120 results on '"Fanciullino, R."'
Search Results
2. Mise en place d’un outil d’aide à la détection des interactions physico-chimiques en Y des médicaments injectables : analyse rétrospective des prescriptions dans un service d’hématologie
- Author
-
Sicard, G., Venton, G., Farnault, L., Costello, R., Fanciullino, R., and Gensollen, S.
- Published
- 2019
- Full Text
- View/download PDF
3. From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer
- Author
-
Rodallec A, Sicard G, Giacometti S, Carré M, Pourroy B, Bouquet F, Savina A, Lacarelle B, Ciccolini J, and Fanciullino R
- Subjects
docetaxel ,trastuzumab ,breast cancer ,immunoliposome ,spheroids ,distribution ,tumor xenograft ,Medicine (General) ,R5-920 - Abstract
Anne Rodallec,1 Guillaume Sicard,1 Sarah Giacometti,1 Manon Carré,1 Bertrand Pourroy,2 Fanny Bouquet,3 Ariel Savina,3 Bruno Lacarelle,1 Joseph Ciccolini,1 Raphaelle Fanciullino1 1SMARTc Unit, Laboratory of Pharmacokinetics and Toxicology UFR Pharmacy, Center for Research on Cancer of Marseille, Inserm UMR1068, CNRS UMR7258, Aix Marseille University, Marseille, France; 2Pharmacy Department, APHM La Conception, Marseille, France; 3Roche Institute, Boulogne Billancourt, France Purpose: Nanoparticles are of rising interest in cancer research, but in vitro canonical cell monolayer models are not suitable to evaluate their efficacy when prototyping candidates. Here, we developed three-dimensional (3D) spheroid models to test the efficacy of trastuzumab-docetaxel immunoliposomes in breast cancer prior to further testing them in vivo. Materials and methods: Immunoliposomes were synthesized using the standard thin film method and maleimide linker. Two human breast cancer cell lines varying in Her2 expression were tested: Her2+ cells derived from metastatic site: mammary breast MDA-MB-453 and triple-negative MDA-MB-231 cells. 3D spheroids were developed and tested with fluorescence detection to evaluate viability. In vivo efficacy and biodistribution studies were performed on xenograft bearing nude mice using fluorescent and bioluminescent imaging. Results: In vitro, antiproliferative efficacy was dependent upon cell type, size of the spheroids, and treatment scheduling, resulting in subsequent changes between tested conditions and in vivo results. Immunoliposomes performed better than free docetaxel + free trastuzumab and ado-trastuzumab emtansine (T-DM1). On MDA-MB-453 and MDA-MB-231 cell growth was reduced by 76% and 25%, when compared to free docetaxel + free trastuzumab and by 85% and 70% when compared to T-DM1, respectively. In vivo studies showed tumor accumulation ranging from 3% up to 15% of the total administered dose in MDA-MB-453 and MDA-MB-231 bearing mice. When compared to free docetaxel + free trastuzumab, tumor growth was reduced by 89% (MDA-MB-453) and 25% (MDA-MB-231) and reduced by 66% (MDA-MB-453) and 29% (MDA-MB-231) when compared to T-DM1, an observation in line with data collected from 3D spheroids experiments. Conclusion: We demonstrated the predictivity of 3D in vitro models when developing and testing nanoparticles in experimental oncology. In vitro and in vivo data showed efficient drug delivery with higher efficacy and prolonged survival with immunoliposomes when compared to current anti-Her2 breast cancer strategies. Keywords: docetaxel, trastuzumab, breast cancer, immunoliposome, spheroids, distribution, tumor xenograft
- Published
- 2018
4. Docetaxel-trastuzumab stealth immunoliposome: development and in vitro proof of concept studies in breast cancer
- Author
-
Rodallec A, Brunel JM, Giacometti S, Maccario H, Correard F, Mas E, Orneto C, Savina A, Bouquet F, Lacarelle B, Ciccolini J, and Fanciullino R
- Subjects
immunoliposomes – biopharmaceutical development –breast cancer – docetaxel - trastuzumab - HER2 ,Medicine (General) ,R5-920 - Abstract
Anne Rodallec,1 Jean-Michel Brunel,2 Sarah Giacometti,1 Helene Maccario,3 Florian Correard,3 Eric Mas,3 Caroline Orneto,4 Ariel Savina,5 Fanny Bouquet,5 Bruno Lacarelle,1 Joseph Ciccolini,1 Raphaelle Fanciullino11SMARTc Unit, Pharmacokinetics Laboratory, CRCM UMR U1068 CNRS UMR 7258 Aix Marseille Université, Marseille, France; 2CRCM CNRS UMR 7258 Aix Marseille Université, Marseille, France; 3CRO2 UMR S_911 Aix Marseille Université, Marseille, France; 4Biopharmacy Laboratory, Aix Marseille Université, Marseille, France; 5Institut Roche, Boulogne Billancourt Cedex, FranceBackground: Trastuzumab plus docetaxel is a mainstay to treat HER2-positive breast cancers. However, developing nanoparticles could help to improve the efficacy/toxicity balance of this doublet by improving drug trafficking and delivery to tumors. This project aimed to develop an immunoliposome in breast cancer, combining docetaxel encapsulated in a stealth liposome engrafted with trastuzumab, and comparing its performances on human breast cancer cell lines with standard combination of docetaxel plus trastuzumab.Methods: Several strategies to engraft trastuzumab to pegylated liposomes were tested. Immunoliposomes made of natural (antibody nanoconjugate-1 [ANC-1]) and synthetic lipids (ANC-2) were synthesized using standard thin film method and compared in size, morphology, docetaxel encapsulation, trastuzumab engraftment rates and stability. Antiproliferative activity was tested on human breast cancer models ranging from almost negative (MDA-MB-231), positive (MDA-MB-453) to overexpressing (SKBR3) HER2. Finally, cell uptake of ANC-1 was studied by electronic microscopy.Results: ANC-1 showed a greater docetaxel encapsulation rate (73%±6% vs 53%±4%) and longer stability (up to 1 week) as compared with ANC-2. Both ANC presented particle size ≤150 nm and showed similar or higher in vitro antiproliferative activities than standard treatment, ANC-1 performing better than ANC-2. The IC50s for docetaxel combined to free trastuzumab were 8.7±4, 2±0.7 and 6±2 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. The IC50s for ANC-1 were 2.5±1, 1.8±0.6 and 3.4±0.8 nM and for ANC-2 were 1.8±0.3 nM, 2.8±0.8 nM and 6.8±1.8 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. Cellular uptake appeared to depend on HER2 expression, the higher the expression, the higher the uptake.Conclusion: In vitro results suggest that higher antiproliferative efficacy and efficient drug delivery can be achieved in breast cancer models using nanoparticles.Keywords: immunoliposomes, biopharmaceutical development, breast cancer, docetaxel, trastuzumab, HER2
- Published
- 2018
5. Prototyping Trastuzumab Docetaxel Immunoliposomes with a New FCM-Based Method to Quantify Optimal Antibody Density on Nanoparticles
- Author
-
Rodallec, A., Franco, C., Robert, S., Sicard, G., Giacometti, S., Lacarelle, B., Bouquet, F., Savina, A., Lacroix, R., Dignat-George, F., Ciccolini, J., Poncelet, P., and Fanciullino, R.
