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1. Avacopan for the treatment of ANCA-associated vasculitis

Author

Jayne, D, Merkel, P, Schall, T, Bekker, P, Pieruzzi, F, Jayne, DRW, Merkel, PA, Schall, TJ, Jayne, D, Merkel, P, Schall, T, Bekker, P, Pieruzzi, F, Jayne, DRW, Merkel, PA, and Schall, TJ

Abstract

BACKGROUND The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority. RESULTS A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; P<0.001 for noninferiority; P = 0.24 for superiority). Sustained remission at week 52 (the second primary end point) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P<0.001 for noninferiority; P = 0.007 for superiority). Serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the patients receiving avacopan and in 39.0% of those receiving prednisone. CONCLUSIONS In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but n

Published
2021

3. Avacopan for the Treatment of ANCA-Associated Vasculitis

Author

Jayne, David R W, Merkel, Peter A, Schall, Thomas J, Bekker, Pirow, ADVOCATE Study Group:, C Au Peh, Chakera, A, Cooper, B, Kurtkoti, J, Langguth, D, Levidiotis, V, Luxton, G, Mount, P, Mudge, D, Noble, E, Phoon, R, Ranganathan, D, Ritchie, A, Ryan, J, Suranyi, M, Rosenkranz, A, Lhotta, K, Kronbichler, A, Demoulin, N, Bovy, C, Hellemans, R, Hougardy, J, Sprangers, B, Wissing, K, Pagnoux, C, Barbour, S, Brachemi, S, Cournoyer, S, Girard, L, Laurin, L, Liang, P, Philibert, D, Walsh, M, Tesar, V, Becvar, R, Horak, P, Rychlik, I, Szpirt, W, Dieperink, H, Gregersen, J, Ivarsen, P, Krarup, E, Lyngsoe, C, Rigothier, C, Augusto, J, Belot, A, Chauveau, D, Cornec, D, Jourde-Chiche, N, Ficheux, M, Karras, A, Klein, A, Maurier, F, Mesbah, R, Moranne, O, Neel, A, Quemeneur, T, Saadoun, D, Terrier, B, Zaoui, P, Schaier, M, Benck, U, Bergner, R, Busch, M, Floege, J, Grundmann, F, Haller, H, Haubitz, M, Hellmich, B, Henes, J, Hohenstein, B, Hugo, C, Iking-Konert, C, Arndt, F, Kubacki, T, Kotter, I, Lamprecht, P, Lindner, T, Halbritter, J, Mehling, H, Schönermarck, U, Venhoff, N, Vielhauer, V, Witzke, O, Szombati, I, Szucs, G, Garibotto, G, Alberici, F, Brunetta, E, Dagna, L, S De Vita, Emmi, G, Gabrielli, A, Manenti, L, Pieruzzi, F, Roccatello, D, Salvarani, C, Dobashi, H, Atsumi, T, Fujimoto, S, Hagino, N, Ihata, A, Kaname, S, Kaneko, Y, Katagiri, A, Katayama, M, Kirino, Y, Kitagawa, K, Komatsuda, A, Kono, H, Kurasawa, T, Matsumura, R, Mimura, T, Morinobu, A, Murakawa, Y, Naniwa, T, Nanki, T, Ogawa, N, Oshima, H, Sada, K, Sugiyama, E, Takeuchi, T, Taki, H, Tamura, N, Tsukamoto, T, Yamagata, K, Yamamura, M, P van Daele, Rutgers, A, Teng, Y, Walker, R, Chua, I, Collins, M, Rabindranath, K, J de Zoysa, Svensson, M, Grevbo, B, Kalstad, S, Little, M, Clarkson, M, Molloy, E, I Agraz Pamplona, Anton, J, V Barrio Lucia, Ciggaran, S, M Cinta Cid, M Diaz Encarnacion, X Fulladosa Oliveras, M Soler, J, H Rusinol, M, Praga, M, L Quintana Porras, Segarra, A, Bruchfeld, A, Segelmark, M, Soveri, I, Thomaidi, E, Westman, K, Neumann, T, Burnier, M, Daikeler, T, Dudler, J, Hauser, T, Seeger, H, Vogt, B, Jayne, D, Burton, J, R Al Jayyousi, Amin, T, Andrews, J, Baines, L, Brogan, P, Dasgupta, B, Doulton, T, Flossmann, O, Griffin, S, Harper, J, Harper, L, Kidder, D, Klocke, R, Lanyon, P, Luqmani, R, Mclaren, J, Makanjuola, D, Mccann, L, Nandagudi, A, Selvan, S, O'Riordan, E, Patel, M, Patel, R, Pusey, C, Rajakariar, R, Robson, J, Robson, M, Salama, A, Smyth, L, Sznajd, J, Taylor, J, Merkel, P, Sreih, A, Belilos, E, Bomback, A, Carlin, J, Y Chang Chen Lin, Derebail, V, Dragoi, S, Dua, A, Forbess, L, Geetha, D, Gipson, P, Gohh, R, T Greenwood, G, Hugenberg, S, Jimenez, R, Kaskas, M, Kermani, T, Kivitz, A, Koening, C, Langford, C, Marder, G, Mohamed, A, Monach, P, Neyra, N, Niemer, G, Niles, J, Obi, R, Owens, C, Parks, D, Podoll, A, Rovin, B, Sam, R, Shergy, W, Silva, A, Specks, U, Spiera, R, Springer, J, Striebich, C, Swarup, A, Thakar, S, Tiliakos, A, Tsai, Y, Waguespack, D, M Chester Wasko, Internal Medicine, Immunology, Jayne, D, Merkel, P, Schall, T, Bekker, P, Pieruzzi, F, Jayne, David RW [0000-0002-1712-0637], Apollo - University of Cambridge Repository, and Translational Immunology Groningen (TRIGR)

Subjects
Male, Receptor, Anaphylatoxin C5a/antagonists & inhibitors, Anaphylatoxin C5a, Anaphylatoxin C5a/antagonists & inhibitors, Nipecotic Acids, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculiti, Administration, Oral, Azathioprine, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, urologic and male genital diseases, Gastroenterology, C5a receptor, Cyclophosphamide/administration & dosage, Rituximab/administration & dosage, Immunosuppressive Agent, renal vasculitis, Prednisone/administration & dosage, 0302 clinical medicine, Glucocorticoid, immune system diseases, Prednisone, Recurrence, Medicine, 030212 general & internal medicine, skin and connective tissue diseases, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy, Aniline Compounds, Remission Induction, General Medicine, Aniline Compound, Middle Aged, Administration, Combination, Rituximab, Drug Therapy, Combination, Female, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Cyclophosphamide, Double-Blind Method, Glucocorticoids, Humans, Immunosuppressive Agents, Receptor, Anaphylatoxin C5a, Vasculitis, Receptor, medicine.drug, Human, Azathioprine/administration & dosage, Oral, medicine.medical_specialty, Nipecotic Acid, ANCA-Associated Vasculitis, 03 medical and health sciences, Drug Therapy, Internal medicine, Aniline Compounds/adverse effects, cardiovascular diseases, Immunosuppressive Agents/administration & dosage, Anti-neutrophil cytoplasmic antibody, business.industry, Glucocorticoids/administration & dosage, medicine.disease, Nipecotic Acids/adverse effects, respiratory tract diseases, business
Abstract

BACKGROUND: The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.METHODS: In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority.RESULTS: A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; PCONCLUSIONS: In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.).

