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4. Fasting glucose and body mass index as predictors of activity in breast cancer patients treated with everolimus-exemestane: The EverExt study

Author

Pizzuti, Laura, primary, Marchetti, Paolo, additional, Natoli, Clara, additional, Gamucci, Teresa, additional, Santini, Daniele, additional, Scinto, Angelo Fedele, additional, Iezzi, Laura, additional, Mentuccia, Lucia, additional, D’Onofrio, Loretta, additional, Botticelli, Andrea, additional, Moscetti, Luca, additional, Sperati, Francesca, additional, Botti, Claudio, additional, Ferranti, Francesca, additional, Buglioni, Simonetta, additional, Sanguineti, Giuseppe, additional, Di Filippo, Simona, additional, di Lauro, Luigi, additional, Sergi, Domenico, additional, Catenaro, Teresa, additional, Tomao, Silverio, additional, Giordano, Antonio, additional, Maugeri-Saccà, Marcello, additional, Barba, Maddalena, additional, and Vici, Patrizia, additional

Published
2017
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5. Erratum to: Elaboration of a nomogram to predict nonsentinel node status in breast cancer patients with positive sentinel node, intraoperatively assessed with one step nucleic amplification: Retrospective and validation phase

Author

Di Filippo, Franco, primary, Di Filippo, Simona, additional, Ferrari, Anna Maria, additional, Antonetti, Raffaele, additional, Battaglia, Alessandro, additional, Becherini, Francesca, additional, Bernet, Laia, additional, Boldorini, Renzo, additional, Bouteille, Catherine, additional, Buglioni, Simonetta, additional, Burelli, Paolo, additional, Cano, Rafael, additional, Canzonieri, Vincenzo, additional, Chiodera, Pierluigi, additional, Cirilli, Alfredo, additional, Coppola, Luigi, additional, Drago, Stefano, additional, Di Tommaso, Luca, additional, Fenaroli, Privato, additional, Franchini, Roberto, additional, Gianatti, Andrea, additional, Giannarelli, Diana, additional, Giardina, Carmela, additional, Godey, Florence, additional, Grassi, Massimo M., additional, Grassi, Giuseppe B., additional, Laws, Siobhan, additional, Massarut, Samuele, additional, Naccarato, Giuseppe, additional, Natalicchio, Maria Iole, additional, Orefice, Sergio, additional, Palmieri, Fabrizio, additional, Perin, Tiziana, additional, Roncella, Manuela, additional, Roncalli, Massimo G., additional, Rulli, Antonio, additional, Sidoni, Angelo, additional, Tinterri, Corrado, additional, Truglia, Maria C., additional, and Sperduti, Isabella, additional

Published
2017
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6. A cut-off of 2150 cytokeratin 19 mRNA copy number in sentinel lymph node may be a powerful predictor of non-sentinel lymph node status in breast cancer patients

Author

Terrenato, Irene, primary, D’Alicandro, Valerio, additional, Casini, Beatrice, additional, Perracchio, Letizia, additional, Rollo, Francesca, additional, De Salvo, Laura, additional, Di Filippo, Simona, additional, Di Filippo, Franco, additional, Pescarmona, Edoardo, additional, Maugeri-Saccà, Marcello, additional, Mottolese, Marcella, additional, and Buglioni, Simonetta, additional

Published
2017
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7. Elaboration of a nomogram to predict nonsentinel node status in breast cancer patients with positive sentinel node, intraoperatively assessed with one step nucleic amplification: Retrospective and validation phase