- Published
- 2020
- Full Text
- View/download PDF
6. Severe renal insufficiency is not an absolute pitfall to autologous stem cell transplantation with BeEAM (bendamustine, etoposide, cytarabine, melphalan) conditioning regimen
- Author
-
Farnault, L., Venton, G., Pourroy, B., Jourde-Chiche, N., Ivanov, V., Arcani, R., Roche, P., Mercier, C., Colle, J., Fanciullino, R., and Costello, RT
- Published
- 2019
- Full Text
- View/download PDF
7. Méthotrexate à haute dose dans les hémopathies malignes : covariables d’intérêt dans l’anticipation de la survenue de toxicités
- Author
-
Ronda, A., Bourguignon, L., Correard, F., Ciccolini, J., and Fanciullino, R.
- Published
- 2024
- Full Text
- View/download PDF
8. Phytothérapie et chimiothérapie orale, des relations qui ne sont pas sans risques : retour d’expérience au sein d’un service d’hématologie
- Author
-
Delpech, C., Saliou, J., Farnault, L., and Fanciullino, R.
- Published
- 2024
- Full Text
- View/download PDF
9. High incidence of CDA deficiency in patients with hematological malignancies: perspectives and therapeutic implications
- Author
-
Donnette, M., Ciccolini, J., Pissier, C., Costello, R., Duffaud, F., Salas, S., Farnault, L., Tichadou, A., Arcani, R., Jarrot, P.A., Ouafik, L.H., Venton, G., Fanciullino, R., Ouafik, L'Houcine, Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Transfert d'Oncologie Biologique [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service d’Oncologie Médicale [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Médecine interne et immunologie clinique [Hôpital de la Conception - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), and Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM)
- Subjects
Oncology ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,MEDLINE ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Humans ,Medicine ,In patient ,ComputingMilieux_MISCELLANEOUS ,B cell ,030304 developmental biology ,0303 health sciences ,business.industry ,Incidence ,Incidence (epidemiology) ,Hematology ,Cytidine deaminase ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,3. Good health ,Leukemia ,medicine.anatomical_structure ,Hematologic Neoplasms ,030220 oncology & carcinogenesis ,High incidence ,business - Abstract
International audience
- Published
- 2021
10. 5PSQ-106 Implementation of advanced therapy medicinal products (ATMP) reconstitution in a university teaching hospital in France: proposal of a decision-making algorithm
- Author
-
Benjamin, F, primary, du Repaire, T, additional, Montana, M, additional, Fanciullino, R, additional, Ausias, N, additional, Deluca, B, additional, Gauthier Villano, L, additional, and Pourroy, B, additional
- Published
- 2022
- Full Text
- View/download PDF
11. Médicaments de haute technologie en oncologie: Atelier du GPCO, groupe de pharmacologie clinique oncologique — Unicancer Vendredi 22 novembre 2013 — Nice
- Author
-
Etienne-Grimaldi, M. -C., Couvreur, P., Benoit, J. -P., Fanciullino, R., Sergent, J. -A., van Miert, E., Pourroy, B., Meshaka, P., Brescianini, A., Corvaia, N., Haeuw, J. -F., Goetsch, L., and Beck, A.
- Published
- 2014
- Full Text
- View/download PDF
12. A reduced Gompertz model for predicting tumor age using a population approach
- Author
-
Vaghi, C., primary, Rodallec, A., additional, Fanciullino, R., additional, Ciccolini, J., additional, Mochel, J., additional, Mastri, M., additional, Poignard, C., additional, Ebos, J. ML, additional, and Benzekry, S., additional
- Published
- 2019
- Full Text
- View/download PDF
13. Micafungin as primary antifungal prophylaxis in patients presenting with acute myeloid leukemia
- Author
-
Venton, G., Adam, H., Colle, J., Labiad, Y., Mercier, C., Ivanov, V., Suchon, P., Fanciullino, R., Farnault, L., and Costello, R.
- Published
- 2016
- Full Text
- View/download PDF
14. Hematopoietic reconstitution after autologous hematopoietic stem cell transplantation: do CD45 (+) CD34 (+) CD38 (−) progenitors really matter in real life?
- Author
-
Venton, G., primary, Suchon, P., additional, Colle, J., additional, Baier, C., additional, Sanderson, F., additional, Poullin, P., additional, Ivanov, V., additional, Mercier, C., additional, Farnault, L., additional, Roche, P., additional, Arcani, R., additional, Fanciullino, R., additional, Brunet, C., additional, Philip, P.J.M., additional, and Costello, R., additional
- Published
- 2018
- Full Text
- View/download PDF
15. Médicaments de haute technologie en oncologie : High-technology drugs in oncology
- Author
-
Etienne-Grimaldi, Marie-Christine, Couvreur, P., Benoit, Jean-Pierre, Fanciullino, R., Sergent, J., Van Miert, E., Pourroy, B., Meshaka, P., Brescianini, A., Corvaia, N., Haeuw, J., Goetsch, L., Beck, A., Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Galien Paris-Sud (IGPS), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Micro et Nanomédecines Biomimétiques (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Bretagne Loire (UBL), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Solvay S.A., Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherche Pierre Fabre (Centre de R&D Pierre Fabre), PIERRE FABRE, Marine Sciences Research Center (New-York, USA), Stony Brook University [SUNY] (SBU), State University of New York (SUNY)-State University of New York (SUNY), and Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
[SDV]Life Sciences [q-bio] ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2014
16. P-540 – Mise en place d'un protocole de reconstitution de l'aciclovir en Néonatologie
- Author
-
Sicard, G., primary, Protesti, E., additional, Fanciullino, R., additional, Darque, A., additional, Buffat, C., additional, and Gensollen, S., additional
- Published
- 2015
- Full Text
- View/download PDF
17. High-technology drugs in oncology
- Author
-
Etienne-Grimaldi, M. -C., primary, Couvreur, P., additional, Benoit, J. -P., additional, Fanciullino, R., additional, Sergent, J. -A., additional, van Miert, E., additional, Pourroy, B., additional, Meshaka, P., additional, Brescianini, A., additional, Corvaia, N., additional, Haeuw, J. -F., additional, Goetsch, L., additional, and Beck, A., additional
- Published
- 2014
- Full Text
- View/download PDF
18. Stratégies anti-infectieuses en néonatalogie : à propos d’une étude sur 6 mois dans un CHU de niveau III
- Author
-
Ballandras, C., primary, Fanciullino, R., additional, Grandvuillemin-matheron, I., additional, Simeoni, U., additional, and Gensollen, S., additional
- Published
- 2014
- Full Text
- View/download PDF
19. Rituximab dans le traitement des hypertriglycéridémies auto-immune à anticorps anti-lipoprotéine lipase : une nouvelle approche thérapeutique prometteuse
- Author
-
Ete, M., primary, Jean, E., additional, Alary, B., additional, Fanciullino, R., additional, Poullin, P., additional, Sanderson, F., additional, Harle, J.-R., additional, Valero, R., additional, and Kaplanski, G., additional
- Published
- 2013
- Full Text
- View/download PDF
20. Hyopglycémies secondaires à la prise de tramadol : deux nouveaux cas
- Author
-
Tagourdeau, S., primary, Chiche, L., additional, Lanfranchi, M.-A., additional, Brah, S., additional, Eldin, C., additional, Jean, R., additional, Thomas, G., additional, Bornet, C., additional, Fanciullino, R., additional, Harle, J.-R., additional, Pastor, M.-J., additional, and Durand, J.-M., additional