Published
2021

4. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

Author

Simona Soverini, Jeffrey H. Lipton, Richard A. Larson, Dietger Niederwieser, Andrey Zaritskey, Fabrizio Pane, Francois-Xavier Mahon, Jeroen Janssen, Richard E. Clark, François Guilhot, Juan Luis Steegmann, Jerald P. Radich, Michael W. Deininger, Andreas Hochhaus, Richard T. Silver, Susanne Saußele, Johan Richter, Timothy P. Hughes, Jane F. Apperley, Jiří Mayer, Henrik Hjorth-Hansen, Hagop M. Kantarjian, Jorge E. Cortes, Anna G. Turkina, Michele Baccarani, Gianantonio Rosti, Franck E. Nicolini, Philippe Rousselot, Giuseppe Saglio, Delphine Rea, Dong-Wook Kim, Ruediger Hehlmann, Charles A. Schiffer, Francisco Cervantes, Hochhaus A., Baccarani M., Silver R.T., Schiffer C., Apperley J.F., Cervantes F., Clark R.E., Cortes J.E., Deininger M.W., Guilhot F., Hjorth-Hansen H., Hughes T.P., Janssen J.J.W.M., Kantarjian H.M., Kim D.W., Larson R.A., Lipton J.H., Mahon F.X., Mayer J., Nicolini F., Niederwieser D., Pane F., Radich J.P., Rea D., Richter J., Rosti G., Rousselot P., Saglio G., Saussele S., Soverini S., Steegmann J.L., Turkina A., Zaritskey A., Hehlmann R., Hochhaus, A., Baccarani, M., Silver, R. T., Schiffer, C., Apperley, J. F., Cervantes, F., Clark, R. E., Cortes, J. E., Deininger, M. W., Guilhot, F., Hjorth-Hansen, H., Hughes, T. P., Janssen, J. J. W. M., Kantarjian, H. M., Kim, D. W., Larson, R. A., Lipton, J. H., Mahon, F. X., Mayer, J., Nicolini, F., Niederwieser, D., Pane, F., Radich, J. P., Rea, D., Richter, J., Rosti, G., Rousselot, P., Saglio, G., Saussele, S., Soverini, S., Steegmann, J. L., Turkina, A., Zaritskey, A., Hehlmann, R., Centre hospitalier universitaire de Poitiers (CHU Poitiers), Institut Bergonié [Bordeaux], UNICANCER, Centre Léon Bérard [Lyon], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Novartis Berlin Mathematical School, BMS Daiichi-Sankyo Janssen Pharmaceuticals Angelini Pharma Pfizer, The ELN panel for recommendations in CML comprises 34 experts from Europe, America, and the Asian-Pacific areas. The panel met six times at international meetings of the American Society of Hematology (2015, 2016), the European School of Hematology (2017), the ELN (2019), the European Investigators on CML (2019), and the European School of Hematology/International CML Foundation (2019). Five sets of key questions were submitted to panel members to complement the meetings. Discordant opinions were harmonized by email discussions, and a consensus of 75–100% was reached in most, but not all instances. Unresolved controversies are described in the discussion section. The costs of the meetings and the preparation of the interim and final reports were born entirely by ELN, a research network of excellence initiated by the European Union, now funded by donations and projects of ELN participants. There was no financial support from industry for any activity. Treatment recommendations are limited to the TKIs that have been approved with at least one indication in CML, either by the US Federal Drug Administration (FDA) or/and by the European Medicine Agency (EMA). The drugs are listed in the order of FDA approval. The panel acknowledges that not all drugs may be available worldwide and that the high price of some makes access to these drugs problematic in some countries., Conflict of interest Members of the expert panel declare the following potential conflicts of interest: AH, Research support: Novartis, BMS, MSD, Pfizer, Incyte. Honoraria: Novartis, BMS, Pfizer, Incyte, Takeda, Fusion Pharma. MB, Honoraria: Novartis, BMS, Pfizer, Incyte, Ariad, Takeda, Fusion Pharma. Logistic support: Novartis, BMS, Pfizer, Incyte, Ariad. CS, Research support: Ariad. Honoraria: Novartis, Teva, Pfizer, Juno, Astellas, Ambit. JFA, Research support: Incyte, Novartis, Pfizer. Honoraria: Incyte, Novartis, Pfizer, BMS. FC, Honoraria: Novartis, BMS, Pfizer, Incyte, Celgene, Italfarmaco. Travel grants: BMS, Celgene. REC, Research support: Novartis, Pfizer, BMS. Honoraria: Novartis, Pfizer, BMS, Ariad/Incyte, Jazz, Abbvie. JEC, Research support: BMS, Novartis, Pfizer, Sun Pharma, Takeda. Honoraria: Novartis, Pfizer, Takeda. MWD, Research support: Takeda, Novartis, Pfizer, Incyte, SPARC, TetraLogic Pharmaceuticals, Blueprint. Honoraria: Blueprint, Fusion Pharma, Novartis, Sangamo, Ascentage Pharma, Adelphi, CTI, BMS, Pfizer, Takeda, Medscape, Incyte, Humana, TRM, Ariad, Galena Biopharma. FG, Research support: Novartis, Roche. Honoraria: Novartis, BMS, Celgene. HHH, Research support: Pfizer, BMS, Merck, Austrian Orphan Pharma, Nordic Cancer Union. Honoraria: Pfizer, Incyte, Austrian Orphan Pharma. TPH, Research support: Novartis, BMS, Celgene. Honoraria: Novartis, BMS, Fusion Pharma. Travel grants: Novartis. JJ, Research support: Novartis, BMS. President, Apps for Care and Science, nonprofit foundation supported by Daiichi-Sankyo, Janssen, Incyte, BMS, Servier, Jazz, Celgene. Honoraria: Abbvie, Novartis, Pfizer, Incyte. HMK, Research support: AbbVie, Agios, Amgen, Ariad, Astex, BMS, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, Pfizer. Honoraria: AbbVie, Actinium, Agios, Amgen, Immunogen, Pfizer, Takeda. DWK, Research support: Novartis, Pfizer, BMS, Takeda, Il-Yang Co. Honoraria: Novartis, BMS, Otsuka, Il-Yang Co. RAL, Research support: Astellas, Celgene, Cellectis, Daiichi Sankyo, Novartis, Rafael Pharmaceuticals. Honoraria: Amgen, Celgene, CVS Caremark, Epizyme, Novartis, Takeda. JHL, Research support and honoraria: Novartis, BMS, Pfizer, Takeda. FXM, Research support and honoraria: Novartis. Travel grants: Celgene, Pfizer, Astra Zeneca. JM, Research support: Angelini, Pfizer, Novartis, BMS. Travel grants: Novartis. FN, Research support: Novartis, Incyte. Honoraria: Incyte biosciences, Novartis, BMS, Sun Pharma. Travel grants: Incyte biosciences, Novartis, BMS. DN, Research support: Daiichi, Honoraria: Cellectis. Travel grants: EUSA, Novartis, and Amgen. FP, Research support: Novartis. Honoraria: Novartis, BMS, Pfizer, Incyte. JPR, Research support: Novartis. Honoraria: Novartis, BMS, Ariad, Amgen, Takeda, Cepheid, Bio-Rad, Adaptive, Seagen, Gilead. DR, Honoraria: BMS, Novartis, Pfizer, Incyte. JR, Honoraria: Novartis, Pfizer. GR, Research support, honoraria, and travel grants: Novartis, BMS, Incyte, Pfizer, Roche. PR, Research support: Incyte, Pfizer. Honoraria: BMS, Incyte, Pfizer, Novartis. GS, Honoraria: Novartis, BMS, Incyte, Pfizer. SiS, Honoraria: Incyte. SuS, Research support: BMS, Incyte, Novartis. Honoraria: BMS, Incyte, Novartis, Pfizer. Travel grants: BMS, Incyte, Novartis. JLS, Research support, honoraria, and travel grants: BMS, Incyte, Novartis, Pfizer. AT, Honoraria: BMS, Novartis, Pfizer, Fusion Pharma. Travel grants: BMS, Novartis, Pfizer. AZ, Research support: Novartis, Celgene, Janssen. Travel grants: Novartis. RTS, RH, none.

Subjects
Oncology, Cancer Research, Consensus Development Conferences as Topic, Dasatinib, Fusion Proteins, bcr-abl, Quinoline, Gene Expression, Review Article, Tyrosine-kinase inhibitor, Antineoplastic Agent, European LeukemiaNet, 0302 clinical medicine, hemic and lymphatic diseases, 0303 health sciences, Aniline Compounds, Myeloid leukemia, Disease Management, Hematology, Aniline Compound, 3. Good health, 030220 oncology & carcinogenesis, Quinolines, Imatinib Mesylate, Bosutinib, Nitrile, medicine.drug, Human, medicine.medical_specialty, medicine.drug_class, Clinical Decision-Making, Protein Kinase Inhibitor, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Targeted therapies, Life Expectancy, Internal medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Nitriles, medicine, Humans, Protein Kinase Inhibitors, Chronic myeloid leukaemia, 030304 developmental biology, Monitoring, Physiologic, business.industry, Imatinib, Survival Analysis, Discontinuation, Pyrimidines, Nilotinib, Pyrimidine, Quality of Life, business
Abstract

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.

Published
2020

5. Long-term mortality rate for cardiovascular disease in 656 chronic myeloid leukaemia patients treated with second- and third-generation tyrosine kinase inhibitors

Author

Gabriele Gugliotta, Francesca Pirillo, Bruno Martino, Fausto Castagnetti, Chiara Elena, Antonella Gozzini, Giorgio La Nasa, Massimiliano Bonifacio, Claudia Baratè, Gianni Binotto, Robin Foà, Daniele Cattaneo, Nicola Sgherza, Alessandra Iurlo, Monica Bocchia, Elisabetta Abruzzese, Mario Annunziata, Claudio Fozza, Fiorenza De Gregorio, Matteo Molica, Luigi Scaffidi, Sara Galimberti, Olga Mulas, Giovanni Caocci, Imma Attolico, Ester Orlandi, Maria Pina Simula, Luigiana Luciano, Massimo Breccia, Francesco Albano, Fabio Stagno, Patrizia Pregno, Anna Sicuranza, Malgorzata Monika Trawinska, Caocci G., Mulas O., Annunziata M., Luciano L., Abruzzese E., Bonifacio M., Orlandi E.M., Albano F., Galimberti S., Iurlo A., Pregno P., Sgherza N., Martino B., Binotto G., Castagnetti F., Gozzini A., Bocchia M., Fozza C., Stagno F., Simula M.P., De Gregorio F., Trawinska M.M., Scaffidi L., Elena C., Attolico I., Barate C., Cattaneo D., Pirillo F., Gugliotta G., Sicuranza A., Molica M., La Nasa G., Foa R., and Breccia M.

