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1. Joint representation learning from french radiological reports and ultrasound images

Author: Dadoun, Hind, Delingette, Hervé, Rousseau, Anne-Laure, de Kerviler, Eric, Ayache, Nicholas, E-Patient : Images, données & mOdèles pour la médeciNe numériquE (EPIONE), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), 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), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de radiologie [Saint-Louis], 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), IEEE, and ANR-19-P3IA-0002,3IA@cote d'azur,3IA Côte d'Azur(2019)
Subjects: multimodal learning, kidneys, ultrasound examinations, multimodal learning deep clustering natural language processing ultrasound examinations kidneys, [INFO]Computer Science [cs], deep clustering, natural language processing
Abstract: International audience; In this study, we explore the value of using a recently proposed multimodal learning method as an initialization for anomaly detection in abdominal ultrasound images. The method efficiently learns visual concepts from radiological reports using natural language supervision and constrastive learning. The underlying requirement of the method is simply the availability of image and textual descriptions pairs. However, in abdominal ultrasound examinations, radiological reports are associated with several images and describe all organs observed during the examination. To address this shortcoming, we automatically construct image and text pairs using 1) deep clustering for abdominal organ classification on ultrasound images and 2) natural language processing tools to extract the corresponding description on the report. We show that pre-training the model with these constructed pairs yields representations that better separate normal classes from abnormal ones on ultrasound images for the kidneys, compared to ImageNet-based representations, with a 10% improvement in macro-average accuracy.
Published: 2023

2. Screening antiproliferative drug for breast cancer from bisbenzylisoquinoline alkaloid tetrandrine and fangchinoline derivatives by targeting BLM helicase

Author: Zhixu He, Weidong Pan, Hong Li, Linchun Bao, Shuang Yang, Jinhe Liu, Yanchao Jiao, Jielin Liu, Wangming Zhang, He Lu, Guizhou Medical University (贵州医科大学), Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique (UMR 1165), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Biomolécules : synthèse, structure et mode d'action (UMR 8642) (BIOSYMA), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique
Subjects: 0301 basic medicine, MTT, Cancer Research, ATPase, [SDV]Life Sciences [q-bio], chemistry.chemical_compound, 0302 clinical medicine, Fluorescence polarization, Drosophila Proteins, Bloom syndrome, RecQ Helicases, biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Small molecule, 3. Good health, DNA-Binding Proteins, Real-time polymerase chain reaction, Oncology, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, ELISA, Female, Research Article, Protein Binding, Signal Transduction, HJNO, RT-PCR, Breast Neoplasms, BLM helicase, Benzylisoquinolines, EMSA, lcsh:RC254-282, Inhibitory Concentration 50, 03 medical and health sciences, Cell Line, Tumor, Escherichia coli, Human Umbilical Vein Endothelial Cells, Genetics, medicine, Humans, IC50, Cell Proliferation, DNA Helicases, Helicase, DNA, medicine.disease, Antineoplastic Agents, Phytogenic, Molecular biology, Tetrandrine, 030104 developmental biology, chemistry, biology.protein, Drug Screening Assays, Antitumor
Abstract: Background The high expression of BLM (Bloom syndrome) helicase in tumors involves its strong association with cell expansion. Bisbenzylisoquinoline alkaloids own an antitumor property and have developed as candidates for anticancer drugs. This paper aimed to screen potential antiproliferative small molecules from 12 small molecules (the derivatives of bisbenzylisoquinoline alkaloids tetrandrine and fangchinoline) by targeting BLM642–1290 helicase. Then we explore the inhibitory mechanism of those small molecules on proliferation of MDA-MB-435 breast cancer cells. Methods Fluorescence polarization technique was used to screen small molecules which inhibited the DNA binding and unwinding of BLM642–1290 helicase. The effects of positive small molecules on the ATPase and conformation of BLM642–1290 helicase were studied by the malachite green-phosphate ammonium molybdate colorimetry and ultraviolet spectral scanning, respectively. The effects of positive small molecules on growth of MDA-MB-435 cells were studied by MTT method, colony formation and cell counting method. The mRNA and protein levels of BLM helicase in the MDA-MB-435 cells after positive small molecule treatments were examined by RT-PCR and ELISA, respectively. Results The compound HJNO (a tetrandrine derivative) was screened out which inhibited the DNA binding, unwinding and ATPase of BLM642–1290 helicase. That HJNO could bind BLM642–1290helicase to change its conformationcontribute to inhibiting the DNA binding, ATPase and DNA unwinding of BLM642–1290 helicase. In addition, HJNO showed its inhibiting the growth of MDA-MB-435 cells. The values of IC50 after drug treatments for 24 h, 48 h and 72 h were 19.9 μmol/L, 4.1 μmol/L and 10.9 μmol/L, respectively. The mRNA and protein levels of BLM helicase in MDA-MB-435 cells increased after HJNO treatment. Those showed a significant difference (P Conclusion The small molecule HJNO was screened out by targeting BLM642–1290 helicase. And it showed an inhibition on MDA-MB-435 breast cancer cells expansion.
Published: 2019

3. IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial

Author: Maarten H. Vermeer, Martine Bagot, Federico Rotolo, Cécile Bonnafous, Hélène Sicard, Anne Marie-Cardine, Hatem A. Azim, Caroline Ram-Wolff, Sean Whittaker, Maxime Battistella, Michael S. Khodadoust, Carine Paturel, Armand Bensussan, Pierluigi Porcu, Basem M. William, Youn H. Kim, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Dermatologie [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche & Développement, and Innate Pharma
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Skin Neoplasms, Maximum Tolerated Dose, [SDV]Life Sciences [q-bio], Population, Phases of clinical research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Internal medicine, medicine, Clinical endpoint, Humans, education, ComputingMilieux_MISCELLANEOUS, Aged, education.field_of_study, Mycosis fungoides, Dose-Response Relationship, Drug, business.industry, Cutaneous T-cell lymphoma, Not Otherwise Specified, Receptors, KIR3DL2, Middle Aged, medicine.disease, Lymphoma, T-Cell, Cutaneous, 3. Good health, Lymphoma, Clinical trial, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Female, Neoplasm Recurrence, Local, business
Abstract: Summary Background IPH4102 is a first-in-class monoclonal antibody targeting KIR3DL2, a cell surface protein that is expressed in cutaneous T-cell lymphoma, and predominantly in its leukaemic form, Sezary syndrome. We aimed to assess the safety and activity of IPH4102 in cutaneous T-cell lymphoma. Methods We did an international, first-in-human, open-label, phase 1 clinical trial with dose-escalation and cohort-expansion parts in five academic hospitals in the USA, France, the UK, and the Netherlands. Eligible patients had histologically confirmed relapsed or refractory primary cutaneous T-cell lymphoma, an Eastern Cooperative Oncology group performance score of 2 or less, were aged 18 years or older, and had received at least two previous systemic therapies. Ten dose levels of IPH4102, administered as an intravenous infusion, ranging from 0·0001 mg/kg to 10 mg/kg, were assessed using an accelerated 3 + 3 design. The primary endpoint was the occurrence of dose-limiting toxicities during the first 2 weeks of treatment, defined as toxicity grade 3 or worse lasting for 8 or more days, except for lymphopenia. Global overall response by cutaneous T-cell lymphoma subtype was a secondary endpoint. Safety and activity analyses were done in the per-protocol population. The study is ongoing and recruitment is complete. This trial is registered with ClinicalTrials.gov , number NCT02593045 . Findings Between Nov 4, 2015, and Nov 20, 2017, 44 patients were enrolled. 35 (80%) patients had Sezary syndrome, eight (18%) had mycosis fungoides, and one (2%) had primary cutaneous T-cell lymphoma, not otherwise specified. In the dose-escalation part, no dose limiting toxicity was reported and the trial's safety committee recommended a flat dose of 750 mg for the cohort-expansion, corresponding to the maximum administered dose. The most common adverse events were peripheral oedema (12 [27%] of 44 patients) and fatigue (nine [20%]), all of which were grade 1–2. Lymphopenia was the most common grade 3 or worse adverse event (three [7%]). One patient developed possibly treatment-related fulminant hepatitis 6 weeks after IPH4102 discontinuation and subsequently died. However, the patient had evidence of human herpes virus-6B infection. Median follow-up was 14·1 months (IQR 11·3–20·5). A confirmed global overall response was achieved in 16 (36·4% [95% CI 23·8–51·1]) of 44 patients, and of those, 15 responses were observed in 35 patients with Sezary syndrome (43% [28·0–59·1]). Interpretation IPH4102 is safe and shows encouraging clinical activity in patients with relapsed or refractory cutaneous T-cell lymphoma, particularly those with Sezary syndrome. If confirmed in future trials, IPH4102 could become a novel treatment option for these patients. A multi-cohort, phase 2 trial (TELLOMAK) is underway to confirm the activity in patients with Sezary syndrome and explore the role of IPH4102 in other subtypes of T-cell lymphomas that express KIR3DL2. Funding Innate Pharma
Published: 2019

4. Comprehensive landscape of immune-checkpoints uncovered in clear cell renal cell carcinoma reveals new and emerging therapeutic targets

