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1. Measurable residual disease, FLT3‐ITD mutation, and disease status have independent prognostic influence on outcome of allogeneic stem cell transplantation in NPM1‐mutated acute myeloid leukemia

Author: Rama Al Hamed, Myriam Labopin, Etienne Daguindau, Riitta Niittyvuopio, Anne Huynh, Gerard Socié, Micha Srour, Jean Henri Bourhis, Nicolaus Kröger, Eleni Tholouli, Goda Choi, Xavier Poiré, Hans Martin, Marie‐Thérèse Rubio, Pavel Jindra, Didier Blaise, Dietrich Beelen, Hélène Labussière‐Wallet, Arnon Nagler, Ali Bazarbachi, Mohamad Mohty, Albert Einstein College of Medicine [New York], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CEREST-TC [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Hôpital JeanMinjoz, Helsinki University Central Hospital [Finland] (HUCH), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Lille, Université de Lille, Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], University Hospital Hamburg-Eppendorf, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Manchester Royal Infirmary, University of Manchester [Manchester], University of Groningen [Groningen], Cliniques universitaires St Luc [Bruxelles], Goethe-Universität Frankfurt am Main, Service d’Hématologie Adulte [Hôpitaux de Brabois, CHU Nancy], Centre Hospitalier Universitaire de Nancy (CHU Nancy), Medicine Charles University and General Faculty Hospital in Prague, 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), University Hospital [Essen, Germany], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Chaim Sheba Medical Center, American University of Beirut [Beyrouth] (AUB), 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)-CHU Saint-Antoine [AP-HP], Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Comprehensive Cancer Center [Helsinki, Finland], Helsinki University Hospital [Finland] (HUS), 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), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Medical Center Groningen [Groningen] (UMCG), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Charles University Hospital Pilsen, Dept. of Bone Marrow Transplantation, University Hospital, Essen, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Gestionnaire, Hal Sorbonne Université, NUNES, Jacques A, HUS Comprehensive Cancer Center, Clinicum, and Department of Oncology
Subjects: Adult, FLT3‐ITD, Cancer Research, FLT3-ITD, 3122 Cancers, Medizin, [SDV.CAN]Life Sciences [q-bio]/Cancer, acute myeloid leukemia, RELAPSE, [SDV.CAN] Life Sciences [q-bio]/Cancer, AML, Recurrence, hemic and lymphatic diseases, VERSUS-HOST-DISEASE, Humans, Radiology, Nuclear Medicine and imaging, NUCLEOPHOSMIN NPM1, RC254-282, Retrospective Studies, ACUTE MYELOGENOUS LEUKEMIA, Hematopoietic Stem Cell Transplantation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, ADULTS, Prognosis, NPM-1 mutation, NPM‐1 mutation, SORAFENIB, Leukemia, Myeloid, Acute, DEFINITION, Oncology, fms-Like Tyrosine Kinase 3, Mutation, SURVIVAL, minimal residual disease, Nucleophosmin
Abstract: Nucleophosmin-1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3-internal tandem duplication (FLT3-ITD). Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified 1572 adult (age >= 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or second complete remission (CR2:22%) who were transplanted from matched sibling donors (30.8%) or unrelated donors (57.4%) between 2007 and 2019 at EBMT participating centers. Median follow-up for survivors was 23.7 months. FLT3-ITD was present in 69.3% of patients and 39.2% had detectable minimal/measurable residual disease (MRD) at transplant. In multivariate analysis, relapse incidence (RI) and leukemia-free survival (LFS) were negatively affected by concomitant FLT3-ITD mutation (HR 1.66 p = 0.0001, and HR 1.53, p < 0.0001, respectively), MRD positivity at transplant (HR 2.18, p < 10(-5) and HR 1.71, p < 10(-5), respectively), and transplant in CR2 (HR 1.36, p = 0.026, and HR 1.26, p = 0.033, respectively), but positively affected by Karnofsky score >= 90 (HR 0.74, p = 0.012, and HR 0.7, p = 0.0002, respectively). Overall survival (OS) was also negatively influenced by concomitant FLT3-ITD (HR 1.6, p = 0.0001), MRD positivity at transplant (HR 1.61, p < 10(-5)), and older age (HR 1.22 per 10 years, p < 0.0001), but positively affected by matched sibling donor (unrelated donor: HR 1.35, p = 0.012; haploidentical donor: HR 1.45, p = 0.037) and Karnofsky score >= 90 (HR 0.73, p = 0.004). These results highlight the independent and significant role of FLT3-ITD, MRD status, and disease status on posttransplant outcomes in patients with NPM1-mutated AML allowing physicians to identify patients at risk of relapse who may benefit from posttransplant prophylactic interventions.
Published: 2022

2. Restrictive vs liberal red blood cell transfusion strategies in patients with acute myocardial infarction and anemia: Rationale and design of the <scp>REALITY</scp> trial

Author: Johanne Silvain, Manuel Martínez-Sellés, Reality Investigators, Gonzalo Calvo, Eric Vicaut, Nicolas Danchin, Cristina Avendaño-Solá, Philippe Gabriel Steg, Gregory Ducrocq, Joan Albert Arnaiz, Alexandra Rousseau, José Ramón González-Juanatey, Carma Karam, Marine Cachanado, Tabassome Simon, Etienne Puymirat, Gilles Lemesle, Isabelle Durand-Zaleski, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, University of Barcelona, Universidade de Santiago de Compostela [Spain] (USC ), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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), Institut Coeur Poumon [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), 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), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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), Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Ministère des Affaires Sociales et de la Santé PI15/01543 Instituto de Salud Carlos III, ISCIII Novartis AstraZeneca France Boehringer Ingelheim Pfizer Merck, The study is funded via a grant from the Programme de Recherche Médico‐Economique (PRME) from the French Ministry of Health, and a grant from the Instituto de Salud Carlos III (Spanish Ministry of Economy and Competitiveness), Grant n° PI15/01543., Editorial support was provided by Jenny Lloyd and Sophie Rushton‐Smith, MedLink Healthcare Communications, London, and was funded by the Programme de Recherche Medico‐Economique (PRME) from the Health Ministry in France., Dr Steg reports grants and nonfinancial support (cochair of the ODYSSEY OUTCOMES trial, as such, he received no personal fees, but his institution has received funding for the time he has devoted to trial coordination, and he has received support for travel related to trial meetings) from Sanofi, research grants and personal fees from Bayer (Steering Committee MARINER, grant for epidemiological study), Merck (speaker fees, grant for epidemiological studies), Sanofi (cochair of the ODYSSEY OUTCOMES trial, cochair of the SCORED trial, consulting, speaking), Servier (Chair of the CLARIFY registry, grant for epidemiological research), and Amarin (executive steering committee for the REDUCE‐IT trial [Disease Reduction of Cardiovascular Events With Icosapent Ethyl‐Intervention Trial], consulting), and and personal fees from Amgen, Bristol‐Myers Squibb, Boehringer Ingelheim, Pfizer, Novartis, Regeneron Pharmaceuticals, Lilly, and AstraZeneca. Dr Steg also has a European application number/patent number, issued on 26 October 2016 (no. 15712241.7), for a method for reducing cardiovascular risk.
Subjects: medicine.medical_specialty, Anemia, Cost effectiveness, medicine.medical_treatment, Trial Designs, Enfermedad cardiovascular, Myocardial Infarction, Ischemia, acute myocardial infarction, 030204 cardiovascular system & hematology, Revascularization, Hemoglobins, Tratamiento médico, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Reacción a la transfusión, Humans, Medicine, Blood Transfusion, cardiovascular diseases, 030212 general & internal medicine, Myocardial infarction, transfusion, Sistema cardiovascular, Transfusión sanguínea, cost effectiveness, business.industry, Insuficiencia cardíaca, General Medicine, medicine.disease, 3. Good health, Sample size determination, Relative risk, Emergency medicine, Erythrocyte Transfusion, Cardiology and Cardiovascular Medicine, business, Mace
Abstract: Background: Anemia is common in patients with acute myocardial infarction (AMI), and is an independent predictor of mortality. The optimal transfusion strategy in these patients is unclear. Hypothesis: We hypothesized that a "restrictive" transfusion strategy (triggered by hemoglobin ≤8 g/dL) is clinically noninferior to a "liberal" transfusion strategy (triggered by hemoglobin ≤10 g/dL), but is less costly. Methods: REALITY is an international, randomized, multicenter, open-label trial comparing a restrictive vs a liberal transfusion strategy in patients with AMI and anemia. The primary outcome is the incremental cost-effectiveness ratio (ICER) at 30 days, using the primary composite clinical outcome of major adverse cardiovascular events (MACE; comprising all-cause death, nonfatal stroke, nonfatal recurrent myocardial infarction, or emergency revascularization prompted by ischemia) as the effectiveness criterion. Secondary outcomes include the ICER at 1 year, and MACE (and its components) at 30 days and at 1 year. Results: The trial aimed to enroll 630 patients. Based on estimated event rates of 11% in the restrictive group and 15% in the liberal group, this number will provide 80% power to demonstrate clinical noninferiority of the restrictive group, with a noninferiority margin corresponding to a relative risk equal to 1.25. The sample size will also provide 80% power to show the cost-effectiveness of the restrictive strategy at a threshold of €50 000 per quality-adjusted life year. Conclusions: REALITY will provide important guidance on the management of patients with AMI and anemia. Sin financiación 3.287 JCR (2021) Q3, 74/143 Cardiac & Cardiovascular Systems 0.983 SJR (2021) Q1, 82/356 Cardiology and Cardiovascular Medicine No data IDR 2021 UEM
Published: 2021