- Published
- 2011
- Full Text
- View/download PDF
21. Nanotechnologies et onco-pharmacologie ?
- Author
-
Fanciullino, R., primary
- Published
- 2011
- Full Text
- View/download PDF
22. Utilisation dans la « vraie vie » du rituximab pour le traitement des thrombopénies auto-immunes : étude monocentrique sur 40 cas
- Author
-
Brah, S., primary, Fanciullino, R., additional, Loustalot, M.-C., additional, Bornet, C., additional, Mancini, J., additional, Thomas, G., additional, Harle, J.-R., additional, Durand, J.-M., additional, Kaplanski, G., additional, and Chiche, L., additional
- Published
- 2010
- Full Text
- View/download PDF
23. Liposome-Encapsulated Anticancer Drugs: Still Waiting for the Magic Bullet?
- Author
-
Fanciullino, R., primary and Ciccolini, J., additional
- Published
- 2009
- Full Text
- View/download PDF
24. In vitro and in vivo reversal of resistance to 5-fluorouracil in colorectal cancer cells with a novel stealth double-liposomal formulation
- Author
-
Fanciullino, R, primary, Giacometti, S, additional, Mercier, C, additional, Aubert, C, additional, Blanquicett, C, additional, Piccerelle, P, additional, and Ciccolini, J, additional
- Published
- 2007
- Full Text
- View/download PDF
25. Efficacy of rituximab in immune thrombocytopenic purpura: a retrospective survey.
- Author
-
Brah S, Chiche L, Fanciullino R, Bornet C, Mancini J, Schleinitz N, Jean R, Kaplanski G, Harlé JR, and Durand JM
- Published
- 2012
26. Hematopoietic reconstitution after autologous hematopoietic stem cell transplantation: do CD45 (+) CD34 (+) CD38 (−) progenitors really matter in real life?
- Author
-
Baier, C., Ivanov, V., Farnault, L., Roche, P., Arcani, R., Brunet, C., Philip, P.J.M., Venton, G., Colle, J., Costello, R., Sanderson, F., Poullin, P., Mercier, C., Suchon, P., and Fanciullino, R.
- Subjects
- *
AUTOTRANSFUSION of blood , *HEMATOPOIETIC stem cell transplantation , *PROGENITOR cells - Published
- 2018
- Full Text
- View/download PDF
27. Poor prognosis of SRSF2 gene mutations in patients treated with VEN-AZA for newly diagnosed acute myeloid leukemia.
- Author
-
Berton G, Sedaki B, Collomb E, Benachour S, Loschi M, Mohty B, Saillard C, Hicheri Y, Rouzaud C, Maisano V, Villetard F, Corda ED', Charbonnier A, Rey J, Hospital MA, Ittel A, Abbou N, Fanciullino R, Dadone-Montaudié B, Vey N, Venton G, Cluzeau T, Alary AS, and Garciaz S
- Subjects
- Humans, Male, Female, Middle Aged, Prognosis, Aged, Adult, Aged, 80 and over, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Azacitidine therapeutic use, Azacitidine administration & dosage, Young Adult, Spliceosomes genetics, Sulfonamides, Serine-Arginine Splicing Factors genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Mutation, Antineoplastic Combined Chemotherapy Protocols therapeutic use
- Abstract
Mutations in spliceosome genes (SRSF2, SF3B1, U2AF1, ZRSR2) correlate with inferior outcomes in patients treated with intensive chemotherapy for Acute Myeloid Leukemia. However, their prognostic impact in patients treated with less intensive protocols is not well known. This study aimed to evaluate the impact of Spliceosome mutations in patients treated with Venetoclax and Azacitidine for newly diagnosed AML. 117 patients treated in 3 different hospitals were included in the analysis. 34 harbored a mutation in at least one of the spliceosome genes (splice-mut cohort). K/NRAS mutations were more frequent in the splice-mut cohort (47% vs 19%, p=0.0022). Response rates did not differ between splice-mut and splice-wt cohorts. With a median follow-up of 15 months, splice mutations were associated with a lower 18-month LFS (p=0.0045). When analyzing splice mutations separately, we found SRSF2 mutations to be associated with poorer outcomes (p=0.034 and p=0.037 for OS and LFS respectively). This negative prognostic impact remained true in our multivariate analysis. We believe this finding should warrant further studies aimed at overcoming this negative impact., Competing Interests: Declaration of Competing Interest Loschi discloses honoraria for AstraZeneca, BMS, Gilead, GSK, Jazz, Kartos, Medac, MSD, Novartis, Pfizer, Sanofi, Sobi, Telios, Alexion. Charbonnier discloses honoraria for Pfizer, Novartis and Incyte Biosciences. Venton discloses consultancy for Novartis, Abbvie, Jazz, BMS, Janssen, GSK, Astrazeneca, Gilead. Cluzeau discloses: Incyte: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Keros: Speakers Bureau; Syros: Speakers Bureau; Jazz Pharma: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
28. Pegylated liposome encapsulating docetaxel using microfluidic mixing technique: Process optimization and results in breast cancer models.
- Author
-
Dacos M, Immordino B, Diroff E, Sicard G, Kosta A, Rodallec A, Giacometti S, Ciccolini J, and Fanciullino R
- Subjects
- Animals, Female, Humans, Cell Line, Tumor, Microfluidics methods, Mice, Particle Size, Cell Proliferation drug effects, Docetaxel pharmacokinetics, Docetaxel administration & dosage, Docetaxel chemistry, Liposomes, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Polyethylene Glycols chemistry, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents chemistry, Mice, Inbred C57BL
- Abstract
The development of nanoparticles could help to improve the efficacy/toxicity balance of drugs. This project aimed to develop liposomes and immunoliposomes using microfluidic mixing technology.Various formulation tests were carried out to obtain liposomes that met the established specifications. The liposomes were then characterized in terms of size, polydispersity index (PDI), docetaxel encapsulation rate and lamellarity. Antiproliferative activity was tested in human breast cancer models ranging from near-negative (MDA-MB-231), positive (MDA-MB-453) to HER2 positive. Pharmacokinetic studies were performed in C57BL/6 mice.Numerous batches of liposomes were synthesised using identical molar ratios and by varying the microfluidic parameters TFR, FRR and buffer. All synthesized liposomes have a size < 200 nm, but only Lipo-1, Lipo-6, Lipo-7, Lipo-8 have a PDI < 0.2, which meets our initial requirements. The size of the liposomes was correlated with the total FRR, for a 1:1 FRR the size is 122.2 ± 12.3 nm, whereas for a 1:3 FRR the size obtained is 163.4 ± 34.0 nm (p = 0.019. Three batches of liposomes were obtained with high docetaxel encapsulation rates > 80 %. Furthermore, in vitro studies on breast cancer cell lines demonstrated the efficacy of liposomes obtained by microfluidic mixing technique. These liposomes also showed improved pharmacokinetics compared to free docetaxel, with a longer half-life and higher AUC (3-fold and 3.5-fold increase for the immunoliposome, respectively).This suggests that switching to the microfluidic process will produce batches of liposomes with the same characteristics in terms of in vitro properties and efficacy, as well as the ability to release the encapsulated drug over time in vivo. This time-efficiency of the microfluidic technique is critical, especially in the early stages of development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mathilde Dacos reports administrative support was provided by Aix-Marseille University. Mathilde Dacos reports a relationship with Aix-Marseille University that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
