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1. Best practices for the management of local-regional recurrent chordoma: a position paper by the chordoma global consensus group

Author

Vittoria Colia, Bernd Kasper, R. Imai, Michael Baumann, Stéphanie Bolle, R. Capanna, Riccardo Casadei, Paolo G. Casali, Claire Alapetite, P. A. Gardner, C. L. A. Vleggeert-Lankamp, C. Heery, Elena Tamborini, Anant Desai, Stefano Radaelli, Alessandro Gronchi, Nadia Hindi, Akira Kawai, Daniel Vanel, C. Sen, Francesco Doglietto, Nicolas Penel, Ziya L. Gokaslan, S. Froelich, Katherine Anne Thornton, Carlo Morosi, Hans Gelderblom, Francis J. Hornicek, O. J. Norum, M. Uhl, Palma Dileo, Sandip Pravin Patel, Piero Fossati, J. Martin Broto, Peter Hohenberger, Rick L. Haas, Andreas Leithner, Toru Akiyama, F. Ricchini, Robin L. Jones, Valter Torri, Josh Sommer, Peter Pal Varga, Y. Yamada, Per-Ulf Tunn, J.-Y. Blay, Augusto Caraceni, Piotr Rutkowski, Jürgen Debus, Lee Jeys, Adrienne M. Flanagan, Diego Mazzatenta, I. Logowska, Marco Krengli, Damien C. Weber, Thomas F. DeLaney, Susanne Scheipl, P. Picci, Beate Timmermann, Piero Nicolai, S. Pilotti, P. Bruzzi, Silvia Stacchiotti, Stefano Boriani, S. Dijkstra, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], European Institute of Oncology [Milan] (ESMO), Saitama University, Institut Curie [Paris], University of Dresden Medical School, Centre Léon Bérard [Lyon], Institut Gustave Roussy (IGR), University of Pisa - Università di Pisa, University Medical Center Heidelberg, Massachusetts General Hospital [Boston], Queen Elizabeth Hospital, University College London Hospitals (UCLH), Universiteit Leiden [Leiden], University of Brescia, Cancer Research UK London Research Institute, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Providence University, Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Hospital Universitario Virgen del Rocío [Sevilla], University of Heidelberg, Medical Faculty, Harvard Medical School [Boston] (HMS), Chiba University Hospital, Queens Elizabeth Hospital [Birmingham], Royal Marsden NHS Foundation Trust, National Cancer Center Research Institute [Tokyo], Università del Piemonte Orientale - Dipartimento DISIT Italy, Medical University Graz, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Hospital Graz, New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), University of Duisbourg-Essen, Helios Klinikum [Erfurt], Memorial Sloane Kettering Cancer Center [New York], SwissFEL, Paul Scherrer Institut, Leiden University Medical Center (LUMC), Universiteit Leiden, CHU Lille, Université de Lille, METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, European Institute of Oncology [Milan] [ESMO], Institut Gustave Roussy [IGR], University College London Hospitals [UCLH], Netherlands Cancer Institute [NKI], National Cancer Institute [Bethesda] [NCI-NIH], Harvard Medical School [Boston] [HMS], Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology [MCMCC], Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS], New York University Langone Medical Center [NYU Langone Medical Center], Leiden University Medical Center [LUMC], Stacchiotti, S., Gronchi, A., Fossati, P., Akiyama, T., Alapetite, C., Baumann, M., Blay, J. Y., Bolle, S., Boriani, S., Bruzzi, P., Capanna, R., Caraceni, A., Casadei, R., Colia, V., Debus, J., Delaney, T., Desai, A., Dileo, P., Dijkstra, S., Doglietto, F., Flanagan, A., Froelich, S., Gardner, P. A., Gelderblom, H., Gokaslan, Z. L., Haas, R., Heery, C., Hindi, N., Hohenberger, P., Hornicek, F., Imai, R., Jeys, L., Jones, R. L., Kasper, B., Kawai, A., Krengli, M., Leithner, A., Logowska, I., Martin Broto, J., Mazzatenta, D., Morosi, C., Nicolai, P., Norum, O. J., Patel, S., Penel, N., Picci, P., Pilotti, S., Radaelli, S., Ricchini, F., Rutkowski, P., Scheipl, S., Sen, C., Tamborini, E., Thornton, K. A., B., Timmermann, Torri, V., Tunn, P. U., Uhl, M., Yamada, Y., Weber, D. C., Vanel, D., Varga, P. P., Vleggeert-Lankamp, C. L. A., Casali, P. G., and Sommer, J.

Subjects
sarcoma, [SDV]Life Sciences [q-bio], Medizin, chemotherapy, Patient advocacy, surgery, 0302 clinical medicine, Neoplasm Recurrence, Medicine, chordoma, relapse, radiotherapy, Relapse, Sarcoma, Hematology, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Practice Guidelines as Topic, chordoma, consensus, recurrence, Sacral Chordoma, musculoskeletal diseases, medicine.medical_specialty, recurrence, Best practice, MEDLINE, Reviews, 610 Medicine & health, 03 medical and health sciences, Chordoma, Humans, Chemotherapy, Medical physics, Radiotherapy, business.industry, medicine.disease, Cervical spine, consensus, Family medicine, Position paper, Surgery, Neoplasm Recurrence, Local, business, 030217 neurology & neurosurgery
Abstract

Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.

Published
2017
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2. Pharmacokinetics of oral vinorelbine in French children with recurrent or progressive primary low‐grade glioma

Author

Alicia Probst, Emilie De Carli, Isabelle Aerts, Pascal Chastagner, Natacha Entz-Werle, Caroline Solas, Anne-Isabelle Bertozzi-Salamon, Nicolas André, Anne Pagnier, Emmanuelle Tresch-Bruneel, Pierre Leblond, Jacques Grill, Didier Frappaz, Mourad Hamimed, Florence Gattacceca, Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), 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), 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), Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), Centre de Recherche en Cancérologie de Marseille (CRCM), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre Hospitalier Universitaire de Nancy (CHU Nancy), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Centre Léon Bérard [Lyon], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Unité des Virus émergents [Marseille] (UVE - Faculté de Médecine), Université de la Méditerranée - Aix-Marseille 2-Faculté de Médecine [Marseille], Université de la Méditerranée - Aix-Marseille 2, and Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
medicine.medical_specialty, Adolescent, Phases of clinical research, Vinorelbine, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Bayesian multivariate linear regression, Glioma, Internal medicine, Humans, Medicine, Pharmacology (medical), Child, Infusions, Intravenous, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Pharmacology, Body surface area, Volume of distribution, 0303 health sciences, business.industry, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Low-Grade Glioma, Neoplasm Recurrence, Local, business, Half-Life, medicine.drug
Abstract

AIM There is a crucial need for pharmacokinetic (PK) data of oral vinorelbine (VNR) in pediatric population. The aim of this work was to assess the PK profile of orally administered VNR in children with recurrent/progressive primary low-grade glioma (LGG). METHODS A multicentric, open-label, single-arm intervention phase II study was conducted. Patients, aged between 6 and 18 years, with histologically confirmed recurrent or progressive primary LGG or non-documented typical optic pathway tumors, were included. PK parameters were estimated by non-compartmental analysis using Phoenix WinNonlin® software (version 8.0, Certara, Inc.). The Influence of demographic and biological covariates on VNR PK parameters was investigated using a multivariate linear regression analysis. RESULTS PK analysis included 36 patients with a median age (range) of 11 (6-17) years. Estimates of apparent oral clearance (CL/F), apparent volume of distribution (V/F), half-life (t1/2 ) and their between-subject variability (CV%) at 60 mg.m-2 dose level, were 472 L.h-1 (51.8%), 7002 L (57.9%) and 10 h (21.0%), respectively. Negligible accumulation of VNR between C1 and C2 was observed. CL/F and V/F were found to increase with body surface area (BSA) (p = 0.004). Lower area under the concentration-time curve (AUC) levels were observed among children in comparison to adults. CONCLUSION Higher doses may be necessary for children with LGG. BSA showed a significant impact on VNR systemic exposure. We believe that our findings will serve as a basis for further studies to better characterize the concentration-response relationships of VNR among pediatric patients.

Published
2021
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3. A polygenic risk score for multiple myeloma risk prediction

Author

Angelica Macauda, Matteo Pelosini, Krzysztof Jamroziak, Mario Petrini, Annette Juul Vangsted, Chiara Piredda, Stephane Minvielle, Marek Dudziński, Hervé Avet-Loiseau, Aleksandra Butrym, Ulla Vogel, Niels Abildgaard, Fabienne Lesueur, Waldemar Tomczak, Vibeke Andersen, Herlander Marques, Daniele Campa, Judit Várkonyi, Rui Manuel Reis, Katalin Kadar, Gabriele Buda, Małgorzata Raźny, Charles Dumontet, Juan Sainz, Anna Suska, Enrico Orciuolo, Agnieszka Druzd-Sitek, Marcin Kruszewski, Daria Zawirska, Niels Frost Andersen, Artur Jurczyszyn, Grzegorz Mazur, Marcin Rymko, Federica Gemignani, Edyta Subocz, Federico Canzian, Katia Beider, Jan Maciej Zaucha, Marzena Wątek, Arnon Nagler, Genomic Epidemiology Group [Heidelberg, Germany] (GEP / DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Pisa - Università di Pisa, University Hospital of Cracow/Szpital Uniwersytecki w Krakowie [Poland] (SUK), Aarhus University Hospital, Chaim Sheba Medical Center, Sea Hospital [Gdynia, Poland] (SH), Wroclaw Medical University [Wrocław, Pologne] (WMU), Hospices Civils de Lyon (HCL), Holycross Cancer Center of Kelce, Hematology Clinic, Kielce, Institute of Hematology and Transfusion Medicine [Warsaw, Poland] (IHTM), Centre for Genomics and Oncological Research Pfizer [Granada, Spain] (GENYO), University of Granada [Granada]-Andalusian Regional Government [Granada, Spain], Hospital Universitario Virgen de las Nieves [Granada, Spain] (HUVN), Semmelweis University [Budapest], Odense University Hospital (OUH), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Teaching Hospital No 1 [Rzeszów, Poland] (TH1), University of Copenhagen = Københavns Universitet (KU), Military Institute of Medicine [Warsaw, Poland] (MIM), Rydygier Specialistic Hospital [Cracow, Poland] (RSH), University of Minho [Braga], Jagiellonian University Medical College [Cracow, Poland] (JUMC), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), The National Research Center for Work Environment [Copenhagen, Denmark] (NRCWE), University of Southern Denmark (SDU), ICVS/3B's - PT Government Associate Laboratory [Braga/Guimarães, Portugal] (AL), Barretos Cancer Hospital [São Paulo, Brazil] (BCH), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Bydgoszcz [Bydgoszcz, Poland] (UHB), Medical University of Lublin, N. Copernicus Town Hospital [Torun, Poland] (NCTH), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Bernardo, Elizabeth, Wrocław Medical University, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidad de Granada = University of Granada (UGR)-Andalusian Regional Government [Granada, Spain], Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Oncology, medicine.medical_specialty, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Risk Factors, Internal medicine, Genetics, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, education, Genetics (clinical), Multiple myeloma, 030304 developmental biology, Genetic association, 0303 health sciences, education.field_of_study, business.industry, medicine.disease, Penetrance, 3. Good health, 030220 oncology & carcinogenesis, Polygenic risk score, Multiple Myeloma, business, Genome-Wide Association Study
Abstract