3. 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

4. Pooled Fecal Allogenic Microbiotherapy for Refractory Gastrointestinal Acute Graft-Versus-Host Disease: Results from the Early Access Program in France

Author: Florent Malard, Michael Loschi, Thomas Cluzeau, Faezeh Legrand, Jean-Baptiste Mear, Faustine Lhomme, Sarah Guenounou, Anne Huynh, Cecile Borel, Deborah Desmier, Niels Moya, Amandine Charbonnier, Delphine Lebon, Hélène Labussière-Wallet, Corentin Orvain, Sylvain Chantepie, Claude-Eric Bulabois, Vincent Camus, Marie-Anne Couturier, Jérôme Cornillon, Patrice Chevallier, Clémence Mediavilla, Patrice Ceballos, David Beauvais, Marion Bruelle, Emilie Plantamura, Mohamad Mohty, DESSAIVRE, Louise, 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), 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), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), CHU Pontchaillou [Rennes], 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-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire d'Hématologie [CHU Amiens], CHU Amiens-Picardie, Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Grenoble, Université Grenoble Alpes (UGA), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Institut de Cancérologie Lucien Neuwirth, CHU Saint-Etienne, Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Lille, MaaT Pharma [Lyon], CEREST-TC [CHU Saint-Antoine], and Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP]
Subjects: [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Immunology, Cell Biology, Hematology, Biochemistry, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Introduction Acute graft-versus-host disease (aGvHD) is a major source of mortality following allogeneic hematopoietic cell transplantation (allo-HCT). Standard 1st line therapy for the treatment of aGvHD involves corticosteroids (CS). However, more than 50% of patients are refractory to CS (SR-aGvHD) and the associated mortality rate is of up to 80%. Recently, Ruxolitinib has been approved as 2nd line treatment for SR-aGvHD. However, patients with severe gastrointestinal (GI) aGvHD seem less likely to respond to Ruxolitinib and have poor outcomes with limited therapeutic options.In this context, fecal microbiotherapy has shown promising results in several pilot studies in patients with refractory GI-aGvHD. Here we report clinical outcomes from 81 patients diagnosed with SR or dependent (SD) GI-aGvHD treated with the pooled allogeneic microbiotherapy MaaT013 as part of the Early Access Program (EAP) in France.Methods 81 patients with SR/SD GI-aGvHD (Classical n=62, late onset n=12, overlap syndrome n=7) were treated with MaaT013 as part of an EAP in France. These patients had failed 1 to 6 prior systemic GvHD treatment lines (median 2; 66/81 received Ruxolitinib). Most patients had grade III-IV aGvHD (11% grade II, 51% grade III, 38% grade IV).For each patient, a total of 3 MaaT013 administrations were planned every 7 +/- 2 days. Each dose comprised 30g of feces in 150 mL of diluent, from 4 to 8 healthy donors, administered by enema (except for 1 patient by nasogastric tube).Treatment response was calculated among all treated patients based on aGvHD staging and grading at day 28 (D28) at the time of the EAP request.Results At D28, the GI-overall response rate (ORR) was 56%: 30 complete response (CR, 37%), 11 very good response rate (VGPR, 14%), 4 partial response (PR, 5%). The GI-ORR was higher in patients with lower grade aGvHD (89% in grade II, 66% in grade III, 32% in grade IV) and higher in SD versus SR patients (92% versus 49%). Including skin and liver symptoms (n=78), response rate was 49%, including 24 CR, 11 VGPR and 3 PR and inversely correlated with aGvHD initial grade (88% in grade II, 55% in grade III, 30% in grade IV).Overall survival (OS) was 51% at 6 months (M6) and 39% at M12. The median follow-up among surviving patients was 355 days (range, 53-731). OS was significantly higher in patients achieving at least GI-PR at D28 (Responder, R; n=45) compared to patients in treatment failure (Non-responder, NR; n=35): 69% versus 28% at M6, 59% versus 14% at M12, respectively. Median survival duration in R was 451 days versus 32 days in NR.Interestingly, aGvHD response was improved in the subgroup of 31 patients previously treated with Ruxolitinib as 2nd line and MaaT013 as 3rd line (65% D28 GI-ORR, OS M6 55% and 49% M12 and 74% versus 15% at M6 and 74% versus 0% at M12 for R and NR respectively).MaaT013 displayed a good overall safety profile in the EAP population: 20 pharmacovigilance cases were reported in 18 patients: sepsis in 11 patients, C. difficile colitis in 2, E. coli osteoarthritis in 1, G. silvicola in stools from 1, P. aeruginosa sinusitis in 1, appearance of air bubbles in the mesorectum in 1, respiratory distress in 1. No pathogen transmission was reported. In 2 patients, non-pathogenic commensal bacteria isolated following infectious events were detected in the administered MaaT013 batch. Causality could not be formally excluded in these cases.The overall incidence of bacteremia (14%) remains low, compared to an incidence of 31% to 74% in bloodstream infections reported in patients with GI-aGvHD. This suggests that fecal microbiotherapy may have a protective effect on bacterial translocation, but this needs to be confirmed in further clinical trials.47 deaths have been reported; the cause of which was GvHD in 21 patients, severe infection in 13, relapse of underlying malignancy in 6, COVID-19 in 3, hemorrhage during surgery in 1, neurological complications post allo-HCT in 1, and cardiac arrest in 2 patients. No causality link with MaaT013 administration has been identified.Conclusion Overall, EAP clinical data showed that MaaT013 was safe and effective for the treatment of SR/SD-GI-aGvHD especially in patients having previously received ruxolitinib. Interestingly, GI-response to aGvHD correlates with increased OS, suggesting a strong favorable benefit-risk profile for MaaT013. A Phase 3 trial is currently ongoing to confirm these results in ruxolitinib-refractory patients (NCT04769895).
Published: 2022