29. Overcoming immuno-resistance by rescheduling anti-VEGF/cytotoxics/anti-PD-1 combination in lung cancer model.
- Author
-
Sicard G, Protzenko D, Giacometti S, Barlési F, Ciccolini J, and Fanciullino R
- Abstract
Background: Many tumors are refractory to immune checkpoint inhibitors, but their combination with cytotoxics is expected to improve sensitivity. Understanding how and when cytotoxics best re-stimulate tumor immunity could help overcome resistance to immune checkpoint inhibitors. Methods: In vivo studies were performed in C57BL/6 mice grafted with immune-refractory LL/2 lung cancer model. A longitudinal immunomonitoring study on tumor, spleen, and blood after multiple treatments including Cisplatin, Pemetrexed, and anti-VEGF, either alone or in combination, was performed, spanning a period of up to 21 days, to determine the optimal time window during which immune checkpoint inhibitors should be added. Finally, an efficacy study was conducted comparing the antiproliferative performance of various schedules of anti-VEGF, Pemetrexed-Cisplatin doublet, plus anti-PD-1 (i.e., immunomonitoring-guided scheduling, concurrent dosing or a random sequence), as well as single agent anti-PD1. Results: Immunomonitoring showed marked differences between treatments, organs, and time points. However, harnessing tumor immunity (i.e., promoting CD8 T cells or increasing the T CD8/Treg ratio) started on D7 and peaked on D14 with the anti-VEGF followed by cytotoxics combination. Therefore, a 14-day delay between anti-VEGF/cytotoxic and anti-PD1 administration was considered the best sequence to test. Efficacy studies then confirmed that this sequence achieved higher antiproliferative efficacy compared to other treatment modalities (i.e., -71% in tumor volume compared to control). Conclusions: Anti-VEGF and cytotoxic agents show time-dependent immunomodulatory effects, suggesting that sequencing is a critical feature when combining these agents with immune checkpoint inhibitors. An efficacy study confirmed that sequencing treatments further enhance antiproliferative effects in lung cancer models compared to concurrent dosing and partly reverse the resistance to cytotoxics and anti-PD1., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2024.)
- Published
- 2024
- Full Text
- View/download PDF
30. Cytidine deaminase status as a marker of response to azacytidine treatment in MDS and AML patients.
- Author
-
Donnette M, Hamimed M, Ciccolini J, Sicard G, Correard F, Farnault L, Ouafik L, Venton G, and Fanciullino R
- Subjects
- Adult, Humans, Azacitidine therapeutic use, Antimetabolites, Antineoplastic therapeutic use, Cytidine Deaminase genetics, Neoplasm Recurrence, Local drug therapy, Treatment Outcome, Myelodysplastic Syndromes genetics, Leukemia, Myeloid, Acute genetics
- Abstract
Azacitidine (Aza) is a mainstay of treatment for patients with acute myeloid leukaemia (AML) ineligible for induction chemotherapy and other high-risk myelodysplastic syndromes (MDS). Only half of patients respond, and almost all will eventually relapse. There are no predictive markers of response to Aza. Aza is detoxified in the liver by cytidine deaminase (CDA). Here, we investigated the association between CDA phenotype, toxicity and efficacy of Aza in real-world adult patients. Median overall survival (OS) was 15 months and 13 months in AML and high-risk MDS patients respectively. In addition, our data suggest that delaying Aza treatment was not associated with lack of efficacy and should not be considered a signal to switch to an alternative treatment. Half of the patients had deficient CDA activity (i.e. <2 UA/mg), with a lower proportion of deficient patients in MDS patients (34%) compared to AML patients (67%). In MDS patients, CDA deficiency correlated with longer landmark OS (14 vs. 8 months; p = 0.03), but not in AML patients. Taken together, our data suggest that CDA is an independent covariate and may therefore be a marker for predicting clinical outcome in MDS patients treated with Aza., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2023
- Full Text
- View/download PDF
31. Determination of 5-azacitidine in human plasma by LC-MS/MS: application to pharmacokinetics pilot study in MDS/AML patients.
- Author
-
Donnette M, Osanno L, Giocanti M, Venton G, Farnault L, Berda-Haddad Y, Costello R, Caroline S, Ouafik L', Ciccolini J, and Fanciullino R
- Subjects
- Humans, Pilot Projects, Chromatography, Liquid, Tandem Mass Spectrometry methods, Reproducibility of Results, Cytidine Deaminase, Azacitidine, Leukemia, Myeloid, Acute drug therapy
- Abstract
Purpose: Azacitidine (Vidaza®, AZA) is a mainstay for treating acute myeloid leukemia (AML) in patients unfit for standard induction and other myelodysplastic syndromes (MDS). However, only half of the patients usually respond to this drug and almost all patients will eventually relapse. Predictive markers for response to AZA are yet to be identified. AZA is metabolized in the liver by a single enzyme, cytidine deaminase (CDA). CDA is a ubiquitous enzyme coded by a highly polymorphic gene, with subsequent great variability in resulting activities in the liver. The quantitative determination of AZA in plasma is challenging due the required sensitivity and because of the instability in the biological matrix upon sampling, possibly resulting in erratic values., Methods: We have developed and validated following EMA standards a simple, rapid, and cost-effective liquid chromatography-tandem mass spectrometry method for the determination of azacitidine in human plasma., Results: After a simple and rapid precipitation step, analytes were successfully separated and quantitated over a 5-500 ng/mL range. The performance and reliability of this method were tested as part of an investigational study in MDS/AML patients treated with standard azacitidine (75 mg/m
2 for 7 days a week every 28 days)., Conclusion: Overall, this new method meets the requirements of current bioanalytical guidelines and could be used to monitor drug levels in MDS/AML patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2023
- Full Text
- View/download PDF
32. Tumor growth monitoring in breast cancer xenografts: A good technique for a strong ethic.
- Author
-
Rodallec A, Vaghi C, Ciccolini J, Fanciullino R, and Benzekry S
- Subjects
- Animals, Female, Heterografts, Humans, Mice, Models, Theoretical, Transplantation, Heterologous, Tumor Burden, Breast Neoplasms
- Abstract
Purpose: Although recent regulations improved conditions of laboratory animals, their use remains essential in cancer research to determine treatment efficacy. In most cases, such experiments are performed on xenografted animals for which tumor volume is mostly estimated from caliper measurements. However, many formulas have been employed for this estimation and no standardization is available yet., Methods: Using previous animal studies, we compared all formulas used by the scientific community in 2019. Data were collected from 93 mice orthotopically xenografted with human breast cancer cells. All formulas were evaluated and ranked based on correlation and lower mean relative error. They were then used in a Gompertz quantitative model of tumor growth., Results: Seven formulas for tumor volume estimation were identified and a statistically significant difference was observed among them (ANOVA test, p < 2.10-16), with the ellipsoid formula (1/6 π × L × W × (L + W)/2) being the most accurate (mean relative error = 0.272 ± 0.201). This was confirmed by the mathematical modeling analysis where this formula resulted in the smallest estimated residual variability. Interestingly, such result was no longer valid for tumors over 1968 ± 425 mg, for which a cubic formula (L x W x H) should be preferred., Main Findings: When considering that tumor volume remains under 1500mm3, to limit animal stress, improve tumor growth monitoring and go toward mathematic models, the following formula 1/6 π × L × W x (L + W)/2 should be preferred., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
- Full Text
- View/download PDF
33. Successful treatment with adapted high dose methotrexate in a hemodialysis patient with primary central nervous system lymphoma: 100mg/m 2 seems sufficient.
