21 results on '"Castellano, D."'
Search Results
2. Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study
- Author
-
Conteduca, V, Wetterskog, D, Sharabiani, M. T. A, Grande, Elisabetta, Fernandez Perez, M. P, Jayaram, A, Salvi, S, Castellano, D, Romanel, Alessandro, Lolli, C, Casadio, V, Gurioli, G, Amadori, D, Font, A, Vazquez Estevez, S, González Del Alba, A, Mellado, B, Fernandez Calvo, O, Méndez Vidal, M. J, Climent, M. A, Duran, I, Gallardo, E, Rodriguez, A, Santander, C, Sáez, M. I, Puente, J, Gasi Tandefelt, D, Wingate, A, Dearnaley, D, Demichelis, Francesca, De Giorgi, U, Gonzalez Billalabeitia, E, and Attard, G.
- Subjects
Adult ,Male ,Time Factors ,plasma DNA ,Antineoplastic Agents, Hormonal ,DNA Mutational Analysis ,Kaplan-Meier Estimate ,urologic and male genital diseases ,Disease-Free Survival ,Circulating Tumor DNA ,abiraterone ,androgen receptor ,biomarker ,castration-resistant prostate cancer ,enzalutamide ,Predictive Value of Tests ,Risk Factors ,Nitriles ,Phenylthiohydantoin ,Biomarkers, Tumor ,Odds Ratio ,Humans ,1112 Oncology and Carcinogenesis ,Prospective Studies ,Oncology & Carcinogenesis ,Precision Medicine ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,Patient Selection ,Middle Aged ,Europe ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,Receptors, Androgen ,Benzamides ,Multivariate Analysis ,Mutation ,Disease Progression ,Androstenes ,Multiplex Polymerase Chain Reaction - Abstract
Background There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC. Methods We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial). Results In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74–9.10; P A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47–not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94–9.68; P
- Published
- 2017
3. Patient-reported outcomes in a phase III, randomized study of sunitinib versus interferon-{alpha} as first-line systemic therapy for patients with metastatic renal cell carcinoma in a European population
- Author
-
Castellano, D. (Daniel), Garcia-del-Muro, X. (X.), Perez-Gracia, J.L. (Jose Luis), Gonzalez-Larriba, J.L. (José Luis), Abrio, M.V. (M. V.), Ruiz, M.A. (M. A.), Pardo, A. (A.), Guzman, C. (C.), Diaz-Cerezo, S. (S.), and Grande-Pulido, E. (E.)
- Subjects
Interferon-alfa ,Patient-reported outcomes ,Health-related quality of life ,Sunitinib - Abstract
BACKGROUND: The purpose of this study is to evaluate the impact on the health-related quality of life (HRQoL) of sunitinib versus interferon-alpha (IFN-alpha) treatment in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: In all, 304 mRCC patients (European cohort) were randomized 1 : 1 to receive sunitinib (50 mg/day for 4 weeks, followed by 2 weeks off) or IFN-alpha (9 million units s.c. injection three times/week). The following questionnaires were completed (days 1 and 28 per cycle): Functional Assessment of Cancer Therapy-General (FACT-G), the FACT-Kidney Symptom Index and the EuroQol Group's EQ-5D self-report questionnaire (EQ-5D). Results correspond to an ongoing trial with progression-free survival time as primary end point, and patients were still being followed up. Data were analyzed using repeated measures mixed effects models (MEMs) that allow the inclusion of initial differences and uncompleted repeated measures, with the assumption of data missing at random. Six-cycle results were included. RESULTS: Results consistently showed that patients in sunitinib group experienced statistically significantly milder kidney-related symptoms, better cancer-specific HRQoL and general health status (in social utility scores) during the study period as measured by these patient-reported outcome end points. No statistical differences between groups were found on the FACT-G physical well-being subscale or the EQ-5D VAS values. CONCLUSIONS: Results from MEM showed the sunitinib's benefit on HRQoL compared with IFN-alpha.
- Published
- 2009
4. EAU-ESMO consensus statements on the management of advanced and variant bladder cancer-an international collaborative multi-stakeholder effort
- Author
-
Antoine G. van der Heijden, Konstantinos Dimitropoulos, Joost L. Boormans, Bogdan Geavlete, Iris Brummelhuis, Andrew K. Williams, Christoph R. Müller, Susanne Vahr Lauridsen, Arturo Chiti, Manish I. Patel, Jonathan E. Rosenberg, Baris Turkbey, Carl Salembier, Thomas Wiegel, Anja Lorch, Valérie Fonteyne, Willem de Blok, Evanguelos Xylinas, Antti Salminen, Ann Henry, Karin Plass, Amir Sherif, Hugh Mostafid, Peter Wiklund, Erik Veskimäe, Hein Van Poppel, Max Bürger, Juan Palou, J. Domínguez-Escrig, Karel Decaestecker, Morgan Rouprêt, Helle Pappot, Paul Sargos, Berardino De Bari, Riccardo Valdagni, Luís Pacheco-Figueiredo, Jorge Huguet, Silke Gillessen, Olivier Rouvière, Maria J. Ribal, Yann Neuzillet, Richard Cathomas, Shaista Hafeez, Robert Jan Smeenk, Mark Frydenberg, Marek Babjuk, Antoni Vilaseca, Maria De Santis, Jonathan Richenberg, Annemarie Leliveld, Tom J.H. Arends, Shomik Sengupta, Vibeke Løgager, Harry W. Herr, Wim J.G. Oyen, Ananya Choudhury, Nicholas D. James, Susanne Osanto, Shahrokh F. Shariat, Vincent Khoo, A. Müller, Neeraj Agarwal, Pieter De Visschere, Bradley R. Pieters, Alberto Briganti, Robert Jones, Peter C. Black, Alberto Bossi, H. Maxim Bruins, Richard P. Meijer, Bertrand Tombal, Ken Herrmann, Donna E. Hansel, M. Carmen Mir, Stéphane Culine, J. Alfred Witjes, Virginia Hernández, Joaquim Bellmunt, Arnulf Stenzl, Eva Compérat, Alan Horwich, Alison Birtle, Jorg R. Oddens, Bernhard Grubmüller, Margitta Retz, Sylvain Ladoire, Marco Moschini, Aristotle Bamias, Simon J. Crabb, Michel Bolla, Theo H. van der Kwast, Steven MacLennan, Michael Rink, Anita Smits, Yohann Loriot, Estefania Linares-Espinós, James N'Dow, Theo M. de Reijke, Thomas Powles, Jurgen