Author

Di Filippo, Franco, primary, Di Filippo, Simona, additional, Ferrari, Anna Maria, additional, Antonetti, Raffaele, additional, Battaglia, Alessandro, additional, Becherini, Francesca, additional, Bernet, Laia, additional, Boldorini, Renzo, additional, Bouteille, Catherine, additional, Buglioni, Simonetta, additional, Burelli, Paolo, additional, Cano, Rafael, additional, Canzonieri, Vincenzo, additional, Chiodera, Pierluigi, additional, Cirilli, Alfredo, additional, Coppola, Luigi, additional, Drago, Stefano, additional, Di Tommaso, Luca, additional, Fenaroli, Privato, additional, Franchini, Roberto, additional, Gianatti, Andrea, additional, Giannarelli, Diana, additional, Giardina, Carmela, additional, Godey, Florence, additional, Grassi, Massimo M., additional, Grassi, Giuseppe B., additional, Laws, Siobhan, additional, Massarut, Samuele, additional, Naccarato, Giuseppe, additional, Natalicchio, Maria Iole, additional, Orefice, Sergio, additional, Palmieri, Fabrizio, additional, Perin, Tiziana, additional, Roncella, Manuela, additional, Roncalli, Massimo G., additional, Rulli, Antonio, additional, Sidoni, Angelo, additional, Tinterri, Corrado, additional, Truglia, Maria C., additional, and Sperduti, Isabella, additional

Published
2016
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8. Neoadjuvant Sequential Docetaxel Followed by High‐Dose Epirubicin in Combination With Cyclophosphamide Administered Concurrently With Trastuzumab. The DECT Trial

Author

Pizzuti, Laura, primary, Barba, Maddalena, additional, Giannarelli, Diana, additional, Sergi, Domenico, additional, Botti, Claudio, additional, Marchetti, Paolo, additional, Anzà, Michele, additional, Maugeri‐Saccà, Marcello, additional, Natoli, Clara, additional, Di Filippo, Simona, additional, Catenaro, Teresa, additional, Tomao, Federica, additional, Amodio, Antonella, additional, Carpano, Silvia, additional, Perracchio, Letizia, additional, Mottolese, Marcella, additional, Di Lauro, Luigi, additional, Sanguineti, Giuseppe, additional, Di Benedetto, Anna, additional, Giordano, Antonio, additional, and Vici, Patrizia, additional

Published
2016
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9. Apoptotic Epitope–Specific CD8+T Cells and Interferon Signaling Intersect in Chronic Hepatitis C Virus Infection

Author

Martini, Helene, primary, Citro, Alessandra, additional, Martire, Carmela, additional, D'Ettorre, Gabriella, additional, Labbadia, Giancarlo, additional, Accapezzato, Daniele, additional, Piconese, Silvia, additional, De Marzio, Paolo, additional, Cavallari, Eugenio N., additional, Calvo, Ludovica, additional, Rizzo, Fabiana, additional, Severa, Martina, additional, Coccia, Eliana M., additional, Grazi, Gian Luca, additional, Di Filippo, Simona, additional, Sidney, John, additional, Vullo, Vincenzo, additional, Sette, Alessandro, additional, and Barnaba, Vincenzo, additional

Published
2015
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12. Non-Pegylated Liposomal Doxorubicin-Cyclophosphamide in Sequential Regimens with Taxanes as Neoadjuvant Chemotherapy in Breast Cancer Patients

Author

Vici, Patrizia, primary, Pizzuti, Laura, additional, Gamucci, Teresa, additional, Sergi, Domenico, additional, Conti, Francesca, additional, Zampa, Germano, additional, Del Medico, Pietro, additional, De Vita, Roy, additional, Pozzi, Marcello, additional, Botti, Claudio, additional, Di Filippo, Simona, additional, Tomao, Federica, additional, Sperduti, Isabella, additional, and Di Lauro, Luigi, additional

Published
2014
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13. Quantitative Molecular Analysis of Sentinel Lymph Node May Be Predictive of Axillary Node Status in Breast Cancer Classified by Molecular Subtypes

Author

Buglioni, Simonetta, primary, Di Filippo, Franco, additional, Terrenato, Irene, additional, Casini, Beatrice, additional, Gallo, Enzo, additional, Marandino, Ferdinando, additional, Maini, Carlo L., additional, Pasqualoni, Rossella, additional, Botti, Claudio, additional, Di Filippo, Simona, additional, Pescarmona, Edoardo, additional, and Mottolese, Marcella, additional

Published
2013
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14. Evaluation of a multiparametric system able to predict nonsentinel lymph node status in breast cancer patients with a micrometastatic sentinel node assessed by the one step nucleic acidamplification (OSNA) assay.