- Author
-
Solignac J, Farnault L, Robert T, Fanciullino R, Choquet S, Brunet P, Venton G, and Bobot M
- Subjects
- Central Nervous System pathology, Female, Humans, Methotrexate therapeutic use, Middle Aged, Renal Dialysis, Central Nervous System Neoplasms complications, Central Nervous System Neoplasms drug therapy, Central Nervous System Neoplasms pathology, Kidney Failure, Chronic complications, Kidney Failure, Chronic therapy, Lymphoma complications, Lymphoma drug therapy, Lymphoma pathology
- Abstract
High dose methotrexate (HD-MTX) based chemoimmunotherapy is a central part of the standard approach to treatment of primary central nervous system lymphoma (PCNSL). Renal dysfunction leads to delayed MTX complete elimination and critical MTX concentration. Despite the recommendations, hemodialysis status should not exclude HD-MTX. We report the case of a 64 years old woman on chronic hemodialysis with PCNSL successfully treated with HD-MTX-based chemoimmunotherapy with an adjusted dose of 100mg/m
2 , instead of the usual dose of 3500mg/m2 , and daily hemodialysis started 24h later. The patient had no significant toxicity and was in complete remission at 1 year after the end of the treatment. We argue that ESRD is not an absolute pitfall to the use of HD-MTX for hematological malignancies. Experts should consider the use of adjusted dose at 100mg/m2 as a viable therapeutic modality in ESRD patients., (Copyright © 2021 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
34. Macro-scale models for fluid flow in tumour tissues: impact of microstructure properties.
- Author
-
Vaghi C, Fanciullino R, Benzekry S, and Poignard C
- Subjects
- Biological Transport, Extracellular Fluid metabolism, Humans, Tumor Microenvironment, Models, Biological, Neoplasms pathology
- Abstract
Understanding the dynamics underlying fluid transport in tumour tissues is of fundamental importance to assess processes of drug delivery. Here, we analyse the impact of the tumour microscopic properties on the macroscopic dynamics of vascular and interstitial fluid flow. More precisely, we investigate the impact of the capillary wall permeability and the hydraulic conductivity of the interstitium on the macroscopic model arising from formal asymptotic 2-scale techniques. The homogenization technique allows us to derive two macroscale tissue models of fluid flow that take into account the microscopic structure of the vessels and the interstitial tissue. Different regimes were derived according to the magnitude of the vessel wall permeability and the interstitial hydraulic conductivity. Importantly, we provide an analysis of the properties of the models and show the link between them. Numerical simulations were eventually performed to test the models and to investigate the impact of the microstructure on the fluid transport. Future applications of our models include their calibration with real imaging data to investigate the impact of the tumour microenvironment on drug delivery., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2022
- Full Text
- View/download PDF
35. Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351.
- Author
-
Donnette M, Hamimed M, Ciccolini J, Berda-Haddad Y, Kaspi E, Venton G, Lacarelle B, Costello R, Ouafik L, Farnault L, and Fanciullino R
- Subjects
- Adult, Cytarabine, Daunorubicin, Humans, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Pharmacogenetics
- Abstract
CPX-351 is a liposome encapsulating cytarabine and daunorubicin for treating Acute Myeloid Leukemia (AML) patients. To what extent differences in cytidine deaminase (CDA) activity, the enzyme that catabolizes free cytarabine in the liver, can affect the pharmacokinetics of liposomal cytarabine as well, is unknown. We have studied the pharmacokinetics (PK) of released, liposomal and total cytarabine using a population-modeling approach in 9 adult AML patients treated with liposomal CPX-351. Exposure levels and PK parameters were compared with respect to the patient's CDA status (i.e., Poor Metabolizer (PM) vs. Extensive Metabolizer (EM)). Overall response rate was 75%, and 56% of patients had non-hematological severe toxicities, including one lethal toxicity. All patients had febrile neutropenia. A large (>60%) inter-individual variability was observed on pharmacokinetics parameters and subsequent drug levels. A trend towards severe toxicities was observed in patients with higher exposure of cytarabine. Results showed that liposomal CPX-351 led to sustained exposure with reduced clearance (Cl = 0.16 L/h) and prolonged half-life (T
1/2 = 28 h). Liposomal nanoparticles were observed transiently in bone marrow with cytarabine levels 2.3-time higher than in plasma. Seven out of 9 patients were PM with a strong impact on the PK parameters, i.e., PM patients showing higher cytarabine levels as compared with EM patients (AUC: 5536 vs. 1784 ng/mL.h), sustained plasma exposure (T1/2 : 33.9 vs. 13.7 h), and reduced clearance (Cl: 0.12 vs. 0.29 L/h). This proof-of-concept study suggests that CDA status has a major impact on cytarabine PK and possibly safety in AML patients even when administered as a liposome., (Copyright © 2021 Elsevier B.V. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
36. Successful treatment with adapted high dose methotrexate in a hemodialysis patient with primary central nervous system lymphoma: 100mg/m 2 seems sufficient.
- Author
-
Solignac J, Farnault L, Robert T, Fanciullino R, Choquet S, Brunet P, Venton G, and Bobot M
- Abstract
High dose methotrexate (HD-MTX) based chemoimmunotherapy is a central part of the standard approach to treatment of primary central nervous system lymphoma (PCNSL). Renal dysfunction leads to delayed MTX complete elimination and critical MTX concentration. Despite the recommendations, hemodialysis status should not exclude HD-MTX. We report the case of a 64 years old woman on chronic hemodialysis with PCNSL successfully treated with HD-MTX-based chemoimmunotherapy with an adjusted dose of 100mg/m
2 , instead of the usual dose of 3500mg/m2 , and daily hemodialysis started 24h later. The patient had no significant toxicity and was in complete remission at 1 year after the end of the treatment. We argue that ESRD is not an absolute pitfall to the use of HD-MTX for hematological malignancies. Experts should consider the use of adjusted dose at 100mg/m2 as a viable therapeutic modality in ESRD patients., (Copyright © 2021 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
37. Could daratumumab induce the maturation of plasmablasts in Plasmablastic lymphoma?-Potential therapeutic applications.
- Author
-
Roché P, Venton G, Berda-Haddad Y, Fritz S, Ivanov V, Mercier C, Colle J, Tichadou A, Fanciullino R, Lepidi H, Costello R, and Farnault L
- Subjects
- Antibodies, Monoclonal therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Humans, Molecular Targeted Therapy, Plasmablastic Lymphoma drug therapy, Antibodies, Monoclonal pharmacology, Antineoplastic Agents, Immunological pharmacology, Cell Differentiation drug effects, Plasma Cells drug effects, Plasma Cells pathology, Plasmablastic Lymphoma pathology
- Published
- 2021
- Full Text
- View/download PDF
38. COVID-19 vaccine race: watch your step for cancer patients.
- Author
-
Fanciullino R, Ciccolini J, and Milano G
- Subjects
- Acceleration, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, COVID-19 epidemiology, COVID-19 Vaccines adverse effects, Frailty epidemiology, Frailty therapy, Humans, Immunization Programs standards, Liposomes administration & dosage, Liposomes adverse effects, Neoplasms epidemiology, Neoplasms immunology, Pandemics, RNA, Messenger administration & dosage, RNA, Messenger standards, Time Factors, Vaccination methods, COVID-19 prevention & control, COVID-19 Vaccines administration & dosage, Drug Carriers standards, Neoplasms therapy, SARS-CoV-2 immunology
- Abstract
Patients with cancer should benefit from COVID-19 vaccination. Some of the most advanced vaccine candidates are mRNAs encapsulated into lipid carriers, and small liposomes are expected to accumulate in tumour tissues through the enhanced and permeation retention effect. However, to what extent solid tumours could take up a significant part of the vaccine dose as well remains unknown. This calls for a careful evaluation of the efficacy of these promising mRNA COVID-19 vaccines administered as lipid carriers for patients with solid tumours, including a possible re-appraisal of the dosing for optimal protection of this specific and frail population.