This work was partially supported by intramural funds of the University of Pisa, DKFZ, and University Hospital of Southern Jutland, Denmark, and by a grant of the French National Cancer Institute (INCA). The authors wish to thank Dr. Dominic Edelmann (Division of Biostatistics, DKFZ) for helpful advice about data analysis., There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 x 10(-15) for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 x 10(-13) for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population., University of Pisa, DKFZ, University Hospital of Southern Jutland, Denmark, Institut National du Cancer (INCA) France

Published
2021
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4. Post-transplant cyclophosphamide versus anti-thymocyte globulin for graft-versus-host disease prevention in haploidentical transplantation for adult acute lymphoblastic leukemia

Author

Mutlu Arat, Fabio Ciceri, Myriam Labopin, Arnon Nagler, Zinaida Peric, Yener Koc, Bipin N. Savani, Johanna Tischer, Emanuele Angelucci, Boris V. Afanasyev, Zafer Gulbas, Hakan Ozdogu, Mohamad Mohty, Pietro Pioltelli, Abraham S. Kanate, Depei Wu, William Arcese, Sebastian Giebel, Nagler, Arnon, Kanate, Abraham S, Labopin, Myriam, Ciceri, Fabio, Angelucci, Emanuele, Koc, Yener, Gülbas, Zafer, Arcese, William, Tischer, Johanna, Pioltelli, Pietro, Ozdogu, Hakan, Afanasyev, Bori, Wu, Depei, Arat, Mutlu, Peric, Zinaida, Giebel, Sebastian, Savani, Bipin, Mohty, Mohamad, Chaim Sheba Medical Center, West Virginia University [Morgantown], Centre International des greffes [CHU Saint-Antoine] (EBMT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CEREST-TC [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ospedale San Raffaele, Ospedale Policlinico San Martino [Genoa], Anadolu [Turkey], Università degli Studi di Roma Tor Vergata [Roma], Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Başkent University Hospital [Adana, Turkey], Pavlov First Saint Petersburg State Medical University [St. Petersburg], Soochow University, University of Zagreb, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Adult, medicine.medical_specialty, Transplantation Conditioning, Cyclophosphamide, [SDV]Life Sciences [q-bio], Graft vs Host Disease, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Refractory, immune system diseases, Internal medicine, medicine, Humans, Antilymphocyte Serum, business.industry, Incidence (epidemiology), Hematopoietic Stem Cell Transplantation, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Settore MED/15, medicine.disease, 3. Good health, Anti-thymocyte globulin, Transplantation, Adult Acute Lymphoblastic Leukemia, surgical procedures, operative, medicine.anatomical_structure, Graft-versus-host disease, Graft-versus-Host-Disease, 030220 oncology & carcinogenesis, Transplantation, Haploidentical, Bone marrow, business, Stem Cell Transplantation, 030215 immunology, medicine.drug
Abstract

Graft-versus-host disease (GvHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation includes posttransplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing data in the European Society for Blood and Marrow Transplantation registry, we compared ATG- versus PTCy-based GvHD prophylaxis in 434 adults with acute lymphoblastic leukemia undergoing haploidentical hematopoietic cell transplantation. Of the 434 patients included in this study, ATG was used in 98 and PTCy in 336.. The median follow-up was approximately 2 years. The baseline characteristics of the patients were similar between the groups except that the ATG group was more likely to have had relapsed/refractory acute lymphoblastic leukemia (P=0.008), had conditioning not including total body irradiation (P

Published
2020
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5. Encapsulation of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in liposomes prepared by thin film hydration and their transfer to mesenchymal stem cells and cord blood hematopoietic stem cells

Author

Jacek Z. Kubiak, Aneta Lewicka, Marek Saracyn, Sławomir Lewicki, Marta Grodzik, Agnieszka Sobolewska-Ruta, Monika Leśniak, Eugeniusz K Machaj, Zygmunt Pojda, Military Institute of Medicine, Warsaw, Warsaw University of Life Sciences (SGGW), National Institute of Public Health - National Institute of Hygiene [Poland], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), USA Defense Advanced Research Project Agency [N10PC20038], and Polish Ministry of National Defense project [571/2016/DA]

Subjects
liposomes, Liposome, business.industry, [SDV]Life Sciences [q-bio], Mesenchymal stem cell, protein transfer to cells in vitro, General Medicine, delivery to stem cells, Thin film hydration, Granulocyte colony-stimulating factor, Cell biology, Haematopoiesis, Granulocyte macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, Cord blood, medicine, Stem cell, granulocyte colony-stimulating factor, business, medicine.drug
Abstract

IntroductionCytokines are important immune modulator factors controlling homeostasis of the body and are involved in tissue regeneration after wound healing. The encapsulation of cytokines in liposomes has many advantages potentially useful for their transfer to the cells. Liposomes protect cytokines from neutralization, improving their pharmacokinetics or biologic activity in vivo. They are targeted to specific cell types and may delay the release of cytokines, allowing their sustained paracrine delivery. Their physicochemical characteristics such as size, shape, charge, and stability are important parameters improving bio-distribution and prolonged pharmacokinetics of encapsulated cytokines.Material and methodsWe developed an efficient protocol for the encapsulation of two types of cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), in liposomes that can be stored long term in the active state.ResultsThis method allows for the encapsulation of 12–13% of the total amount of cytokines and 50% of encapsulated cytokines are entrapped in liposomes of more than ≤ 600 nm in diameter. We show that in the studied cell lines the liposome-encapsulated cytokines do not affect cell morphology, proliferation or mortality.ConclusionsThe G-CSF or GM-CSF can be delivered to the cells in working concentrations through the encapsulation in the liposomes. Before the clinical application, the efficiency of these liposomes should be confirmed by an in vivo study.

Published
2022
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6. European Reference Network for rare adult solid cancers, statement and integration to health care systems of member states

Author

Blay, J-Y, Casali, P, Bouvier, C, Dehais, C, Galloway, I, Gietema, J, Halámková, J, Hindi, N, Idbaih, A, Kinloch, E, Klümpen, H-J, Kolarova, T, Kopeckova, K, Lovey, J, Magalhaes, M, Oselin, K, Piperno-Neumann, S, Ravnsbaek, A, Rogasik, M, Safwat, A, Scheipl, S, Seckl, M, Taylor, J, Temnyk, M, Trama, A, Urbonas, M, Wartenberg, M, Weinman, A, EURACAN Network, Oncology, CCA - Cancer Treatment and Quality of Life, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], University of Milan, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Royal Free Hospital [London, UK], Service de neurologie 2 [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University Medical Center Groningen [Groningen] (UMCG), Masaryk Memorial Cancer Institute (RECAMO), Hospital Universitario Virgen del Rocío [Sevilla], University of Amsterdam [Amsterdam] (UvA), University Hospital Motol [Prague], National Institute of Oncology [Budapest, Hungary], Centro Hospitalar do Porto, North Estonia Medical Center, Institut Curie [Paris], Aarhus University Hospital, Karl-Franzens-Universität [Graz, Autriche], Charing Cross Hospital & Imperial College, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Kaunas University of Technology (KTU), EURORDIS-Rare Diseases Europe (Bureau de Paris), EURORDIS - Plateforme Maladies Rares [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and University of Graz

Subjects
Cancer Research, medicine.medical_specialty, Statement (logic), MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, News, GUIDELINES, DIAGNOSIS, 03 medical and health sciences, 0302 clinical medicine, EURACAN Network, Health care, medicine, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, business.industry, Member states, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Family medicine, SURVIVAL, Position paper, SARCOMA PATIENTS, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, BURDEN
Abstract

International audience

Published
2021
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7. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial

Author

Christoph Hoeller, Marie-Francoise Avril, Pietro Quaglino, François Aubin, Lars Bastholt, Takashi Inozume, Virginia Ferraresi, Michael B. Jameson, Kevin B. Kim, Oliver Bechter, Dirk Schadendorf, Kenji Yokota, Carmen Loquai, Maria-Jose Passos, Inge Marie Svane, Michele Maio, Catherine Barrow, Frank Meiss, Nageatte Ibrahim, Andrzej Mackiewicz, Phillip Parente, Tatsuya Takenouchi, Caroline Dutriaux, Piotr Rutkowski, Alfonsus J M van den Eertwegh, Paola Queirolo, Catriona M. McNeil, Peter Mohr, Felix Kiecker, Susana Puig, Friedegund Meier, Lutz Kretschmer, Alexander C.J. van Akkooi, Alex Menzies, Timothy Crook, Christian U. Blank, Suzana Matkovic, Michael C. Brown, Ragini R. Kudchadkar, Max Levin, Rüdiger Hein, Tanja Skytta, Gerald P. Linette, Clemens Krepler, Adnan Khattak, Ernest Marshall, Joseph Kerger, Oddbjorn Straume, Laurent Mortier, Jochen Utikal, Micaela Hernberg, James Larkin, Yoshio Kiyohara, Mario Mandalà, Henrik Schmidt, Daniil Stroyakovskiy, Pablo Luis Ortiz Romero, Naoya Yamazaki, John Walker, Anna Maria Di Giacomo, Lionel Geoffrois, Jean-Philippe Lacour, Caroline Robert, Vincent Descamps, Shahneen Sandhu, Gil Bar-Sela, Paul C. Nathan, Marcin Dzienis, Ralf Gutzmer, Claus Garbe, Andrey Meshcheryakov, Patrick Combemale, Martin Fehr, Guzel Mukhametshina, Helena Kapiteijn, Geke A. P. Hospers, Jun Aoi, Andrew Haydon, Rutger H. T. Koornstra, Marie-Thérèse Leccia, Sigrun Hallmeyer, Pier Francesco Ferrucci, Jean-Jacques Grob, Leonel Hernandez-Aya, Jan-Christoph Simon, Vanna Chiarion Sileni, Alain Algazi, Lidija Sekulovic, Sandrine Marreaud, Bernard Fitzharris, Jacob Schachter, Xinni Song, Wolf-Henning Boehncke, Rahima Jamal, Paul Lorigan, Maureen J.B. Aarts, Reinhard Dummer, Mike McCrystal, César Martins, Reiner Hofmann-Wellenhof, Alexander M.M. Eggermont, Carola Berking, Elaine Dunwoodie, Bernard Guillot, Michal Kicinski, Philippe Saiag, Céleste Lebbé, Thierry Lesimple, Stefan Suciu, Michal Lotem, Paula Ferreira, Mohammed M. Milhem, Laurent Machet, Patrick Terheyden, Anna Katharina Winge-Main, Peter Hersey, Jean-Francois Baurain, Axel Hauschild, Stéphane Dalle, Jean-Philippe Arnault, Paolo A. Ascierto, Gerard Groenewegen, Florent Grange, Georgina V. Long, Victoria Atkinson, Philippa Corrie, Matteo S. Carlino, Thomas Jouary, Daniel Hendler, Richard Casasola, Ashita Waterston, Jessica C. Hassel, University Medical Center [Utrecht], Azienda Ospedaliera Ospedale Papa Giovanni XXIII [Bergamo, Italy], The University of Sydney, Princess Alexandra Hospital, Brisbane, University of Queensland [Brisbane], Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), N.N. Blokhin National Medical Research Center of Oncology, Edith Cowan University (ECU), Royal Marsden NHS Foundation Trust, Universitat de Barcelona (UB), Instituto de Salud Carlos III [Madrid] (ISC), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Radboud University Medical Center [Nijmegen], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), University Hospital of Siena, Amsterdam UMC - Amsterdam University Medical Center, Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Hannover Medical School [Hannover] (MHH), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), The Christie NHS Foundation Trust [Manchester, Royaume-Uni], Merck & Co. Inc, European Organisation for Research and Treatment of Cancer [Bruxelles] (EORTC), European Cancer Organisation [Bruxelles] (ECCO), Institut Gustave Roussy (IGR), Oncologie dermatologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Internal medicine, and CCA - Cancer Treatment and quality of life