J. Fütterer, Arndt Hartmann, Daniel Castellano, Mesut Remzi, Paolo Gontero, Dickon Hayne, Anne E. Kiltie, Richard Zigeuner, Georgios Gakis, Franklin A. Vives Rivera, Stefano Fanti, Susanne Krege, Pedro C. Lara, Mihai Dorin Vartolomei, Ashish M. Kamat, Jan Oldenburg, Peter Hoskin, Andrea Necchi, Barbara Alicja Jereczek-Fossa, George N. Thalmann, Bernard H. Bochner, Florian Roghmann, Horwich, A, Babjuk, M, Bellmunt, J, Bruins, Hm, De Reijke, Tm, De Santis, M, Gillessen, S, James, N, Maclennan, S, Palou, J, Powles, T, Ribal, Mj, Shariat, Sf, Van der Kwast, T, Xylinas, E, Agarwal, N, Arends, T, Bamias, A, Birtle, A, Black, Pc, Bochner, Bh, Bolla, M, Boormans, Jl, Bossi, A, Briganti, A, Brummelhuis, I, Burger, M, Castellano, D, Cathomas, R, Chiti, A, Choudhury, A, Comperat, E, Crabb, S, Culine, S, De Bari, B, De Blok, W, De Visschere, Pjl, Decaestecker, K, Dimitropoulos, K, Dominguez-Escrig, Jl, Fanti, S, Fonteyne, V, Frydenberg, M, Futterer, Jj, Gakis, G, Geavlete, B, Gontero, P, Grubmuller, B, Hafeez, S, Hansel, De, Hartmann, A, Hayne, D, Henry, Am, Hernandez, V, Herr, H, Herrmann, K, Hoskin, P, Huguet, J, Jereczek-Fossa, Ba, Jones, R, Kamat, Am, Khoo, V, Kiltie, Ae, Krege, S, Ladoire, S, Lara, Pc, Leliveld, A, Linares-Espinos, E, Logager, V, Lorch, A, Loriot, Y, Meijer, R, Mir, Mc, Moschini, M, Mostafid, H, Muller, Ac, Muller, Cr, N'Dow, J, Necchi, A, Neuzillet, Y, Oddens, Jr, Oldenburg, J, Osanto, S, Oyen, Wjg, Pacheco-Figueiredo, L, Pappot, H, Patel, Mi, Pieters, Br, Plass, K, Remzi, M, Retz, M, Richenberg, J, Rink, M, Roghmann, F, Rosenberg, Je, Roupret, M, Rouviere, O, Salembier, C, Salminen, A, Sargos, P, Sengupta, S, Sherif, A, Smeenk, Rj, Smits, A, Stenzl, A, Thalmann, Gn, Tombal, B, Turkbey, B, Lauridsen, Sv, Valdagni, R, Van der Heijden, Ag, Van Poppel, H, Vartolomei, Md, Veskimae, E, Vilaseca, A, Rivera, Fav, Wiegel, T, Wiklund, P, Williams, A, Zigeuner, R, Witjes, Ja, Radiation Oncology, Horwich A, Babjuk M, Bellmunt J, Bruins HM, De Reijke TM, De Santis M, Gillessen S, James N, Maclennan S, Palou J, Powles T, Ribal MJ, Shariat SF, Van Der Kwast T, Xylinas E, Agarwal N, Arends T, Bamias A, Birtle A, Black PC, Bochner BH, Bolla M, Boormans JL, Bossi A, Briganti A, Brummelhuis I, Burger M, Castellano D, Cathomas R, Chiti A, Choudhury A, Compérat E, Crabb S, Culine S, De Bari B, DeBlok W, De Visschere PJL, Decaestecker K, Dimitropoulos K, Dominguez-Escrig JL, Fanti S, Fonteyne V, Frydenberg M, Futterer JJ, Gakis G, Geavlete B, Gontero P, Grubmüller B, Hafeez S, Hansel DE, Hartmann A, Hayne D, Henry AM, Hernandez V, Herr H, Herrmann K, Hoskin P, Huguet J, Jereczek-Fossa BA, Jones R, Kamat AM, Khoo V, Kiltie AE, Krege S, Ladoire S, Lara PC, Leliveld A, Linares-Espinós E, Løgager V, Lorch A, Loriot Y, Meijer R, Carmen Mir M, Moschini M, Mostafid H, Müller AC, Müller CR, N'Dow J, Necchi A, Neuzillet Y, Oddens JR, Oldenburg J, Osanto S, Oyen WJG, Pacheco-Figueiredo L, Pappot H, Patel MI, Pieters BR, Plass K, Remzi M, Retz M, Richenberg J, Rink M, Roghmann F, Rosenberg JE, Rouprêt M, Rouvière O, Salembier C, Salminen A, Sargos P, Sengupta S, Sherif A, Smeenk RJ, Smits A, Stenzl A, Thalmann GN, Tombal B, Turkbey B, Vahr Lauridsen S, Valdagni R, Van Der Heijden AG, Van Poppel H, Vartolomei MD, Veskimäe E, Vilaseca A, Vives Rivera FA, Wiegel T, Wiklund P, Williams A, Zigeuner R, Witjes JA., Universidade do Minho, APH - Personalized Medicine, APH - Quality of Care, CCA - Cancer Treatment and Quality of Life, Urology, Radiotherapy, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, UCL - (SLuc) Service d'urologie, and Pathology
- Subjects
0301 basic medicine ,Delphi Technique ,diagnosis ,International Cooperation ,Medicina Básica [Ciências Médicas] ,Delphi method ,Medizin ,CISPLATIN-INELIGIBLE PATIENTS ,Medical Oncology ,Delphi ,0302 clinical medicine ,PROGNOSTIC-FACTORS ,Multidisciplinary approach ,Surveys and Questionnaires ,consensu ,follow-up ,SINGLE-ARM ,Medicine ,Statistical analysis ,Multi stakeholder ,TRANSITIONAL-CELL CARCINOMA ,Societies, Medical ,computer.programming_language ,treatment ,Consensus conference ,Hematology ,3. Good health ,Europe ,diagnosi ,Oncology ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,030220 oncology & carcinogenesis ,Ciências Médicas::Medicina Básica ,Practice Guidelines as Topic ,TUMOR RESPONSE ,Special article ,bladder cancer ,RADICAL CYSTECTOMY ,LYMPHOCYTE RATIO ,medicine.medical_specialty ,METASTATIC UROTHELIAL CARCINOMA ,Urology ,Urinary Bladder ,education ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,LONG-TERM-SURVIVAL ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Stakeholder Participation ,Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15] ,Journal Article ,Humans ,Oligometastatic disease ,Neoplasm Staging ,Science & Technology ,Bladder cancer ,business.industry ,medicine.disease ,030104 developmental biology ,Urinary Bladder Neoplasms ,consensus ,Family medicine ,business ,computer - Abstract
Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. Setting: Online Delphi survey and consensus conference. Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. Outcome measurements and statistical analysis: Statements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), 7–9 (agree). A priori (level 1) consensus was defined as 70% agreement and 15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). Results and limitations: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach, The authors would like to thank Peter E. Clark from Atrium Health, Levine Cancer Institute, Charlotte, NC, USA, for his contribution to the Delphi survey. Angela Corstorphine of Kstorfin Medical Communications Ltd provided medical writing support with the preparation of this manuscript; this support was funded jointly by EAU and ESMO.