Subjects
Male, Chronic myeloid leuk, Dasatinib, emia, Long Term Adverse Effects, Long Term Adverse Effect, 030204 cardiovascular system & hematology, Antineoplastic Agent, chemistry.chemical_compound, 0302 clinical medicine, Cardiovascular Disease, Cardiovascular toxicity, Ischemic heart disease, TKI, Aged, Antineoplastic Agents, Female, Humans, Italy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Life Expectancy, Mortality, Protein Kinase Inhibitors, Risk Adjustment, Aniline Compounds, Cardiotoxicity, Cardiovascular Diseases, Imidazoles, Nitriles, Pyridazines, Pyrimidines, Quinolines, 030212 general & internal medicine, Chronic, education.field_of_study, Leukemia, Mortality rate, Ponatinib, Aniline Compound, a, Pyridazine, Cardiology and Cardiovascular Medicine, Nitrile, Bosutinib, Human, medicine.drug, medicine.medical_specialty, Population, Protein Kinase Inhibitor, 03 medical and health sciences, Internal medicine, medicine, education, Imidazole, Survival rate, business.industry, Standardized mortality ratio, Pyrimidine, Nilotinib, chemistry, BCR-ABL Positive, business, Myelogenous
Abstract

Background Limited information is available regarding the rate of long-term cardiovascular (CV) mortality in chronic myeloid leukaemia (CML) patients treated with second- and third-generation tyrosine kinase inhibitors (2ndG/3rdG TKIs) in the real-life practice. Methods We identified 656 consecutive CML patients treated with nilotinib, dasatinib, bosutinib and ponatinib. Results The 15-year CV-mortality free survival was 93 ± 2.8%. Age ≥65 years (p = 0.005) and a positive history of CV disease (p = 0.04) were significantly associated with a lower CV-mortality free survival. CV disease accounted for 16.5% and 5% of potential years of life lost (PYLL) in male and female patients, respectively. The standard mortality ratio (SMR) following ischemic heart disease (IHD) was 3.9 in males and 3.8 in female patients, meaning an excess of IHD deaths observed, in comparison with the population of control. Conclusion. Prevention strategies based on CV risk factors, in particular in those patients with a previous history of CV disease, should be considered.

Published
2019

6. Long‐term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors

Author

Tim H. Brümmendorf, Kathleen Turnbull, Eric Leip, Ewa Matczak, Hanna Jean Khoury, Nathalie Bardy-Bouxin, Mark Shapiro, Carlo Gambacorti-Passerini, Hagop M. Kantarjian, Jorge E. Cortes, Dong-Wook Kim, Anna G. Turkina, GAMBACORTI PASSERINI, C, Kantarjian, H, Kim, D, Khoury, H, Turkina, A, Brümmendorf, T, Matczak, E, Bardy Bouxin, N, Shapiro, M, Turnbull, K, Leip, E, and Cortes, J

Subjects
Male, Quinoline, Gastroenterology, Piperazines, Blast Crisi, Antineoplastic Agent, 0302 clinical medicine, Aged, 80 and over, Aniline Compounds, Hematology, Myeloid leukemia, Aniline Compound, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, 3. Good health, Leukemia, Treatment Outcome, 030220 oncology & carcinogenesis, Benzamides, Toxicity, Imatinib Mesylate, Quinolines, Female, Survival Analysi, Nitrile, Bosutinib, Human, Research Article, medicine.drug, Adult, Diarrhea, medicine.medical_specialty, Adolescent, Fever, Protein Kinase Inhibitor, Antineoplastic Agents, Follow-Up Studie, 03 medical and health sciences, Benzamide, Internal medicine, Nitriles, medicine, Humans, Piperazine, Protein Kinase Inhibitors, Survival analysis, Aged, business.industry, Imatinib, Pneumonia, Original Articles, medicine.disease, Survival Analysis, Surgery, Pyrimidines, Imatinib mesylate, Pyrimidine, Drug Resistance, Neoplasm, Blast Crisis, business, Follow-Up Studies, 030215 immunology
Abstract

Long‐term efficacy and safety of bosutinib (≥4 years follow‐up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated‐phase [AP, n = 79] chronic myeloid leukemia [CML], blast‐phase [BP, n = 64] CML, acute lymphoblastic leukemia [ALL, n = 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1–88.6), 2.8 (0.03–55.9), 0.97 (0.3–89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan‐Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (n = 9) for AP and pyrexia (n = 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib‐related [AP] per investigator). Responses were durable in ∼50% AP responders at 4 years (∼25% BP patients responded at year 1, suggesting possible bridge‐to‐transplant role in BP patients); toxicity was manageable.Am. J. Hematol. 90:755–768, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.

Published
2015

7. Low Cognitive Awareness, but Not Complaint, is a Good Marker of Preclinical Alzheimer's Disease

Author

Cacciamani, Federica, Tandetnik, Caroline, Gagliardi, Geoffroy, Bertin, Hugo, Habert, Marie-Odile, Hampel, Harald, Boukadida, Laurie, Révillon, Marie, Epelbaum, Stéphane, Dubois, Bruno, Audrain, C, Auffret, A, Bakardjian, H, Baldacci, F, Batrancourt, B, Benakki, I, Benali, H, Bertin, H, Bertrand, A, Boukadida, L, Cacciamani, F, Causse, V, Cavedo, E, Cherif Touil, S, Chiesa, P A, Colliot, O, Dalla Barba, G, Depaulis, M, Dos Santos, A, Dubois, B, Dubois, M, Epelbaum, S, Fontaine, B, Francisque, H, Gagliardi, G, Genin, A, Genthon, R, Glasman, P, Gombert, F, Habert, M O, Hampel, H, Hewa, H, Houot, M, Jungalee, N, Kas, A, Kilani, M, La Corte, V, Le Roy, F, Lehericy, S, Letondor, C, Levy, M, Lista, S, Lowrey, M, Ly, J, Makiese, O, Masetti, I, Mendes, A, Metzinger, C, Michon, A, Mochel, F, Nait Arab, R, Nyasse, F, Perrin, C, Poirier, F, Poisson, C, Potier, M C, Ratovohery, S, Revillon, M, Rojkova, K, Santos-Andrade, K, Schindler, R, Servera, M C, Seux, L, Simon, V, Skovronsky, D, Thiebaut, M, Uspenskaya, O, Vlaincu, M, Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Mécanique et d'Ingénierie de Bordeaux (I2M), Institut National de la Recherche Agronomique (INRA)-Université de Bordeaux (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neuroradiologie [CHU Pitié-Salpêtrière], École Nationale Supérieure d'Arts et Métiers (ENSAM), HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Institut National de la Recherche Agronomique (INRA), Service de médecine nucléaire [CHU Pitié-Salpétrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Inria de Paris, Service d'Explorations Fonctionnelles Neurologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], HESAM Université (HESAM)-HESAM Université (HESAM)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP]-Inria de Paris, Cacciamani, Federica, Tandetnik, Caroline, Gagliardi, Geoffroy, Bertin, Hugo, Habert, Marie-Odile, Hampel, Harald, Boukadida, Laurie, Révillon, Marie, Epelbaum, Stéphane, Dubois, Bruno, Audrain, C, Auffret, A, Bakardjian, H, Baldacci, F, Batrancourt, B, Benakki, I, Benali, H, Bertin, H, Bertrand, A, Boukadida, L, Cacciamani, F, Causse, V, Cavedo, E, Cherif Touil, S, Chiesa, P A, Colliot, O, Dalla Barba, G, Depaulis, M, Dos Santos, A, Dubois, B, Dubois, M, Epelbaum, S, Fontaine, B, Francisque, H, Gagliardi, G, Genin, A, Genthon, R, Glasman, P, Gombert, F, Habert, M O, Hampel, H, Hewa, H, Houot, M, Jungalee, N, Kas, A, Kilani, M, La Corte, V, Le Roy, F, Lehericy, S, Letondor, C, Levy, M, Lista, S, Lowrey, M, Ly, J, Makiese, O, Masetti, I, Mendes, A, Metzinger, C, Michon, A, Mochel, F, Nait Arab, R, Nyasse, F, Perrin, C, Poirier, F, Poisson, C, Potier, M C, Ratovohery, S, Revillon, M, Rojkova, K, Santos-Andrade, K, Schindler, R, Servera, M C, Seux, L, Simon, V, Skovronsky, D, Thiebaut, M, Uspenskaya, O, Vlaincu, M, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service de Médecine nucléaire [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris

Subjects
Male, Ethylene Glycol, [SDV]Life Sciences [q-bio], awarene, Neuropsychological Tests, Alzheimer’s disease, awareness, biomarkers, cognitive complaints, subjective cognitive decline, Aged, Aged, 80 and over, Alzheimer Disease, Analysis of Variance, Aniline Compounds, Brain, Brain Mapping, Cognitive Dysfunction, Ethylene Glycols, Female, Functional Laterality, Humans, Positron-Emission Tomography, Psychiatric Status Rating Scales, Surveys and Questionnaires, Awareness, cognitive complaint, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 80 and over, Surveys and Questionnaire, Aniline Compound, Psychiatric Status Rating Scale, Alzheimer's disease, Clinical Psychology, Psychiatry and Mental Health, biomarker, Neuropsychological Test, Geriatrics and Gerontology, Human
Abstract

International audience; Background:Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer’s disease (AD). Objective:In this study, we searched for a specific pattern of SCD in asymptomatic individuals at risk for AD. Methods:Cognitively normal older adults (N = 318) reporting SCD and their informants were enrolled in the INSIGHT-PreAD cohort. We examined the relationship between six SCD measures and both cognitive scores and AD neuroimaging markers (amyloid burden, hippocampal atrophy and brain hypometabolism). An awareness of cognitive decline index (ACDI) has been introduced based on the subject-informant discrepancy in a questionnaire of SCD and participants with low versus high awareness were compared. Results:Scores in the INSIGHT-PreAD SCD questionnaires did not correlate with AD neuroimaging markers. As well, no correlation has been found between SCD measures and cognitive scores. Comparing subjects with a low (n = 19) and high (n = 86) level of awareness, no significant difference in terms of demography, neuropsychiatric symptoms, autonomy, quality of life, cognition, and hippocampal volume was found. However, the “low awareness” group showed greater amyloid burden and lower cortical metabolism, compared to the “high awareness” group. Conclusion:This study provided additional evidence that reporting SCD by itself is not a specific symptom of preclinical AD. Conversely, a low cognitive awareness (namely, when subjects report fewer difficulties than their relatives do) may represent a very early form of anosognosia and serve as a specific indicator of preclinical AD. This finding is of key importance as an enrichment factor to consider in both clinical practice and research trials.