- Published
- 2021
- Full Text
- View/download PDF
39. Enhanced Antisense Oligonucleotide Delivery Using Cationic Liposomes Grafted with Trastuzumab: A Proof-of-Concept Study in Prostate Cancer.
- Author
-
Sicard G, Paris C, Giacometti S, Rodallec A, Ciccolini J, Rocchi P, and Fanciullino R
- Abstract
Prostate cancer (PCa) is the second most common cancer in men worldwide and the fifth leading cause of death by cancer. The overexpression of TCTP protein plays an important role in castration resistance. Over the last decade, antisense technology has emerged as a rising strategy in oncology. Using antisense oligonucleotide (ASO) to silence TCTP protein is a promising therapeutic option-however, the pharmacokinetics of ASO does not always meet the requirements of proper delivery to the tumor site. In this context, developing drug delivery systems is an attractive strategy for improving the efficacy of ASO directed against TCTP. The liposome should protect and deliver ASO at the intracellular level in order to be effective. In addition, because prostate cancer cells express Her2, using an anti-Her2 targeting antibody will increase the affinity of the liposome for the cell and optimize the intratumoral penetration of the ASO, thus improving efficacy. Here, we have designed and developed pegylated liposomes and Her2-targeting immunoliposomes. Mean diameter was below 200 nm, thus ensuring proper enhanced permeation and retention (EPR) effect. Encapsulation rate for ASO was about 40%. Using human PC-3 prostate cancer cells as a canonical model, free ASO and ASO encapsulated into either liposomes or anti-Her2 immunoliposomes were tested for efficacy in vitro using 2D and 3D spheroid models. While the encapsulated forms of ASO were always more effective than free ASO, we observed differences in efficacy of encapsulated ASO. For short exposure times (i.e., 4 h) ASO liposomes (ASO-Li) were more effective than ASO-immunoliposomes (ASO-iLi). Conversely, for longer exposure times, ASO-iLi performed better than ASO-Li. This pilot study demonstrates that it is possible to encapsulate ASO into liposomes and to yield antiproliferative efficacy against PCa. Importantly, despite mild Her2 expression in this PC-3 model, using a surface mAb as targeting agent provides further efficacy, especially when exposure is longer. Overall, the development of third-generation ASO-iLi should help to take advantage of the expression of Her2 by prostate cancer cells in order to allow greater specificity of action in vivo and thus a gain in efficacy.
- Published
- 2020
- Full Text
- View/download PDF
40. Towards Rational Cancer Therapeutics: Optimizing Dosing, Delivery, Scheduling, and Combinations.
- Author
-
Ferrer F, Fanciullino R, Milano G, and Ciccolini J
- Subjects
- Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Biological Products administration & dosage, Clinical Decision-Making, Drug Administration Schedule, Drug Dosage Calculations, Humans, Immune Checkpoint Inhibitors administration & dosage, Molecular Targeted Therapy, Neoplasms genetics, Neoplasms metabolism, Neoplasms pathology, Patient Safety, Precision Medicine, Risk Assessment, Antineoplastic Agents administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Neoplasms drug therapy, Patient-Centered Care
- Abstract
The current trend to personalize anticancer therapies mostly relies on selecting the best drug or combination of drugs to achieve optimal efficacy in patients. In addition to the comprehensive genetic and molecular knowledge of each tumor before choosing the drugs to be given, there is probably much room left for improvement by further personalizing the very modes by which the drugs are given, once they have been carefully selected. In particular, shifting from standard dosing to tailored dosing should help in maintaining drug exposure levels in the right therapeutic window, thus ensuring that the efficacy/toxicity balance is optimal. This paper covers the current knowledge regarding pharmacokinetic/pharmacodynamic relationships of anticancer agents, from decades-old cytotoxics to the latest immune checkpoint inhibitors, the most frequent sources for long-neglected interpatient variability impacting on drug exposure levels, and what could be done to achieve real personalized medicine in oncology such as implementing therapeutic drug monitoring with adaptive dosing strategies or using model-driven modalities for personalized dosing and scheduling., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2020
- Full Text
- View/download PDF
41. Like a Rolling Stone: Sting-Cgas Pathway and Cell-Free DNA as Biomarkers for Combinatorial Immunotherapy.
- Author
-
Sicard G, Fina F, Fanciullino R, Barlesi F, and Ciccolini J
- Abstract
Combining immune checkpoint inhibitors with other treatments likely to harness tumor immunity is a rising strategy in oncology. The exact modalities of such a combinatorial regimen are yet to be defined, and most attempts have relied so far on concomitant dosing, rather than sequential or phased administration. Because immunomodulating features are likely to be time-, dose-, and-schedule dependent, the need for biomarkers providing real-time information is critical to better define the optimal time-window to combine immune checkpoint inhibitors with other drugs. In this review, we present the various putative markers that have been investigated as predictive tools with immune checkpoint inhibitors and could be used to help further combining treatments. Whereas none of the current biomarkers, such as the PDL1 expression of a tumor mutational burden, is suitable to identify the best way to combine treatments, monitoring circulating tumor DNA is a promising strategy, in particular to check whether the STING-cGAS pathway has been activated by cytotoxics. As such, circulating tumor DNA could help defining the best time-window to administrate immune checkpoint inhibitors after that cytotoxics have been given.
- Published
- 2020
- Full Text
- View/download PDF
42. Tumor uptake and associated greater efficacy of anti-Her2 immunoliposome does not rely on Her2 expression status: study of a docetaxel-trastuzumab immunoliposome on Her2+ breast cancer model (SKBR3).
- Author
-
Rodallec A, Sicard G, Giacometti S, Carre M, Maia T, Valette M, Bouquet F, Savina A, Lacarelle B, Ciccolini J, and Fanciullino R
- Subjects
- Animals, Apoptosis, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Proliferation, Docetaxel administration & dosage, Female, Humans, Liposomes chemistry, Mice, Mice, Nude, Tissue Distribution, Trastuzumab administration & dosage, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols pharmacology, Breast Neoplasms drug therapy, Liposomes administration & dosage, Receptor, ErbB-2 metabolism
- Abstract
Nanoparticles have been used for decades in breast cancer. More recently, anti-human epidermal receptor 2 (Her2) immunoliposomes are of rising interest. However, recent studies have questioned the actual relevance of using anti-Her2 antibodies to improve liposome distribution and efficacy. Using standard thin-film method and maleimide linker, we have synthesized a 140-nm docetaxel-trastuzumab immunoliposome. This nanoparticle was then tested on a canonical Her2-overexpressing breast cancer model (i.e., SKBR3), using 3D spheroids and xenografted mice. Its efficacy was compared with free docetaxel + trastuzumab, liposomal docetaxel + free trastuzumab and to reference antibody-drug conjugate trastuzumab-emtansine (T-DM1). Immunoliposomes resulted in better efficacy as compared with all other treatments, both in vitro and in vivo. To explain such an improvement, immunoliposome biodistribution was investigated using live imaging in xenografted mice. Surprisingly, no difference in tumor uptake was found between anti-Her2 immunoliposomes and standard docetaxel liposomes (i.e., 1.9 ± 1.2 vs. 1.7 ± 0.5% at the end of treatment and 1.4 ± 0.6 vs. 1.6 ± 0.4% at the end of the study, respectively, P > 0.05). We hypothesized that passive targeting (i.e., enhanced permeation and retention effect) contributed more to tumor distribution than active targeting and that the observed differences in efficacy could come from a better internalization of immunoliposomes into Her2+ cells as compared with standard liposomes, and not from a higher specificity towards tumor tissue.