- Published
- 2019
5. Metabolomic profile of neuroendocrine tumors identifies methionine, porphyrin, and tryptophan metabolisms as key dysregulated pathways associated with patient survival.
- Author
-
La Salvia A, Lens-Pardo A, López-López A, Carretero-Puche C, Capdevila J, Benavent M, Jiménez-Fonseca P, Castellano D, Alonso T, Teule A, Custodio A, Tafuto S, La Casta A, Spada F, Lopez-Gonzalvez A, Gil-Calderon B, Espinosa-Olarte P, Barbas C, Garcia-Carbonero R, and Soldevilla B
- Subjects
- Humans, Metabolomics, Methionine therapeutic use, Tryptophan, Case-Control Studies, Neuroendocrine Tumors pathology, Porphyrins therapeutic use
- Abstract
Objective: Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways., Design and Methods: Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA)., Results: Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs., Conclusions: We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients., Competing Interests: Conflict of interest: J.C. has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA, Advanz Pharma, Amgen, Bayer, Esteve, Hutchmed, Ipsen, Merck, Novartis, Roche, Sanofi, Lilly, Eisai, Bayer, and ITM, and has received research support from Pfizer, Novartis, Astrazeneca, Eisai, AAA, Amgen, Bayer, Roche, Gilead, and ITM. M.B. reports Advisory from Novartis, Ipsen, and Pfizer. P.J.-F. has received speaker honoraria or consultant honoraria from Adacap, Astellas, BMS, Lilly, and MSD. D.C. has provided scientific advice and/or received honoraria or funding for continuous medical education from Janssen Oncology, Roche/Genetech, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Ipsen, BMS, MSD, Bayer, Lilly, Sanofi, Pierre Fabre, and Boerhinger. F.S. has received honoraria for medical education and research activity from Ipsen, Novartis, Pfizer, Advanced Accelerator Applications, MSD/Merck, and Hutchmed. A.T. has provided scientific advice and/or received honoraria from ADACAP, Ipsen, Novartis, and Pfizer. R.G.-C. has provided scientific advice and/or received honoraria or funding for continuous medical education from ADACAP, Advanz Pharma, Amgen, Bayer, BMS, Boerhinger, Esteve, Hutchmed, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pierre Fabre, Roche, Servier, and Sanofi, and has received research support from Pfizer, BMS, and MSD. The remaining authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)
- Published
- 2024
- Full Text
- View/download PDF
6. Safety and efficacy of immune checkpoint inhibitors in advanced penile cancer: report from the Global Society of Rare Genitourinary Tumors.
- Author
-
El Zarif T, Nassar AH, Pond GR, Zhuang TZ, Master V, Nazha B, Niglio S, Simon N, Hahn AW, Pettaway CA, Tu SM, Abdel-Wahab N, Velev M, Flippot R, Buti S, Maruzzo M, Mittra A, Gheeya J, Yang Y, Rodriguez PA, Castellano D, de Velasco G, Roviello G, Antonuzzo L, McKay RR, Vincenzi B, Cortellini A, Hui G, Drakaki A, Glover M, Khaki AR, El-Am E, Adra N, Mouhieddine TH, Patel V, Piedra A, Gernone A, Davis NB, Matthews H, Harrison MR, Kanesvaran R, Giudice GC, Barata P, Farolfi A, Lee JL, Milowsky MI, Stahlfeld C, Appleman L, Kim JW, Freeman D, Choueiri TK, Spiess PE, Necchi A, Apolo AB, and Sonpavde GP
- Subjects
- Male, Humans, Middle Aged, Aged, Nivolumab adverse effects, Immune Checkpoint Inhibitors adverse effects, Retrospective Studies, Antineoplastic Combined Chemotherapy Protocols adverse effects, Penile Neoplasms drug therapy, Penile Neoplasms etiology, Penile Neoplasms pathology, Antineoplastic Agents, Immunological adverse effects, Carcinoma, Squamous Cell drug therapy
- Abstract
Background: Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors., Methods: This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons., Results: Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher., Conclusions: Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2023
- Full Text
- View/download PDF
7. Health-Related Quality of Life Outcomes With Two Different Starting Doses of Lenvatinib in Combination With Everolimus for Previously Treated Renal Cell Carcinoma.
- Author
-
Bergerot C, Young Rha S, Pal S, Koralewski P, Stroyakovskiy D, Alekseev B, Parnis F, Castellano D, Lyun Lee J, Sunela K, Ciuleanu T, Heng D, Glen H, Wang J, Bennett L, Pan J, O'Hara K, and Puente J
- Subjects
- Humans, Everolimus therapeutic use, Quality of Life, Vascular Endothelial Growth Factor A, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell pathology, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology, Antineoplastic Agents administration & dosage
- Abstract
Background: Preserving health-related quality of life (HRQOL) is an important goal during renal cell carcinoma treatment. We report HRQOL outcomes from a phase II trial (NCT03173560)., Patients and Methods: HRQOL data were collected during a multicenter, randomized, open-label phase II study comparing the safety and efficacy of 2 different starting doses of lenvatinib (18 mg vs. 14 mg daily) in combination with everolimus (5 mg daily), following one prior vascular endothelial growth factor-targeted treatment. HRQOL was measured using 3 different instruments-FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L-which were all secondary endpoints. Change from baseline was assessed using linear mixed-effects models. Deterioration events for time to deterioration (TTD) analyses were defined using established thresholds for minimally important differences in the change from baseline for each scale. TTD for each treatment arm was estimated using the Kaplan-Meier method., Results: Baseline characteristics of the 343 participants randomly assigned to 18 mg lenvatinib (n = 171) and 14 mg lenvatinib (n = 172) were well balanced. Least-squares mean estimates for change from baseline were favorable for the 18 mg group over the 14 mg group for the FKSI-DRS and most EORTC QLQ-C30 scales, but differences between treatments did not exceed the minimally important thresholds. Median TTD was longer among participants in the 18 mg group than those in the 14 mg group for most scales., Conclusions: Participants who received an 18 mg lenvatinib starting dose had favorable HRQOL scores and longer TTD on most scales compared with those who received a 14 mg starting dose., (© The Author(s) 2022. Published by Oxford University Press.)