Author

Buglioni, Simonetta, primary, Mottolese, Marcella, additional, Casini, Beatrice, additional, Gallo, Enzo, additional, Terrenato, Irene, additional, Pescarmona, Edoardo, additional, Di Filippo, Simona, additional, Marandino, Ferdinando, additional, Ferretti, Gianluigi, additional, and Di Filippo, Franco, additional

Published
2012
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16. Apoptotic Epitope-Specific CD8+ T Cells and Interferon Signaling Intersect in Chronic Hepatitis C Virus Infection.

Author

Martini, Helene, Citro, Alessandra, Martire, Carmela, D'Ettorre, Gabriella, Labbadia, Giancarlo, Accapezzato, Daniele, Piconese, Silvia, Marzio, Paolo De, Cavallari, Eugenio N., Calvo, Ludovica, Rizzo, Fabiana, Severa, Martina, Coccia, Eliana M., Grazi, Gian Luca, Di Filippo, Simona, Sidney, John, Vullo, Vincenzo, Sette, Alessandro, Barnaba, Vincenzo, and De Marzio, Paolo

Subjects
EPITOPES, INTERFERONS, HEPATITIS C virus, T helper cells, TUMOR necrosis factors, APOPTOSIS, CELLULAR signal transduction, INTERLEUKIN-2, CIRRHOSIS of the liver, T cells, CHRONIC hepatitis C
Abstract

CD8(+) T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a principal player in chronic immune activation. Here, we found that both apoptotic epitope-specific and hepatitis C virus (HCV)-specific CD8(+) T cells were mostly confined within the effector memory (EM) or terminally differentiated EM CD45RA(+) cell subsets expressing a dysfunctional T-helper 1-like signature program in chronic HCV infection. However, apoptotic epitope-specific CD8(+) T cells produced tumor necrosis factor α and interleukin 2 at the intrahepatic level significantly more than HCV-specific CD8(+) T cells, despite both populations expressing high levels of programmed death 1 receptor. Contextually, only apoptotic epitope-specific CD8(+) T cells correlated with both interferon-stimulated gene levels in T cells and hepatic fibrosis score. Together, these data suggest that, compared with HCV-specific CD8(+) T cells, apoptotic epitope-specific CD8(+) T cells can better sustain chronic immune activation, owing to their capacity to produce tumor necrosis factor α, and exhibit greater resistance to inhibitory signals during chronic HCV infection. [ABSTRACT FROM AUTHOR]

Published
2016
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18. Apoptotic epitope-specific CD8+ T cells and interferon signaling intersect in chronic Hepatitis C virus infection

Author

Daniele Accapezzato, Paolo De Marzio, Giancarlo Labbadia, Vincenzo Vullo, Simona Di Filippo, Gabriella d'Ettorre, Martina Severa, Eugenio Nelson Cavallari, Silvia Piconese, Vincenzo Barnaba, Helene Martini, Eliana M. Coccia, Alessandra Citro, Carmela Martire, G. Grazi, John Sidney, Fabiana Rizzo, Alessandro Sette, Ludovica Calvo, Martini, Helene, Citro, Alessandra, Martire, Carmela, D'Ettorre, Gabriella, Labbadia, Giancarlo, Accapezzato, Daniele, Piconese, Silvia, De Marzio, Paolo, Cavallari, Eugenio N., Calvo, Ludovica, Rizzo, Fabiana, Severa, Martina, Coccia, Eliana M., Grazi, Gian Luca, Di Filippo, Simona, Sidney, John, Vullo, Vincenzo, Sette, Alessandro, and Barnaba, Vincenzo