Subjects
Male, Skin Neoplasms, Medizin, Pembrolizumab, law.invention, Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2], MESH: Aged, 80 and over, 0302 clinical medicine, Randomized controlled trial, law, Monoclonal, 80 and over, MESH: Double-Blind Method, 030212 general & internal medicine, Neoplasm Metastasis, Humanized, Melanoma, MESH: Aged, Aged, 80 and over, education.field_of_study, MESH: Middle Aged, Hazard ratio, MESH: Neoplasm Staging, Middle Aged, Oncology, 030220 oncology & carcinogenesis, Female, Adult, Aged, Antibodies, Monoclonal, Humanized, Double-Blind Method, Humans, Neoplasm Staging, medicine.medical_specialty, MESH: Melanoma, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Placebo, Antibodies, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Internal medicine, medicine, Adjuvant therapy, education, Cancer staging, MESH: Humans, business.industry, MESH: Skin Neoplasms, MESH: Adult, MESH: Neoplasm Metastasis, MESH: Male, Clinical trial, MESH: Antibodies, Monoclonal, Humanized, business, MESH: Female
Abstract

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43–0·74], p1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37. Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5–45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9–69·5] in the pembrolizumab group vs 49·4% [44·8–53·8] in the placebo group; HR 0·60 [95% CI 0·49–0·73]; p

Published
2021
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8. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial

Author

Bottomley, A., Coens, C., Mierzynska, J., Blank, C. U., Mandalà, M., Long, G. V., Atkinson, V. G., Dalle, S., Haydon, A. M., Meshcheryakov, A., Khattak, A., Carlino, M. S., Sandhu, S., Puig, S., Ascierto, P. A., Larkin, J., Lorigan, P. C., Rutkowski, P., Schadendorf, D., Koornstra, R., Hernandez-Aya, L., Di Giacomo, A. M., van den Eertwegh, A. J. M., Grob, J. -J., Gutzmer, R., Jamal, R., van Akkooi, A. C. J., Krepler, C., Ibrahim, N., Marreaud, S., Kicinski, M., Suciu, S., Robert, C., Eggermont, A. M. M., EORTC Melanoma Group, Lesimple, T., Maio, M., Linette, G., Mortier, L., Svane, I. M., Schachter, J., Brown, M., Hersey, P., Barrow, C., Kudchadkar, R., Dutriaux, C., Song, X., Quaglino, P., Queirolo, P., Meier, F., Stroyakovskiy, D., Guillot, B., Romero, P. L. O., Bastholt, L., Garbe, C., Grange, F., Mohr, P., Algazi, A., Bechter, O., Hernberg, M., Loquai, C., Meiss, F., Chiarion Sileni, V., Bar-Sela, G., Fitzharris, B., Saiag, P., Arnault, J. -P., Simon, J. -C., Stephens, R., Baurain, J. -F., Lebbe, C., Combemale, P., Dummer, R., Hauschild, A., Parente, P., Yamazaki, N., Milhem, M., Leccia, M. -T., Geoffrois, L., Kretschmer, L., Dunwoodie, E., Walker, J., Lotem, M., Hendler, D., Mackiewicz, A., Sekulovic, L., Dzienis, M., Hospers, G. A. P., Siano, M., Hassel, J., Corrie, P., Passos, M. -J., Levin, M., Hoeller, C., Machet, L., Hallmeyer, S., Waterston, A., Descamps, V., Kiecker, F., Aarts, M., Schmidt, H., Raimundo, A., Nyakas, M., Lacour, J. -P., Berking, C., Ferrucci, P. F., Jameson, M., Kim, K., Yokota, K., Kerger, J., Aubin, F., Groenewegen, G., Kapiteijn, H., Boehncke, W. -H., Utikal, J., Casasola, R., Marshall, E., Ferraresi, V., Richtig, E., Matkovic, S., Inozume, T., Crook, T., Mcneil, C., Kiyohara, Y., Avril, M. -F., Hein, R., Terheyden, P., Nathan, P., Aoi, J., Skytta, T., Jouary, T., Takenouchi, T., Straume, O., Martins, C., Mukhametshina, G., Boehncke, Wolf-Henning, Internal medicine, CCA - Cancer Treatment and quality of life, European Organisation for Research and Treatment of Cancer [Bruxelles] (EORTC), European Cancer Organisation [Bruxelles] (ECCO), Ospedale 'Santa Maria della Misericordia' = University Hospital 'Santa Maria della Misericordia', The University of Sydney, Princess Alexandra Hospital, Brisbane, University of Queensland [Brisbane], Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Edith Cowan University (ECU), Universitat de Barcelona (UB), The Christie NHS Foundation Trust [Manchester, Royaume-Uni], Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Radboud University Medical Center [Nijmegen], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), University Hospital of Siena, Amsterdam UMC - Amsterdam University Medical Center, Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Hannover Medical School [Hannover] (MHH), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Merck & Co. Inc, AP-HP. Université Paris Saclay, Institut Gustave Roussy (IGR), University Medical Center [Utrecht], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Merck Sharp & Dohme., and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Male, Skin Neoplasms, Medizin, Skin Neoplasms / drug therapy, Pembrolizumab, law.invention, Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2], MESH: Aged, 80 and over, 0302 clinical medicine, Melanoma / pathology, Randomized controlled trial, law, Monoclonal, 80 and over, Clinical endpoint, MESH: Double-Blind Method, 030212 general & internal medicine, Humanized, Melanoma, MESH: Aged, ddc:616, Aged, 80 and over, education.field_of_study, MESH: Middle Aged, Antibodies, Monoclonal, Humanized, Neoplasm Staging, Quality of Life, Double-Blind Method, Adult, Aged, Middle aged, Humans [MeSH], Hazard ratio, MESH: Neoplasm Staging, Middle Aged, Oncology, 030220 oncology & carcinogenesis, Female, Humans, medicine.medical_specialty, Melanoma / psychology, Skin Neoplasms / psychology, MESH: Melanoma, Antibodies, Monoclonal, Humanized / therapeutic use, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Placebo, Antibodies, Melanoma / mortality, 03 medical and health sciences, Internal medicine, medicine, Adjuvant therapy, education, Skin Neoplasms / pathology, MESH: Humans, Melanoma / drug therapy, business.industry, MESH: Skin Neoplasms, MESH: Quality of Life, MESH: Adult, Skin Neoplasms / mortality, MESH: Male, Clinical trial, MESH: Antibodies, Monoclonal, Humanized, business, MESH: Female
Abstract

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; pMethods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing.Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant.Interpretation: Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting. placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting. placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting.

Published
2021
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9. Thiotepa-busulfan-fludarabine (TBF) conditioning regimen in patients undergoing allogeneic hematopoietic cell transplantation for myelofibrosis: an outcome analysis from the Chronic Malignancies Working Party of the EBMT

Author

Giuseppe Marotta, Didier Blaise, Matjaz Sever, Patrizia Chiusolo, Ibrahim Yakoub-Agha, Tomasz Czerw, Carlos Solano, Giorgia Battipaglia, Nicolaus Kröger, Stella Santarone, Marie-Thérèse Rubio, Maria Laura Fox, Anna Paola Iori, William Arcese, Patrick Hayden, Mohamad Mohty, Liesbeth C. de Wreede, Yves Chalandon, Lotus Wendel, Juan Carlos Hernández-Boluda, Renato Fanin, Pietro Pioltelli, Emanuele Angelucci, Donal P. McLornan, Katya Mauff, Nathalie Contentin, University of Naples Federico II = Università degli studi di Napoli Federico II, European Society for Blood and Marrow Transplantation (EBMT), Ospedale Policlinico San Martino [Genoa], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Roma Tor Vergata [Roma], Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi di Udine - University of Udine [Italie], Hôpitaux Universitaires de Genève (HUG), Azienda Ospedaliera Universitaria Senese, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), University of Ljubljana, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Leiden University Medical Center (LUMC), Universiteit Leiden, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Trinity College Dublin, NHS Foundation Trust [London], The Royal Marsden, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
medicine.medical_specialty, Transplantation Conditioning, Platelet Engraftment, [SDV]Life Sciences [q-bio], Vidarabine / analogs & derivatives, Graft vs Host Disease, ThioTEPA, Gastroenterology, Conditioning regimen, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Neoplasms, medicine, Humans, In patient, Vidarabine / therapeutic use, Myelofibrosis, Busulfan, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, ddc:616, Transplantation, Hematopoietic cell, business.industry, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Hematology, Middle Aged, Settore MED/15, medicine.disease, surgical procedures, operative, Primary Myelofibrosis, 030220 oncology & carcinogenesis, Stem cell, business, Thiotepa, Vidarabine, 030215 immunology, medicine.drug
Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative option in MF. There is no consensus on the optimal conditioning regimen. We report outcomes of 187 patients with MF transplanted between 2010 and 2017 conditioned with TBF. Median age was 58 years. Median interval from diagnosis to allo-HCT was 44 months. Donors were haploidentical (41%), unrelated (36%) or HLA-identical siblings (23%). Stem cell source was PB in 60%. Conditioning was myeloablative in 48% of cases. Antithymocyte globulin (ATG) was used in 41% of patients. At 100 days, neutrophil and platelet engraftment were 91% and 63% after a median of 21 and 34 days, respectively. Grade II-IV and III-IV acute GVHD occurred in 24% and 12%, while at 3 years, all grade chronic GVHD and chronic extensive GVHD had been diagnosed in 38% and 11%. At 3 years, OS, RFS and GRFS were 55%, 49% and 43%, respectively. RI and NRM were 17% and 33%. On multivariate analysis, poor KPS and the use of unrelated donors were associated with worse GRFS and a higher grade II-IV acute GVHD, respectively. Neither donor type nor intensity of the conditioning regimen influenced survival outcomes. TBF is a feasible conditioning regimen in allo-HCT for MF in all donor settings although longer term outcomes are required.

Published
2020
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10. Post-transplant cyclophosphamide versus antithymocyte globulin in patients with acute myeloid leukemia in first complete remission undergoing allogeneic stem cell transplantation from 10/10 HLA-matched unrelated donors

Author

Gwendolyn Van Gorkom, Montserrat Rovira, Edouard Forcade, Myriam Labopin, Eolia Brissot, Annalisa Ruggeri, Alexandros Spyridonidis, Eric Deconinck, Martin Mistrik, Jan J. Cornelissen, Claude Eric Bulabois, Ian Moiseev, Ellen Meijer, Stephan Mielke, Laimonas Griskevicius, Sebastian Giebel, Didier Blaise, Riitta Niittyvuopio, Bipin N. Savani, Fabio Ciceri, Arnon Nagler, Jaime Sanz, Mohamad Mohty, 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), Hematology, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CEREST-TC [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pavlov First Saint Petersburg State Medical University [St. Petersburg], Erasmus University Medical Center [Rotterdam] (Erasmus MC), VU University Medical Center [Amsterdam], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], University of Barcelona, IRCCS Ospedale San Raffaele [Milan, Italy], Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Vilnius University [Vilnius], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Comenius University in Bratislava, University Hospital of Würzburg, Centre Hospitalier Universitaire [Grenoble] (CHU), Hôpital JeanMinjoz, Universitat de València (UV), General University Hospital of Patras, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Gestionnaire, Hal Sorbonne Université, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), HUS Comprehensive Cancer Center, Clinicum, Department of Oncology, Brissot, E., Labopin, M., Moiseev, I., Cornelissen, J. J., Meijer, E., Van Gorkom, G., Rovira, M., Ciceri, F., Griskevicius, L., Blaise, D., Forcade, E., Mistrik, M., Mielke, S., Bulabois, C. E., Niittyvuopio, R., Deconinck, E., Ruggeri, A., Sanz, J., Spyridonidis, A., Savani, B., Giebel, S., Nagler, A., Mohty, M., RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: MA Hematologie (9), CCA - Cancer Treatment and quality of life, and CHU Saint-Antoine [AP-HP]