- Published
- 2023
- Full Text
- View/download PDF
8. Randomized Phase II Trial of Sapanisertib ± TAK-117 vs. Everolimus in Patients With Advanced Renal Cell Carcinoma After VEGF-Targeted Therapy.
- Author
-
Choueiri TK, Porta C, Suárez C, Hainsworth J, Voog E, Duran I, Reeves J, Czaykowski P, Castellano D, Chen J, Sedarati F, and Powles T
- Subjects
- Humans, Everolimus adverse effects, Vascular Endothelial Growth Factor A, Phosphatidylinositol 3-Kinases, Carcinoma, Renal Cell drug therapy
- Abstract
Background: Sapanisertib, a dual mTORC1/2 inhibitor, may offer more complete inhibition of the PI3K/AKT/mTOR pathway than mTORC1 inhibitors, such as everolimus. This phase II study evaluated the efficacy and safety of single-agent sapanisertib and sapanisertib plus the PI3Kα inhibitor TAK-117, vs. everolimus in patients with advanced clear cell renal cell carcinoma (ccRCC) that had progressed on or after VEGF-targeted therapy., Materials and Methods: Patients with histologically confirmed, advanced ccRCC were randomized 1:1:1 to receive single-agent everolimus 10 mg once daily, single-agent sapanisertib 30 mg once weekly, or sapanisertib 4 mg plus TAK-117 200 mg, both once daily for 3 days/week, in 28-day cycles. The primary endpoint was progression-free survival (PFS)., Results: Ninety-five patients were treated with everolimus or sapanisertib (n = 32 each), or sapanisertib plus TAK-117 (n = 31). There were no significant differences in PFS among the 3 groups or across any subgroups. Median PFS was 3.8 months with everolimus vs. 3.6 months with sapanisertib (HR, 1.33; 95% CI, 0.75-2.36), and 3.1 months with sapanisertib plus TAK-117 (HR, 1.37; 95% CI, 0.75-2.52). No significant differences in overall survival were seen among groups. Overall response rate was 16.7%, 0%, and 7.1%, respectively. Discontinuations due to treatment-emergent adverse events were 15.6%, 28.1%, and 29.0%., Conclusion: Sapanisertib with or without TAK-117 was less tolerable and did not improve efficacy vs. everolimus in patients with advanced ccRCC who had relapsed after or were refractory to VEGF-targeted therapies. Dual mTORC1/2 inhibition may not be an effective therapeutic approach for these patients., (© The Author(s) 2022. Published by Oxford University Press.)
- Published
- 2022
- Full Text
- View/download PDF
9. Cabazitaxel versus abiraterone or enzalutamide in metastatic castration-resistant prostate cancer: post hoc analysis of the CARD study excluding chemohormonal therapy for castrate-naive disease.
- Author
-
Suzuki H, Castellano D, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wülfing C, Foster MC, Ozatilgan A, Geffriaud-Ricouard C, and de Wit R
- Subjects
- Aged, Disease-Free Survival, Humans, Male, Prostate-Specific Antigen, Treatment Outcome, Androstenes, Benzamides, Nitriles, Phenylthiohydantoin, Prostatic Neoplasms, Castration-Resistant drug therapy, Taxoids
- Abstract
Background: In the CARD study (NCT02485691), cabazitaxel significantly improved clinical outcomes versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and the alternative androgen-signalling-targeted inhibitor. However, some patients received docetaxel or the prior alternative androgen-signalling-targeted inhibitor in the metastatic hormone-sensitive (mHSPC) setting. Therefore, the CARD results cannot be directly translated to a Japanese population., Methods: Patients (N = 255) received cabazitaxel (25 mg/m2 IV Q3W, prednisone, G-CSF) versus abiraterone (1000 mg PO, prednisone) or enzalutamide (160 mg PO) after prior docetaxel and progression ≤12 months on the alternative androgen-signalling-targeted inhibitor. Patients who received combination therapy for mHSPC were excluded (n = 33) as docetaxel is not approved in this setting in Japan., Results: A total of 222 patients (median age 70 years) were included in this subanalysis. Median number of cycles was higher for cabazitaxel versus androgen-signalling-targeted inhibitors (7 versus 4). Clinical outcomes favoured cabazitaxel over abiraterone or enzalutamide including, radiographic progression-free survival (rPFS; median 8.2 versus 3.4 months; P < 0.0001), overall survival (OS; 13.9 versus 11.8 months; P = 0.0102), PFS (4.4 versus 2.7 months; P < 0.0001), confirmed prostate-specific antigen response (37.0 versus 14.4%; P = 0.0006) and objective tumour response (38.9 versus 11.4%; P = 0.0036). For cabazitaxel versus androgen-signalling-targeted inhibitor, grade ≥ 3 adverse events occurred in 55% versus 44% of patients, with adverse events leading to death on study in 2.7% versus 5.7%., Conclusions: Cabazitaxel significantly improved outcomes including rPFS and OS versus abiraterone or enzalutamide and are reflective of the Japanese patient population. Cabazitaxel should be considered the preferred treatment option over abiraterone or enzalutamide in this setting., (© The Author(s) 2021. Published by Oxford University Press.)
- Published
- 2021
- Full Text
- View/download PDF
10. Impact of Mutation Rate and Selection at Linked Sites on DNA Variation across the Genomes of Humans and Other Homininae.
