele of the VNTR polymorphism in PSGL-1 is likely to be associated with PP-MS. As this allele has been demonstrated to have a very low efficiency in mediating lymphocyte binding to brain endothelium during attacks, its high frequency in PP-MS could be related to the absence of exacerbations in such patients.
- Published
- 2005
48. A Large-Scale Study of Bone Marrow Involvement in Patients with Hodgkin's Lymphoma
- Author
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Eugenio Gallo, Paolo Gavarotti, Umberto Vitolo, Delia Rota Scalabrini, G. Ciravegna, Mario Boccadoro, Laura Godio, Tommasina Guglielmelli, Andrea Gallamini, Giuseppe Saglio, Flavia Salvi, Massimo Aglietta, Ermanno Raviolo, Anna Tonso, Alessandro Levis, Enzo Scassa, Lorella Orsucci, Daniela Pietrasanta, and Francesco Di Vito
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,Databases, Factual ,Blood Sedimentation ,Gastroenterology ,Disease registry ,Bone Marrow ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biopsy ,medicine ,Humans ,Extranodal Involvement ,Aged ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Lymphoma, Non-Hodgkin ,Middle Aged ,medicine.disease ,Hodgkin's lymphoma ,Surgery ,Lymphoma ,medicine.anatomical_structure ,B symptoms ,Female ,Lymph Nodes ,Bone marrow ,medicine.symptom ,business - Abstract
This study was designed to identify variables that can predict bone marrow involvement (BMI) in Hodgkin's lymphoma (HL), and to analyze the benefit of bilateral over unilateral bone marrow trephine biopsy (BMB). From 1982 to 2000, BMB had been performed at diagnosis in 1161 patients with HL who had been followed from the institutions participating in the Piemonte Hodgkin's Disease Registry. Six hundred and sixteen patients (53%) had received bilateral BMB, and the remaining 545 patients (47%) received unilateral BMB. The relationships between BMB results and other clinical features were retrospectively studied with both univariate and multivariate analyses. Ninety-two patients (8%) showed BMI: 51 of them were staged with bilateral and 41 with unilateral BMB. Among the 92 patients with BMI, a second extranodal involvement was present in only 25 patients (27%). In multivariate analysis, the 5 independent factors that predicted for BMI were B symptoms, infradiaphragmatic involvement, mixed cellularity (MC) and lymphocyte depleted (LD) histology, involvement ofor = 4 lymphatic areas, and liver involvement. The probability of BMI according to the presence of these variables was distributed as follows: 0.3%, 2.5%, 7.6%, and 27% in patients positive for 0, 1, 2, andor = 3 factors, respectively. Among 51 patients staged with bilateral BMB, BMI was shown in both specimens in 33 cases (65%), whereas the positivity was limited to only 1 of the 2 specimens in the remaining 18 cases (35%). A score based on 5 variables can predict the probability of BMI, and BMB could be avoided in patients with a score of 0 and a probability of BMI of0.5%. When BMB is needed, the superiority of bilateral over unilateral biopsy is suggested.