Subjects
Liver Cirrhosis, 0301 basic medicine, Adult, Male, Liver Cirrhosi, Apoptosis, T-Lymphocyte Subset, Infectious Disease, CD8-Positive T-Lymphocytes, Biology, 03 medical and health sciences, Interleukin 21, T-Lymphocyte Subsets, Humans, Cytotoxic T cell, hepatitis C viru, Immunology and Allergy, IL-2 receptor, Antigen-presenting cell, Interleukin 3, Aged, chronic immune activation, Tumor Necrosis Factor-alpha, ZAP70, Medicine (all), Apoptosi, CD8-Positive T-Lymphocyte, Hepatitis C, Chronic, Middle Aged, Natural killer T cell, 030104 developmental biology, Infectious Diseases, Immunology, Interleukin 12, Cancer research, Interferon, Interleukin-2, Female, Interferons, CD8+ T cell, Human, Signal Transduction
Abstract

CD8(+) T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a principal player in chronic immune activation. Here, we found that both apoptotic epitope-specific and hepatitis C virus (HCV)-specific CD8(+) T cells were mostly confined within the effector memory (EM) or terminally differentiated EM CD45RA(+) cell subsets expressing a dysfunctional T-helper 1-like signature program in chronic HCV infection. However, apoptotic epitope-specific CD8(+) T cells produced tumor necrosis factor AŽÂ± and interleukin 2 at the intrahepatic level significantly more than HCV-specific CD8(+) T cells, despite both populations expressing high levels of programmed death 1 receptor. Contextually, only apoptotic epitope-specific CD8(+) T cells correlated with both interferon-stimulated gene levels in T cells and hepatic fibrosis score. Together, these data suggest that, compared with HCV-specific CD8(+) T cells, apoptotic epitope-specific CD8(+) T cells can better sustain chronic immune activation, owing to their capacity to produce tumor necrosis factor AŽÂ±, and exhibit greater resistance to inhibitory signals during chronic HCV infection.

Published
2016

19. Elaboration of a nomogram to predict nonsentinel node status in breast cancer patients with positive sentinel node, intraoperatively assessed with one step nucleic amplification: Retrospective and validation phase

Author

Pierluigi Chiodera, Corrado Tinterri, Francesca Becherini, Giuseppe B. Grassi, Maria Iole Natalicchio, Samuele Massarut, Luca Di Tommaso, Florence Godey, Fabrizio Palmieri, Angelo Sidoni, Laia Bernet, Rafael Cano, Simonetta Buglioni, Sergio Orefice, Massimo Grassi, Luigi Michele Coppola, Roberto Franchini, Vincenzo Canzonieri, Isabella Sperduti, Tiziana Perin, Franco Di Filippo, Raffaele Antonetti, Privato Fenaroli, Carmela Giardina, Stefano Drago, Alessandro Battaglia, Catherine Bouteille, Andrea Gianatti, Simona Di Filippo, Paolo Burelli, Anna Maria Ferrari, G. Naccarato, Manuela Roncella, Siobhan Laws, Antonio Rulli, Massimo Roncalli, Renzo Boldorini, Diana Giannarelli, Maria C. Truglia, Alfredo Cirilli, Di Filippo, Franco, Di Filippo, Simona, Ferrari, Anna Maria, Antonetti, Raffaele, Battaglia, Alessandro, Becherini, Francesca, Bernet, Laia, Boldorini, Renzo, Bouteille, Catherine, Buglioni, Simonetta, Burelli, Paolo, Cano, Rafael, Canzonieri, Vincenzo, Chiodera, Pierluigi, Cirilli, Alfredo, Coppola, Luigi, Drago, Stefano, Di Tommaso, Luca, Fenaroli, Privato, Franchini, Roberto, Gianatti, Andrea, Giannarelli, Diana, Giardina, Carmela, Godey, Florence, Grassi, Massimo M., Grassi, Giuseppe B., Laws, Siobhan, Massarut, Samuele, Naccarato, Giuseppe, Natalicchio, Maria Iole, Orefice, Sergio, Palmieri, Fabrizio, Perin, Tiziana, Roncella, Manuela, Roncalli, Massimo G., Rulli, Antonio, Sidoni, Angelo, Tinterri, Corrado, Truglia, Maria C., and Sperduti, Isabella