Published
2017

8. More than 5000 patients with metastatic melanoma in Europe per year do not have access to recommended first-line innovative treatments

Author

Ketty Peris, Lev V. Demidov, Lars Bastholt, J.-J. Grob, Paul Nathan, M. Banjin, M. Kukushkina, Alexandros Stratigos, A.M. Forsea, A. Ymeri, Matilda Bylaite-Bucinskiene, Christoph Hoeller, A. Zhukavets, V. Todorovic, G. Weinlich, Claus Garbe, K. Putnik, L. Kandolf Sekulovic, Piotr Rutkowski, M. Risteski, K. Kirov, Iris Zalaudek, J. Ocvirk, Reinhard Dummer, D. Herceg, J. Maric-Brozic, Helen Gogas, Ricardo Vieira, Judit Oláh, Ivana Krajsová, N. Babovic, L. De La Cruz Merino, C. Blank, Johan Hansson, Bart Neyns, Axel Hauschild, C. Lebbé, Laboratory of Molecullar and Cellular Therapy, Laboratory for Medical and Molecular Oncology, Clinical sciences, [Sekulovic, L. Kandolf] Mil Med Acad, Fac Med, Dept Dermatol, Belgrade, Serbia, [Peris, K.] Univ Cattolica Sacro Cuore, Inst Dermatol, Rome, Italy, [Hauschild, A.] Univ Hosp Schleswig Holstein UKSH, Dept Dermatol, Campus Kiel, Kiel, Germany, [Stratigos, A.] Univ Athens, Athens, Greece, [Gogas, H.] Univ Athens, Athens, Greece, [Grob, J. -J.] Hop la Timone, Serv Dermatol & Cancerol Cutanee, Marseille, France, [Nathan, P.] Mt Vernon Canc Ctr, Northwood, Middx, England, [Dummer, R.] Univ Hosp, Univ Spital Zurich, Skin Canc Ctr, Zurich, Switzerland, [Forsea, A. -M.] Carol Davila Univ Med & Pharm, Elias Univ Hosp Bucharest, Bucharest, Romania, [Hoeller, C.] Med Univ Vienna, Dept Dermatol, Vienna, Austria, [Demidov, L.] NN Blokhin Russian Canc Res Ctr, Moscow, Russia, [Lebbe, C.] Hosp St Louis, APHP, Paris, France, [Blank, C.] Netherland Canc Inst, Amsterdam, Netherlands, [Olah, J.] Univ Szeged, Dept Dermatol & Allergol, Szeged, Hungary, [Bastholt, L.] Odense Univ Hosp, Dept Oncol, Odense, Denmark, [Herceg, D.] Univ Hosp Zagreb, Dept Oncol, Zagreb, Croatia, [Neyns, B.] VUB, Univ Ziekenhuis Brussel, Dept Med Oncol, Brussels, Belgium, [Vieira, R.] Univ Coimbra, Fac Med, Dept Dermatol, Coimbra, Portugal, [Hansson, J.] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden, [Hansson, J.] Karolinska Univ Hosp Solna, Stockholm, Sweden, [Rutkowski, P.] Maria Sklodowska Curie Mem Canc Ctr, Warsaw, Poland, [Rutkowski, P.] Inst Oncol, Warsaw, Poland, [Krajsova, I.] Gen Teaching Hosp, Prague, Czech Republic, [Bylaite-Bucinskiene, M.] Vilnius Univ, Dept Dermatol, Vilnius, Lithuania, [Zalaudek, I.] Med Univ Graz, Div Dermatol & Venerol, Graz, Austria, [Maric-Brozic, J.] Univ Hosp Ctr Sestre Milosrdnice, Zagreb, Croatia, [Babovic, N.] Inst Oncol & Radiol Serbia, Belgrade, Serbia, [Banjin, M.] Univ Hosp Sarajevo, Dept Oncol, Sarajevo, Bosnia & Herceg, [Putnik, K.] North Estonia Med Ctr, Tallinn, Estonia, [Weinlich, G.] Med Univ Innsbruck, Dept Dermatol & Venerol & Allergy, Innsbruck, Austria, [Todorovic, V.] Clin Oncol & Radiotherapy, Podgorica, Montenegro, [Kirov, K.] Natl Canc Ctr, Clin Oncodermatol, Sofia, Bulgaria, [Ocvirk, J.] Inst Oncol Ljubljana, Ljubljana, Slovenia, [Zhukavets, A.] NN Alexandrov Natl Canc Ctr Belarus NCCB, Minsk, BELARUS, [Kukushkina, M.] Natl Canc Inst, Kiev, Ukraine, [De La Cruz Merino, L.] Hosp Univ Virgen Macarena, Dept Clin Oncol, Seville, Spain, [Ymeri, A.] Univ Hosp Mother Theresa, Tirana, Albania, [Risteski, M.] Univ Clin Radiotherapy & Oncol, Skopje, Macedonia, [Garbe, C.] Eberhard Karls Univ Tubingen, Dept Dermatol, Ctr Dermatooncol, Tubingen, Germany, Kandolf Sekulovic, L., Peris, K., Hauschild, A., Stratigos, A., Grob, J. -J., Nathan, P., Dummer, R., Forsea, A. -M., Hoeller, C., Gogas, H., Demidov, L., Lebbe, C., Blank, C., Olah, J., Bastholt, L., Herceg, D., Neyns, B., Vieira, R., Hansson, J., Rutkowski, P., Krajsova, I., Bylaite-Bucinskiene, M., Zalaudek, I., Maric-Brozic, J., Babovic, N., Banjin, M., Putnik, K., Weinlich, G., Todorovic, V., Kirov, K., Ocvirk, J., Zhukavets, A., Kukushkina, M., De La Cruz Merino, L., Ymeri, A., Risteski, M., and Garbe, C.

Subjects
Human development index, Male, Cancer Research, Skin Neoplasms, Survival, medicine.medical_treatment, Access, Health expenditure per capita, Immunooncology, Innovative medicines, Metastatic melanoma, Targeted therapy, Treatment, Acrylonitrile, Aniline Compounds, Antibodies, Monoclonal, Humanized, Europe, Female, Health Services Accessibility, Healthcare Disparities, Humans, Immunotherapy, Melanoma, Programmed Cell Death 1 Receptor, Proto-Oncogene Proteins B-raf, Reimbursement Mechanisms, Therapies, Investigational, Oncology, Investigational, Reimbursement Mechanism, Melanoma/economics, Disparities, Immuno oncology, Medicines, 0302 clinical medicine, Diagnosis, Health care, Monoclonal, 030212 general & internal medicine, Healthcare Disparities/economics, Acce, Acrylonitrile/analogs & derivatives, Humanized, Proto-Oncogene Proteins B-raf/antagonists & inhibitors, Reimbursement, Programmed Cell Death 1 Receptor/antagonists & inhibitors, Aniline Compound, Healthcare Disparitie, Health Services Accessibility/economics, 030220 oncology & carcinogenesis, Targeted therapy Health, Innovative medicine, Health-care, Settore MED/35 - MALATTIE CUTANEE E VENEREE, Treatment Immunooncology, Human, medicine.medical_specialty, Reimbursement Mechanisms/statistics & numerical data, Union, Antibodies, Europe/epidemiology, Malignant-melanoma, 03 medical and health sciences, Pharmacotherapy, Internal medicine, medicine, Skin Neoplasm, Human Development Index, Mortality, Therapies, Investigational/economics, Skin Neoplasms/economics, Health policy, business.industry, Cancer, medicine.disease, access, innovative medicines, metastatic melanoma, treatment, immunooncologytargeted therapyhealth expenditure per capita, human development index, Surgery, Immunotherapy/economics, Therapies, Aniline Compounds/economics, Skin cancer, business, Cancer incidence, Antibodies, Monoclonal, Humanized/economics
Abstract

Background. Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europeand estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF). Materials and methods Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes. Results The recommended BRAF inhibitor (BRAFi)+MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), (r=0.662; p Previous article in issue

Published
2017

9. Exogenous -Synuclein Decreases Raft Partitioning of Cav2.2 Channels Inducing Dopamine Release

Author

Liudmila Mus, Gary J. Stephens, Raul R. Gainetdinov, Evelina Chieregatti, Mark L. Dallas, Camille H. Soubrane, Lorenzo A. Cingolani, Agnes Thalhammer, Giuseppe Ronzitti, Giovanna Bucci, Sumiko Mochida, Tatyana D. Sotnikova, Damiana Leo, Marco Emanuele, Ronzitti, Giuseppe, Bucci, Giovanna, Emanuele, Marco, Leo, Damiana, Sotnikova, Tatyana D., Mus, Liudmila V., Soubrane, Camille H., Dallas, Mark L., Thalhammer, Agne, Cingolani, Lorenzo A., Mochida, Sumiko, Gainetdinov, Raul R., Stephens, Gary J., and Chieregatti, Evelina