- Published
- 2020
- Full Text
- View/download PDF
43. Different sensitivity of CD19-positive bone marrow and lymph node lymphoblasts may cause resistance to blinatumomab in relapsed B-cell acute lymphoblastic leukemia/lymphoma.
- Author
-
Ivanov V, Farnault L, Mercier C, Colavolpe C, Venton G, Colle J, Lepidi H, Arnoux I, Nicolino-Brunet C, Berda-Haddad Y, Fanciullino R, Ivanov G, and Costello R
- Subjects
- Antigens, CD19, B-Lymphocytes, Bone Marrow, Humans, Lymph Nodes, Antibodies, Bispecific therapeutic use, Antineoplastic Agents therapeutic use, Lymphoma, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
- Published
- 2020
- Full Text
- View/download PDF
44. Population modeling of tumor growth curves and the reduced Gompertz model improve prediction of the age of experimental tumors.
- Author
-
Vaghi C, Rodallec A, Fanciullino R, Ciccolini J, Mochel JP, Mastri M, Poignard C, Ebos JML, and Benzekry S
- Subjects
- Animals, Bayes Theorem, Cell Proliferation, Disease Models, Animal, Mice, Computer Simulation, Neoplasms, Experimental pathology
- Abstract
Tumor growth curves are classically modeled by means of ordinary differential equations. In analyzing the Gompertz model several studies have reported a striking correlation between the two parameters of the model, which could be used to reduce the dimensionality and improve predictive power. We analyzed tumor growth kinetics within the statistical framework of nonlinear mixed-effects (population approach). This allowed the simultaneous modeling of tumor dynamics and inter-animal variability. Experimental data comprised three animal models of breast and lung cancers, with 833 measurements in 94 animals. Candidate models of tumor growth included the exponential, logistic and Gompertz models. The exponential and-more notably-logistic models failed to describe the experimental data whereas the Gompertz model generated very good fits. The previously reported population-level correlation between the Gompertz parameters was further confirmed in our analysis (R2 > 0.92 in all groups). Combining this structural correlation with rigorous population parameter estimation, we propose a reduced Gompertz function consisting of a single individual parameter (and one population parameter). Leveraging the population approach using Bayesian inference, we estimated times of tumor initiation using three late measurement timepoints. The reduced Gompertz model was found to exhibit the best results, with drastic improvements when using Bayesian inference as compared to likelihood maximization alone, for both accuracy and precision. Specifically, mean accuracy (prediction error) was 12.2% versus 78% and mean precision (width of the 95% prediction interval) was 15.6 days versus 210 days, for the breast cancer cell line. These results demonstrate the superior predictive power of the reduced Gompertz model, especially when combined with Bayesian estimation. They offer possible clinical perspectives for personalized prediction of the age of a tumor from limited data at diagnosis. The code and data used in our analysis are publicly available at https://github.com/cristinavaghi/plumky., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
- Full Text
- View/download PDF
45. Response to trametinib of histiocytosis with an activating PTPN11 mutation.
- Author
-
Farnault L, Hélias-Rodzewicz Z, Venton G, Fanciullino R, Gabriel S, Mescam L, Haroche J, Donadieu J, and Emile JF
- Subjects
- Humans, Mutation, Protein Tyrosine Phosphatase, Non-Receptor Type 11 genetics, Pyridones therapeutic use, Histiocytosis, Pyrimidinones therapeutic use
- Published
- 2020
- Full Text
- View/download PDF
46. Pulmonary hypertension in patients with myeloproliferative neoplasms: A large cohort of 183 patients.
- Author
-
Venton G, Turcanu M, Colle J, Thuny F, Chebrek S, Farnault L, Mercier C, Ivanov V, Fanciullino R, Suchon P, Jarrot PA, Aissi K, Roche P, Cautela J, Arcani R, and Costello R
- Subjects
- Adult, Aged, Aged, 80 and over, Cardiac Catheterization, Echocardiography, Female, Humans, Hypertension, Pulmonary diagnostic imaging, Hypertension, Pulmonary epidemiology, Male, Middle Aged, Young Adult, Bone Marrow Neoplasms complications, Hypertension, Pulmonary etiology
- Abstract
Background: Chronic myeloproliferative neoplasms (MPN) are recognized as a cause of pulmonary hypertension (pH). We ought to describe the prevalence and characteristics of PH in a cohort of MPN who were screened using transthoracic echocardiography (TTE)., Methods: One hundred eighty-three newly diagnosed consecutive MPN patients were prospectively evaluated using TTE to detect PH., Results: Two patients were diagnosed with chronic eosinophilic leukemia, two patients had post-essential thrombocythemia (ET) myelofibrosis (MF), two patients had post-polycythemia vera (PV) MF, 11 patients had primary myelofibrosis (PMF), 28 patients had chronic myeloid leukemia (CML), 51 patients had PV, and 87 patients had ET. TTE was used to determine PH, and PH was suspected in 16 of 183 patients as follows: four with PV, seven with ET, two with PMF, and three with CML. Two patients with ET were excluded because of global cardiac failure. Three patients underwent right heart catheterization to confirm PH. The 14 (7.7%) patients with PH had no cardiac or lung disease that directly involved MPN in PH development., Conclusion: In this large cohort of 183 MPN patients, TTE was used to diagnose PH, and 14 patients (7.7%) developed PH. This prevalence was lower than expected based on previously reported data, but it remains higher than in the general population., (Copyright © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
47. Efficacy and safety of autologous stem cell transplantation after induction therapy with lenalidomide, bortezomib, and dexamethasone.