5. Early Cardiac Toxicity Associated With Post-Transplant Cyclophosphamide in Allogeneic Stem Cell Transplantation

Author: Anne Banet, Ollivier Legrand, Tounes Ledraa, Simona Lapusan, Annalisa Paviglianiti, Giorgia Battipaglia, Florent Malard, Rosa Adaeva, Clemence Mediavilla, Simona Sestili, Anne Vekhoff, Eolia Brissot, Agnès Bonnin, Razan Mohty, Françoise Isnard, Ramdane Belhocine, Stéphane Ederhy, M. Labopin, Mohamad Mohty, Ariel Cohen, Zoé Van de Wyngaert, Remy Dulery, 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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-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), CEREST-TC [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Service de Cardiologie [CHU Saint-Antoine], Gestionnaire, Hal Sorbonne Université, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Oncology, CVRF, cardiovascular risk factor, medicine.medical_specialty, Standard of care, Cyclophosphamide, Post transplant cyclophosphamide, post-transplant cyclophosphamide, medicine.medical_treatment, [SDV]Life Sciences [q-bio], cardiotoxicity, Hematopoietic stem cell transplantation, CVD, cardiovascular disease, GVHD, graft-versus-host disease, 03 medical and health sciences, HSCT, hematopoietic stem cell transplantation, PT-Cy, post-transplant cyclophosphamide, 0302 clinical medicine, allogeneic stem cell transplantation, Cardiac toxicity, Internal medicine, LVEF, left ventricular ejection fraction, medicine, haploidentical transplantation, Original Research, Cardiotoxicity, LVSD, left ventricular systolic dysfunction, business.industry, HR, hazard ratio, 3. Good health, [SDV] Life Sciences [q-bio], Transplantation, CI, confidence interval, ECE, early cardiac events, surgical procedures, operative, 030220 oncology & carcinogenesis, Stem cell, Cardiology and Cardiovascular Medicine, business, Cy, cyclophosphamide, GRFS, graft-versus-host disease-free, relapse-free survival, left ventricular systolic dysfunction, 030215 immunology, medicine.drug
Abstract: Background Post-transplant cyclophosphamide (PT-Cy) has become a standard of care in haploidentical hematopoietic stem cell transplantation (HSCT) to reduce the risk of graft-versus-host disease. However, data on cardiac events associated with PT-Cy are scarce. Objectives This study sought to assess the incidence and clinical features of cardiac events associated with PT-Cy. Methods The study compared clinical outcomes between patients who received PT-Cy (n = 136) and patients who did not (n = 195), with a focus on early cardiac events (ECE) occurring within the first 100 days after HSCT. All patients had the same systematic cardiac monitoring. Results The cumulative incidence of ECE was 19% in the PT-Cy group and 6% in the no–PT-Cy group (p < 0.001). The main ECE occurring after PT-Cy were left ventricular systolic dysfunction (13%), acute pulmonary edema (7%), pericarditis (4%), arrhythmia (3%), and acute coronary syndrome (2%). Cardiovascular risk factors were not associated with ECE. In multivariable analysis, the use of PT-Cy was associated with ECE (hazard ratio: 2.7; 95% confidence interval: 1.4 to 4.9; p = 0.002]. Older age, sequential conditioning regimen, and Cy exposure before HSCT were also associated with a higher incidence of ECE. Finally, a history of cardiac events before HSCT and ECE had a detrimental impact on overall survival. Conclusions PT-Cy is associated with a higher incidence of ECE occurring within the first 100 days after HSCT. Patients who have a cardiac event after HSCT have lower overall survival. These results may help to improve the selection of patients who are eligible to undergo HSCT with PT-Cy, especially older adult patients and patients with previous exposure to Cy., Central Illustration
Published: 2021

6. Measurable residual disease status and outcome of transplant in acute myeloid leukemia in second complete remission: a study by the acute leukemia working party of the EBMT

Author: Stephen D. Robinson, Mohamad Mohty, Gérard Socié, Myriam Labopin, Henrik Sengeloev, Ali Ünal, Ibrahim Yakoub-Agha, Arnold Ganser, Maria H. Gilleece, Dietrich W. Beelen, Eleni Tholouli, Avichai Shimoni, Arnon Nagler, Antonin Vitek, Emmanuelle Polge, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Chaim Sheba Medical Center, 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), University Hospitals Bristol, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hannover Medical School [Hannover] (MHH), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Manchester Royal Infirmary, University of Manchester [Manchester], 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)-CHU Saint-Antoine [AP-HP], Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Adult, Male, Oncology, medicine.medical_specialty, Disease status, Neoplasm, Residual, [SDV]Life Sciences [q-bio], Medizin, Disease, Human leukocyte antigen, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, Humans, Medicine, RC254-282, Aged, Proportional Hazards Models, 030304 developmental biology, 0303 health sciences, Acute leukemia, business.industry, Marrow transplantation, Remission Induction, Hematopoietic Stem Cell Transplantation, Complete remission, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Myeloid leukemia, Hematology, Middle Aged, Prognosis, 3. Good health, body regions, Leukemia, Myeloid, Acute, Treatment Outcome, 030220 oncology & carcinogenesis, Cohort, Female, business
Abstract: Measurable residual disease (MRD) prior to hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML) in first complete morphological remission (CR1) is an independent predictor of outcome, but few studies address CR2. This analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation registry assessed HCT outcomes by declared MRD status in a cohort of 1042 adult patients with AML CR2 at HCT. Patients were transplanted 2006–2016 from human leukocyte antigen (HLA) matched siblings (n = 719) or HLA 10/10 matched unrelated donors (n = 293). Conditioning was myeloablative (n = 610) or reduced-intensity (n = 432) and 566 patients (54%) had in-vivo T cell depletion. At HCT, 749 patients (72%) were MRD negative (MRD NEG) and 293 (28%) were MRD positive (MRD POS). Time from diagnosis to HCT was longer in MRD NEG than MRD POS patients (18 vs. 16 months (P P P = 0.001), but there was no difference in terms of overall survival. Prognostic factors for relapse and LFS were MRD NEG status, good risk cytogenetics, and longer time from diagnosis to HCT. In-vivo T cell depletion predicted relapse.
Published: 2021

7. Comparison of long-term outcome for AML patients alive free of disease 2 years after allogeneic hematopoietic cell transplantation with umbilical cord blood versus unrelated donor: a study from the ALWP of the EBMT

Author: Martin Bornhäuser, Gérard Socié, Maud Ngoya, Frédéric Baron, Arnold Ganser, Henrik Sengeloev, Annalisa Ruggeri, Hans Christian Reinhardt, Jan J. Cornelissen, Edouard Forcade, Mohamad Mohty, Arnon Nagler, Myriam Labopin, Nicolaus Kröger, Didier Blaise, Thomas Valerius, GIGA [Université Liège], Université de Liège, Centre Hospitalier Universitaire de Liège (CHU-Liège), CEREST-TC [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-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), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hannover Medical School [Hannover] (MHH), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], National University Hospital, Rigshospitalet, Copenhagen, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), Medizinische Klinik und Poliklinik I [Dresden, Germany], Universitätsklinikum 'Carl Gustav Carus' Dresden, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Universität Duisburg-Essen = University of Duisburg-Essen [Essen], University Hospital Hamburg-Eppendorf, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), IRCCS San Raffaele Scientific Institute [Milan, Italie], Chaim Sheba Medical Center, and Hematology
Subjects: Male, medicine.medical_specialty, Multivariate analysis, Transplantation Conditioning, Medizin, Graft vs Host Disease, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease, Umbilical cord, Unrelated Donor, Internal medicine, Medicine, Humans, Retrospective Studies, Transplantation, Hematopoietic cell, business.industry, Incidence (epidemiology), Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Hematology, Fetal Blood, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Female, business, Unrelated Donors
Abstract: International audience; Since cord blood transplantation (CBT) has been associated with high graft-versus-leukemia effects and a low incidence of chronic graft-versus-host disease (GVHD), we hypothesized that long-term outcomes might be better in CBT patients than in those given grafts from unrelated donors (UD). Therefore, we performed a landmark study comparing long-term outcomes in acute myeloid leukemia (AML) patients alive and disease-free 2 years after transplantation who received grafts from either CBT or UD. A total of 364 CBT recipients, 2648 UD 10/10 patients and 681 patients given grafts from UD 9/10 were included. Median follow-up was 6.0 years. Five-year leukemia-free survival (LFS) from transplantation was 86% in CBT patients, 84% in UD 10/10 patients (P = 0.36) and 84% in UD 9/10 patients (P = 0.86). On multivariate analysis, donor type had no impact on LFS. Similarly, no impact of donor type was observed on relapse incidence or non-relapse mortality. Factors associated with poorer LFS on multivariate analysis included higher age at transplantation (P < 0.001), male gender (P < 0.001), second complete remission (CR2) versus CR1 (P = 0.05), secondary AML (P = 0.01), antecedent of chronic GVHD (P < 0.001) and poor-risk cytogenetics (P = 0.01). In conclusion, our study shows that long-term outcome for AML patients in CR two years after transplantation is not impacted by donor type.
Published: 2021