Subjects
Male, Antibodie, Dopamine, animal diseases, Wistar, Synaptic Transmission, Membrane Potentials, N-Type, Sodium Channel Blocker, chemistry.chemical_compound, Calcium Channels, N-Type, Dopamine release, Membrane Microdomain, Neurotransmitter, Cells, Cultured, Neurons, Cerebral Cortex, Membrane potential, Aniline Compounds, Cultured, Voltage-dependent calcium channel, General Neuroscience, Extracellular alpha-synuclein, Synapsin, Aniline Compound, Cell biology, Embryo, alpha-Synuclein, Lipid rafts, Animals, Antibodies, Embryo, Mammalian, Excitatory Postsynaptic Potentials, Membrane Microdomains, Rats, Rats, Wistar, Sodium Channel Blockers, Superior Cervical Ganglion, Synaptophysin, Xanthenes, Neuroscience (all), Cells, Neurotransmission, Biology, Membrane Potential, Synaptic vesicle, Xanthene, Neurotransmitter receptor, mental disorders, Active zone, Animal, Mammalian, Neuron, nervous system diseases, Lipid raft, Excitatory Postsynaptic Potential, nervous system, chemistry, Rat, Calcium Channels
Abstract

alpha-Synuclein is thought to regulate neurotransmitter release through multiple interactions with presynaptic proteins, cytoskeletal elements, ion channels, and synaptic vesicles membrane. alpha-Synuclein is abundant in the presynaptic compartment, and its release from neurons and glia has been described as responsible for spreading of alpha-synuclein-derived pathology. alpha-Synuclein-dependent dysregulation of neurotransmitter release might occur via its action on surface-exposed calcium channels. Here, we provide electrophysiological and biochemical evidence to show that alpha-synuclein, applied to rat neurons in culture or striatal slices, selectively activates Cav2.2 channels, and said activation correlates with increased neurotransmitter release. Furthermore, in vivo perfusion of alpha-synuclein into the striatum also leads to acute dopamine release. We further demonstrate that alpha-synuclein reduces the amount of plasma membrane cholesterol and alters the partitioning of Cav2.2 channels, which move from raft to cholesterol-poor areas of the plasma membrane. We provide evidence for a novel mechanism through which alpha-synuclein acts from the extracellular milieu to modulate neurotransmitter release and propose a unifying hypothesis for the mechanism of alpha-synuclein action on multiple targets: the reorganization of plasma membrane microdomains.

Published
2014

10. Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

Author

Caterina Carmi, Silvia Rivara, Simonetta Russo, Fabrizio Bordi, Federica Vacondio, Gabriele Costantino, Andrea Cavazzoni, Andrea Ardizzoni, Roberta Alfieri, Elena Galvani, Marco Mor, Pier Giorgio Petronini, Stefania Aiello, Alessio Lodola, Carmi, C, Galvani, E, Vacondio, F, Rivara, S, Lodola, A, Russo, S, Aiello, S, Bordi, F, Costantino, G, Cavazzoni, A, Alfieri, RR, Ardizzoni, A, Petronini, PG, Mor, M, Carmi, Caterina, Galvani, Elena, Vacondio, Federica, Rivara, Silvia, Lodola, Alessio, Russo, Simonetta, Aiello, Stefania, Bordi, Fabrizio, Costantino, Gabriele, Cavazzoni, Andrea, Alfieri, Roberta R., Ardizzoni, Andrea, Petronini, Pier Giorgio, and Mor, Marco

Subjects
Amide, Cell Survival, EGFR inhibitors, Quinoline, Antineoplastic Agents, Antineoplastic Agent, Structure-Activity Relationship, T790M, Gefitinib, Cell Line, Tumor, Drug Discovery, Propionate, medicine, Humans, Structure–activity relationship, Epidermal growth factor receptor, Phosphorylation, Aniline Compounds, biology, Chemistry, Drug Discovery3003 Pharmaceutical Science, Autophosphorylation, Quinazoline, Aniline Compound, Amides, Settore CHIM/08 - Chimica Farmaceutica, ErbB Receptors, Biochemistry, Protein kinase domain, Drug Resistance, Neoplasm, Quinazolines, Quinolines, biology.protein, Molecular Medicine, Receptor, Epidermal Growth Factor, Propionates, Drug Screening Assays, Antitumor, Tyrosine kinase, Human, medicine.drug
Abstract

Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3- carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6- yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups. © 2012 American Chemical Society.

Published
2012

11. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia : results from the 24-month follow-up of the BELA trial

Author

Karin Gogat, Tim H. Brümmendorf, Ladan Duvillie, Carmino Antonio De Souza, François Guilhot, Dmitri Pavlov, Athena Countouriotis, Jorge E. Cortes, Carlo Gambacorti-Passerini, Brümmendorf, T, Cortes, J, de Souza, C, Guilhot, F, Duvillié, L, Pavlov, D, Gogat, K, Countouriotis, A, and GAMBACORTI PASSERINI, C

Subjects
Male, Oncology, Quinoline, Fusion Proteins, bcr-abl, Piperazines, Tyrosine-kinase inhibitor, Antineoplastic Agent, tyrosine kinase inhibitor, hemic and lymphatic diseases, Odds Ratio, CML, Aged, 80 and over, Aniline Compounds, Hematology, medicine.diagnostic_test, Haematological Malignancy, Aniline Compound, Middle Aged, Treatment Outcome, Tolerability, Benzamides, Leukemia, Myeloid, Chronic-Phase, Imatinib Mesylate, Quinolines, Female, Nitrile, Bosutinib, Human, medicine.drug, medicine.medical_specialty, chronic myeloid leukaemia, medicine.drug_class, Protein Kinase Inhibitor, Antineoplastic Agents, bosutinib, Neutropenia, Follow-Up Studie, Benzamide, Internal medicine, Nitriles, medicine, Humans, ddc:610, Adverse effect, Piperazine, Protein Kinase Inhibitors, Aged, business.industry, Imatinib, medicine.disease, BCR-ABL1, Pyrimidines, Pyrimidine, Mutation, Immunology, business, Liver function tests, Follow-Up Studies
Abstract

British journal of haematology 168(1), 69-81 (2015). doi:10.1111/bjh.13108, Published by Wiley-Blackwell, Oxford [u.a.]

Published
2015
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12. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors

Author

GAMBACORTI PASSERINI, C, Kantarjian, H, Kim, D, Khoury, H, Turkina, A, Brümmendorf, T, Matczak, E, Bardy Bouxin, N, Shapiro, M, Turnbull, K, Leip, E, Cortes, J, GAMBACORTI PASSERINI, CARLO, Cortes, J., GAMBACORTI PASSERINI, C, Kantarjian, H, Kim, D, Khoury, H, Turkina, A, Brümmendorf, T, Matczak, E, Bardy Bouxin, N, Shapiro, M, Turnbull, K, Leip, E, Cortes, J, GAMBACORTI PASSERINI, CARLO, and Cortes, J.

Abstract

Long-term efficacy and safety of bosutinib (≥4 years follow-up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated-phase [AP, n = 79] chronic myeloid leukemia [CML], blast-phase [BP, n = 64] CML, acute lymphoblastic leukemia [ALL, n = 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1-88.6), 2.8 (0.03-55.9), 0.97 (0.3-89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan-Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (n = 9) for AP and pyrexia (n = 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib-related [AP] per investigator). Responses were durable in ∼50% AP responders at 4 years (∼25% BP patients responded at year 1, suggesting possible bridge-to-transplant role in BP patients); toxicity was manageable.

Published
2015

13. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: Results from the 24-month follow-up of the BELA trial

Author

Brümmendorf, T, Cortes, J, de Souza, C, Guilhot, F, Duvillié, L, Pavlov, D, Gogat, K, Countouriotis, A, GAMBACORTI PASSERINI, C, GAMBACORTI PASSERINI, CARLO, Brümmendorf, T, Cortes, J, de Souza, C, Guilhot, F, Duvillié, L, Pavlov, D, Gogat, K, Countouriotis, A, GAMBACORTI PASSERINI, C, and GAMBACORTI PASSERINI, CARLO

Abstract

Bosutinib is an oral, dual SRC/ABL1 tyrosine kinase inhibitor for resistant/intolerant chronic myeloid leukaemia (CML). We assessed the efficacy and safety of bosutinib 500 mg/d (n = 250) versus imatinib 400 mg/d (n = 252) after >24 months from accrual completion in newly diagnosed chronic phase (CP)-CML (Bosutinib Efficacy and Safety in Newly Diagnosed CML trial [BELA]). Cumulative complete cytogenetic response (CCyR) rates by 24 months were similar (bosutinib, 79%; imatinib, 80%); cumulative major molecular response (MMR) rates were 59% for bosutinib and 49% for imatinib. Responses were durable; 151/197 vs. 172/204 and 125/153 vs. 117/131 responders remained on treatment and maintained CCyR and MMR, respectively. Since the 12-month primary analysis, no new accelerated-/blast-phase transformations occurred with bosutinib; four occurred with imatinib. Early response (BCR-ABL1/ABL1 ≤ 10%, 3 months) was associated with better CCyR and MMR rates by 12 and 24 months (both arms). Gastrointestinal events and liver function test elevations were more common, and neutropenia, musculoskeletal events and oedema were less common with bosutinib. Discontinuations due to adverse events were more common with bosutinib versus imatinib (most commonly alanine aminotransferase elevation: 4% vs. <1%); most occurred within the first 12 months. Cardiovascular adverse events were similar in both arms. Bosutinib continues to demonstrate good efficacy and manageable tolerability in newly diagnosed CP-CML patients.