- Author
-
Arcani R, Venton G, Colle J, Suchon P, Ivanov V, Mercier C, Farnault L, Roche P, Lafage M, Brunet C, Azouza W, Pourroy B, Fanciullino R, and Costello R
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bortezomib administration & dosage, Combined Modality Therapy, Dexamethasone administration & dosage, Female, Humans, Induction Chemotherapy, Lenalidomide administration & dosage, Male, Middle Aged, Multiple Myeloma diagnosis, Multiple Myeloma mortality, Neoplasm Staging, Prognosis, Retrospective Studies, Survival Analysis, Transplantation, Autologous, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, Multiple Myeloma therapy
- Abstract
Objectives: Recently, phase III trials assessed a new combination of lenalidomide, bortezomib, and dexamethasone (RVD) in induction therapy in transplantation-eligible multiple myeloma (MM) patients, before consolidation with RVD and lenalidomide maintenance. We present a retrospective study evaluating this approach with patients from the real life., Methods: We conducted a retrospective single-arm study to assess efficacy and safety of RVD combination in induction therapy before high-dose chemotherapy with melphalan followed by autologous stem cell transplantation, and RVD consolidation followed by lenalidomide maintenance, from February 2011 to May 2016., Results: Forty patients were enrolled. The mean age at diagnosis was 56 years. Median progression-free survival was 45 months, and median overall survival was 76 months. The only factor found associated with better PFS was a negative minimal residual disease (P < .01). Twenty-six (65%) patients experimented adverse events: 8 patients (20%) underwent 12 serious AE (≥grade 3). Treatment discontinuation occurred in 2 patients (5%) because of severe AE., Conclusion: To our knowledge, this work provides the first evidence of the efficacy and the safety of RVD combination in patients treated in common practice., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2019
- Full Text
- View/download PDF
48. Simultaneous determination of cytosine arabinoside and its metabolite uracil arabinoside in human plasma by LC-MS/MS: Application to pharmacokinetics-pharmacogenetics pilot study in AML patients.
- Author
-
Donnette M, Solas C, Giocanti M, Venton G, Farnault L, Berda-Haddad Y, Hau LTT, Costello R, Ouafik L, Lacarelle B, Ciccolini J, and Fanciullino R
- Subjects
- Antimetabolites, Antineoplastic metabolism, Antimetabolites, Antineoplastic pharmacokinetics, Antimetabolites, Antineoplastic therapeutic use, Arabinofuranosyluracil metabolism, Arabinofuranosyluracil pharmacokinetics, Arabinofuranosyluracil therapeutic use, Cytarabine metabolism, Cytarabine pharmacokinetics, Cytarabine therapeutic use, Drug Monitoring, Humans, Leukemia, Myeloid, Acute drug therapy, Linear Models, Pilot Projects, Reproducibility of Results, Sensitivity and Specificity, Antimetabolites, Antineoplastic blood, Arabinofuranosyluracil blood, Chromatography, High Pressure Liquid methods, Cytarabine blood, Tandem Mass Spectrometry methods
- Abstract
Purine analogs like aracytine (AraC) are a mainstay for treating acute myeloid leukemia (AML). There are marked differences in drug dosing and scheduling depending on the protocols when treating AML patients with AraC. Large inter-patient pharmacokinetics variability has been reported, and genetic polymorphisms affecting cytidine deaminase (CDA), the liver enzyme responsible for the conversion of Ara-C to inactive uracil arabinoside (AraU) could be a culprit for either life-threatening toxicities or poor efficacy related to substantial changes in plasma exposure levels among patients. The quantitative determination of Ara-C in plasma is challenging due the required sensitivity because of the short half-life of this drug (i.e., <10 min) and the metabolic instability in biological matrix upon sampling possibly resulting in erratic values. We developed and validated a liquid chromatography tandem mass spectrometry method (UPLC-MS/MS) for the simultaneous determination of Ara-C and Ara-U metabolite in human plasma. After simple and rapid precipitation, analytes were successfully separated and quantitated over a 1-500 ng/ml range for Ara-C and 250-7500 ng/ml range for AraU. The performance and reliability of this method was tested as part of an investigational study in AML patients treated with low dose cytarabine and confirmed marked differences in drug exposure levels and metabolic ratio, depending on the CDA status of the patients. Overall, this new method meets the requirements of current bioanalytical guidelines and could be used to monitor drug levels in AML patients with respect to their CDA phenotypes., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
49. Lethal toxicities after capecitabine intake in a previously 5-FU-treated patient: why dose matters with dihydropryimidine dehydrogenase deficiency.
- Author
-
Gbeto CC, Quaranta S, Mari R, Fanciullino R, Roche C, Nahon S, Solas C, Ouafik L, Lacarelle B, Allegre T, and Ciccolini J
- Subjects
- Antimetabolites, Antineoplastic administration & dosage, Breast Neoplasms drug therapy, Capecitabine administration & dosage, Dihydropyrimidine Dehydrogenase Deficiency metabolism, Dihydrouracil Dehydrogenase (NADP) metabolism, Female, Humans, Middle Aged, Antimetabolites, Antineoplastic adverse effects, Capecitabine adverse effects, Dihydropyrimidine Dehydrogenase Deficiency chemically induced, Fluorouracil therapeutic use
- Abstract
Dihydropryimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome associated with severe or lethal toxicities with oral capecitabine. Usually, patients with history of 5-FU-based therapy with no signs for life-threatening toxicities are considered as not DPD-deficient individuals who can be safely treated next with capecitabine if required. Here we describe the case of a woman originally treated with standard FEC100 protocol for metastatic breast cancer with little severe toxicities but grade-3 mucosities that were quickly resolved by symptomatic treatment. When switched to capecitabine + vinorelbine combo, extremely severe toxicities with fatal outcome were unexpectedly observed. Pharmacogenetic investigations were performed on cytidine deaminase and DPYD , and showed that this patient was heterozygous for the 2846A>T mutation on the DPYD gene. DPD phenotyping (i.e., uracil plasma levels >250 ng/ml, dihydrouracil/uracil ratio <0.5) confirmed that this patient was profoundly DPD deficient. Differences in fluoropyrimidine dosing between FEC100 (i.e., 500 mg/m
2 5-FU) and capecitabine (i.e., 2250 mg daily) could explain why initial 5-FU-based protocol did not lead to life-threatening toxicities, whereas capecitabine rapidly triggered toxic death. Overall, this case report suggests that any toxicity, even when not life threatening, should be considered as a warning signal for possible underlying profound DPD deficiency syndrome, especially with low-dose protocols.- Published
- 2019
- Full Text
- View/download PDF
50. Is There Any Room for Pharmacometrics With Immuno-Oncology Drugs? Input from the EORTC-PAMM Course on Preclinical and Early-phase Clinical Pharmacology.
- Author
-
Rodallec A, Fanciullino R, Benzekry S, and Ciccolini J
- Subjects
- Animals, Antineoplastic Agents, Immunological therapeutic use, Humans, Immunotherapy, Neoplasms drug therapy, Neoplasms metabolism, Pharmacology, Clinical methods, Antineoplastic Agents, Immunological pharmacokinetics
- Abstract
As part of the Pharmacology & Molecular Mechanisms (PAMM) Group, European Organization for Research and Treatment on Cancer (EORTC) 2019 winter Meeting Educational sessions, special focus has been placed on strategies to be undertaken to reduce the attrition rate when developing immune-oncology drugs. Immune checkpoint inhibitors have been game-changing drugs in several settings over the past decade such as melanoma and lung cancer. However, during the last years a rising number of studies failing to further improve clinical outcome in patients with cancer was recorded. Extensive pharmacometrics such as pharmacokinetics/pharmacodynamics modeling support should help to overcome the current glass ceiling that has apparently been reached with immuno-oncology drugs (IOD). In particular, it should help in the issue of setting up combinatorial regimen (i.e. combining immune checkpoint inhibitors with cytotoxics, anti-angiogenesis or targeted therapies) that can no longer be addressed when following standard trial-and-error approaches, but rather by using mathematical-derived algorithms as decision-making tools by investigators for rational design. In routine clinical setting, developing therapeutic drug monitoring of immune checkpoint inhibitors with adaptive dosing strategies has been a long-neglected strategy. Still, substantial improvements might be achieved using dedicated tools for precision medicine and personalized medicine in immunotherapy., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.