Subjects
Oncology, Male, Cancer Research, BLOOD, [SDV]Life Sciences [q-bio], MULTICENTER, Graft vs Host Disease, Kaplan-Meier Estimate, HEMATOLOGICAL MALIGNANCIES, PROPHYLAXIS, 0302 clinical medicine, antithymocyte globulin, prevention, Recurrence, immune system diseases, Cause of Death, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, skin allograft tolerance, Medicine, Cumulative incidence, ComputingMilieux_MISCELLANEOUS, free survival, Hematology, Incidence (epidemiology), Incidence, Graft Survival, Remission Induction, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, lcsh:Diseases of the blood and blood-forming organs, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Allografts, Combined Modality Therapy, 3. Good health, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, surgical procedures, operative, 030220 oncology & carcinogenesis, Histocompatibility, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Post-transplant cyclophosphamide, Unrelated Donors, Immunosuppressive Agents, medicine.drug, Adult, medicine.medical_specialty, Cyclophosphamide, Adolescent, post-transplant cyclophosphamide, 3122 Cancers, matched unrelated donor, Human leukocyte antigen, acute myeloid leukemia, open-label, lcsh:RC254-282, Disease-Free Survival, MECHANISMS, versus-host-disease, 03 medical and health sciences, Young Adult, Internal medicine, Humans, Matched unrelated donor, Propensity Score, Molecular Biology, Aged, Antilymphocyte Serum, Retrospective Studies, Acute myeloid leukemia, business.industry, lcsh:RC633-647.5, Research, Transplantation, Propensity score matching, Antithymocyte globulin, business, 030215 immunology
Abstract

International audience; Full text linksfull-text provider logoActionsFavoritesSharePage navigation Title & authors Abstract Conflict of interest statement Figures References Related information LinkOut - more resourcesJ Hematol Oncol. 2020 Jul 3;13(1):87.doi: 10.1186/s13045-020-00923-0.Post-transplant cyclophosphamide versus antithymocyte globulin in patients with acute myeloid leukemia in first complete remission undergoing allogeneic stem cell transplantation from 10/10 HLA-matched unrelated donorsEolia Brissot 1 2 , Myriam Labopin 3 , Ian Moiseev 4 , J J Cornelissen 5 , Ellen Meijer 6 , Gwendolyn Van Gorkom 7 , Montserrat Rovira 8 , Fabio Ciceri 9 10 , Laimonas Griskevicius 11 , Didier Blaise 12 , Edouard Forcade 13 , Martin Mistrik 14 , Stephan Mielke 15 , Claude Eric Bulabois 16 , Riitta Niittyvuopio 17 , Eric Deconinck 18 , Annalisa Ruggeri 9 10 , Jaime Sanz 19 20 , Alexandros Spyridonidis 21 , Bipin Savani 22 , Sebastian Giebel 23 , Arnon Nagler 24 , Mohamad Mohty 25 26Affiliations PMID: 32620146 PMCID: PMC7333262 DOI: 10.1186/s13045-020-00923-0 Free PMC articleAbstractBackground: Graft-versus-host disease (GVHD) remains a major contributor to mortality and morbidity after allogeneic stem-cell transplantation (allo-HSCT). The updated recommendations suggest that rabbit antithymocyte globulin or anti-T-lymphocyte globulin (ATG) should be used for GVHD prophylaxis in patients undergoing matched-unrelated donor (MUD) allo-HSCT. More recently, using post-transplant cyclophosphamide (PTCY) in the haploidentical setting has resulted in low incidences of both acute (aGVHD) and chronic GVHD (cGVHD). Therefore, the aim of our study was to compare GVHD prophylaxis using either PTCY or ATG in patients with acute myeloid leukemia (AML) who underwent allo-HSCT in first remission (CR1) from a 10/10 HLA-MUD.Methods: Overall, 174 and 1452 patients from the EBMT registry receiving PTCY and ATG were included. Cumulative incidence of aGVHD and cGVHD, leukemia-free survival, overall survival, non-relapse mortality, cumulative incidence of relapse, and refined GVHD-free, relapse-free survival were compared between the 2 groups. Propensity score matching was also performed in order to confirm the results of the main analysis RESULTS: No statistical difference between the PTCY and ATG groups was observed for the incidence of grade II-IV aGVHD. The same held true for the incidence of cGVHD and for extensive cGVHD. In univariate and multivariate analyses, no statistical differences were observed for all other transplant outcomes. These results were also confirmed using matched-pair analysis.Conclusion: These results highlight that, in the10/10 HLA-MUD setting, the use of PTCY for GVHD prophylaxis may provide similar outcomes to those obtained with ATG in patients with AML in CR1.

Published
2020
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11. Management of patients with acute leukemia during the COVID-19 outbreak: practical guidelines from the acute leukemia working party of the European Society for Blood and Marrow Transplantation

Author

Myriam Labopin, Sebastian Giebel, Annalisa Ruggeri, Zinaida Peric, Jordi Esteve, Mohamad Mohty, Norbert Claude Gorin, Jurjen Versluis, Jaime Sanz, Gesine Bug, Eolia Brissot, Arnon Nagler, Ali Bazarbachi, Maria H. Gilleece, Fabio Ciceri, Frédéric Baron, Francesco Lanza, Roni Shouval, Christoph Schmid, Bipin N. Savani, Alexandros Spyridonidis, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Liège, American University of Beirut Faculty of Medicine and Medical Center (AUB), Goethe-University Frankfurt am Main, Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Barcelona Centre for International Health Research, Hospital Clinic (CRESIB), Universitat de Barcelona (UB), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Leeds Institute of Cancer and Pathology [U.K.], Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Alma Mater Studiorum University of Bologna (UNIBO), University Hospital Center Rebro, Universitat de València (UV), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Universität Augsburg [Augsburg], Memorial Sloane Kettering Cancer Center [New York], General University Hospital of Patras, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Chaim Sheba Medical Center, Hematology, Gestionnaire, HAL Sorbonne Université 5, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Brissot, E., Labopin, M., Baron, F., Bazarbachi, A., Bug, G., Ciceri, F., Esteve, J., Giebel, S., Gilleece, M. H., Gorin, N. -C., Lanza, F., Peric, Z., Ruggeri, A., Sanz, J., Savani, B. N., Schmid, C., Shouval, R., Spyridonidis, A., Versluis, J., Nagler, A., and Mohty, M.

Subjects
2019-20 coronavirus outbreak, medicine.medical_specialty, Tissue and Organ Procurement, Coronavirus disease 2019 (COVID-19), [SDV]Life Sciences [q-bio], Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), chemotherapy, NO, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, medicine, Leukaemia, Humans, Acute leukemia, COVID-19, chemotherapy, aplasia, immune-deficiency, Pandemics, Societies, Medical, ComputingMilieux_MISCELLANEOUS, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Acute leukemia, Transplantation, Leukemia, SARS-CoV-2, business.industry, Marrow transplantation, Hematopoietic Stem Cell Transplantation, COVID-19, Outbreak, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, 3. Good health, Europe, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, aplasia, 030220 oncology & carcinogenesis, Perspective, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, immune-deficiency, business, Haematological diseases, 030215 immunology
Abstract

International audience

Published
2020
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12. Safety, efficacy and patient-reported outcomes with trifluridine/tipiracil in pretreated metastatic colorectal cancer: results of the PRECONNECT study

Author

Loick Vidot, Julien Taieb, Irfan Cicin, Ahmet Ozet, Martin Becquart, Fabienne Portales, Timothy J. Price, Chiara Cremolini, Dan Atlan, Jean-Marc Phelip, Jean-Baptiste Bachet, Nadjat Mounedji, Eric Van Cutsem, Alfredo Falcone, Lucjan Wyrwicz, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Queen Elizabeth Hospital, University of Pisa - Università di Pisa, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Gazi University, Trakya Universitesi [Edirne], Institut de Recherches Internationales Servier [Suresnes] (IRIS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Gestionnaire, Hal Sorbonne Université, and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Vascular Endothelial Growth Factor A, Cancer Research, Pyrrolidines, Colorectal cancer, [SDV]Life Sciences [q-bio], Trifluridine, trifluridine tipiracil, chemistry.chemical_compound, 0302 clinical medicine, Quality of life, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, colorectal cancer, metastatic, quality of life, safety, Original Research, 0303 health sciences, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, Female, medicine.symptom, Colorectal Neoplasms, medicine.drug, medicine.medical_specialty, Nausea, Placebo, lcsh:RC254-282, 03 medical and health sciences, Internal medicine, medicine, Humans, Patient Reported Outcome Measures, Adverse effect, 030304 developmental biology, Tipiracil, Aged, business.industry, medicine.disease, chemistry, business, Thymine
Abstract

BACKGROUND: In RECOURSE (, trifluridine/tipiracil significantly improved overall survival and progression-free survival (PFS) versus placebo in patients with pretreated metastatic colorectal cancer (mCRC). PRECONNECT was designed to further characterise safety and clinical use of trifluridine/tipiracil. METHODS: In this ongoing, international, multicentre, open-label trial, patients with pretreated mCRC received oral trifluridine/tipiracil 35 mg/m2 twice daily on days 1-5 and 8-12 of each 28-day cycle. The primary endpoint was safety; secondary endpoints included PFS and quality of life (QoL). RESULTS: 793 patients (median age 62 years) from 13 countries received trifluridine/tipiracil for a median of 2.84 months (IQR 2.64). Adverse events (AEs) were experienced by 96.7%; the most common (≥20% of patients) were neutropaenia, asthenia/fatigue, nausea, anaemia and diarrhoea. Grade ≥3 AEs occurred in 73.9% of patients, with the most common being neutropaenia (39.1% of patients), anaemia (9.8%) and asthenia/fatigue (5.0%). Median PFS was 2.8 months (95% CI 2.7 to 2.9). Median time to Eastern Cooperative Oncology Group performance status deterioration (≥2) was 8.9 months (range 0.03-14.72). There was no clinically relevant change from baseline in QoL. CONCLUSIONS: PRECONNECT showed consistent results with the previously demonstrated safety and efficacy profile of trifluridine/tipiracil, with no new safety concerns identified. QoL was maintained during treatment. TRIAL REGISTRATION NUMBER: NCT03306394. ispartof: ESMO OPEN vol:5 issue:3 ispartof: location:England status: published

Published
2020
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13. Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial

Author

Sandrine Marreaud, Hans Gelderblom, Pierre Meeus, Marco Rastrelli, Antonino De Paoli, Claudia Sangalli, Alessandro Gronchi, Elizabeth H. Baldini, Piotr Rutkowski, Jean-Yves Blay, Chandrajit P. Raut, Frits van Coevorden, Charles Honoré, Marco Fiore, Aisha Miah, Rick L. Haas, Angelo Paolo Dei Tos, Carol Jane Swallow, Dirk C. Strauss, Daphne Hompes, Eberhard Stoeckle, Sylvie Bonvalot, Cécile Le Péchoux, Jean Jacques Stelmes, Saskia Litière, Peter Chung, Stephan Stoldt, Université Paris sciences et lettres (PSL), Fondazione Ospedale San Camillo [Venezia] (IRCCS), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Département de radiothérapie [Gustave Roussy], Princess Margaret Hospital, University of Toronto, Centre Léon Bérard [Lyon], Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Dana-Farber Cancer Institute [Boston], Harvard Medical School [Boston] (HMS), Centro San Giovanni di Dio, Fatebenefratelli, Brescia (IRCCS), Università degli Studi di Brescia [Brescia], European Organisation for Research and Treatment of Cancer [Bruxelles] (EORTC), European Cancer Organisation [Bruxelles] (ECCO), and Leiden University Medical Center (LUMC)