Published
2015

14. Advances in management of follicular lymphoma

Author

PIER LUIGI ZINZANI and P. L. Zinzani

Subjects
Murine-Derived, administration /&/ dosage, Vincristine, Prednisolone, Antibodies, Monoclonal, Murine-Derived, administration /&/ dosage, Radioimmunotherapy, Sulfonamide, Antineoplastic Combined Chemotherapy Protocols, Drug Discovery, Monoclonal, Humans, CD20, Molecular Targeted Therapy, genetics/immunology/therapy, Molecular Targeted Therapy, Neoplasm Staging, Prednisolone, Prednisone, administration /&/ dosage, Doxorubicin, Drug Discovery, Hematopoietic Stem Cell Transplantation, Humans, Lymphoma, Autografts, administration /&/ dosage, Cyclophosphamide, Lymphoma, Follicular, Neoplasm Staging, Sulfonamides, Aniline Compounds, administration /&/ dosage/therapeutic use, Autografts, Combined Modality Therapy, Cyclophosphamide, Hematopoietic Stem Cell Transplantation, Follicular, Antibodies, Monoclonal, Radioimmunotherapy, Aniline Compound, Antigens, CD20, Combined Modality Therapy, administration /&/ dosage, Antibodie, Doxorubicin, Vincristine, Prednisone, immunology, Antineoplastic Combined Chemotherapy Protocol, Rituximab, administration /&/ dosage, Antigen
Abstract

No abstract available.

Published
2014

15. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors

Author

Virginia Kelly, Dong-Wook Kim, Eric Leip, H. Jean Khoury, Tim H. Brümmendorf, Hagop M. Kantarjian, Jorge E. Cortes, Simon Durrant, Carlo Gambacorti-Passerini, Giovanni Martinelli, Kimmo Porkka, Kathleen Turnbull, Nadine Besson, Kantarjian, H, Cortes, J, Kim, D, Khoury, H, Brümmendorf, T, Porkka, K, Martinelli, G, Durrant, S, Leip, E, Kelly, V, Turnbull, K, Besson, N, and GAMBACORTI PASSERINI, C

Subjects
Male, Clinical Trials and Observations, Quinoline, Pharmacology, Biochemistry, Gastroenterology, Piperazines, hemic and lymphatic diseases, Protein-Tyrosine Kinase, Aged, 80 and over, Aniline Compounds, Myeloid leukemia, Hematology, Protein-Tyrosine Kinases, Aniline Compound, Middle Aged, Dasatinib, Tolerability, Benzamides, Imatinib Mesylate, Quinolines, Female, Bosutinib, Nitrile, medicine.drug, Human, Adult, medicine.medical_specialty, Drug-Related Side Effects and Adverse Reactions, Adolescent, Immunology, Protein Kinase Inhibitor, Young Adult, Benzamide, Acute lymphocytic leukemia, Internal medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Nitriles, medicine, Humans, Protein Kinase Inhibitors, Piperazine, Aged, Dose-Response Relationship, Drug, business.industry, Imatinib, Cell Biology, medicine.disease, Imatinib mesylate, Pyrimidines, Nilotinib, Pyrimidine, Withholding Treatment, Drug Resistance, Neoplasm, business, Drug-Related Side Effects and Adverse Reaction
Abstract

Bosutinib is an oral, dual SRC/ABL tyrosine kinase inhibitor (TKI) with clinical activity in Philadelphia chromosome-positive (Ph(+)) leukemia. We assessed the safety and tolerability of bosutinib 500 mg per day in a phase 1/2 study in chronic-phase (CP) chronic myeloid leukemia (CML) or advanced Ph(+) leukemia following resistance/intolerance to imatinib and possibly other TKIs. Patient cohorts included second-line CP CML (n = 286), third-/fourth-line CP CML (n = 118), and advanced leukemia (n = 166). Median bosutinib duration was 11.1 (range, 0.03-83.4) months. Treatment-emergent adverse events (TEAEs) in each cohort were primarily gastrointestinal (diarrhea [86%/83%/74%], nausea [46%/48%/48%], and vomiting [37%/38%/43%]). Diarrhea presented early, with few (8%) patients experiencing grade 3/4 events; dose reduction due to diarrhea occurred in 6% of affected patients. Grade 3/4 myelosuppression TEAEs were reported in 41% of patients; among affected patients, 46% were managed with bosutinib interruption and 32% with dose reduction. Alanine aminotransferase elevation TEAEs occurred in 17% of patients (grade 3/4, 7%); among patients managed with dose interruption, bosutinib rechallenge was successful in 74%. Bosutinib demonstrated acceptable safety with manageable toxicities in Ph(+) leukemia. This trial (NCT00261846) was registered at www.ClinicalTrials.gov (this manuscript is based on a different data snapshot from that in ClinicalTrials.gov).

Published
2013

16. A nanostructured composite based on polyaniline and gold nanoparticles: synthesis and gas sensing properties

Author

Andrea Bearzotti, Iole Venditti, Maria Vittoria Russo, Ilaria Fratoddi, Venditti, I., Fratoddi, I., Russo, M. V., and Bearzotti, A.

Subjects
Materials science, Inorganic chemistry, Composite number, NANOTUBES, Metal Nanoparticles, Bioengineering, Nanomaterials, Metal Nanoparticle, chemistry.chemical_compound, Ammonia, Polyaniline, SENSORS, Nanotechnology, General Materials Science, Electrical and Electronic Engineering, Acetonitrile, Nanocomposite, Aniline Compounds, Mechanical Engineering, Gase, POLYMER, General Chemistry, Aniline Compound, NANOCOMPOSITES, Amorphous solid, chemistry, Mechanics of Materials, Colloidal gold, Microscopy, Electron, Scanning, Spectrophotometry, Ultraviolet, Gases, Gold, Methanol, NANOFIBERS
Abstract

Nanostructured composite materials based on polyaniline (PANI) and gold nanoparticles have been prepared by means of an osmosis based method. Several morphologies have been obtained for the pristine nanoPANI and for nanoPANI-Au composite, ranging from amorphous to sponge-like and spherical shapes. On the basis of this morphological investigation, different materials with high surface area have been selected and tested as chemical interactive materials for room temperature gas and vapor sensing. The resistive sensor devices have been exposed to different vapor organic compounds (VOCs) of interest in the fields of environmental monitoring and biomedical applications, such as toluene, acetic acid, ethanol, methanol, acetonitrile, water, ammonia and nitrogen dioxide. The effect of doping with H2SO4 has been studied for both nanoPANI and nanoPANI-Au samples. In particular, nanoPANI-Au showed sensitivity to ammonia (up to 10 ppm) higher than that to other VOCs or interfering analytes. The facile preparation method and the improved properties achieved for the polyaniline-gold composite materials are significant in the nanomaterials field and have promise for applications in ammonia vapor monitoring. © 2013 IOP Publishing Ltd.

Published
2013

17. The prognostic value of amyloid imaging

Author

David J. Brooks, Giorgio Gelosa, Gelosa, G, and Brooks, D

Subjects
Oncology, medicine.medical_specialty, Pathology, Radiology, Nuclear Medicine and Imaging, Amyloid, Mild Cognitive Impairment, Amyloid beta-Peptide, Prognosi, Pittsburgh Compound B (PiB), Plaque, Amyloid, Neuropathology, Disease, Amyloid imaging, Alzheimer Disease, Internal medicine, Stilbenes, medicine, Humans, Cognitive Dysfunction, Effects of sleep deprivation on cognitive performance, Mild cognitive impairment (MCI), Amyloid beta-Peptides, Aniline Compounds, business.industry, General Medicine, Aniline Compound, medicine.disease, Prognosis, Clinical trial, Thiazoles, Ageing, Positron emission tomography (PET), Stilbene, Positron-Emission Tomography, Alzheimer's disease (AD), Radiopharmaceutical, Alzheimer's disease, Thiazole, Radiopharmaceuticals, business, Human
Abstract

Mild cognitive impairment is characterized by a decline in cognitive performance without interference with activities of daily living. The amnestic subtype of mild cognitive impairment progresses to Alzheimer's disease at a rate of 10-15 % per year and in the majority the neuropathology is intermediate between the neuropathological changes of typical ageing and Alzheimer's disease. Amyloid deposition occurs over a decade before the development of noticeable cognitive symptoms in a continuous process that starts in healthy elderly individuals. Newly developed PET amyloid imaging agents provide noninvasive biomarkers for the early in vivo detection of Alzheimer's pathology in healthy elderly individuals and those with mild cognitive impairment. Exclusion of amyloid pathology should allow a more accurate prognosis to be given and ensure appropriate recruitment into clinical trials testing the efficacy of new putative antiamyloid agents at an earlier disease stage. The development of 18F-labelled amyloid imaging agents has increased the availability of this new technology for clinical and research use since they can be used in PET centres where a cyclotron and radiochemistry are not available. This review discusses the role of PET imaging for assessing the amyloid load in cognitively normal elderly subjects and subjects with mild cognitive impairment at risk of conversion to Alzheimer's disease. © 2012 Springer-Verlag.