Subjects
0301 basic medicine, medicine.medical_specialty, Cancer Research, Non Sentinel Node status, Sentinel lymph node, Gene Dosage, Nomogram, OSNA method, CK19 mRNA number copies, Breast Neoplasms, 03 medical and health sciences, Intraoperative Period, 0302 clinical medicine, Breast cancer, Theoretical, Models, medicine, Humans, Lymph node, Retrospective Studies, Keratin-19, Receiver operating characteristic, business.industry, Research, Axillary Lymph Node Dissection, Nucleic acid amplification technique, Sentinel node, medicine.disease, Surgery, Nomograms, 030104 developmental biology, medicine.anatomical_structure, ROC Curve, Oncology, Female, Lymph Node Excision, Lymphatic Metastasis, Models, Theoretical, Neoplasm Grading, Neoplasm Micrometastasis, Nucleic Acid Amplification Techniques, Non Sentinel Node statu, 030220 oncology & carcinogenesis, Radiology, business
Abstract

Background: Tumor-positive sentinel lymph node (SLN) biopsy results in a risk of non sentinel node metastases in micro-and macro-metastases ranging from 20 to 50%, respectively. Therefore, most patients underwent unnecessary axillary lymph node dissections. We have previously developed a mathematical model for predicting patient-specific risk of non sentinel node (NSN) metastases based on 2460 patients. The study reports the results of the validation phase where a total of 1945 patients were enrolled, aimed at identifying a tool that gives the possibility to the surgeon to choose intraoperatively whether to perform or not axillary lymph node dissection (ALND). Methods: The following parameters were recorded: Clinical: hospital, age, medical record number; Bio pathological: Tumor (T) size stratified in quartiles, grading (G), histologic type, lymphatic/vascular invasion (LVI), ER-PR status, Ki 67, molecular classification (Luminal A, Luminal B, HER-2 Like, Triple negative); Sentinel and non-sentinel node related: Number of NSNs removed, number of positive NSNs, cytokeratin 19 (CK19) mRNA copy number of positive sentinel nodes stratified in quartiles. A total of 1945 patients were included in the database. All patient data were provided by the authors of this paper. Results: The discrimination of the model quantified with the area under the receiver operating characteristics (ROC) curve (AUC), was 0.65 and 0.71 in the validation and retrospective phase, respectively. The calibration determines the distance between predicted outcome and actual outcome. The mean difference between predicted/observed was 2.3 and 6.3% in the retrospective and in the validation phase, respectively. The two values are quite similar and as a result we can conclude that the nomogram effectiveness was validated. Moreover, the ROC curve identified in the risk category of 31% of positive NSNs, the best compromise between false negative and positive rates i.e. when ALND is unnecessary (< 31%) or recommended (> 31%). Conclusions: The results of the study confirm that OSNA nomogram may help surgeons make an intraoperative decision on whether to perform ALND or not in case of positive sentinel nodes, and the patient to accept this decision based on a reliable estimation on the true percentage of NSN involvement. The use of this nomogram achieves two main gools: 1) the choice of the right treatment during the operation, 2) to avoid for the patient a second surgery procedure.