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Population, Phases of clinical research, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Clinical endpoint, Medicine, Humans, 030212 general & internal medicine, Retroperitoneal Neoplasms, Adverse effect, education, ComputingMilieux_MISCELLANEOUS, Aged, education.field_of_study, Performance status, business.industry, Hazard ratio, Sarcoma, Middle Aged, Neoadjuvant Therapy, 3. Good health, Surgery, Clinical trial, Radiation therapy, Europe, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, North America, Female, Radiotherapy, Adjuvant, Radiotherapy, Conformal, business
Abstract

Summary Background Unlike for extremity sarcomas, the efficacy of radiotherapy for retroperitoneal sarcoma is not established. The aim of this study was to evaluate the impact of preoperative radiotherapy plus surgery versus surgery alone on abdominal recurrence-free survival. Methods EORTC-62092 is an open-label, randomised, phase 3 study done in 31 research institutions, hospitals, and cancer centres in 13 countries in Europe and North America. Adults (aged ≥18 years) with histologically documented, localised, primary retroperitoneal sarcoma that was operable and suitable for radiotherapy, who had not been previously treated and had a WHO performance status and American Society of Anesthesiologists score of 2 or lower, were centrally randomly assigned (1:1), using an interactive web response system and a minimisation algorithm, to receive either surgery alone or preoperative radiotherapy followed by surgery. Randomisation was stratified by hospital and performance status. Radiotherapy was delivered as 50·4 Gy (in 28 daily fractions of 1·8 Gy) in either 3D conformal radiotherapy or intensity modulated radiotherapy, and the objective of surgery was a macroscopically complete resection of the tumour mass with en-bloc organ resection as necessary. The primary endpoint was abdominal recurrence-free survival, as assessed by the investigator, and was analysed in the intention-to-treat population. Safety was analysed in all patients who started their allocated treatment. This trial is registered with ClinicalTrials.gov , NCT01344018 . Findings Between Jan 18, 2012 and April 10, 2017, 266 patients were enrolled, of whom 133 were randomly assigned to each group. The median follow-up was 43·1 months (IQR 28·8–59·2). 128 (96%) patients from the surgery alone group had surgery, and 119 (89%) patients in the radiotherapy and surgery group had both radiotherapy and surgery. Median abdominal recurrence-free survival was 4·5 years (95% CI 3·9 to not estimable) in the radiotherapy plus surgery group and 5·0 years (3·4 to not estimable) in the surgery only group (hazard ratio 1·01, 95% CI 0·71–1·44; log rank p=0·95). The most common grade 3–4 adverse events were lymphopenia (98 [77%] of 127 patients in the radiotherapy plus surgery group vs one [1%] of 128 patients in the surgery alone group), anaemia (15 [12%] vs ten [8%]), and hypoalbuminaemia (15 [12%] vs five [4%]). Serious adverse events were reported in 30 (24%) of 127 patients in the radiotherapy plus surgery group, and in 13 (10%) of 128 patients in the surgery alone group. One (1%) of 127 patients in the radiotherapy plus surgery group died due to treatment-related serious adverse events (gastropleural fistula), and no patients in the surgery alone group died due to treatment-related serious adverse events. Interpretation Preoperative radiotherapy should not be considered as standard of care treatment for retroperitoneal sarcoma. Funding European Organisation for Research and Treatment of Cancer, and European Clinical Trials in Rare Sarcomas.

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2020
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14. Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma

Author

Vanna Chiarion-Sileni, Céleste Lebbé, Catriona M. McNeil, Joanna Pikiel, Jean-Jacques Grob, Luc Thomas, Lars Bastholt, Andrzej Mackiewicz, Michele Maio, Omid Hamid, Virginia Ferraresi, Marta Nyakas, Caroline Robert, Michelle Del Vecchio, Burcin Simsek, Michael Smylie, Laurent Mortier, Dirk Schadendorf, Carmen Loquai, Inge Marie Svane, Ana Arance, Gabriella Liszkay, Fareeda Hosein, Piotr Rutkowski, Paolo A. Ascierto, Florent Grange, Christoph Hoeller, Brigitte Dréno, Ralf Gutzmer, Claus Garbe, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale [Naples, Italy] (INT-FGP), IRCCS Istituto Nazionale dei Tumori [Milano], Poznan University of Medical Sciences [Poland] (PUMS), Institut Gustave Roussy (IGR), Université Paris-Sud - Paris 11 (UP11), Oncologie dermatologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Istituto Oncologico Veneto I.R.C.C.S. [Padova, Italy], Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), CIC Saint Louis (CIC-1427), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Herlev and Gentofte Hospital, Copenhagen University Hospital, Royal Prince Alfred Hospital [Camperdown, Australia] (RPAH), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), University Medical Center [Mainz], Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Claude Huriez [Lille], CHU Lille, Odense University Hospital (OUH), Centre hospitalier universitaire de Nantes (CHU Nantes), University Hospital [Essen, Germany], German Cancer Consortium [Heidelberg] (DKTK), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Oslo University Hospital [Oslo], Aix Marseille Université (AMU), Assistance Publique - Hôpitaux de Marseille (APHM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), National Institute of Oncology [Budapest, Hungary], Cross Cancer Institute [Edmonton, AB, Canada], Medizinische Universität Wien = Medical University of Vienna, Regina Elena National Cancer Institute [Rome], Centre Hospitalier Universitaire de Reims (CHU Reims), Medizinische Hochschule Hannover (MHH), Wojewodzkie Centrum Oncologii [Gdańsk, Poland], Bristol-Myers Squibb [Princeton], University Hospital of Siena, and Malbec, Odile

Subjects
Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, Medizin, Ipilimumab, randomized trials, Gastroenterology, Asymptomatic, law.invention, immunology, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Clinical endpoint, Immunology and Allergy, 030212 general & internal medicine, Adverse effect, RC254-282, Clinical/Translational Cancer Immunotherapy, Pharmacology, business.industry, Incidence (epidemiology), Melanoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, oncology, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, Molecular Medicine, medicine.symptom, business, Brain metastasis, medicine.drug
Abstract

BackgroundWe have previously reported significantly longer overall survival (OS) with ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with advanced melanoma, with higher incidences of adverse events (AEs) at 10 mg/kg. This follow-up analysis reports a 5-year update of OS and safety.MethodsThis randomized, multicenter, double-blind, phase III trial included patients with untreated or previously treated unresectable stage III or IV melanoma. Patients were randomly assigned (1:1) to ipilimumab 10 mg/kg or 3 mg/kg every 3 weeks for 4 doses. The primary end point was OS.ResultsAt a minimum follow-up of 61 months, median OS was 15.7 months (95% CI 11.6 to 17.8) at 10 mg/kg and 11.5 months (95% CI 9.9 to 13.3) at 3 mg/kg (HR 0.84, 95% CI 0.71 to 0.99; p=0.04). In a subgroup analysis, median OS of patients with asymptomatic brain metastasis was 7.0 months (95% CI 4.0 to 12.8) in the 10 mg/kg group and 5.7 months (95% CI 4.2 to 7.0) in the 3 mg/kg group. In patients with wild-type or mutantBRAFtumors, median OS was 13.8 months (95% CI 10.2 to 17.0) and 33.2 months (95% CI 19.4 to 45.2) in the 10 mg/kg group, and 11.2 months (95% CI 9.2 to 13.8) and 19.7 months (95% CI 11.6 to 25.3) in the 3 mg/kg group, respectively. The incidence of grade 3/4 treatment-related AEs was 36% in the 10 mg/kg group vs 20% in the 3 mg/kg group, and deaths due to treatment-related AEs occurred in four (1%) and two patients (1%), respectively.ConclusionsThis 61-month follow-up of a phase III trial showed sustained long-term survival in patients with advanced melanoma who started metastatic treatment with ipilimumab monotherapy, and confirmed the significant benefit for those who received ipilimumab 10 mg/kg vs 3 mg/kg. These results suggest the emergence of a plateau in the OS curve, consistent with previous ipilimumab studies.Trial registration numberNCT01515189.

Published
2020
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15. Radiotherapy-Induced Changes in the Systemic Immune and Inflammation Parameters of Head and Neck Cancer Patients

Author

Udo S. Gaipl, Eric Andreas Rutten, Serge M. Candéias, Géza Sáfrány, Benjamin Frey, Enikő Kis, Katalin Lumniczky, Zsuzsa S Kocsis, Zsolt Jurányi, Enikő Noémi Bogdándi, Katalin Balázs, Christophe Badie, Piotr Widlak, Lourdes Cruz Garcia, Iwona Domińczyk, Department of Radiation Medicine, Centre for Radiation, Chemical and Environmental Hazards, Public Health England [London], Protéomique, Métaux et Différenciation (ProMD ), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Department of Radiation Oncology, Department of Radiobiology and Diagnostic Onco-Cytogenetics, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, regulatory T cell, Regulatory T cell, dendritic cell, medicine.medical_treatment, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Article, Natural killer cell, 03 medical and health sciences, 0302 clinical medicine, Immune system, immune phenotyping, Medizinische Fakultät, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, ddc:610, radiotherapy, business.industry, Head and neck cancer, PBMC, Dendritic cell, natural killer cell, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Blood proteins, 3. Good health, Radiation therapy, 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, gene expression, head and neck cancer, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, plasma proteins
Abstract

International audience; Though radiotherapy is a local therapy, it has systemic effects mainly influencing immune and inflammation processes. This has important consequences in the long-term prognosis and therapy individualization. Our objective was to investigate immune and inflammation-related changes in the peripheral blood of head and neck cancer patients treated with radiotherapy. Peripheral blood cells, plasma and blood cell-derived RNA were isolated from 23 patients before and at two time points after radiotherapy and cellular immune parameters, plasma protein changes and gene expression alterations were studied. Increased regulatory T cells and increased CTLA4 and PD-1 expression on CD4 cells indicated an immune suppression induced by the malignant condition, which was accentuated by radiotherapy. Circulating dendritic cells were strongly elevated before treatment and were not affected by radiotherapy. Decreased endoglin levels in the plasma of patients before treatment were further decreased by radiotherapy. Expression of the FXDR, SESN1, GADD45, DDB2 and MDM2 radiation-response genes were altered in the peripheral blood cells of patients after radiotherapy. All changes were long-lasting, detectable one month after radiotherapy. In conclusion we demonstrated radiotherapy-induced changes in systemic immune parameters of head and neck cancer patients and proposed markers suitable for patient stratification worth investigating in larger patient cohorts.