- Author
-
Castellano D, Eyre-Walker A, and Munch K
- Subjects
- Animals, Base Sequence, Conserved Sequence, DNA chemistry, Gene Conversion, Genome, Humans, Recombination, Genetic, Selection, Genetic, Genetic Variation, Genome, Human, Hominidae genetics, Mutation Rate
- Abstract
DNA diversity varies across the genome of many species. Variation in diversity across a genome might arise from regional variation in the mutation rate, variation in the intensity and mode of natural selection, and regional variation in the recombination rate. We show that both noncoding and nonsynonymous diversity are positively correlated to a measure of the mutation rate and the recombination rate and negatively correlated to the density of conserved sequences in 50 kb windows across the genomes of humans and nonhuman homininae. Interestingly, we find that although noncoding diversity is equally affected by these three genomic variables, nonsynonymous diversity is mostly dominated by the density of conserved sequences. The positive correlation between diversity and our measure of the mutation rate seems to be largely a direct consequence of regions with higher mutation rates having more diversity. However, the positive correlation with recombination rate and the negative correlation with the density of conserved sequences suggest that selection at linked sites also affect levels of diversity. This is supported by the observation that the ratio of the number of nonsynonymous to noncoding polymorphisms is negatively correlated to a measure of the effective population size across the genome. We show these patterns persist even when we restrict our analysis to GC-conservative mutations, demonstrating that the patterns are not driven by GC biased gene conversion. In conclusion, our comparative analyses describe how recombination rate, gene density, and mutation rate interact to produce the patterns of DNA diversity that we observe along the hominine genomes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)
- Published
- 2020
- Full Text
- View/download PDF
11. Comparison of the Full Distribution of Fitness Effects of New Amino Acid Mutations Across Great Apes.
- Author
-
Castellano D, Macià MC, Tataru P, Bataillon T, and Munch K
- Subjects
- Animals, Epistasis, Genetic, Evolution, Molecular, Genetic Fitness, Hominidae genetics, Mutation, Missense, Selection, Genetic
- Abstract
The distribution of fitness effects (DFE) is central to many questions in evolutionary biology. However, little is known about the differences in DFE between closely related species. We use >9000 coding genes orthologous one-to-one across great apes, gibbons, and macaques to assess the stability of the DFE across great apes. We use the unfolded site frequency spectrum of polymorphic mutations ( n = 8 haploid chromosomes per population) to estimate the DFE. We find that the shape of the deleterious DFE is strikingly similar across great apes. We confirm that effective population size ( N
e ) is a strong predictor of the strength of negative selection, consistent with the nearly neutral theory. However, we also find that the strength of negative selection varies more than expected given the differences in Ne between species. Across species, mean fitness effects of new deleterious mutations covaries with Ne , consistent with positive epistasis among deleterious mutations. We find that the strength of negative selection for the smallest populations, bonobos and western chimpanzees, is higher than expected given their Ne This may result from a more efficient purging of strongly deleterious recessive variants in these populations. Forward simulations confirm that these findings are not artifacts of the way we are inferring Ne and DFE parameters. All findings are replicated using only GC-conservative mutations, thereby confirming that GC-biased gene conversion is not affecting our conclusions., (Copyright © 2019 by the Genetics Society of America.)- Published
- 2019
- Full Text
- View/download PDF
12. Adaptation and Conservation throughout the Drosophila melanogaster Life-Cycle.
- Author
-
Coronado-Zamora M, Salvador-Martínez I, Castellano D, Barbadilla A, and Salazar-Ciudad I
- Subjects
- Animals, Base Sequence, Conserved Sequence, Drosophila melanogaster growth & development, Drosophila melanogaster metabolism, Female, Gene Expression Profiling, Genome, Insect, Male, Adaptation, Biological, Drosophila melanogaster genetics, Evolution, Molecular, Life Cycle Stages, Selection, Genetic
- Abstract
Previous studies of the evolution of genes expressed at different life-cycle stages of Drosophila melanogaster have not been able to disentangle adaptive from nonadaptive substitutions when using nonsynonymous sites. Here, we overcome this limitation by combining whole-genome polymorphism data from D. melanogaster and divergence data between D. melanogaster and Drosophila yakuba. For the set of genes expressed at different life-cycle stages of D. melanogaster, as reported in modENCODE, we estimate the ratio of substitutions relative to polymorphism between nonsynonymous and synonymous sites (α) and then α is discomposed into the ratio of adaptive (ωa) and nonadaptive (ωna) substitutions to synonymous substitutions. We find that the genes expressed in mid- and late-embryonic development are the most conserved, whereas those expressed in early development and postembryonic stages are the least conserved. Importantly, we found that low conservation in early development is due to high rates of nonadaptive substitutions (high ωna), whereas in postembryonic stages it is due, instead, to high rates of adaptive substitutions (high ωa). By using estimates of different genomic features (codon bias, average intron length, exon number, recombination rate, among others), we also find that genes expressed in mid- and late-embryonic development show the most complex architecture: they are larger, have more exons, more transcripts, and longer introns. In addition, these genes are broadly expressed among all stages. We suggest that all these genomic features are related to the conservation of mid- and late-embryonic development. Globally, our study supports the hourglass pattern of conservation and adaptation over the life-cycle., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)
- Published
- 2019
- Full Text
- View/download PDF
13. Phase II Study of Everolimus and Octreotide LAR in Patients with Nonfunctioning Gastrointestinal Neuroendocrine Tumors: The GETNE1003_EVERLAR Study.
- Author
-
Capdevila J, Teulé A, Barriuso J, Castellano D, Lopez C, Manzano JL, Alonso V, García-Carbonero R, Dotor E, Matos I, Custodio A, Casanovas O, and Salazar R
- Subjects
- Aged, Everolimus pharmacology, Female, Humans, Intestinal Neoplasms pathology, Male, Neuroendocrine Tumors pathology, Octreotide pharmacology, Pancreatic Neoplasms pathology, Prospective Studies, Stomach Neoplasms pathology, Everolimus therapeutic use, Intestinal Neoplasms drug therapy, Neuroendocrine Tumors drug therapy, Octreotide therapeutic use, Pancreatic Neoplasms drug therapy, Stomach Neoplasms drug therapy
- Abstract
Background: Antitumor activity of the combination of somatostatin analogues (SSAs) and the mammalian target of rapamycin (mTOR) inhibitor everolimus in patients with neuroendocrine tumors (NETs) has been reported but not confirmed in prospective trials., Materials and Methods: This prospective, multicenter, single-arm phase II EVERLAR study evaluated everolimus 10 mg/day and the SSA octreotide 30 mg every 28 days in patients with advanced nonfunctioning well-differentiated gastrointestinal NETs (GI-NETs) that progressed in the last 12 months (ClinicalTrials.gov NCT01567488). Prior treatment with SSAs and any systemic or locoregional therapy was allowed except for mTOR inhibitors. Patients continued treatment until disease progression or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS) at 12 months; secondary endpoints included early biochemical response, objective response rate (ORR) by RECIST v1.0, overall survival (OS), AEs, activation of mTOR pathway (insulin-like growth factor 1 receptor [IGF1R] and phosphoS6 [pS6] expression)., Results: Forty-three patients were included in the intent-to-treat analyses. After 12 months of treatment, 62.3% (95% confidence interval [CI] 48%-77%) of patients had not progressed or died. The 24-month PFS rate was 43.6% (95% CI 29%-58%). The confirmed ORR was 2.3%, and stable disease was 58.1%. Median OS was not reached after 24 months of median follow-up. Dose reductions and temporary interruptions due to AEs were required in 14 (33%) and 33 (77%) patients, respectively. The most frequent AEs were diarrhea, asthenia, mucositis, rash, and hyperglycemia. No correlation was observed between IGFR1 and pS6 expression and PFS/OS., Conclusion: The everolimus-octreotide combination provided clinically relevant efficacy in nonfunctioning GI-NETs, similar to the results of RADIANT-2 in functioning setting., Implications for Practice: The EVERLAR study reports prospective data of somatostatin analogue in combination with everolimus in nonfunctioning gastrointestinal neuroendocrine tumors suggesting meaningful activity and favorable toxicity profile that supports drug combination in this setting., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)