Published
2016

20. Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue

Author

Gianluca Mennini, Silvia Piconese, Massimo Sanchez, G. Grazi, Guido Antonelli, Vincenzo Barnaba, Massimo Rossi, Ilenia Pacella, Claudio Tripodo, Eleonora Timperi, Stefania Brozzetti, Simona Di Filippo, Katia Fazzi, Maria A ntonietta Lozzi, V. Schinzari, Nicola Guglielmo, Department of Internal Medicine and Medical Specialities, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli studi di Palermo - University of Palermo, Dip di Chirurgia Generale e Trapianti d’Organo - Sapienza Università, Dipartimento di Chirurgia - Sapienza Università, Department of Molecular Medicine, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], CISDEM-CSIC, Institute of Construction Science 'Eduardo Torreja', Réseau International des Instituts Pasteur (RIIP), This work was supported by the following grants obtained by V.B.: Associazione Italiana per la Ricerca sul Cancro (AIRC, progetto 'Investigator Grant' [IG]-2010/13 no. 10756), European Union grants (IMECS no. 201169, FP7-Health-2007-A, and SPHYNX no. 261365, FP7-Health-2010), Ministero della Sanità (Ricerca finalizzata [RFPS-2006-3-337923 and RFPS-2007-1-636647] and Istituto Superiore di Sanità [Progetto AIDS-2008]), Ministero dell’Istruzione,dell’Università e della Ricerca (MIUR, Programmi di ricerca di interesse nazionale [PRIN]-2008/10 no. 7245/1, [PRIN]-2011/13 no. 2010LC747T-004, AteneoSapienza [2009-C26A09PELN, 2010-C26A1029ZS, 2011-C26A11BYWP, and 2012-C26A12JL55], and Fondo per gli investimenti di ricerca di base [FIRB]-2011/13 no. RBAP10TPXK), Fondazione Cariplo (progetti no. 13535 and 3603 2010/12), FISM (Fondazione Italiana Sclerosi Multipla onlus) grant no. 2011/R/4, Fondazione Italiana per la Ricerca sull’Artrite (FIRA 2010), and Istituto Italiano di Tecnologia (IIT, A2 project 2013). This work was also supported bygrants obtained by S.P. from Associazione Italiana Ricerca sul Cancro (MFAG 8726) and from Ministero dell’Istruzione, dell’Università e della Ricerca (FIRB-Futuro in ricerca RBFR12I3UB_002)., The authors thank Marco Cassatella and Federica Calzetti (Università di Verona) for providing anti‐M‐DC8 antibody, Maria Cristina Gagliardi (Istituto Superiore di Sanità, Rome) for providing anti‐CD206 antibody, Carla Guarnotta (Università di Palermo) for technical assistance in immunohistochemical stainings, and Stefania Morrone ('Sapienza' Università di Roma, Rome) for help with cell sorting. The authors also acknowledge Massimo Locati and Alberto Mantovani for their helpful discussion., Piconese, Silvia, Timperi, Eleonora, Pacella, Ilenia, Schinzari, Valeria, Tripodo, Claudio, Rossi, Massimo, Guglielmo, Nicola, Mennini, Gianluca, Grazi, Gian Luca, Di Filippo, Simona, Brozzetti, Stefania, Fazzi, Katia, Antonelli, Guido, Lozzi, Maria Antonietta, Sanchez, Massimo, Barnaba, Vincenzo, Piconese, S, Timperi, E, Pacella, I, Schinzari, V, Tripodo, C, Rossi, M, Guglielmo, N, Mennini, G, Grazi, GL, Di Filippo, S, Brozzetti, S, Fazzi, K, Antonelli, G, Lozzi, MA, Sanchez, M, and Barnaba, V.

Subjects
MESH: Receptors, OX40/metabolism, MESH: Interleukin-12/metabolism, Liver Cirrhosis, Male, Macrophage, medicine.disease_cause, MESH: Carcinoma, Hepatocellular/immunology, T-Lymphocytes, Regulatory, MESH: OX40 Ligand/metabolism, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: T-Lymphocytes, Regulatory/physiology, MESH: Up-Regulation, OX40, MESH: Aged, Aged, 80 and over, 0303 health sciences, education.field_of_study, T REG, MESH: Middle Aged, Medicine (all), MESH: Liver Cirrhosis/immunology, Liver Neoplasms, hemic and immune systems, Middle Aged, MESH: Liver Neoplasms/immunology, Phenotype, Hepatitis C, Interleukin-12, 3. Good health, Up-Regulation, Liver Neoplasm, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Interleukin 12, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, MESH: Hepatitis C/immunology, HEPATITIS C VIRUS, Human, medicine.medical_specialty, Carcinoma, Hepatocellular, Hepatitis C virus, Liver Cirrhosi, Population, Inflammation, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, OX40 Ligand, Biology, MESH: Phenotype, MESH: Liver Neoplasms/virology, 03 medical and health sciences, Ikaros Transcription Factor, Downregulation and upregulation, Internal medicine, medicine, Humans, MESH: Macrophages/metabolism, education, 030304 developmental biology, Aged, MESH: Humans, Hepatology, Macrophages, MESH: Carcinoma, Hepatocellular/virology, Receptors, OX40, MESH: Ikaros Transcription Factor/metabolism, MESH: Hepatitis C/complications, MESH: Male, OX40 ligand, Immunology, MESH: Liver Cirrhosis/virology, MESH: Female, 030215 immunology
Abstract