Published
2019
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16. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network

Author

Georg Maschmeyer, Bernd Metzner, Corinne Haioun, Richard Delarue, Thomas Fischer, Ulrich Dührsen, Michal Szymczyk, Jan Walewski, Mathias Hänel, Michael Unterhalt, Catherine Thieblemont, Norma Peter, Kamal Bouabdallah, Christiane Pott, Michael Hallek, Vincent Ribrag, Stephan Stilgenbauer, André Bosly, Catherine Sebban, Josef Birkmann, Christian Schmidt, Marie-Hélène Delfau-Larue, Jürgen Finke, Wolfgang Hiddemann, Nicole Brousse, Elizabeth Macintyre, Gilles Salles, Pierre Feugier, Wolfram Klapper, Roswitha Forstpointner, Eva Hoster, Michael Kneba, Rene-Olivier Casasnovas, Martin Dreyling, Lothar Kanz, Reda Bouabdallah, Olivier Hermine, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Department of Internal Medicine III, University of Munich, Institute of Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology ( MCMCC ), CHU Dinant-Godinne UCL Namur, Internal Medicine III, Universität Ulm, APHP Hôpital Saint Louis, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier ( ICGM ICMMM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Département d'Hematologie, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Second Medical Department, University Hospital Schleswig-Holstein, University of Cologne, Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Hématologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Paracelsus Medical University, Ludwig-Maximilians University Hospital, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Klinikum Chemnitz, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), University Hospital Freiburg, Carl Thiem Hospital Cottbus, Université Mohamed Boudiaf de M'sila, Centre Léon Bérard [Lyon], Agence départementale d’architecture et d’urbanisme du Haut-Rhin ( ADAUHR ), University Hospital Essen, Medizinische Klinik, Hämatologie und Onkologie, Klinikum Ernst von Bergmann, Department of Internal Medicine II (Oncology, Hematology, Immunology, Rheumatology, Pulmonology), University Hospital Tuebingen, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire d'anatomie pathologique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Department of Pathology, Hematopathology Section and Lymph Node Registry, Universityhospital Schleswig-Holstein, Campus Kiel, Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service d'immunologie biologique, University Hospital Schleswig–Holstein, III. Medizinische Klinik, Technische Universität München [München] ( TUM ), Institut Imagine (UMR 1163), Laboratory of Cellular and Molecular Mechanisms of Hemathological Disorders and Therapeutic Implication, Maria Sklodowska-Curie Memorial Cancer Center, Institut Charles Gerhardt - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICG ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM) - Université Montpellier 2 - Sciences et Techniques (UM2) - Université Montpellier 1 (UM1) - Centre National de la Recherche Scientifique (CNRS), Institut Paoli Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC) - Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service de Radio-Oncologie [Lyon], Hospices Civils de Lyon - Centre Hospitalier Lyon Sud [Pierre Bénite], Hôpital Edouard Herriot, Hospices Civils de Lyon - Hôpital Edouard Herriot, Institut Gustave Roussy (IGR), Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Henri Mondor - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), University Medical Centre Freiburg, Centre Hospitalier Universitaire de Bordeaux, Agence départementale d’architecture et d’urbanisme du Haut-Rhin (ADAUHR), Laboratoire d'Informatique de l'Université du Maine (LIUM), Université du Maine (UM), Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5) - AP-HP Hôpital Necker - Enfants Malades [Paris], AP-HP Hôpital Necker - Enfants Malades [Paris], Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) - Groupe Hospitalier Necker-Enfants Malades, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM) - IFR10 - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Technische Universität München [München] (TUM)

Subjects
Adult, Male, medicine.medical_specialty, Vincristine, Transplantation Conditioning, Medizin, Lymphoma, Mantle-Cell, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, International Prognostic Index, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Treatment Failure, Cyclophosphamide, ComputingMilieux_MISCELLANEOUS, business.industry, Cytarabine, Hematopoietic Stem Cell Transplantation, General Medicine, Middle Aged, medicine.disease, Combined Modality Therapy, Surgery, Transplantation, Doxorubicin, 030220 oncology & carcinogenesis, Prednisone, Female, Rituximab, Mantle cell lymphoma, Immunotherapy, business, Immunosuppressive Agents, Febrile neutropenia, 030215 immunology, medicine.drug
Abstract

Summary Background Mantle cell lymphoma is characterised by a poor long-term prognosis. The European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves outcome. Methods This randomised, open-label, parallel-group, phase 3 trial was done in 128 haemato-oncological hospital departments or private practices in Germany, France, Belgium, and Poland. Patients aged 65 years or younger with untreated stage II–IV mantle cell lymphoma were centrally randomised (1:1), with computer-assisted random block selection, to receive either six courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and ASCT (control group), or six courses of alternating R-CHOP or R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and ASCT (cytarabine group). Patients were stratified by study group and international prognostic index. The primary outcome was time to treatment failure from randomisation to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II–IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomisation. For safety analyses, patients were assessed according to the treatment actually started. This study is registered with ClinicalTrials.gov, number NCT00209222. Findings Of 497 patients (median age 55 years [IQR 49–60]) randomised from July 20, 2004, to March 18, 2010, 234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6·1 years (95% CI 5·4–6·4), time to treatment failure was significantly longer in the cytarabine group (median 9·1 years [95% CI 6·3–not reached], 5 year rate 65% [95% CI 57–71]) than in the control group (3·9 years [3·2–4·4], 40% [33–46]; hazard ratio 0·56; p=0·038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 [29%] of 241m vs 19 [8%] of 227 controls; platelets 176 [73%] of 240 vs 21 [9%] of 225), grade 3 or 4 febrile neutropenia (39 [17%] of 230 vs 19 [8%] of 224), and grade 1 or 2 renal toxicity (creatinine 102 [43%] of 236 vs 22 [10%] of 224). The number of ASCT-related deaths was similar (eight [3·4%]) in both groups. Interpretation Immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma. Funding European Commission, Lymphoma Research Foundation, and Roche.

Published
2016
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17. Five-year outcomes from a phase 3 METRIC study in patients with BRAF V600 E/K-mutant advanced or metastatic melanoma

Author

Mohammed M. Milhem, Peter Mohr, Paul Nathan, Piotr Rutkowski, Anthony D'Amelio, Peter Hersey, Felix Kiecker, Jochen Utikal, Lev V. Demidov, Caroline Robert, Reinhard Dummer, Claus Garbe, Dirk Schadendorf, Jessica C. Hassel, Bijoyesh Mookerjee, James Larkin, Keith T. Flaherty, Department of Dermatology (CHU Besançon), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), N.N. Blokhin Russian Cancer Research Center, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Novartis Pharmaceutical Corporation, University of Zurich, and Robert, Caroline

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, Skin Neoplasms, Time Factors, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Medizin, Phases of clinical research, Targeted therapy, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, 1306 Cancer Research, Melanoma, Trametinib, Aged, 80 and over, Brain Neoplasms, MEK inhibitor, Hazard ratio, 10177 Dermatology Clinic, Middle Aged, Prognosis, 3. Good health, Dacarbazine, Survival Rate, 030220 oncology & carcinogenesis, 2730 Oncology, Female, medicine.drug, Adult, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, Paclitaxel, Pyridones, 610 Medicine & health, Pyrimidinones, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Humans, Adverse effect, Aged, Chemotherapy, business.industry, 030104 developmental biology, Mutation, business, Follow-Up Studies
Abstract

Background Primary findings from the METRIC (TMT212A2301) study demonstrated that trametinib improved progression-free survival (PFS) and overall survival (OS) compared with chemotherapy in patients with unresectable or metastatic cutaneous melanoma with a BRAF V600 E/K mutation. However, clinical data characterising the long-term use of these therapies in combination with BRAF inhibitors or as monotherapies are limited. Methods In this open-label, phase 3 study, 322 patients with BRAF V600 E/K–mutant metastatic melanoma were randomised in a 2:1 ratio to receive trametinib (2 mg orally, once daily; n = 214) or chemotherapy (dacarbazine [1000 mg/m2] or paclitaxel [175 mg/m2] intravenously, every 3 weeks; n = 108). Patients who progressed on chemotherapy were allowed to cross over and receive trametinib. Five-year results of efficacy and safety analyses are reported. Results The median PFS was 4.9 months in the trametinib arm versus 1.5 months in the chemotherapy arm (hazard ratio, 0.54; 95% confidence interval, 0.41–0.73). Landmark OS rates for trametinib versus chemotherapy arms at 1 year, 2 years and 5 years were 60.9% versus 49.6%, 32.0% versus 29.4% and 13.3% versus 17.0%, respectively. Most patients (n = 70 [65%]) from the chemotherapy arm crossed over to the trametinib arm early in their treatment. No unexpected adverse events were reported. Conclusions This 5-year follow-up of patients with BRAF V600 E/K–mutant metastatic melanoma on a targeted therapy demonstrates that long-term use of trametinib is possible with no new or unexpected adverse events. Some patients experienced long-term survival benefit with trametinib monotherapy (METRIC ClinicalTrials.gov number, NCT01245062.).

Published
2018
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18. Influence of Confounding Factors on Radiation Dose Estimation Using In Vivo Validated Transcriptional Biomarkers

Author

Antoine Laval, Grzegorz Woźniak, Navita Somaiah, Piotr Widlak, Lucyna Ponge, Ellen M. Donovan, Grainne O’Brien, Leszek Miszczyk, Lone Gothard, Serge M. Candéias, Isabelle Testard, Elizabeth A. Ainsbury, Christophe Badie, Lourdes Cruz-Garcia, Sue Boyle, Centre for Radiation, Chemical and Environmental Hazards, Public Health England [London], Centre for Vision, Speech and Signal Processing (CVSSP), University of Surrey (UNIS), Institute for Cancer Research/Royal Marsden NHS Foundation Trust, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
0301 basic medicine, Adult, Lipopolysaccharides, Male, Curcumin, Epidemiology, Cyclin G1, Health, Toxicology and Mutagenesis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Pharmacology, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, In vivo, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Neoplasms, Gene expression, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Transcription factor, Aged, Regulation of gene expression, Aged, 80 and over, business.industry, Confounding, Cancer, Radiotherapy Dosage, Middle Aged, medicine.disease, Phosphoric Monoester Hydrolases, 3. Good health, Gene Expression Regulation, Neoplastic, 030104 developmental biology, chemistry, 13. Climate action, 030220 oncology & carcinogenesis, Case-Control Studies, Female, Radiotherapy, Intensity-Modulated, business, Ex vivo, Biomarkers
Abstract

International audience; For triage purposes following a nuclear accident, blood-based gene expression biomarkers can provide rapid dose estimates for a large number of individuals. Ionizing-radiation-responsive genes are regulated through the DNA damage-response pathway, which includes activation of multiple transcription factors. Modulators of this pathway could potentially affect the response of these biomarkers and consequently compromise accurate dose estimation calculations. In the present study, four potential confounding factors were selected: cancer condition, sex, simulated bacterial infection (lipopolysaccharide), and curcumin, an anti-inflammatory/antioxidant agent. Their potential influence on the transcriptional response to radiation of the genes CCNG1 and PHPT1, two biomarkers of radiation exposure ex vivo, was assessed. First, both CCNG1 and PHPT1 were detected in vivo in blood samples from radiotherapy patients and as such were validated as biomarkers of exposure. Importantly, their basal expression level was slightly but significantly affected in vivo by patients' cancer condition. Moreover, lipopolysaccharide stimulation of blood irradiated ex vivo led to a significant modification of CCNG1 and PHPT1 transcriptional response in a dose- and time-dependent manner with opposite regulatory effects. Curcumin also affected CCNG1 and PHPT1 transcriptional response counteracting some of the radiation induction. No differences were observed based on sex. Dose estimations calculated using linear regression were affected by lipopolysaccharide and curcumin. In conclusion, several confounding factors tested in this study can indeed modulate the transcriptional response of CCNG1 and PHPT1 and consequently can affect radiation exposure dose estimations but not to a level which should prevent the biomarkers' use for triage purposes.