Published
2012

18. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure

Author

Tim H. Brümmendorf, Nadine Besson, Virginia Kelly, Carlo Gambacorti-Passerini, Athena Countouriotis, Michele Baccarani, Andrey Zaritskey, Hagop M. Kantarjian, Eric Leip, Jorge E. Cortes, H. Jean Khoury, Dong-Wook Kim, Khoury, H, Cortes, J, Kantarjian, H, GAMBACORTI PASSERINI, C, Baccarani, M, Kim, D, Zaritskey, A, Countouriotis, A, Besson, N, Leip, E, Kelly, V, and Brümmendorf, T

Subjects
Oncology, Male, Clinical Trials and Observations, Quinoline, Dasatinib, Pharmacology, Biochemistry, Piperazines, Antineoplastic Agent, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Treatment Failure, Aniline Compounds, Myeloid leukemia, Hematology, Aniline Compound, Middle Aged, Rash, Algorithm, Leukemia, Chemotherapy, Adjuvant, Benzamides, Leukemia, Myeloid, Chronic-Phase, Imatinib Mesylate, Quinolines, Female, medicine.symptom, Bosutinib, Nitrile, Algorithms, medicine.drug, Human, Adult, medicine.medical_specialty, Immunology, Antineoplastic Agents, Young Adult, Internal medicine, Nitriles, medicine, Humans, Piperazine, Aged, Antineoplastic Combined Chemotherapy Protocol, business.industry, Imatinib, Cell Biology, medicine.disease, Thiazoles, Imatinib mesylate, Pyrimidines, Nilotinib, Pyrimidine, Drug Resistance, Neoplasm, Thiazole, business
Abstract

Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has shown potent activity against chronic myeloid leukemia (CML). This phase 1/2 study evaluated the efficacy and safety of once-daily bosutinib 500 mg in leukemia patients after resistance/intolerance to imatinib. The current analysis included 118 patients with chronic-phase CML who had been pretreated with imatinib followed by dasatinib and/or nilotinib, with a median follow-up of 28.5 months. In this subpopulation, major cytogenetic response was attained by 32% of patients; complete cytogenetic response was attained by 24%, including in one of 3 patients treated with 3 prior TKIs. Complete hematologic response was achieved/maintained in 73% of patients. On-treatment transformation to accelerated/blast phase occurred in 5 patients. At 2 years, Kaplan-Meier–estimated progression-free survival was 73% and estimated overall survival was 83%. Responses were seen across Bcr-Abl mutations, including those associated with dasatinib and nilotinib resistance, except T315I. Bosutinib had an acceptable safety profile; treatment-emergent adverse events were primarily manageable grade 1/2 gastrointestinal events and rash. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (8%) and rash (4%). Bosutinib may offer a new treatment option for patients with chronic-phase CML after treatment with multiple TKIs. This trial was registered at www.clinicaltrials.gov as NCT00261846.

Published
2012

19. Influence of processing and storage time on the lipidic fraction of taralli

Author

Francesco Caponio, Antonella Pasqualone, Vito Michele Paradiso, Tommaso Gomes, Carmine Summo, Caponio, F., Summo, C., Pasqualone, A., Paradiso, V. M., and Gomes, T.

Subjects
Time Factors, Time Factor, Food Handling, Fast Food, Food storage, Fraction (chemistry), Shelf life, Fats, Taralli, Principal Component Analysi, Phase (matter), Cooking, Dietary Fat, Triglycerides, chemistry.chemical_classification, Principal Component Analysis, Chromatography, Aniline Compounds, Shelf-life, Polar compound, Food preservation, Oxidative degradation, Aniline Compound, Dietary Fats, Warehouse, chemistry, Fat, Fatty Acids, Unsaturated, Degradation (geology), Fast Foods, lipids (amino acids, peptides, and proteins), Oxidation-Reduction, Lipidic fraction, Food Science, Polyunsaturated fatty acid
Abstract

An experimental investigation was carried out to evaluate the influence of processing and storage time on the lipidic fraction of taralli. The data obtained pointed out that the kneading phase caused a significant increase of the oxidized triacylglycerols and triacylglycerol oligopolymers, primary and secondary oxidation compounds, respectively, accompanied by a significant decrease of the content of polyunsaturated fatty acids. The successive baking step caused the degradation of a part of the oxidized compounds to volatile substances, as confirmed by the p-Anisidine values, whereas the storage time determined a further significant increase of the level of oxidized triacylglycerols. Finally, the level of diacylglycerols, monoacylglycerols, and free fatty acids, indicative of hydrolytic degradation, did not show significant changes. The principal component analysis allowed one to clearly distinguish among samples obtained through processing conditions. © 2009 Institute of Food Technologists®.

Published
2010

20. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors

Author

Kantarjian, H, Cortes, J, Kim, D, Khoury, H, Brümmendorf, T, Porkka, K, Martinelli, G, Durrant, S, Leip, E, Kelly, V, Turnbull, K, Besson, N, GAMBACORTI PASSERINI, C, GAMBACORTI PASSERINI, CARLO, Kantarjian, H, Cortes, J, Kim, D, Khoury, H, Brümmendorf, T, Porkka, K, Martinelli, G, Durrant, S, Leip, E, Kelly, V, Turnbull, K, Besson, N, GAMBACORTI PASSERINI, C, and GAMBACORTI PASSERINI, CARLO

Abstract

Bosutinib is an oral, dual SRC/ABL tyrosine kinase inhibitor (TKI) with clinical activity in Philadelphia chromosome-positive (Ph(+)) leukemia. We assessed the safety and tolerability of bosutinib 500 mg per day in a phase 1/2 study in chronic-phase (CP) chronic myeloid leukemia (CML) or advanced Ph(+) leukemia following resistance/intolerance to imatinib and possibly other TKIs. Patient cohorts included second-line CP CML (n = 286), third-/fourth-line CP CML (n = 118), and advanced leukemia (n = 166). Median bosutinib duration was 11.1 (range, 0.03-83.4) months. Treatment-emergent adverse events (TEAEs) in each cohort were primarily gastrointestinal (diarrhea [86%/83%/74%], nausea [46%/48%/48%], and vomiting [37%/38%/43%]). Diarrhea presented early, with few (8%) patients experiencing grade 3/4 events; dose reduction due to diarrhea occurred in 6% of affected patients. Grade 3/4 myelosuppression TEAEs were reported in 41% of patients; among affected patients, 46% were managed with bosutinib interruption and 32% with dose reduction. Alanine aminotransferase elevation TEAEs occurred in 17% of patients (grade 3/4, 7%); among patients managed with dose interruption, bosutinib rechallenge was successful in 74%. Bosutinib demonstrated acceptable safety with manageable toxicities in Ph(+) leukemia. This trial (NCT00261846) was registered at www.ClinicalTrials.gov (this manuscript is based on a different data snapshot from that in ClinicalTrials.gov).

Published
2013

21. Bosutinib: A review of preclinical studies in chronic myelogenous leukaemia

Author

Kim Arndt, Carlo Gambacorti-Passerini, Frank Boschelli, Boschelli, F, Arndt, K, and Gambacorti-Passerini, C

Subjects
Cancer Research, Quinoline, Tyrosine kinase inhibitor, Cell Communication, Tyrosine-kinase inhibitor, Antineoplastic Agent, Mice, Breast cancer, hemic and lymphatic diseases, Transplantation, Heterologou, Enzyme Inhibitor, Enzyme Inhibitors, Clinical Trials as Topic, Aniline Compounds, ABL, Aniline Compound, Clinical trial, src-Family Kinases, Oncology, Quinolines, Bosutinib, src-Family Kinase, Nitrile, medicine.drug, Bcr-Abl, Src, Human, medicine.drug_class, Transplantation, Heterologous, Protein Kinase Inhibitor, Antineoplastic Agents, Biology, Philadelphia chromosome, Cyclic N-Oxides, Myelogenous, Cell Line, Tumor, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Nitriles, medicine, Animals, Humans, Imatinib resistance, Protein Kinase Inhibitors, neoplasms, Animal, Imatinib, medicine.disease, Chronic myelogenous leukaemia, Transplantation, Cyclic N-Oxide, Drug Resistance, Neoplasm, Cancer research, SKI-606, Tumour, Neoplasm Transplantation, Chronic myelogenous leukemia
Abstract

Bosutinib (SKI-606) is an orally active Src and Abl kinase inhibitor presently in Phase III trials for treatment of chronic myelogenous leukaemia (CML), and in Phase II trials for treatment of breast cancer. Bosutinib is a potent antiproliferative and proapoptotic agent in CML cells and inhibits Bcr-Abl mediated signalling at nanomolar concentrations. Short-term administration of bosutinib causes regression of K562 and KU812 CML tumour xenografts. BaF3 murine myeloid cells expressing wild-type Bcr-Abl are sensitive to bosutinib treatment, as are BaF3 cells expressing many imatinib-resistant forms of Bcr-Abl. Recent studies indicate that bosutinib is active against a broader spectrum of kinases than originally believed. These additional inhibitory activities have interesting possibilities for further clinical development. This review will focus on preclinical studies supporting the clinical development of bosutinib for treatment of CML, with a discussion on the broader potential of this agent in other oncology indications. © 2010 Elsevier Ltd. All rights reserved

Published
2010

22. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure

Author

Khoury, H, Cortes, J, Kantarjian, H, GAMBACORTI PASSERINI, C, Baccarani, M, Kim, D, Zaritskey, A, Countouriotis, A, Besson, N, Leip, E, Kelly, V, Brümmendorf, T, GAMBACORTI PASSERINI, CARLO, Brümmendorf, T., Khoury, H, Cortes, J, Kantarjian, H, GAMBACORTI PASSERINI, C, Baccarani, M, Kim, D, Zaritskey, A, Countouriotis, A, Besson, N, Leip, E, Kelly, V, Brümmendorf, T, GAMBACORTI PASSERINI, CARLO, and Brümmendorf, T.