- Published
- 2019
- Full Text
- View/download PDF
14. Nearly Neutral Evolution across the Drosophila melanogaster Genome.
- Author
-
Castellano D, James J, and Eyre-Walker A
- Subjects
- Animals, Drosophila melanogaster genetics, Genetic Drift, Genome, Insect
- Abstract
Under the nearly neutral theory of molecular evolution, the proportion of effectively neutral mutations is expected to depend upon the effective population size (Ne). Here, we investigate whether this is the case across the genome of Drosophila melanogaster using polymorphism data from North American and African lines. We show that the ratio of the number of nonsynonymous and synonymous polymorphisms is negatively correlated to the number of synonymous polymorphisms, even when the nonindependence is accounted for. The relationship is such that the proportion of effectively neutral nonsynonymous mutations increases by ∼45% as Ne is halved. However, we also show that this relationship is steeper than expected from an independent estimate of the distribution of fitness effects from the site frequency spectrum. We investigate a number of potential explanations for this and show, using simulation, that this is consistent with a model of genetic hitchhiking: Genetic hitchhiking depresses diversity at neutral and weakly selected sites, but has little effect on the diversity of strongly selected sites.
- Published
- 2018
- Full Text
- View/download PDF
15. Neuroendocrine Tumor Heterogeneity Adds Uncertainty to the World Health Organization 2010 Classification: Real-World Data from the Spanish Tumor Registry (R-GETNE).
- Author
-
Nuñez-Valdovinos B, Carmona-Bayonas A, Jimenez-Fonseca P, Capdevila J, Castaño-Pascual Á, Benavent M, Pi Barrio JJ, Teule A, Alonso V, Custodio A, Marazuela M, Segura Á, Beguiristain A, Llanos M, Martinez Del Prado MP, Diaz-Perez JA, Castellano D, Sevilla I, Lopez C, Alonso T, and Garcia-Carbonero R
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Carcinoma, Neuroendocrine metabolism, Carcinoma, Neuroendocrine mortality, Cell Differentiation, Child, Female, Humans, Intestinal Neoplasms metabolism, Intestinal Neoplasms mortality, Ki-67 Antigen metabolism, Male, Middle Aged, Neoplasm Grading, Neoplasm Staging, Neuroendocrine Tumors metabolism, Neuroendocrine Tumors mortality, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms mortality, Prognosis, Proportional Hazards Models, Spain, Stomach Neoplasms metabolism, Stomach Neoplasms mortality, Survival Rate, World Health Organization, Young Adult, Carcinoma, Neuroendocrine classification, Carcinoma, Neuroendocrine pathology, Intestinal Neoplasms classification, Intestinal Neoplasms pathology, Neuroendocrine Tumors classification, Neuroendocrine Tumors pathology, Pancreatic Neoplasms classification, Pancreatic Neoplasms pathology, Registries statistics & numerical data, Stomach Neoplasms classification, Stomach Neoplasms pathology
- Abstract
Background: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a complex family of tumors of widely variable clinical behavior. The World Health Organization (WHO) 2010 classification provided a valuable tool to stratify neuroendocrine neoplasms (NENs) in three prognostic subgroups based on the proliferation index. However, substantial heterogeneity remains within these subgroups, and simplicity sometimes entails an ambiguous and imprecise prognostic stratification. The purpose of our study was to evaluate the prognostic impact of histological differentiation within the WHO 2010 grade (G) 1/G2/G3 categories, and explore additional Ki-67 cutoff values in GEP-NENs., Subjects, Materials, and Methods: A total of 2,813 patients from the Spanish National Tumor Registry (RGETNE) were analyzed. Cases were classified by histological differentiation as NETs (neuroendocrine tumors [well differentiated]) or NECs (neuroendocrine carcinomas [poorly differentiated]), and by Ki-67 index as G1 (Ki-67 <2%), G2 (Ki-67 3%-20%), or G3 (Ki-67 >20%). Patients were stratified into five cohorts: NET-G1, NET-G2, NET-G3, NEC-G2, and NEC-G3., Results: Five-year survival was 72%. Age, gender, tumor site, grade, differentiation, and stage were all independent prognostic factors for survival. Further subdivision of the WHO 2010 grading improved prognostic stratification, both within G2 (5-year survival: 81% [Ki-67 3%-5%], 72% [Ki-67 6%-10%], 52% [Ki-67 11%-20%]) and G3 NENs (5-year survival: 35% [Ki-67 21%-50%], 22% [Ki-67 51%-100%]). Five-year survival was significantly greater for NET-G2 versus NEC-G2 (75.5% vs. 58.2%) and NET-G3 versus NEC-G3 (43.7% vs. 25.4%)., Conclusion: Substantial clinical heterogeneity is observed within G2 and G3 GEP-NENs. The WHO 2010 classification can be improved by including the additive effect of histological differentiation and the proliferation index., Implications for Practice: Gastroenteropancreatic neuroendocrine neoplasms are tumors of widely variable clinical behavior, roughly stratified by the World Health Organization (WHO) 2010 classification into three subgroups based on proliferation index. Real-world data from 2,813 patients of the Spanish Registry RGETNE demonstrated substantial clinical heterogeneity within grade (G) 2 and G3 neuroendocrine neoplasms. Tumor morphology and further subdivision of grading substantially improves prognostic stratification of these patients and may help individualize therapy. This combined, additive effect shall be considered in future classifications of neuroendocrine tumors and incorporated for stratification purposes in clinical trials., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)