Published
2018
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19. Treatment for patients with relapsed/refractory mantle cell lymphoma: European-based recommendations

Author

Steven Le Gouill, Jan Walewski, Pier Luigi Zinzani, Marek Trněný, Francesco Zaja, Carlo Visco, Martin Dreyling, Igor Aurer, Georg Hess, Olivier Hermine, Vincent Ribrag, Mats Jerkeman, Sergio Cortelazzo, Dreyling, Martin, Aurer, Igor, Cortelazzo, Sergio, Hermine, Olivier, Hess, Georg, Jerkeman, Mat, Le Gouill, Steven, Ribrag, Vincent, TrnÄ›ný, Marek, Visco, Carlo, Walewski, Jan, Zaja, Francesco, Zinzani, Pier Luigi, III. Medizinische Klinik, Technische Universität München [München] ( TUM ), Department of Oncology and Hematology, University of Modena and Reggio Emilia, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Department of Oncology and Pathology [Lund], Lund University [Lund], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy ( IGR ), Charles University and General University Hospital, Department of Hematology, Ospedale San Bortolo, Institute of Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology ( MCMCC ), L. and A. Seràgnoli Hospital, University of Bologna, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Trněný, Marek

Subjects
Oncology, Cancer Research, Lymphoma, Drug Resistance, Lymphoma, Mantle-Cell, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, chemistry.chemical_compound, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Medicine, Chemotherapy, clinical trials, mantle cell lymphoma, molecular targeted therapy, Bortezomib, Combination chemotherapy, clinical trial, Hematology, Temsirolimus, Europe, Local, 030220 oncology & carcinogenesis, Ibrutinib, Practice Guidelines as Topic, Rituximab, medicine.drug, medicine.medical_specialty, 03 medical and health sciences, Clinical Trials, Phase II as Topic, Internal medicine, Humans, Lenalidomide, business.industry, Phase II as Topic, Mantle-Cell, medicine.disease, Clinical trial, Drug Resistance, Neoplasm, Neoplasm Recurrence, Local, Neoplasm Recurrence, chemistry, Neoplasm, Mantle cell lymphoma, business, 030215 immunology
Abstract

International audience; Patients with mantle cell lymphoma (MCL) usually respond to initial combination chemotherapy, but the disease inevitably relapses and often follows an aggressive course. Here, clinical study results published since 2008 for patients with relapsed/refractory MCL were reviewed to compare available evidence for treatment guidance. Most trials identified were non-randomized, phase II studies performed at a limited number of sites, and many evaluated MCL as one of multiple non-Hodgkin lymphoma subtypes. Additional randomized, comparative trials are needed. Treatment selection generally depends on patient need, age and fitness, time of relapse, and line of therapy. Combination regimens typically produce higher response rates than single agents, and adding rituximab generally improves outcomes. The inclusion of ibrutinib, lenalidomide, temsirolimus, and bortezomib, represents an important advance for patients ineligible for, unable to tolerate, or failing high-intensity combination chemotherapy. A high need for effective treatments in relapsed/refractory MCL remains, particularly for elderly and frail patients.

Published
2017
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20. Genomic Grade Index predicts postoperative clinical outcome of GIST

Author

Jerzy Ostrowski, H.J. Kim, David Jérémie Birnbaum, Annalisa Astolfi, W K Kim, Marcin Polkowski, François Bertucci, Pascal Finetti, Maria Abbondanza Pantaleo, 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), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Yonsei University College of Medicine [Seoul, Republic of Korea], University of Bologna/Università di Bologna, Medical Center of Postgraduate Education [Warsaw] (MCPE), FINETTI, Pascal, Bertucci F, Finetti P, Ostrowski J, Kim WK, Kim H, Pantaleo MA, Astolfi A, Polkowski M, and Birnbaum D

Subjects
Male, Oncology, Cancer Research, medicine.medical_specialty, Pathology, Multivariate analysis, Gastrointestinal Stromal Tumors, Expression Signature, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, DNA microarray, Gene expression, GIST, Imatinib, Profiling, Prognosis, Piperazines, NO, Text mining, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Relapse risk, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Oligonucleotide Array Sequence Analysis, GiST, business.industry, Gene Expression Profiling, Genetics and Genomics, Middle Aged, Pyrimidines, Treatment Outcome, imatinib, Benzamides, gene expression, Imatinib Mesylate, Genomic grade index, Learning set, Female, profiling, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business, medicine.drug
Abstract

International audience; Background: Prognosis of localised gastrointestinal stromal tumour (GIST) is heterogeneous, notably for patients with AFIP intermediate or high risk of relapse, who are candidates to adjuvant imatinib. We hypothesised that gene expression profiles might improve the prognostication and help to refine the indications for imatinib.Methods: We collected gene expression and histoclinical data of 146 pre-treatment localised GIST samples treated with surgery alone. We searched for a gene expression signature (GES) predictive for relapse-free survival (RFS) and compared its performances to that of three published prognostic proliferation-based GES (Genomic Grade Index (GGI), 16-Kinase, and CINSARC) and AFIP classification. We also analysed a data set from 28 patients with advanced GIST treated with neo-adjuvant imatinib.Results: We identified a 275-gene GES (gene expression signature) predictive of RFS in a learning set and validated its robustness in an independent set. However, the GGI outperformed its prognostic performances, and those of the two other signatures and the AFIP intermediate-risk classification in two independent tests sets in uni- and multivariate analyses. Importantly, GGI could split the AFIP intermediate/high-risk samples into two groups with different RFS. Genomic Grade Index 'high-risk' tumours were more proliferative and genetically unstable than 'low-risk' tumours, and more sensitive to imatinib.Conclusion: GGI refines the prediction of RFS in localised GIST and might help tailor adjuvant imatinib.

Published
2012
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21. Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial

Author

Sudeep Gupta, Peter Reichardt, George D. Demetri, Jochen Schuette, Piotr Rutkowski, Seock-Ah Im, Jean-Yves Blay, Xin Huang, Michael Heinrich, Yoon-Koo Kang, Denis Soulières, Jean-Francois Martini, Kolette D. Fly, Patrick Schöffski, Maria Jose Lechuga, David Goldstein, Hans Gelderblom, Massimo Corsaro, Leids Universitair Medisch Centrum [Leiden, The Netherlands], Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Tata Memorial Centre, Asan Medical Center [Seoul], University of Ulsan, Department of General Medical Oncology [Leuven], University Hospitals Leuven [Leuven], Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Remote Sensing, School of Remote Sensing and Information Engineering Wuhan University, and Wuhan University [China]

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, Indoles, Receptor, Platelet-Derived Growth Factor alpha, Survival, analysis, Growth, 0302 clinical medicine, Belgium, Germany, Sunitinib, Overall survival, Stromal tumor, Aged, 80 and over, Platelet-Derived Growth Factor, education.field_of_study, GiST, Imatinib-resistant GIST, Progression-free survival, KIT, Middle Aged, Prognosis, 3. Good health, Berlin, Proto-Oncogene Proteins c-kit, Italy, 030220 oncology & carcinogenesis, Medicine, Female, France, secondary, Research Article, medicine.drug, GIST, Adult, medicine.medical_specialty, Canada, Adolescent, Genotype, Patients, Gastrointestinal Stromal Tumors, Population, KIT mutation, [SDV.CAN]Life Sciences [q-bio]/Cancer, PDGFRA, Disease-Free Survival, methods, Time, 03 medical and health sciences, Internal medicine, medicine, Genetics, Humans, Pyrroles, education, Protein Kinase Inhibitors, Aged, therapy, business.industry, Imatinib, digestive system diseases, Clinical trial, 030104 developmental biology, Drug Resistance, Neoplasm, Immunology, Mutation, business, Laboratories
Abstract

Background Several small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-α (PDGFRA) contributes in part to the level of clinical effectiveness of sunitinib in gastrointestinal stromal tumor (GIST) patients. This study aimed to correlate KIT and PDGFRA mutational status with clinical outcome metrics (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) in a larger international patient population. Methods This is a non-interventional, retrospective analysis in patients with imatinib-resistant or intolerant GIST who were treated in a worldwide, open-label treatment-use study (Study 1036; NCT00094029) in which sunitinib was administered at a starting dose of 50 mg/day on a 4-week-on, 2-week-off schedule. Molecular status was obtained in local laboratories with tumor samples obtained either pre-imatinib, post-imatinib/pre-sunitinib, or post-sunitinib treatment, and all available data were used in the analyses regardless of collection time. The primary analysis compared PFS in patients with primary KIT exon 11 versus exon 9 mutations (using a 2-sided log-rank test) and secondary analyses compared OS (using the same test) and ORR (using a 2-sided Pearson χ2 test) in the same molecular subgroups. Results Of the 1124 sunitinib-treated patients in the treatment-use study, 230 (20 %) were included in this analysis, and baseline characteristics were similar between the two study populations. Median PFS was 7.1 months. A significantly better PFS was observed in patients with a primary mutation in KIT exon 9 (n = 42) compared to those with a primary mutation in exon 11 (n = 143; hazard ratio = 0.59; 95 % confidence interval, 0.39–0.89; P = 0.011), with median PFS times of 12.3 and 7.0 months, respectively. Similarly, longer OS and higher ORR were observed in patients with a primary KIT mutation in exon 9 versus exon 11. The data available were limited to investigate the effects of additional KIT or PDGFRA mutations on the efficacy of sunitinib treatment. Conclusions This large retrospective analysis confirms the prognostic significance of KIT mutation status in patients with GIST. This analysis also confirms the effectiveness of sunitinib as a post-imatinib therapy, regardless of mutational status. Trial registration NCT01459757. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2051-5) contains supplementary material, which is available to authorized users.

Published
2016
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22. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial

Author

David Belada, Boris V. Afanasyev, Jiri Mayer, Agnieszka Giza, Simon Rule, Marek Trněný, Kazimierz Kuliczkowski, Julia Alexeeva, Antoine Thyss, Lorenz Trümper, Tsvetan Biyukov, Franck Morschhauser, Wojciech Jurczak, John Radford, Jan Walewski, Caterina Stelitano, K. D. Kaplanov, Sergey Voloshin, Marie Laure Casadebaig Bravo, Reinhard Marks, Meera Patturajan, Noel Milpied, Thierry Lamy, Alexej Kuzmin, Luca Arcaini, Jonchère, Laurent, Department of Hematology and Oncology, Georg-August-University = Georg-August-Universität Göttingen, Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Università degli Studi di Pavia = University of Pavia (UNIPV), Charles University Hospital, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Institute of Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Department of Internal Medicine, Hemato-Oncology, Faculty of Medicine [Brno] (MED / MUNI), Masaryk University [Brno] (MUNI)-Masaryk University [Brno] (MUNI), Medical Oncology, The University of Manchester and Christie NHS Foundation Trust, Service d'hématologie, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Haematology, Derriford Hospital, Haematology, Centre Hospitalier Universitaire de Nice (CHU Nice), Klinika Haematologii, Akademia Medyczna w Wroclawiu, Service d'Hématologie et Thérapie Cellulaire, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Divisione di Ematologia, Pres. Osp. Riuniti 'Bianchi, Melacrito, Morelli', Georg-August-University [Göttingen], University of Pavia, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Population, Angiogenesis Inhibitors, Antineoplastic Agents, Kaplan-Meier Estimate, Lymphoma, Mantle-Cell, Disease-Free Survival, Drug Administration Schedule, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Confidence Intervals, medicine, Clinical endpoint, Humans, Neoplasm Invasiveness, Prospective Studies, education, Lenalidomide, Aged, Neoplasm Staging, Proportional Hazards Models, education.field_of_study, Dose-Response Relationship, Drug, business.industry, Middle Aged, medicine.disease, Survival Analysis, Thalidomide, 3. Good health, Surgery, Transplantation, [SDV] Life Sciences [q-bio], Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Refractory Mantle Cell Lymphoma, Female, Mantle cell lymphoma, Neoplasm Recurrence, Local, business, Progressive disease, Follow-Up Studies, 030215 immunology, medicine.drug
Abstract