- Published
- 2004
49. GSK3β genetic variability in patients with Multiple Sclerosis
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David E. Comings, Nereo Bresolin, Francesca Cortini, Milena De Riz, Elisa Ridolfi, Diego Scalabrini, Ma Hin Fardipoor, Francesco Monaco, Chiara Villa, James P. MacMurray, Maurizio Leone, Maria Serpente, Claudia Cantoni, Elio Scarpini, Daniela Galimberti, Chiara Fenoglio, Cristoforo Comi, Galimberti, D, Macmurray, J, Scalabrini, D, Fenoglio, C, De Riz, M, Comi, C, Comings, D, Cortini, F, Villa, C, Serpente, M, Cantoni, C, Ridolfi, E, Fardipoor, M, Leone, M, Monaco, F, Bresolin, N, and Scarpini, E
- Subjects
Male ,medicine.medical_specialty ,Multiple Sclerosis ,Genotype ,Neuroprotection ,Polymorphism, Single Nucleotide ,Glycogen Synthase Kinase 3 ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic variability ,Remyelination ,Glycogen synthase ,Glycogen Synthase Kinase 3 beta ,biology ,Kinase ,General Neuroscience ,Multiple sclerosis ,Promoter ,Middle Aged ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,biology.protein ,Female - Abstract
Glycogen synthase kinase-3 beta (GSK3β) is a ubiquitous kinase that is part of multiple signaling pathways. It has neurotrophic/neuroprotective effects by mediating the actions of neurotrophic molecules in the brain, thus providing neuroprotection through modulation of energy metabolism. Notably, it has been demonstrated that GSK3β is involved in Wnt-beta-catenin signaling, which contributes to the inhibition of myelination and remyelination processes in mammals. Three-hundred nineteen patients with MS and 294 age-matched controls were genotyped by allelic discrimination for four common GSK3β variants (rs2199503, rs9826659, rs334558 and rs6438552) tagging about 100% of GSK-3β variability. A statistically significant increased frequency of the rs334558 GG genotype was observed in patients as compared with controls (25.4% versus 17.7%, P= 0.02; OR:1.58, 95%CI: 1.07-2.34). Stratifying MS patients according to the disease subtype, a statistically significant difference of rs334558 GG frequency was found between Relapsing Remitting (RR), but not Primary Progressive or Secondary MS, and controls (27.0% versus 17.7%, P= 0.01; OR: 1.72, 95%CI: 1.13-2.61). GSK3β rs334558 is a susceptibility factor for MS. As it is located in the promoter region, a possible explanatory mechanism could be an influence of the variant on the gene transcription rate. © 2011 Elsevier Ireland Ltd.
- Published
- 2011
50. Phase II Trial of the Use of Gemcitabine and 5-Fluorouracil in the Treatment of Advanced Pancreatic and Biliary Tract Cancer
- Author
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Victor H. Rodrigues, Flavio C. Moore, Rodrigo C. Guimaraes, Charles A. J. Padua, Andre M. Murad, Bruno C. Aragao, and Antonio O. Scalabrini-Neto
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Pancreatic disease ,medicine.drug_class ,medicine.medical_treatment ,education ,Adenocarcinoma ,Deoxycytidine ,Antimetabolite ,Gastroenterology ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Prospective Studies ,Aged ,Chemotherapy ,business.industry ,Middle Aged ,medicine.disease ,Survival Analysis ,Gemcitabine ,Surgery ,Pancreatic Neoplasms ,Biliary Tract Neoplasms ,medicine.anatomical_structure ,Oncology ,Fluorouracil ,Biliary tract ,Female ,business ,Pancreas ,medicine.drug - Abstract
In this phase II trial, we used the combination of gemcitabine and 5-fluorouracil (5-FU) to treat 26 patients: 17 (65%) with advanced pancreatic adenocarcinoma and 9 (35%) with advanced biliary tract adenocarcinoma (10 locally advanced and 16 metastatic); 15 (57.7%) male and 11 (42.3%) female; median age 58 (range, 39-68); median performance status 2 (range, 1-3). A total of 102 cycles were administered (median, 4 per patient). There were 8 objective responses, plus 1 complete response not confirmed by second-look laparotomy, thus the overall objective response rate was 30.7% (95% CI 12%-47%). Among the patients with biliary tract carcinoma, 33% (3/9) had PR. Six (23%) patients had stable disease (SD). All 8 responders and 3 of the patients with SD experienced clinical benefit (42%). The median overall survival was 9 months (range, 6-38), and the 1-year survival rate was 30%. The regimen was very well tolerated. One patient developed reversible World Health Organization grade IV febrile neutropenia. We observed grade III neutropenia in 11 (11%) cycles; grade III thrombocytopenia in 7 (7%) cycles; grade III mucositis in 7 (7%) cycles; and grade III diarrhea in 10 (10%) cycles. Asthenia grades I and II occurred in 30% of cycles and flulike syndrome grade II in 11 (11%) cycles. The combination of gemcitabine and 5-FU in patients with advanced pancreatic or biliary tract cancer produces promising activity and tolerability with the added potential for clinical benefit, and thus warrants further investigation.
- Published
- 2003
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