- Published
- 2018
- Full Text
- View/download PDF
16. Mapping Selection within Drosophila melanogaster Embryo's Anatomy.
- Author
-
Salvador-Martínez I, Coronado-Zamora M, Castellano D, Barbadilla A, and Salazar-Ciudad I
- Subjects
- Amino Acid Substitution genetics, Animals, Drosophila Proteins genetics, Evolution, Molecular, Gene Expression Regulation, Developmental genetics, Genetic Association Studies methods, Genomic Structural Variation genetics, Genomics methods, Models, Genetic, Phylogeny, Polymorphism, Genetic genetics, Recombination, Genetic genetics, Selection, Genetic genetics, Spatio-Temporal Analysis, Drosophila melanogaster anatomy & histology, Drosophila melanogaster embryology, Drosophila melanogaster genetics
- Abstract
We present a survey of selection across Drosophila melanogaster embryonic anatomy. Our approach integrates genomic variation, spatial gene expression patterns, and development with the aim of mapping adaptation over the entire embryo's anatomy. Our adaptation map is based on analyzing spatial gene expression information for 5,969 genes (from text-based annotations of in situ hybridization data directly from the BDGP database, Tomancak et al. 2007) and the polymorphism and divergence in these genes (from the project DGRP, Mackay et al. 2012).The proportion of nonsynonymous substitutions that are adaptive, neutral, or slightly deleterious are estimated for the set of genes expressed in each embryonic anatomical structure using the distribution of fitness effects-alpha method (Eyre-Walker and Keightley 2009). This method is a robust derivative of the McDonald and Kreitman test (McDonald and Kreitman 1991). We also explore whether different anatomical structures differ in the phylogenetic age, codon usage, or expression bias of the genes they express and whether genes expressed in many anatomical structures show more adaptive substitutions than other genes.We found that: 1) most of the digestive system and ectoderm-derived structures are under selective constraint, 2) the germ line and some specific mesoderm-derived structures show high rates of adaptive substitution, and 3) the genes that are expressed in a small number of anatomical structures show higher expression bias, lower phylogenetic ages, and less constraint., (© The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2018
- Full Text
- View/download PDF
17. Potency of Human Cardiosphere-Derived Cells from Patients with Ischemic Heart Disease Is Associated with Robust Vascular Supportive Ability.
- Author
-
Harvey E, Zhang H, Sepúlveda P, Garcia SP, Sweeney D, Choudry FA, Castellano D, Thomas GN, Kattach H, Petersen R, Blake DJ, Taggart DP, Frontini M, Watt SM, and Martin-Rendon E
- Subjects
- Apoptosis physiology, Blotting, Western, Cell Movement physiology, Flow Cytometry, Humans, Immunohistochemistry, Coronary Artery Disease therapy, Myocardial Ischemia therapy, Stem Cells cytology
- Abstract
Cardiosphere-derived cell (CDC) infusion into damaged myocardium has shown some reparative effect; this could be improved by better selection of patients and cell subtype. CDCs isolated from patients with ischemic heart disease are able to support vessel formation in vitro but this ability varies between patients. The primary aim of our study was to investigate whether the vascular supportive function of CDCs impacts on their therapeutic potential, with the goal of improving patient stratification. A subgroup of patients produced CDCs which did not efficiently support vessel formation (poor supporter CDCs), had reduced levels of proliferation and increased senescence, despite them being isolated in the same manner and having a similar immunophenotype to CDCs able to support vessel formation. In a rodent model of myocardial infarction, poor supporter CDCs had a limited reparative effect when compared to CDCs which had efficiently supported vessel formation in vitro. This work suggests that not all patients provide cells which are suitable for cell therapy. Assessing the vascular supportive function of cells could be used to stratify which patients will truly benefit from cell therapy and those who would be better suited to an allogeneic transplant or regenerative preconditioning of their cells in a precision medicine fashion. This could reduce costs, culture times and improve clinical outcomes and patient prognosis. Stem Cells Translational Medicine 2017;6:1399-1411., (© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)
- Published
- 2017
- Full Text
- View/download PDF
18. Prognostic Significance of Venous Thromboembolic Events in Disseminated Germ Cell Cancer Patients.
- Author
-
Gonzalez-Billalabeitia E, Castellano D, Sobrevilla N, Guma J, Hervas D, Luengo MI, Aparicio J, Sanchez-Muñoz A, Mellado B, Saenz A, Valverde C, Fernandez A, Margeli M, Duran I, Fernandez S, Sastre J, Ros S, Maroto P, Manneh R, Cerezuela P, Carmona-Bayonas A, Ayala de la Peña F, Luis Aguilar J, Rivera S, García Del Muro X, and Germà-Lluch JR
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Bleomycin administration & dosage, Child, Cisplatin administration & dosage, Disease-Free Survival, Etoposide administration & dosage, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasms, Germ Cell and Embryonal diagnosis, Neoplasms, Germ Cell and Embryonal drug therapy, Neoplasms, Germ Cell and Embryonal pathology, Prognosis, Proportional Hazards Models, Registries, Survival Rate, Young Adult, Neoplasms, Germ Cell and Embryonal complications, Venous Thromboembolism complications
- Abstract
Background: Disseminated germ cell cancers are at high risk of developing thromboembolic complications. We evaluated the prognostic value of venous thromboembolic events (VTE) in disseminated germ cell cancer., Methods: Patients with germ cell cancer receiving upfront platinum-containing chemotherapy between 2004 and 2014 were pooled from the Spanish Germ Cell Cancer Group (SGCCG) registry and reviewed for the presence of VTE. Results were validated in an independent international group of patients. We used a penalized Cox proportional hazards model including VTE as a time-varying covariate to identify and validate prognostic factors. All statistical tests were two-sided., Results: The SGCCG registry identified 416 patients from 14 referral institutions. With a median follow-up of 49 months, VTEs were observed in 9% of patients (n = 38). Events occurred at diagnosis, during chemotherapy, and after chemotherapy in 2.6%, 5.0%, and 1.4% of patients, respectively. VTE was associated with shorter progression-free survival (PFS; hazard ratio [HR] = 2.29, 95% confidence interval [CI] = 1.18 to 4.47, P = .02) and overall survival (OS; HR = 5.14, 95% CI = 2.22 to 11.88, P < .001). In multivariable analysis, the effect was consistent in the intermediate-risk group, both for PFS (HR = 9.52 95% CI = 2.48 to 36.58, P < .001) and OS (HR = 12.84, 95% CI = 2.01 to 82.02, P = .007). VTE at diagnosis is also an adverse prognostic variable for progression-free survival (HR = 4.64, 95% CI = 2.04 to 10.54, P < .001) and for overall survival (HR = 6.28, 95% CI = 1.68 to 17.10, P = .01). These results were validated in an independent international cohort that included 241 patients from four hospitals., Conclusions: VTE is an independent adverse prognostic factor in disseminated germ cell cancers, in particular for the intermediate prognostic group of the International Germ Cell Cancer Collaborative Group classification. The presence of VTE at diagnosis has also prognostic significance and should be further explored in future prognostic classifications., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2017