8. 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

9. Assessment of individual tumor buds using keratin immunohistochemistry: moderate interobserver agreement suggests a role for machine learning

Author: J.A.W.M. van der Laak, John-Melle Bokhorst, Heather Dawson, Francesco Ciompi, Scarlet Brockmoeller, Richard Kirsch, Inti Zlobec, L.L. Rijstenberg, Alessandro Lugli, Jean-François Fléjou, Michael Vieth, Iris D. Nagtegaal, M Urbanowicz, Annika Blank, Radboud University Medical Center [Nijmegen], University of Bern, University of Bayreuth, University of Leeds, European Organisation for Research and Treatment of Cancer [Bruxelles] (EORTC), European Cancer Organisation [Bruxelles] (ECCO), 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), University of Toronto, and Linköping University (LIU)
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Colorectal cancer, [SDV]Life Sciences [q-bio], Fleiss' kappa, 610 Medicine & health, Biology, Machine learning, computer.software_genre, Article, Pathology and Forensic Medicine, Prognostic markers, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Tumor budding, Keratin, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], medicine, Complete Agreement, chemistry.chemical_classification, Cancer och onkologi, business.industry, medicine.disease, Colon cancer, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Cancer and Oncology, Biomarker (medicine), Immunohistochemistry, Tumor buds, 570 Life sciences, biology, Artificial intelligence, business, computer, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Tumor budding is a promising and cost-effective biomarker with strong prognostic value in colorectal cancer. However, challenges related to interobserver variability persist. Such variability may be reduced by immunohistochemistry and computer-aided tumor bud selection. Development of computer algorithms for this purpose requires unequivocal examples of individual tumor buds. As such, we undertook a large-scale, international, and digital observer study on individual tumor bud assessment. From a pool of 46 colorectal cancer cases with tumor budding, 3000 tumor bud candidates were selected, largely based on digital image analysis algorithms. For each candidate bud, an image patch (size 256 × 256 µm) was extracted from a pan cytokeratin-stained whole-slide image. Members of an International Tumor Budding Consortium (n = 7) were asked to categorize each candidate as either (1) tumor bud, (2) poorly differentiated cluster, or (3) neither, based on current definitions. Agreement was assessed with Cohen's and Fleiss Kappa statistics. Fleiss Kappa showed moderate overall agreement between observers (0.42 and 0.51), while Cohen's Kappas ranged from 0.25 to 0.63. Complete agreement by all seven observers was present for only 34% of the 3000 tumor bud candidates, while 59% of the candidates were agreed on by at least five of the seven observers. Despite reports of moderate-to-substantial agreement with respect to tumor budding grade, agreement with respect to individual pan cytokeratin-stained tumor buds is moderate at most. A machine learning approach may prove especially useful for a more robust assessment of individual tumor buds.
Published: 2020

10. Inferior outcome of allogeneic stem cell transplantation for secondary acute myeloid leukemia in first complete remission as compared to de novo acute myeloid leukemia

Author: Maija Itälä-Remes, Christoph Schmid, Dietrich W. Beelen, Ibrahim Yakoub-Agha, Arnon Nagler, Ann-Kristin Schmaelter, Arnold Ganser, Bipin N. Savani, Jan J. Cornelissen, Jakob Passweg, Gérard Socié, Hélène Labussière-Wallet, Myriam Labopin, Didier Blaise, Mohamad Mohty, Edouard Forcade, Universität Augsburg [Augsburg], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), 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), CEREST-TC [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Haematology, Haemostasis, Oncology and Stem Cell Transplantation (MHH), Hannover Medical School [Hannover] (MHH), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), University Hospital Basel [Basel], Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Following EBMT publication rules, co-authorship was offered to centers contributing the highest number of patients. We also highly appreciate the contribution by many physicians and data managers throughout the EBMT, who made this analysis possible, as well as the contribution by the patients themselves. A list of contributing centers and responsible physicians is provided in supplemental Table 12., 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, Laboratoire d'Hématologie et d'Immunologie [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), 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 International des greffes [CHU Saint-Antoine] (EBMT), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Hematology, and Gestionnaire, Hal Sorbonne Université
Subjects: Male, Oncology, Transplantation Conditioning, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Medizin, RELAPSE, THERAPY, 0302 clinical medicine, AML, Secondary Acute Myeloid Leukemia, Cumulative incidence, ComputingMilieux_MISCELLANEOUS, Cancer stem cells, Remission Induction, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Neoplasms, Second Primary, Hematology, Middle Aged, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, CYTOGENETICS, Stem-cell research, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, 030220 oncology & carcinogenesis, SURVIVAL, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Adult, medicine.medical_specialty, Adolescent, 3122 Cancers, Context (language use), lcsh:RC254-282, Article, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, Transplantation, Homologous, ddc:610, Risk factor, Aged, Chemotherapy, business.industry, Proportional hazards model, Transplantation, business, 030215 immunology
Abstract: Following chemotherapy, secondary acute myeloid leukemia (sAML), occurring after antecedent hematologic diseases, previous chemotherapy or radiation, has an inferior prognosis compared with de novo AML. To define the outcome of sAML in the context of allogeneic stem cell transplantation (alloSCT), a retrospective, registry-based comparison was performed, including 11,439 patients with de novo and 1325 with sAML. Among transplants in first complete remission (CR1) (n = 8,600), the 3-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) was 28.5% and 16.4% for de novo, and 35% and 23.4% for sAML. Three-year overall survival (OS), leukemia-free survival (LFS) and Graft-versus-Host Disease/relapse-free survival (GRFS) was 60.8%, 55.1%, and 38.6% for de novo, and 46.7%, 41.6%, and 28.4% for sAML, respectively. In multivariate analysis, sAML was associated with a lower OS (HR = 1.33 [95% CI = 1.21–1.48]; p −5), LFS (HR = 1.32 [95% CI = 1.19–1.45]; p −5) and GRFS (HR = 1.2 [95% CI = 1.1–1.31]; p −4) and higher NRM (HR = 1.37 [95% CI = 1.17–1.59]; p −4) and RI (HR = 1.27 [95% CI = 1.12–1.44]; p −3). Results of the Cox model were confirmed in a matched-pair analysis. In contrast, results did not differ between de novo and sAML after alloSCT in induction failure or relapse. Hence, this analysis identified sAML as an independent risk factor for outcome after alloSCT in CR1.
Published: 2020

11. Open ADAMTS13, induced by antibodies, is a biomarker for subclinical immune-mediated thrombotic thrombocytopenic purpura