Abstract

Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has shown potent activity against chronic myeloid leukemia (CML). This phase 1/2 study evaluated the efficacy and safety of once-daily bosutinib 500 mg in leukemia patients after resistance/intolerance to imatinib. The current analysis included 118 patients with chronic-phase CML who had been pretreated with imatinib followed by dasatinib and/or nilotinib, with a median follow-up of 28.5 months. In this subpopulation, major cytogenetic response was attained by 32% of patients; complete cytogenetic response was attained by 24%, including in one of 3 patients treated with 3 prior TKIs. Complete hematologic response was achieved/maintained in 73% of patients. On-treatment transformation to accelerated/blast phase occurred in 5 patients. At 2 years, Kaplan-Meier-estimated progression-free survival was 73% and estimated overall survival was 83%. Responses were seen across Bcr-Abl mutations, including those associated with dasatinib and nilotinib resistance, except T315I. Bosutinib had an acceptable safety profile; treatment-emergent adverse events were primarily manageable grade 1/2 gastrointestinal events and rash. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (8%) and rash (4%). Bosutinib may offer a new treatment option for patients with chronic-phase CML after treatment with multiple TKIs. This trial was registered at www.clinicaltrials.gov as NCT00261846.

Published
2012

23. The prognostic value of amyloid imaging

Author

Gelosa, G, Brooks, D, GELOSA, GIORGIO, Brooks, D., Gelosa, G, Brooks, D, GELOSA, GIORGIO, and Brooks, D.

Abstract

Mild cognitive impairment is characterized by a decline in cognitive performance without interference with activities of daily living. The amnestic subtype of mild cognitive impairment progresses to Alzheimer's disease at a rate of 10-15 % per year and in the majority the neuropathology is intermediate between the neuropathological changes of typical ageing and Alzheimer's disease. Amyloid deposition occurs over a decade before the development of noticeable cognitive symptoms in a continuous process that starts in healthy elderly individuals. Newly developed PET amyloid imaging agents provide noninvasive biomarkers for the early in vivo detection of Alzheimer's pathology in healthy elderly individuals and those with mild cognitive impairment. Exclusion of amyloid pathology should allow a more accurate prognosis to be given and ensure appropriate recruitment into clinical trials testing the efficacy of new putative antiamyloid agents at an earlier disease stage. The development of 18F-labelled amyloid imaging agents has increased the availability of this new technology for clinical and research use since they can be used in PET centres where a cyclotron and radiochemistry are not available. This review discusses the role of PET imaging for assessing the amyloid load in cognitively normal elderly subjects and subjects with mild cognitive impairment at risk of conversion to Alzheimer's disease. © 2012 Springer-Verlag.

Published
2012

24. Synergistic activity of the Src/Abl inhibitor bosutinib in combination with imatinib

Author

Redaelli, S, Boschelli, F, Perini, P, Pirola, A, Viltadi, M, GAMBACORTI PASSERINI, C, REDAELLI, SARA, PERINI, PIETRO, PIROLA, ALESSANDRA, VILTADI, MICHELA, GAMBACORTI PASSERINI, CARLO, Redaelli, S, Boschelli, F, Perini, P, Pirola, A, Viltadi, M, GAMBACORTI PASSERINI, C, REDAELLI, SARA, PERINI, PIETRO, PIROLA, ALESSANDRA, VILTADI, MICHELA, and GAMBACORTI PASSERINI, CARLO

Published
2010

25. Bosutinib: A review of preclinical studies in chronic myelogenous leukaemia

Author

Boschelli, F, Arndt, K, Gambacorti-Passerini, C, Boschelli, F, Arndt, K, and Gambacorti-Passerini, C

Abstract

Bosutinib (SKI-606) is an orally active Src and Abl kinase inhibitor presently in Phase III trials for treatment of chronic myelogenous leukaemia (CML), and in Phase II trials for treatment of breast cancer. Bosutinib is a potent antiproliferative and proapoptotic agent in CML cells and inhibits Bcr-Abl mediated signalling at nanomolar concentrations. Short-term administration of bosutinib causes regression of K562 and KU812 CML tumour xenografts. BaF3 murine myeloid cells expressing wild-type Bcr-Abl are sensitive to bosutinib treatment, as are BaF3 cells expressing many imatinib-resistant forms of Bcr-Abl. Recent studies indicate that bosutinib is active against a broader spectrum of kinases than originally believed. These additional inhibitory activities have interesting possibilities for further clinical development. This review will focus on preclinical studies supporting the clinical development of bosutinib for treatment of CML, with a discussion on the broader potential of this agent in other oncology indications. © 2010 Elsevier Ltd. All rights reserved

Published
2010

26. Total urinary hydroxyproline determined with rapid and simple high-performance liquid chromatography

Author

P. A. Bonini, Luisa Diomede, E. De Vecchi, C. Arcelloni, Isabella Fermo, Fulvio Magni, Rita Paroni, Paroni, R, De Vecchi, E, Fermo, I, Arcelloni, C, Diomede, L, Magni, F, and Bonini, P

Subjects
Detection limit, Chromatography, Sodium, Biochemistry (medical), Clinical Biochemistry, chemistry.chemical_element, Urine, Cysteic acid, Hydrogen-Ion Concentration, Aniline Compound, High-performance liquid chromatography, Regression Analysi, Adduct, Indicators and Reagent, chemistry.chemical_compound, Hydroxyproline, chemistry, Ninhydrin, Triethylamine, Chromatography, High Pressure Liquid, Human
Abstract

A precolumn derivatization method was optimized for rapid and specific analysis of total urinary hydroxyproline by HPLC. After an overnight hydrolysis, urine samples dried and reconstituted with the internal standard cysteic acid (in sodium hydrogen carbonate, pH 9.3) were derivatized with N,N-diethyl-2,4-dinitro-5-fluoroaniline (FDNDEA) at 100 degrees C for 20 min. The DNDEA-hydroxyproline adduct was separated on an Ultrasphere ODS column with a mobile phase of acetate buffer (containing triethylamine, 6 mL/L, pH 4.3) and acetonitrile (80/20, by vol), and was detected at 360 nm. A single run took 18 min with a hydroxyproline retention time of 7.3 min. The assay showed a linear response to hydroxyproline concentrations from 5 to 100 mg/L with a detection limit of 0.8 ng injected, corresponding to 2 mg/L in urine. Mean (SD) analytical recovery was 94.2 (13)% and 104 (9)% at 10 and 50 mg/L, respectively. Within-run and between-run CVs (n = 10) were 3.74% and 4.33%, respectively, for 25 mg/L. Results for samples (n = 50) analyzed by HPLC (y) vs ion-exchange chromatography with postcolumn ninhydrin reaction (x) correlated well: y = 0.98x + 1.02 (r = 0.985, Sxy = 3.13). In another comparison, involving 173 samples, a colorimetric procedure (Hypronosticon, x) gave slightly higher values than the HPLC method (y): y = 0.83x + 2.21 (r = 0.937, Sxy = 4.6).

Published
1992

27. Total urinary hydroxyproline determined with rapid and simple high-performance liquid chromatography

Author

Paroni, R, De Vecchi, E, Fermo, I, Arcelloni, C, Diomede, L, Magni, F, Bonini, P, Bonini, P., MAGNI, FULVIO, Paroni, R, De Vecchi, E, Fermo, I, Arcelloni, C, Diomede, L, Magni, F, Bonini, P, Bonini, P., and MAGNI, FULVIO

Abstract

A precolumn derivatization method was optimized for rapid and specific analysis of total urinary hydroxyproline by HPLC. After an overnight hydrolysis, urine samples dried and reconstituted with the internal standard cysteic acid (in sodium hydrogen carbonate, pH 9.3) were derivatized with N,N-diethyl-2,4-dinitro-5-fluoroaniline (FDNDEA) at 100 degrees C for 20 min. The DNDEA-hydroxyproline adduct was separated on an Ultrasphere ODS column with a mobile phase of acetate buffer (containing triethylamine, 6 mL/L, pH 4.3) and acetonitrile (80/20, by vol), and was detected at 360 nm. A single run took 18 min with a hydroxyproline retention time of 7.3 min. The assay showed a linear response to hydroxyproline concentrations from 5 to 100 mg/L with a detection limit of 0.8 ng injected, corresponding to 2 mg/L in urine. Mean (SD) analytical recovery was 94.2 (13)% and 104 (9)% at 10 and 50 mg/L, respectively. Within-run and between-run CVs (n = 10) were 3.74% and 4.33%, respectively, for 25 mg/L. Results for samples (n = 50) analyzed by HPLC (y) vs ion-exchange chromatography with postcolumn ninhydrin reaction (x) correlated well: y = 0.98x + 1.02 (r = 0.985, Sxy = 3.13). In another comparison, involving 173 samples, a colorimetric procedure (Hypronosticon, x) gave slightly higher values than the HPLC method (y): y = 0.83x + 2.21 (r = 0.937, Sxy = 4.6).

Published
1992

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