Summary Background Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, showed activity in many single-group studies in relapsed or refractory mantle cell lymphoma. The aim of this randomised study was to examine the efficacy and safety of lenalidomide versus best investigator's choice of single-agent therapy in relapsed or refractory mantle cell lymphoma. Methods The MCL-002 (SPRINT) study was a randomised, phase 2 study of patients with mantle cell lymphoma aged 18 years or older at 67 clinics and academic centres in 12 countries who relapsed one to three times, had Eastern Cooperative Oncology Group performance status of 0–2, at least one measurable lesion to be eligible, and who were ineligible for intensive chemotherpy or stem-cell transplantation. Using a centralised interactive voice response system, we randomly assigned (2:1) patients in a permuted block size of six to receive lenalidomide (25 mg orally on days 1–21 every 28 days) until progressive disease or intolerability, or single-agent investigator's choice of either rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine. Randomisation was stratified by time from diagnosis, time from last anti-lymphoma therapy, and previous stem-cell transplantation. Individual treatment assignment between lenalidomide and investigator's choice was open label, but investigators had to register their choice of comparator drug before randomly assigning a patient. Patients who progressed on investigator's choice could cross over to lenalidomide treatment. We present the prespecified primary analysis results in the intention-to-treat population for the primary endpoint of progression-free survival, defined as the time from randomisation to progressive disease or death, whichever occurred first. Patient enrolment is complete, although treatment and collection of additional time-to-event data are ongoing. This study is registered with ClinicalTrials.gov, number NCT00875667. Findings Between April 30, 2009, and March 7, 2013, we enrolled 254 patients in the intention-to-treat population (170 [67%] were randomly assigned to receive lenalidomide, 84 [33%] to receive investigator's choice monotherapy). Patients had a median age of 68·5 years and received a median of two previous regimens. With a median follow-up of 15·9 months (IQR 7·6–31·7), lenalidomide significantly improved progression-free survival compared with investigator's choice (median 8·7 months [95% CI 5·5–12·1] vs 5·2 months [95% CI 3·7–6·9]) with a hazard ratio of 0·61 (95% CI 0·44–0·84; p=0·004). In the 167 patients in the lenalidomide group and 83 patients in the investigator's choice group who received at least one dose of treatment the most common grade 3–4 adverse events included neutropenia (73 [44%] of 167 vs 28 [34%] of 83) without increased risk of infection, thrombocytopenia (30 [18%] vs 23 [28%]), leucopenia (13 [8%] vs nine [11%]), and anaemia (14 [8%] vs six [7%]). Interpretation Patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell transplantation have longer progression-free survival, with a manageable safety profile when treated with lenalidomide compared with monotherapy investigator's choice options. Funding Celgene Corporation.

Published
2016
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23. Exposure-Response Analyses of Asbestos and Lung Cancer Subtypes in a Pooled Analysis of Case-Control Studies

Author

Olsson, Ann C, Vermeulen, Roel, Schüz, Joachim, Kromhout, Hans, Pesch, Beate, Peters, Susan, Behrens, Thomas, Portengen, Lützen, Mirabelli, Dario, Gustavsson, Per, Kendzia, Benjamin, Almansa, Josue, Luzon, Veronique, Vlaanderen, Jelle, Stücker, Isabelle, Guida, Florence, Consonni, Dario, Caporaso, Neil, Landi, Maria Teresa, Field, John, Brüske, Irene, Wichmann, Heinz-Erich, Siemiatycki, Jack, Parent, Marie-Elise, Richiardi, Lorenzo, Merletti, Franco, Jöckel, Karl-Heinz, Ahrens, Wolfgang, Pohlabeln, Hermann, Plato, Nils, Tardón, Adonina, Zaridze, David, McLaughlin, John, Demers, Paul, Szeszenia-Dabrowska, Neonila, Lissowska, Jolanta, Rudnai, Peter, Fabianova, Eleonora, Stanescu Dumitru, Rodica, Bencko, Vladimir, Foretova, Lenka, Janout, Vladimir, Boffetta, Paolo, Bueno-de-Mesquita, Bas, Forastiere, Francesco, Brüning, Thomas, Straif, Kurt, LS IRAS EEPI GRA (Gezh.risico-analyse), LS IRAS EEPI EXAS (Arb.hyg+bl.st.kar.), Sub IRAS EEPI Algemeen, dIRAS RA-2, Nofer Institute of Occupational Medicine, Łódź, Poland, Olsson, A.C., Vermeulen, R., Schüz, J., Kromhout, H., Pesch, B., Peters, S., Behrens, T., Portengen, L., Mirabelli, D., Gustavsson, P., Kendzia, B., Almansa, J., Luzon, V., Vlaanderen, J., Stücker, I., Guida, F., Consonni, D., Caporaso, N., Landi, M.T., Field, J., Brüske, I., Wichmann, H.-E., Siemiatycki, J., Parent, M.-E., Richiardi, L., Merletti, F., Jöckel, K.-H., Ahrens, W., Pohlabeln, H., Plato, N., Tardon, A., Zaridze, D., McLaughlin, J., Demers, P., Szeszenia-Dabrowska, N., Lissowska, J., Rudnai, P., Fabianova, E., Stanescu Dumitru, R., Bencko, V., Foretova, L., Janout, V., Boffetta, P., Bueno-De-Mesquita, B., Forastiere, F., Brüning, T., Straif, K., LS IRAS EEPI GRA (Gezh.risico-analyse), LS IRAS EEPI EXAS (Arb.hyg+bl.st.kar.), Sub IRAS EEPI Algemeen, dIRAS RA-2, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Karolinska Institutet [Stockholm], Institute for Risk Assessment Sciences, Utrecht University [Utrecht], Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), The University of Western Australia (UWA), University of Turin, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris-Sud - Paris 11 (UP11), Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Institute of Translational Medicine, University of Liverpool, Helmholtz-Zentrum München (HZM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Universität Duisburg-Essen [Essen], Bremen Institute for Prevention Research and Social Medicine (BIPS), CIBER de Epidemiología y Salud Pública (CIBERESP), Russian Cancer Research Centre, Public Health Ontario - Santé publique Ontario, Cancer Care Ontario, Nofer Institute of Occupational Medicine (NIOM), Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), National center for public health [Hungary], Regional Authority of Public Health [Slovaquia] (RAPH), Ministry of Health of the Slovak Republic [Slovaquia], National Institute of Public Health [Romania] (INSP), Charles University [Prague] (CU), Masaryk University [Brno] (MUNI), Palacky University Olomouc, Icahn School of Medicine at Mount Sinai [New York] (MSSM), National Institute for Public Health and the Environment [Bilthoven] (RIVM), Azienda Sanitaria Locale [ROMA] (ASL), The SYNERGY project is funded by the German Social Accident Insurance (DGUV), Grant FP 271. The original studies were funded as follows: in Canada by Canadian Institutes for Health Research and Guzzo-SRC Chair in Environment and Cancer, National Cancer Institute of Canada, Canadian Cancer Society, Occupational Cancer Research Centre, Workplace Safety and Insurance Board, Canadian Cancer Society, and Cancer Care Ontario, in France by the French Agency of Health Security (ANSES), Fondation de France, French National Research Agency (ANR), National Institute of Cancer (INCA), Fondation pour la Recherche Médicale, French Institute for Public Health Surveillance (InVS), Health Ministry (DGS), Organization for the Research on Cancer (ARC), and French Ministry of work, solidarity, and public function (DGT), in Germany by Federal Ministry of Education, Science, Research, and Technology (Grant 01 HK 173/0), Federal Ministry of Science (Grant 01 HK 546/8), and the Ministry of Labour and Social Affairs (Grant IIIb7-27/13), in Italy by Environmental Epidemiology Program of the Lombardy Region, INAIL, Italian Association for Cancer Research, Region Piedmont, Compagnia di San Paolo, and Lazio Region, in Poland by Polish State Committee for Scientific Research (Grant SPUB-M-COPERNICUS/P-05/ DZ-30/99/2000), in Czech Republic by MH CZ - DRO (MMCI, 00209805), in Spain by Instituto Universitario de Oncologia, Universidad de Oviedo, Asturias, Fondo de Investigacion Sanitaria (FIS) and Ciber de Epidemiologia y Salud Publica (CIBERESP), in Sweden by Swedish Council for Work Life Research and Swedish Environmental Protection Agency, in the Netherlands by Dutch Ministry of Health, Welfare and Sports, National Institute of Public Health and the Environment, and Europe Against Cancer Program, in the UK by Roy Castle Foundation, in the USA by Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, the IARC multicenter study in Central and Eastern Europe was funded by the European Commission’s INCO Copernicus program (Contract IC15-CT96-0313)., and Joachim Schüz and Kurt Straif are part of a collaborative study with the State Russian Institute of Occupational Health (SRIOH) on asbestos and cancer risk, which includes financial support from SRIOH to IARC. Paolo Boffetta acted as expert witness for Edison SpA in asbestos-related litigation, outside the submitted work. Beate Pesch, Thomas Behrens, Benjamin Kendzia, and Thomas Brüning, as staff of the Institute for Prevention and Occupational Medicine (IPA), are employed at the 'Berufsgenossenschaft Rohstoffe und chemische Industrie' (BG RCI), a public body, which is a member of the study’s main sponsor, the German Social Accident Insurance (DGUV). IPA is an independent research institute of the Ruhr-Universität Bochum. The authors are independent from the German Social Accident Insurance in study design, access to the collected data, responsibility for data analysis and interpretation, and the right to publish

Subjects
Adult, Male, Canada, Pathology, medicine.medical_specialty, Lung Neoplasms, Epidemiology, [SDV]Life Sciences [q-bio], Population, Medizin, Cumulative Exposure, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease_cause, Asbestos, 03 medical and health sciences, asbestos exposure, 0302 clinical medicine, Occupational Exposure, Odds Ratio, medicine, Humans, 030212 general & internal medicine, Lung cancer, education, Aged, education.field_of_study, business.industry, Occupational asbestos exposure, lung cancer, Smoking, Case-control study, Absolute risk reduction, Odds ratio, Middle Aged, Occupational Epidemiology, medicine.disease, Small Cell Lung Carcinoma, 030210 environmental & occupational health, Confidence interval, 3. Good health, Europe, lung cancer, Logistic Models, Case-Control Studies, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Carcinoma, Squamous Cell, Female, business, Demography
Abstract

Supplemental Digital Content is available in the text., Background: Evidence is limited regarding risk and the shape of the exposure–response curve at low asbestos exposure levels. We estimated the exposure–response for occupational asbestos exposure and assessed the joint effect of asbestos exposure and smoking by sex and lung cancer subtype in general population studies. Methods: We pooled 14 case–control studies conducted in 1985–2010 in Europe and Canada, including 17,705 lung cancer cases and 21,813 controls with detailed information on tobacco habits and lifetime occupations. We developed a quantitative job-exposure-matrix to estimate job-, time period-, and region-specific exposure levels. Fiber-years (ff/ml-years) were calculated for each subject by linking the matrix with individual occupational histories. We fit unconditional logistic regression models to estimate odds ratios (ORs), 95% confidence intervals (CIs), and trends. Results: The fully adjusted OR for ever-exposure to asbestos was 1.24 (95% CI, 1.18, 1.31) in men and 1.12 (95% CI, 0.95, 1.31) in women. In men, increasing lung cancer risk was observed with increasing exposure in all smoking categories and for all three major lung cancer subtypes. In women, lung cancer risk for all subtypes was increased in current smokers (ORs ~two-fold). The joint effect of asbestos exposure and smoking did not deviate from multiplicativity among men, and was more than additive among women. Conclusions: Our results in men showed an excess risk of lung cancer and its subtypes at low cumulative exposure levels, with a steeper exposure–response slope in this exposure range than at higher, previously studied levels. (See video abstract at, http://links.lww.com/EDE/B161.)

Published
2017
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