International audience; Regulatory T cells (Tregs) can be considered as a mixed population of distinct subsets, endowed with a diverse extent and quality of adaptation to microenvironmental signals. Here, we uncovered an opposite distribution of Treg expansion, phenotype, and plasticity in different microenvironments in the same organ (liver) derived from patients with chronic hepatitis C: On the one side, cirrhotic and tumor fragments were moderately and highly infiltrated by Tregs, respectively, expressing OX40 and a T-bet high IFN-c – " T-helper (Th)1-suppressing " phenotype; on the other side, noncirrhotic liver specimens contained low frequencies of Tregs that expressed low levels of OX40 and highly produced interferon-gamma (IFN-c; T-bet 1 IFN-c 1), thus becoming " Th1-like " cells. OX40-expressing and Th1-suppressing Tregs were enriched in the Helios-positive subset, carrying highly demethylated Treg cell-specific demethylated region that configures committed Tregs stably expressing forkhead box protein 3. OX40 ligand, mostly expressed by M2-like monocytes and macrophages, boosted OX40 1 Treg proliferation and antagonized the differentiation of Th1-like Tregs. However, this signal is counteracted in non-cirrhotic liver tissue (showing various levels of inflammation) by high availability of interleukin-12 and IFN-c, ultimately leading to complete, full Th1-like Treg differentiation. Conclusion: Our data demonstrate that Tregs can finely adapt, or even subvert, their classical inhibitory machinery in distinct microenvironments within the same organ. (HEPATOLOGY 2014;60:1494-1507)

Published
2014
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21. Liposomal doxorubicin with and without TNFalpha in the perfusional treatment of advanced soft tissue limb sarcoma: preliminary results.

Author

Di Filippo F, Anzà M, Garinei R, Cavaliere F, Perri P, Botti C, Di Angelo P, Di Filippo S, Maini CL, Pasqualoni R, Di Segni S, Colantonio S, Bruno P, Piarulli L, and Principi F

Subjects
Adult, Aged, Chemotherapy, Cancer, Regional Perfusion, Combined Modality Therapy, Dose-Response Relationship, Drug, Doxorubicin administration & dosage, Female, Humans, Male, Middle Aged, Sarcoma pathology, Sarcoma surgery, Soft Tissue Neoplasms pathology, Soft Tissue Neoplasms surgery, Treatment Outcome, Tumor Necrosis Factor-alpha administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Sarcoma drug therapy, Soft Tissue Neoplasms drug therapy
Abstract