Author: Ygal Benhamou, Andreas Greinacher, Rob Fijnheer, Gilles Kaplanski, Aline Vandenbulcke, Agnès Veyradier, An Sofie Schelpe, György Sinkovits, Bernhard Lämmle, Charlotte Dekimpe, Marienn Réti, Jan Voorberg, Tanja Falter, Elien Roose, Karen Vanhoorelbeke, Flora Peyvandi, Charis von Auer, Ilaria Mancini, Maelle Le Besnerais, Hans Deckmyn, Inge Pareyn, Heidi Rossmann, Edwige Tellier, Hendrik B. Feys, Bérangère S. Joly, Paul Coppo, Zoltán Prohászka, Simon F. De Meyer, Lucas, Nelly, Innovative training network: Immunoprofile-directed stratification of patients with the autoimmune disorder thrombotic thrombocytopenic purpura - PROFILE - - H20202015-10-01 - 2019-09-30 - 675746 - VALID, Université Catholique de Louvain = Catholic University of Louvain (UCL), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hungarian Academy of Sciences (MTA), Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Ghent University Hospital, Central European University [Budapest, Hongrie] (CEU), University of Amsterdam [Amsterdam] (UvA), Greifswald University Hospital, University Medical Center [Utrecht], Department of Physics [Budapest], Budapest University of Technology and Economics [Budapest] (BME), 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), Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Cité (UPCité), KU Leuven OT/14/071Projet National de Recherche Clinique 2007 (Marseille, France) 2007/23Agency for Innovation and Entrepreneurship (Flanders, Belgium) 141136, European Project: 675746,H2020,H2020-MSCA-ITN-2015,PROFILE(2015), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Johannes Gutenberg - Universität Mainz (JGU), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université de Paris (UP), Experimental Vascular Medicine, Landsteiner Laboratory, AII - Inflammatory diseases, and ACS - Microcirculation
Subjects: Male, 0301 basic medicine, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, Settore MED/09 - Medicina Interna, Protein Conformation, Immunology, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, Biochemistry, Immunoglobulin G, 03 medical and health sciences, 0302 clinical medicine, Von Willebrand factor, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Autoantibodies, Subclinical infection, Purpura, Thrombocytopenic, Idiopathic, Hematology, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, business.industry, Autoantibody, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Middle Aged, medicine.disease, ADAMTS13, 3. Good health, 030104 developmental biology, biology.protein, Female, Rituximab, business, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies, 030215 immunology, medicine.drug
Abstract: Recently, we showed that ADAMTS13 circulates in an open conformation during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP). Although the cause of this conformational change remains elusive, ADAMTS13 is primarily closed in iTTP patients in remission with ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, as well as after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, immunoglobulin G from 18 acute iTTP patients was purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14 of 18 (78%) samples, proving that anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n = 197) that also included plasma samples from iTTP patients in remission in whom ADAMTS13 activity was 50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus, open ADAMTS13 is a hallmark of acute iTTP, as well as a novel biomarker that can be used to detect subclinical iTTP in patients in remission. Finally, a long-term follow-up study in 1 iTTP patient showed that the open conformation precedes a substantial drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management. ispartof: BLOOD vol:136 issue:3 pages:353-361 ispartof: location:United States status: published
Published: 2020

12. Testing for ROS1, ALK, MET, and HER2 rearrangements and amplifications in a large series of biliary tract adenocarcinomas

Author: Dominique Wendum, Françoise Praz, Claire Calmel, Aurelie Scriva, François Paye, Pascale Cervera, Caroline Gabignon, Olivier Scatton, Jérémy Augustin, Jean-François Fléjou, Laëtitia Menu, Service d'anatomie et cytologie pathologiques [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), 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), CEREST-TC [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Service de chirurgie générale et digestive [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), Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), 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), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Service d'Anatomopathologie [CHU Saint-Antoine], Service d'Anatomie et cytologie pathologiques [CHU Saint-Antoine], 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), and Gestionnaire, Hal Sorbonne Université
Subjects: 0301 basic medicine, Pathology, Lung Neoplasms, Receptor, ErbB-2, Aneuploidy, Chromosomal translocation, 0302 clinical medicine, Chromosome instability, Anaplastic Lymphoma Kinase, Biliary Tract, In Situ Hybridization, Fluorescence, ComputingMilieux_MISCELLANEOUS, Gene Rearrangement, Bile duct, General Medicine, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-met, Immunohistochemistry, 3. Good health, medicine.anatomical_structure, Biliary tract, 030220 oncology & carcinogenesis, MET, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], ROS1, medicine.medical_specialty, Adenocarcinoma of Lung, [SDV.CAN]Life Sciences [q-bio]/Cancer, Adenocarcinoma, Fluorescent in situ hybridization, Pathology and Forensic Medicine, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Biliary tract adenocarcinoma, Proto-Oncogene Proteins, HER2, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Molecular Biology, business.industry, Gallbladder, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030104 developmental biology, business
Abstract: International audience; Biliary tract carcinomas are divided into intrahepatic, perihilar, distal extrahepatic cholangiocarcinomas, and gallbladder adenocarcinomas. Therapies targeting ROS1, ALK, MET, and HER2 alterations are currently evaluated in clinical trials. We assessed ROS1 and ALK translocations/amplifications as well as MET and HER2 amplifications for each tumor subtype by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) in 73 intrahepatic, 40 perihilar bile duct, 36 distal extrahepatic cholangiocarcinomas, and 45 gallbladder adenocarcinomas (n = 194). By FISH, we detected targetable alterations in 5.2% of cases (n = 10): HER2 and MET amplifications were found in 4.1% (n = 8) and 1.0% (n = 2), respectively. The HER2-amplified cases were mostly gallbladder adenocarcinomas (n = 5). The MET- and HER2-amplified cases were all positive by IHC. Fourteen cases without MET amplification were positive by IHC, whereas HER2 over-expression was detected by IHC only in HER2-amplified cases. We detected no ALK or ROS1 translocation or amplification. Several alterations were consistent with aneuploidy: 24 cases showed only one copy of ROS1 gene, 4 cases displayed a profile of chromosomal instability, and an over-representation of centromeric alpha-satellite sequences was found in five cases. We confirm a relatively high rate of HER2 amplifications in gallbladder adenocarcinomas and the efficacy of IHC to screen these cases. Our results also suggest the value of IHC to screen MET amplification. Contrary to initial publications, ROS1 rearrangements seem to be very rare in biliary tract adenocarcinomas. We confirm a relatively high frequency of aneuploidy and chromosomal instability and reveal the over-representation of centromeric alpha-satellite sequences in intrahepatic cholangiocarcinomas.
Published: 2020