- Full Text
- View/download PDF
19. Adaptive Evolution Is Substantially Impeded by Hill-Robertson Interference in Drosophila.
- Author
-
Castellano D, Coronado-Zamora M, Campos JL, Barbadilla A, and Eyre-Walker A
- Subjects
- Animals, Drosophila melanogaster genetics, Genome, Insect, Models, Genetic, Mutation, Open Reading Frames, Polymorphism, Genetic, Recombination, Genetic, Adaptation, Biological, Biological Evolution, Drosophila genetics, Selection, Genetic
- Abstract
Hill-Robertson interference (HRi) is expected to reduce the efficiency of natural selection when two or more linked selected sites do not segregate freely, but no attempt has been done so far to quantify the overall impact of HRi on the rate of adaptive evolution for any given genome. In this work, we estimate how much HRi impedes the rate of adaptive evolution in the coding genome of Drosophila melanogaster. We compiled a data set of 6,141 autosomal protein-coding genes from Drosophila, from which polymorphism levels in D. melanogaster and divergence out to D. yakuba were estimated. The rate of adaptive evolution was calculated using a derivative of the McDonald-Kreitman test that controls for slightly deleterious mutations. We find that the rate of adaptive amino acid substitution at a given position of the genome is positively correlated to both the rate of recombination and the mutation rate, and negatively correlated to the gene density of the region. These correlations are robust to controlling for each other, for synonymous codon bias and for gene functions related to immune response and testes. We show that HRi diminishes the rate of adaptive evolution by approximately 27%. Interestingly, genes with low mutation rates embedded in gene poor regions lose approximately 17% of their adaptive substitutions whereas genes with high mutation rates embedded in gene rich regions lose approximately 60%. We conclude that HRi hampers the rate of adaptive evolution in Drosophila and that the variation in recombination, mutation, and gene density along the genome affects the HRi effect., (© The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)
- Published
- 2016
- Full Text
- View/download PDF
20. Everolimus plus octreotide long-acting repeatable in patients with colorectal neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-2 study.
- Author
-
Castellano D, Bajetta E, Panneerselvam A, Saletan S, Kocha W, O'Dorisio T, Anthony LB, and Hobday T
- Subjects
- Adult, Antineoplastic Agents, Hormonal administration & dosage, Antineoplastic Agents, Hormonal adverse effects, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Clinical Trials, Phase III as Topic, Colorectal Neoplasms epidemiology, Colorectal Neoplasms pathology, Disease-Free Survival, Everolimus, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Staging, Neuroendocrine Tumors epidemiology, Neuroendocrine Tumors pathology, Octreotide adverse effects, Sirolimus administration & dosage, Sirolimus adverse effects, Colorectal Neoplasms drug therapy, Neuroendocrine Tumors drug therapy, Octreotide administration & dosage, Sirolimus analogs & derivatives
- Abstract
Introduction: The incidence of colorectal neuroendocrine tumors (NETs) is increasing, and patients with this disease have particularly poor prognoses. Treatment options are limited, and survival times have not improved in the past decade., Methods: A post hoc analysis of the efficacy and tolerability of everolimus plus octreotide long-acting repeatable (LAR) was conducted in patients with colorectal NETs enrolled in the phase III RAD001 in Advanced Neuroendocrine Tumors, Second Trial (RADIANT-2) study. The primary endpoint (progression-free survival [PFS]), secondary endpoints (including objective response rate), and safety were assessed., Results: Patients with colorectal NETs receiving everolimus plus octreotide LAR had a significantly longer median PFS (29.9 months; n = 19) than did those receiving placebo plus octreotide LAR (6.6 months; n = 20). Everolimus plus octreotide LAR treatment also significantly reduced the risk for disease progression (hazard ratio: 0.34; 95% confidence interval: 0.13-0.89; p = .011). Although no objective responses were observed, tumor shrinkage was more frequently noted in the everolimus plus octreotide LAR arm than in the placebo plus octreotide LAR arm (67% vs. 37%, respectively). The combination of everolimus plus octreotide LAR was generally well tolerated by patients with colorectal NETs; rash and stomatitis were the most commonly reported adverse events., Conclusions: Everolimus plus octreotide LAR treatment had significant benefits and improved outcomes for patients with advanced colorectal NETs compared with placebo plus octreotide LAR treatment. Results of this exploratory analysis are consistent with those reported from the RADIANT-2 primary analysis. These findings support additional investigations of everolimus plus octreotide LAR in patients with colorectal NETs.
- Published
- 2013
- Full Text
- View/download PDF
21. The role of RANK-ligand inhibition in cancer: the story of denosumab.
- Author
-
Castellano D, Sepulveda JM, García-Escobar I, Rodriguez-Antolín A, Sundlöv A, and Cortes-Funes H
- Subjects
- Antibodies, Monoclonal, Humanized, Bone Remodeling drug effects, Breast Neoplasms pathology, Clinical Trials as Topic, Denosumab, Humans, Male, Multiple Myeloma pathology, Osteoclasts drug effects, Osteoclasts metabolism, Prostatic Neoplasms pathology, RANK Ligand metabolism, RANK Ligand therapeutic use, Receptor Activator of Nuclear Factor-kappa B metabolism, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents therapeutic use, Bone Neoplasms drug therapy, Bone Neoplasms secondary, RANK Ligand antagonists & inhibitors
- Abstract
The diagnosis of bone metastases is an event with certain consequences for the patient. They often mean pain and can also mean pathological fractures, hypercalcemia, and spinal cord compression, all synonymous with a diminished quality of life and often also hospitalization. Since the advent of the intravenous bisphosphonates, things began to look a bit brighter for patients with bone metastases-bone destruction was kept at bay a little longer. The next generation of bone metastasis treatments is well on its way in clinical development, and among them, the most advanced drug is denosumab. Denosumab is a fully human monoclonal antibody that inhibits osteoclast maturation, activation, and function by binding to receptor activator of nuclear factor kappa B ligand, with the final result being a reduced rate of bone resorption. In this review, we give an overview of relevant preclinical and clinical data regarding the use of denosumab in patients with solid tumors in general and prostate cancer in particular.
- Published
- 2011
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.