Background: A combination of doxorubicin and tumor necrosis factor alpha (TNFalpha) has been proven to be very effective in the perfusional treatment of advanced soft tissue limb sarcoma both in terms of tumor necrosis and limb conservative surgery rate. Unfortunately, in some patients a grade IV limb reaction has been recorded. The key solution might be the use of liposomal doxorubicin (Caelyx) because the carrier seems to release the drug preferentially in the tumor rather than in the healthy tissue., Patients and Methods: Twenty patients were treated with Caelyx: 14 with Caelyx alone and 6 in combination with a low TNFalpha dose (1 mg). In the first series of 14 patients a dose escalation study was carried out starting from a dose of 10 mg/L of limb volume. Six patients were treated with Caelyx (16 mg) and TNFalpha (1 mg)., Results: The maximum tolerated dose (MTD) was 16 mg/L as in two patients treated with 18 mg/L a grade IV limb reaction was observed. Tumor response was satisfactory and conservative surgery was carried out in 13 patients. In 6 patients treated with Caelyx and TNFalpha, only a grade I limb reaction was recorded, thus, confirming that TNFalpha did not increase toxicity, at least at a dose of 1 mg. The Caelyx-TNFalpha combination did increase treatment efficacy. Tumor necrosis > or = 70% was observed in 4 out of 6 patients, one with 100% necrosis (pathological complete response). All the patients underwent conservative surgery., Conclusion: The Caelyx-TNFalpha combination was proven to increase the efficacy of Caelyx alone, with a very low toxicity. These preliminary results have to be tested in a larger patient population.

Published
2006

22. Hyperthermic isolation limb perfusion with TNFalpha in the treatment of in-transit melanoma metastasis.

Author

Di Filippo F, Rossi CR, Santinami M, Cavaliere F, Garinei R, Anzà M, Perri P, Botti C, Di Angelo P, Pasqualoni R, and Di Filippo S

Subjects
Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Alkylating administration & dosage, Chemotherapy, Cancer, Regional Perfusion, Combined Modality Therapy, Drug Therapy, Combination, Extremities, Female, Humans, Male, Melanoma secondary, Melphalan administration & dosage, Middle Aged, Neoplasm Staging, Skin Neoplasms pathology, Hyperthermia, Induced, Melanoma therapy, Skin Neoplasms therapy, Tumor Necrosis Factor-alpha administration & dosage
Abstract

Background: Hyperthermic isolation limb perfusion (HILP) with tumor necrosis factor alpha (TNFalpha) and IFNgamma was pioneered by Liénard and Lejeune in 1988. The TNFalpha was empirically employed at a dosage of 3-4 mg, that is ten times the systemic maximum tolerated dose (MTD). After eighteen years from its first clinical application, more than 300 patients have been treated. The aim of this study is to clarify two major arguments: the TNFalpha dose and eligibility criteria for patient selection., Patients and Methods: A phase I-II study has previously been conducted in 20 patients with in-transit melanoma metastases using a combination of melphalan and TNFalpha at dosages ranging from 0.5 to 3.3 mg. Twenty patients were treated and a complete pathological response of 70% was recorded, with no correlation between tumor response and TNFalpha. The dose of 1 mg of TNFalpha provided the best results regarding efficacy and toxicity. On the basis of this results a large phase II SITILO study was undertaken. Patients with stage IIIA - IIIAB (presence of in transit metastases and/or regional node involvement) were considered eligible; a total of 113 patients were enrolled in the study. The disease was bulky (> 10 nodules or fewer nodules with a diameter > or = 3 cm) in 42.5% of the patients and unresectable in 33%. Forty patients were treated with a TNFalpha dosage > 1 mg and 73 with 1 mg. All the patients were submitted to HILP via axillary and iliac vessels for tumor of upper and lower limb, respectively. TNFalpha was injected in the extracorporal circuit at the pre-established dose, followed after 30 minutes by melphalan (13 and 10 mg/L of limb volume for upper and lower limbs, respectively)., Results: A grade 1 and 2 limb toxicity was found in 52.9% and 30.1% of the patients, respectively, 5.5% of patients exhibited a grade 3 and 4, whereas grade 5 limb toxicity was not found. The complete and partial responses were 63% and 24.5%, respectively, with an objective response of 87.5%. We tried to correlate the typed tumor response (CR or not CR) and the TNFalpha dosage < or = 1 mg or > 1 mg, but no statistically significant difference was found between the two groups. The bulky disease was the only prognostic factor able to influence the tumor response., Conclusion: Only patients with bulky melanoma disease can benefit from HILP with TNFalpha at a low dose of 1 mg.

Published
2006

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