13. Stool for fecal microbiota transplantation should be classified as a transplant product and not as a drug

Author: Keller, J.J., Vehreschild, M.J.G.T., Hvas, C.L., Jorgensen, S.M.D., Kupciskas, J., Link, A., Mulder, C.J.J., Goldenberg, S.D., Arasaradnam, R., Sokol, H., Gasbarrini, A., Hoegenauer, C., Terveer, E.M., Kuijper, E.J., Arkkila, P., Gridnyev, O., Megraud, F., Kump, P.K., Nakov, R., Satokari, R., Tkatch, S., Sanguinetti, M., Cammarota, G., Dorofeev, A., Gubska, O., Ianiro, G., Mattila, E., Ooijevaar, R.E., Sarin, S.K., Sood, A., Putignani, L., Alric, L., Williams, H.R.T., Goorhuis, A., Verspaget, H.W., Hold, G.L., Tilg, H., Ponsioen, C.Y., Standards Guidelines Initiative, Leiden University Medical Center (LUMC), Goethe-University Frankfurt am Main, University of Cologne, Aarhus University Hospital, Hospital of Lithuanian University of Health Sciences Kauno Klinikos [Kaunas, Lithuania], Otto-von-Guericke University [Magdeburg] (OVGU), Free University Medical Center [Amsterdam], Guy's and St Thomas NHS Trust Foundation & King's College London School of Medicine, Haemostasis Research Unit, Centre for Haemostasis and Trombosis, Warwick Medical School, University of Warwick [Coventry], MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, CEREST-TC [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-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), French Group of Fecal Microbiota Transplantation [Paris] (GFTF), Fondazione 'Policlinico Universitario A. Gemelli' [Rome], Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, University of Helsinki, UEG Standards and Guidelines Activity grant (2018)., and Gastroenterology and hepatology
Subjects: Drug, medicine.medical_specialty, [SDV]Life Sciences [q-bio], media_common.quotation_subject, MEDLINE, Transplants, Feces, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, Product (category theory), Letters to the Editor, Enterocolitis, Pseudomembranous, media_common, Enterocolitis, business.industry, Gastroenterology, Fecal bacteriotherapy, Fecal Microbiota Transplantation, 3. Good health, Oncology, 030211 gastroenterology & hepatology, medicine.symptom, business
Abstract: International audience; Fecal microbiota transplantation (FMT) or donor feces infusion is a therapy that aims to restore a perturbed gut microbiota composition and function. FMT is effective for treatment of patients with (multiple) recurrent Clostridioides difficile infections1–3 and recommended by current guidelines.4–6 In the near future, FMT may also become an accepted treatment option for other intestinal or extra-intestinal diseases.7FMT is performed using suspensions made of donor stool from carefully selected and screened healthy individuals.1,7 Donor screening is time consuming and costly. Before the establishment of stool banks, physicians and patients had to find their own donors. This resulted in uncontrolled application of FMT, and the logistical challenge made physicians reluctant to offer FMT to their patients. To overcome these problems, stool banks have been established.8,9 The mission of those stool banks is :to produce ready-to-use donor feces suspensions for treatment of patients,to improve the quality and safety of FMT by centralization and standardization,to increase the cost effectiveness of FMT, andto facilitate research.Stool banks are built in concordance with the model of blood banks and should follow quality standards applied to other transplantation products. Most stool banks are non-profit institutions, operating at a local (institution-based), national or international level. Recently, a UEG-funded working group was initiated to define quality standards for stool banking and FMT, which will result in further standardization of this new treatment approach. The current costs to deliver a ready-to-use stool suspension are €1050–1700 in Europe.9,10 There are also commercial initiatives,11 which may aim for much higher prices.Driven by the needs of patients, stool banks have emerged as new entities in a landscape without existing regulatory boundaries. This lack of guidance and National or European legislation may become a serious threat to providing the treatment for severely ill patients. This is also illustrated by the recent safety alert in the US about the transmission of multi-drug resistant organisms through FMT,12 which underlines the need for standardization, quality assurance, and a regulatory framework supporting the activities of stool banks. Legislation requires classification of stool as a product to treat patients. We strongly believe that stool should be considered a transplant product, or be regarded equivalent in status to blood products used for transplantation or transfusion purposes. The EU Tissue and Cells Directive (2004/23/EC) is best suited to guide FMT. Currently, this Directive does not cover FMT because the mechanism of action is not mediated by human cells. An adjustment to align this directive with the new reality of fecal transplantation is thus urgently needed. Only in the case of modification to the donated feces, other than those necessary for the conservation of the microbial community, does the product made of the donated feces become comparable to a drug and is best covered within the European directive for medicinal products intended for human use (2001/83/EC).Unfortunately, the misclassification of donor feces suspensions as a drug or pharmaceutical product, although difficult to imagine, is still one of the possible outcomes of the current discussion about classification. Currently, stool has already been classified as a drug in countries such as France, Germany, and the United Kingdom. Recently, companies have formed the “Pharmabiotic Research Institute” in Europe and the “Microbiome Therapeutics Innovation Group (MTIG)” in the US. The mission of those groups is “to improve market access,” and to “enhance the regulatory, investment, and commercial environment for microbiome therapeutic drug product development.” Both groups have published statements about the classification of FMT as a drug.13,14 MTIG actively collaborates with the Food and Drug Administration for the evaluation of safety parameters related to microbiota-based therapeutic products. Concern has been raised by the MTIG that the existence and accessibility of material from stool banks limits enrollment into clinical trials for microbiome therapeutics. This illustrates how companies are active to influence the current discussion about classification and regulation of FMT. In fact, this discussion has already been troubled by commercial interest in the US some years ago.15In this regard, it is important to mention the overall major disadvantages of classification as a drug, which will result in time-consuming and costly registration processes, and a sharp and unjustified rise in costs. Most importantly, this will negatively impact availability and innovation, obstructing, for example, the future development of single-donor individualized solutions due to the requirements for standardization of active substances. We postulate that stool treatment defined as drug treatment is counterproductive. Stool is not a standardized product that is produced in a factory, but a highly diverse and donor-specific substance of human origin (SoHO) delivered by healthy, usually unpaid, volunteer donors. Therefore, stool suspensions require suitable guidance of quality and safety measures comparable to guidance of other SoHO (blood, tissues, cells and organs) within the EU.If government authorities seek affordable and quality-assured FMT, a supportive regulatory framework, in combination with appropriate funding or reimbursement, is required for stool banks. This will not only guarantee broad access and safety of FMT, but also enable the future innovation of this new treatment strategy targeting the gut microbiota. If eventually future research results in the replacement of FMT by standardized mixtures of bacteria (or another yet undiscovered stool extract that could theoretically underly the clinical effects of FMT), these should indeed be regulated as a drug or pharmaceutical product.
Published: 2019

14. General information for patients and carers considering haematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases (ADs) : A position statement from the EBMT Autoimmune Diseases Working Party (ADWP), the EBMT Nurses Group, the EBMT Patient, Family and Donor Committee and the Joint Accreditation Committee of ISCT and EBMT (JACIE)

Author: Jessop, H., Farge, D., Saccardi, R., Alexander, T., Rovira Tarrats, Montserrat, Sharrack, B., Greco, R., Wulffraat, N., Moore, J., Kazmi, M., Badoglio, M., Adams, G., Verhoeven, B., Murray, J., Snowden, J.A., Universitat Autònoma de Barcelona, Service de Médecine Interne [Saint-Louis], Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), McGill University = Université McGill [Montréal, Canada], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), University of Sheffield [Sheffield], San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, St. Vincent's Hospital, Sydney, Guy's Hospital [London], Laboratoire d'Hématologie et d'Immunologie [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), Centre International des greffes [CHU Saint-Antoine] (EBMT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), McGill University, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Sorbonne Université (SU)-CHU Saint-Antoine [APHP]
Subjects: medicine.medical_specialty, Autoimmune diseases, MEDLINE, Disease, Stem cells, Hospitals, Special, Transplantation, Autologous, Accreditation, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Medicine, Humans, Intensive care medicine, 030203 arthritis & rheumatology, Autoimmune disease, Transplantation, business.industry, Standard treatment, Hematopoietic Stem Cell Transplantation, Hematology, medicine.disease, Tissue Donors, 3. Good health, Haematopoiesis, surgical procedures, operative, Caregivers, 030220 oncology & carcinogenesis, Perspective, [SDV.IMM]Life Sciences [q-bio]/Immunology, Stem cell, business
Abstract: International audience; Over the last 20 years, haematopoietic stem cell transplantation (HSCT) has been used to treat patients with severe autoimmune and inflammatory diseases whose response to standard treatment options has been limited, resulting in a poor long-term prognosis in terms of survival or disability. The vast majority of patients have received autologous HSCT where an increasing evidence-base supports its use in a wide range of autoimmune diseases, particularly relapsing remitting MS, systemic sclerosis and Crohn’s disease. Compared with standard treatments for autoimmune diseases, HSCT is associated with greater short-term risks, including a risk of treatment-related mortality and long-term complications. There is a need for a careful appraisal of potential benefits and risks by disease and transplant specialists working closely together with patients and carers to determine individual suitability for HSCT. HSCT should be conducted in accredited transplant centres with robust arrangements for long-term follow-up with both disease and transplant specialists. The aim of this open-access position statement is to provide plainly worded guidance for patients and non-specialist clinicians considering HSCT for an autoimmune disease, especially when treatment abroad is being considered. Recent technical publications in the field have been referenced to support the statement and provide more detail for clinicians advising patients.
Published: 2019

15. Penetrating Crohn Disease Is Not Associated With a Higher Risk of Recurrence After Surgery

Author: Maggiori, Léon, Brouquet, Antoine, Zerbib, Philippe, Lefêvre, Jérémie, Denost, Quentin, Germain, Adeline, Cotte, Eddy, BEYER-BERJOT, Laura, Munoz-Bongrand, Nicolas, Desfourneaux, Véronique, Rahili, Amine, Duffas, Jean-Pierre, Pautrat, Karine, Denet, Christine, Bridoux, Valérie, Meurette, Guillaume, Faucheron, Jean-Luc, Loriau, Jérôme, Souche, Regis, Vicaut, Eric, PANIS, Yves, Benoist, Stéphane, Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Bicêtre, Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), 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), Bioingénierie tissulaire (BIOTIS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Marseille, Hopital Saint-Louis [AP-HP] (AP-HP), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire de Nice (CHU Nice), Chirurgie Générale et Digestive [Rangueil], CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Hôpital Lariboisière-Fernand-Widal [APHP], Hôpital Lariboisière, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mutualiste de Montsouris (IMM), Service de chirurgie digestive [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre hospitalier Saint-Joseph [Paris], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)
Subjects: MESH: Colon/surgery, Crohn Disease/surgery, Crohn Disease/diagnosis, Digestive System Surgical Procedures/methods, Ileum/surgery, Intestinal Perforation/surgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; OBJECTIVE:The aim of this study was to assess recurrence risk factors following ileocolonic resection (ICR) for Crohn disease (CD) in a nationwide cohort study SUMMARY BACKGROUND DATA:: Recurrence rate after ICR for CD can be up to 60%, but its predictive factors have never been evaluated in large prospective cohort studies.METHODS:From 2013 to 2015, 346 consecutive patients undergoing ICR for CD and a postoperative ileocoloscopy within 6 to 12 months after surgery at 19 academic French centers were included prospectively.RESULTS:Twelve-month postoperative endoscopic (Rutgeerts score ≥i2) and clinical recurrence rates were 57.6% [95% confidence interval (CI), 54.2-61.0] and 11.3% (95% CI, 9-13.6), respectively. A total of 185 patients (54%) had a postoperative CD prophylaxis, comprising thiopurine in 69 (20%), or anti-tumor necrosis factor (TNF) therapy in 93 (27%). In multivariate Cox regression analysis, absence of postoperative smoking {odds ratio [OR] = 0.60 (95% CI, 0.40-0.91); P = 0.016}, postoperative prophylaxis [OR = 0.60 (95% CI, 0.41-0.88); P = 0.009], and penetrating disease behavior [OR = 0.58 (95% CI, 0.39-0.86); P = 0.007] were the only independent predictors of reduced endoscopic recurrence risk. Postoperative prophylaxis [OR 0.31 (95% CI, 0.15-0.66); P = 0.002), and penetrating behavior [OR = 00.36 (95% CI, 0.16-0.81); P = 0.013), were the only independent predictors of reduced clinical recurrence risk. Postoperative anti-TNF therapy was associated with a significant reduction of both 12-month risks of endoscopic (P < 0.001) and clinical (P = 0.019) recurrences.CONCLUSION:Absence of postoperative smoking, CD prophylaxis, and penetrating disease behavior could be independent predictors of reduced postoperative recurrence after ICR for CD. Prophylactic anti-TNF therapy reduces both endoscopic and clinical recurrence rates. It suggests that upfront surgery followed by postoperative anti-TNF therapy is probably the best therapeutic approach for complex CD (penetrating disease behavior).
Published: 2019

16. Faecal microbiota study reveals specific dysbiosis in spondyloarthritis

Author: Ariane Leboime, Maxime Breban, Philippe Langella, Julien Tap, Gilles Chiocchia, Harry Sokol, Jean-Pierre Furet, Roula Said-Nahal, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR-S 606, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, PRES Sorbonne Paris-Cité, and Université Paris Denis Diderot, Université Paris Diderot - Paris 7 (UPD7), Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines - Institut d'études culturelles et internationales (UVSQ IECI), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Université Paris Saclay (COmUE), CEREST-TC [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Université Paris Descartes - Paris 5 (UPD5), Microorganismes et physiopathologie intestinale (ERL INSERM U1157 - CNRS UMR 7203), Laboratoire des biomolécules (LBM UMR 7203), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Cellule Pasteur UPMC, Institut Pasteur [Paris] (IP)-Sorbonne Université (SU), Laboratoire d'excellence Inflamex, Sorbonne Paris Cité, Service de Rhumatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: 0301 basic medicine, rheumatoid arthritis, Male, [SDV]Life Sciences [q-bio], Disease, Gut flora, Inflammatory bowel disease, Pathogenesis, Arthritis, Rheumatoid, Cohort Studies, Feces, 0302 clinical medicine, Ruminococcus gnavus, RNA, Ribosomal, 16S, Ruminococcus, Immunology and Allergy, HLA-B27 Antigen, biology, spondyloarthritis, Middle Aged, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Female, musculoskeletal diseases, Adult, Immunology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Rheumatology, ankylosing spondylitis, medicine, Humans, Aged, 030203 arthritis & rheumatology, Ankylosing spondylitis, Siblings, Case-control study, medicine.disease, biology.organism_classification, Inflammatory Bowel Diseases, infection, Gastrointestinal Microbiome, 030104 developmental biology, Cross-Sectional Studies, inflammation, Case-Control Studies, Multivariate Analysis, Dysbiosis, Spondylarthropathies
Abstract: ObjectiveAltered microbiota composition or dysbiosis is suspected to be implicated in the pathogenesis of chronic inflammatory diseases, such as spondyloarthritis (SpA) and rheumatoid arthritis (RA).Methods16S ribosomal RNA gene sequencing was performed on faecal DNA isolated from stool samples in two consecutive cross-sectional cohorts, each comprising three groups of adult volunteers: SpA, RA and healthy controls (HCs). In the second study, HCs comprised a majority of aged-matched siblings of patients with known HLA-B27 status. Alpha and beta diversities were assessed using QIIME, and comparisons were performed using linear discriminant analysis effect size to examine differences between groups.ResultsIn both cohorts, dysbiosis was evidenced in SpA and RA, as compared with HCs, and was disease specific. A restriction of microbiota biodiversity was detected in both disease groups. The most striking change was a twofold to threefold increased abundance of Ruminococcus gnavus in SpA, as compared with both RA and HCs that was significant in both studies and positively correlated with disease activity in patients having a history of inflammatory bowel disease (IBD). Among HCs, significant difference in microbiota composition were also detected between HLA-B27+ and HLA-B27 negative siblings, suggesting that genetic background may influence gut microbiota composition.ConclusionOur results suggest that distinctive dysbiosis characterise both SpA and RA and evidence a reproducible increase in R. gnavus that appears specific for SpA and a marker of disease activity. This observation is consistent with the known proinflammatory role of this bacteria and its association with IBD. It may provide an explanation for the link that exists between SpA and IBD.
Published: 2016

17. Sequential Intensified Conditioning Regimen Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Intermediate or High-Risk Acute Myeloid Leukemia in Complete Remission: a Study From the ALWP of the EBMT

Author: Malard, Florent, Labopin, Myriam, Stuhler, Gernot, Bittenbring, Jörg, Ganser, Arnold, Tischer, Johanna, Michallet, Mauricette, Kröger, Nicolaus, Schmid, Christoph, Huynh, Anne, Hallek, Michael, Savani, Bipin N, Mohty, Mohamad, Nagler, Arnon, 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), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), German diagnostic clinic [Wiesbaden], Leibniz Centre for Tropical Marine Research (ZMT), Saarland University [Saarbrücken], Hannover Medical School [Hannover] (MHH), University Hospital of the Ludwig-Maximilians University, CHU Lyon, Hospices Civils de Lyon (HCL), University Hospital Eppendorf, Augsburg Hospital, 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 of Cologne, Vanderbilt University [Nashville], CEREST-TC [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Centre International des greffes [CHU Saint-Antoine] (EBMT), 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), 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), HAL-UPMC, Gestionnaire, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Acute myeloid leukemia, [SDV.CAN] Life Sciences [q-bio]/Cancer, complete remission, hemic and lymphatic diseases, intermediate intensity conditioning regimen, allogeneic hematopoietic-stem-cell transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.CAN]Life Sciences [q-bio]/Cancer, sequential conditioning regimen
Abstract: International audience; Post-transplant relapse is the leading cause of treatment failure in acute myeloid leukemia (AML) patients after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to improve their outcome, we evaluated the outcome of a sequential intermediate intensity conditioning regimen combining fludarabine, cytosine arabinoside, amsacrine, cyclophosphamide and either total body irradiation or busulfan (FLAMSA) in patients with intermediate or high risk AML in first or second complete remission (CR). A total of 265 patients (median age 55 years; range, 19-76 years) with AML who underwent allo-HSCT using a FLAMSA regimen were included. At the time of transplant, 216 (81.5%) were in CR1 and 49 (18.5%) in CR2.
Published: 2016

18. Cost-effectiveness and clinical outcomes of double versus single cord blood transplantation in adults with acute leukemia in France

Author: Eliane Gluckman, Vanderson Rocha, Mauricette Michallet, Norbert Claude Gorin, Catherine Faucher, Didier Blaise, Gérard Socié, Nathalie Fegueux, Myriam Labopin, Jean-Yves Cahn, Stéphanie Nguyen, Eric Deconinck, Federico Garnier, Dominique Bertrand, Thierry de Revel, Fernanda Volt, Chantal Kenzey, Namik Taright, Noel Milpied, Lionel Mannone, Mohamad Mohty, Ibrahim Yakoub Agha, Annalisa Ruggeri, 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), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Eurocord, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Università degli Studi di Roma Tor Vergata [Roma], CEREST-TC [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpital l'Archet, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Claude Huriez [Lille], CHU Lille, Hôpital JeanMinjoz, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital Lapeyronie [Montpellier] (CHU), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Michallon, Hôpital d'Instruction des Armées Percy, Service de Santé des Armées, Agence de la biomédecine [Saint-Denis la Plaine], DIM Paris, Centre national gestion Paris, Churchill Hospital, Churchill Hospital Oxford Centre for Haematology, HAL UPMC, Gestionnaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and CHU Saint-Antoine [AP-HP]
Subjects: Adult, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, Transplantation Conditioning, Cord, Adolescent, Cost effectiveness, Cost-Benefit Analysis, Graft vs Host Disease, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cord Blood Stem Cell Transplantation, Young Adult, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Recurrence, Risk Factors, medicine, Humans, Transplantation, Homologous, Aged, Acute leukemia, Leukemia, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, medicine.disease, 3. Good health, Surgery, Transplantation, Treatment Outcome, 030220 oncology & carcinogenesis, Cord blood, Acute Disease, France, business, 030215 immunology
Abstract: on behalf of Eurocord and Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC); International audience; Double cord blood transplantation extends the use of cord blood to adults for whom a single unit is not available, but the procedure is limited by its cost. To evaluate outcomes and cost-effectiveness of double compared to single cord blood transplantation, we analyzed 134 transplants in adults with acute leukemia in first remission. Transplants were performed in France with reduced intensity or myeloablative conditioning regimens. Costs were estimated from donor search to 1 year after transplantation. A Markov decision analysis model was used to calculate quality-adjusted life-years and cost-effectiveness ratio within 4 years. The overall survival at 2 years after single and double cord blood transplants was 42% versus 62%, respectively (P=0.03), while the leukemia-free-survival was 33% versus 53%, respectively (P=0.03). The relapse rate was 21% after double transplants and 42% after a single transplant (P=0.006). No difference was observed for non-relapse mortality or chronic graft-versus-host-disease. The estimated costs up to 1 year after reduced intensity conditioning for single and double cord blood transplantation were € 165,253 and €191,827, respectively. The corresponding costs after myeloablative conditioning were € 192,566 and € 213,050, respectively. Compared to single transplants, double cord blood transplantation was associated with supplementary costs of € 21,302 and € 32,420 up to 4 years, but with increases in quality-adjusted life-years of 0.616 and 0.484, respectively, and incremental cost-effectiveness ratios of € 34,581 and €66,983 in the myeloablative and reduced intensity conditioning settings, respectively. Our results showed that for adults with acute leukemia in first complete remission in France, double cord transplantation is more cost-effective than single cord blood transplantation, with better outcomes, including quality-adjusted life-years.
Published: 2014

19. Impact of genotype on survival of children with T-cell acute lymphoblastic leukemia treated according to the French protocol FRALLE-93: the effect of TLX3/HOX11L2 gene expression on outcome

Author: André Baruchel, Yves Perel, Anne Hagemejier, Guy Leverger, Judith Landman-Parker, Paola Ballerini, Virginie Gandemer, François Sigaux, Gérard Michel, Claudine Schmitt, Vahid Asnafi, Jean Michel Cayuela, Sylvie Fasola, Marie Françoise Auclerc, Luc Douay, Thierry Leblanc, Myriam Labopin, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'hématologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'hématologie, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CEREST-TC [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-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), Service d'onco-hématologie pédiatrique, hôpital Sud, Service d'hématologie pédiatrique et oncologie, CHU Bordeaux [Bordeaux]-Hôpital Pellegrin, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'hématologie, Service d'oncologie et hématologie, Hôpital d'enfants, Department of Human Genetics, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), supported by Chugai France (Dr. Thierry Guillot) and SFCE (Société Française des Cancers de l'Enfant)., Service d'hématologie-immunologie-oncologie pédiatrique, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CHU Saint-Antoine [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Hôpital Sud, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Catholic University of Leuven ( KU Leuven ), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], 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)-Université Paris Diderot - Paris 7 (UPD7), 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 Pierre et Marie Curie - Paris 6 (UPMC), and De Villemeur, Hervé
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Oncology, Time Factors, Transcription, Genetic, MESH : Genotype, MESH : Child, Preschool, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Genotype, 0302 clinical medicine, MESH : Child, hemic and lymphatic diseases, MESH: Child, Gene expression, Genotype, MESH : Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia-Lymphoma, Adult T-Cell, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Medicine, MESH : Female, MESH : Homeodomain Proteins, MESH: Leukemia-Lymphoma, Adult T-Cell, Child, Regulation of gene expression, 0303 health sciences, MESH : Prognosis, Hematology, Hazard ratio, MESH : Infant, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: Follow-Up Studies, MESH: Gene Expression Regulation, Neoplastic, Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH : Adult, Prognosis, MESH : Survival Rate, MESH: Infant, 3. Good health, Gene Expression Regulation, Neoplastic, Survival Rate, NUP214-ABL1, Child, Preschool, 030220 oncology & carcinogenesis, outcome, Female, France, TLX3/HOX11L2, MESH : Time Factors, Adult, medicine.medical_specialty, Adolescent, MESH: Survival Rate, MESH : Gene Expression Regulation, Neoplastic, MESH : Male, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Prognosis, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH : Adolescent, Internal medicine, MESH: Homeodomain Proteins, Humans, MESH : France, Survival rate, 030304 developmental biology, Homeodomain Proteins, MESH: Adolescent, MESH: Precursor Cell Lymphoblastic Leukemia-Lymphoma, MESH: Humans, business.industry, MESH: Transcription, Genetic, MESH : Humans, MESH: Time Factors, MESH: Child, Preschool, Infant, MESH : Transcription, Genetic, childhood T-cell acute lymphoblastic leukemia, MESH : Follow-Up Studies, MESH: Adult, MESH : Leukemia-Lymphoma, Adult T-Cell, MESH: Male, MESH: France, El Niño, Fusion transcript, Immunology, SIL-TAL1, business, MESH: Female, Follow-Up Studies
Abstract: International audience; BACKGROUND: The prognostic value of the ectopic activation of TLX3 gene expression, a major oncogenetic event associated with pediatric T-cell acute lymphoblastic leukemia, is controversial. Likewise, the frequency and the prognostic significance in pediatric T-cell acute lymphoblastic leukemia of the newly characterized NUP214-ABL1 fusion transcript is not yet clear. DESIGN AND METHODS: Two hundred children with T-cell acute lymphoblastic leukemia were treated in the French FRALLE-93 study from 1993 to 1999. The expression of TLX3, TLX1 and SILTAL1 genes was analyzed in samples from 92 patients by real-time quantitative reverse transcriptase polymerase chain reaction. Most of these samples were further studied for NUP214-ABL1 and CALM-AF10 fusion transcripts. RESULTS: The median follow-up was 7.9 years. At 5 years the overall survival (+/- standard deviation, %) was 62 (+/-3%) and leukemia-free survival was 58 (+/-3%). Patients with T-cell acute lymphoblastic leukemia positive for TLX3 had a poorer survival compared to those with T-ALL negative for TLX3 (overall survival: 45+/-11% vs. 57+/-5%, p=0.049). In multivariate analysis, TLX3 expression was an independent adverse risk factor predicting relapse with a hazard ratio of 2.44 (p=0.017) and an overall survival with a hazard ratio of 3.7 (p=0.001). NUP214-ABL1 was expressed in 16.6% of patients with TLX3-positive T-ALL (3 of 18); all of the patients with this association died before completion of the treatment. SILTAL expression did not significantly affect the prognosis of patients with T-cell acute lymphoblastic leukemia. Only three of 92 patients expressed the TLX1 gene and all three are alive. CONCLUSIONS: TLX3 gene expression is an independent risk factor predicting poor survival in childhood T-cell acute lymphoblastic leukemia. When co-expressed with TLX3, NUP214-ABL1 transcripts may increase the risk of poor survival.
Published: 2008

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19. Impact of genotype on survival of children with T-cell acute lymphoblastic leukemia treated according to the French protocol FRALLE-93: the effect of TLX3/HOX11L2 gene expression on outcome

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