Author: Mathilde Sautreuil, Diana Tronik-Le Roux, Sarah Lemler, Maria Belén Palma, Jérôme Verine, François Desgrandchamps, Paul-Henry Cournède, Edgardo D. Carosella, Joel LeMaoult, Marina Daouya, Fatiha Bouhidel, Mahmoud Bentriou, CEA/DSV, Commissariat à L'Energie Atomique Et Aux Energies Alternatives (CEA), Direction de La Recherche Fondamentale (DRF), Service de Recherche en Hémato-Immunologie (SRHI), Hôpital Saint-Louis, Mathématiques et Informatique pour la Complexité et les Systèmes (MICS), CentraleSupélec-Université Paris-Saclay, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cátedra de Citología, Histología Y Embriología A, Facultad de Ciencias Médicas, UNLP, Service de Recherche en Hémato-Immunologie (SRHI - UMR_E 05), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7), Service d'Urologie [CHU Saint-Louis], 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), and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
Subjects: Male, Cancer Research, LAG3, [SDV]Life Sciences [q-bio], HLA-G, Immune-checkpoints, Transcriptome, Leukocyte Immunoglobulin-like Receptor B1, 0302 clinical medicine, Renal cell carcinoma, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Immunology and Allergy, Receptors, Immunologic, CD70, Aged, 80 and over, Membrane Glycoproteins, Middle Aged, Prognosis, RNAseq, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Kidney Neoplasms, 3. Good health, Oncology, Immunohistochemistry, Female, Adult, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Antigens, CD, Biomarkers, Tumor, medicine, Humans, Carcinoma, Renal Cell, Aged, Retrospective Studies, HLA-G Antigens, CD86, Gene Expression Profiling, ccRCC, Cancer, TCGA, medicine.disease, Clear cell renal cell carcinoma, Case-Control Studies, Cancer research, Follow-Up Studies, 030215 immunology
Abstract: International audience; Clear cell renal cell carcinoma (ccRCC) constitutes the most common renal cell carcinoma subtype and has long been recognized as an immunogenic cancer. As such, significant attention has been directed toward optimizing immune-checkpoints (IC)-based therapies. Despite proven benefits, a substantial number of patients remain unresponsive to treatment, suggesting that yet unreported, immunosuppressive mechanisms coexist within tumors and their microenvironment. Here, we comprehensively analyzed and ranked forty-four immune-checkpoints expressed in ccRCC on the basis of in-depth analysis of RNAseq data collected from the TCGA database and advanced statistical methods designed to obtain the group of checkpoints that best discriminates tumor from healthy tissues. Immunohistochemistry and flow cytometry confirmed and enlarged the bioinformatics results. In particular, by using the recursive feature elimination method, we show that HLA-G, B7H3, PDL-1 and ILT2 are the most relevant genes that characterize ccRCC. Notably, ILT2 expression was detected for the first time on tumor cells. The levels of other ligand-receptor pairs such as CD70:CD27; 4-1BB:4-1BBL; CD40:CD40L; CD86:CTLA4; MHC-II:Lag3; CD200:CD200R; CD244:CD48 were also found highly expressed in tumors compared to adjacent non-tumor tissues. Collectively, our approach provides a comprehensible classification of forty-four IC expressed in ccRCC, some of which were never reported before to be co-expressed in ccRCC. In addition, the algorithms used allowed identifying the most relevant group that best discriminates tumor from healthy tissues. The data can potentially assist on the choice of valuable immune-therapy targets which hold potential for the development of more effective anti-tumor treatments.
Published: 2020

5. Netrin-1 and Its Receptor DCC Are Causally Implicated in Melanoma Progression

Author: Anne Janin, Antonin Tortereau, Maxime Battistella, Jonathan Vial, Lionel Larue, Nicolas Gadot, Céleste Lebbé, Ambroise Manceau, Christophe Leboeuf, David Neves, Andrea Paradisi, Patrick Mehlen, Amina Boussouar, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université de Lyon, Interactions Cellules Environnement - UR (ICE), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Apoptose Cancer et Développement, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Anipath, UFR Médecine Lyon-RTH Laennec, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade de Brasilia [Brasília] (UnB), Ctr Rech, Institut Curie [Paris], Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Proto-Oncogene Proteins B-raf, 0301 basic medicine, Cancer Research, Skin Neoplasms, animal structures, Deleted in Colorectal Cancer, Dacarbazine, Antineoplastic Agents, Mice, Transgenic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, law.invention, Mice, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, law, Cell Line, Tumor, Netrin, medicine, Animals, Humans, Gene silencing, Melanoma, ComputingMilieux_MISCELLANEOUS, Skin, business.industry, Tumor Suppressor Proteins, fungi, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Netrin-1, DCC Receptor, medicine.disease, Xenograft Model Antitumor Assays, Up-Regulation, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer cell, Disease Progression, Cancer research, Suppressor, Female, business, Follow-Up Studies, medicine.drug
Abstract: Deleted in colorectal cancer (DCC), the receptor for the multifunctional cue netrin-1, acts as a tumor suppressor in intestinal cancer and lung metastasis by triggering cancer cell death when netrin-1 is lowly expressed. Recent genomic data highlighted that DCC is the third most frequently mutated gene in melanoma; we therefore investigated whether DCC could act as a melanoma tumor suppressor. Reexpressing DCC in human melanoma cell lines promoted tumor cell death and tumor growth inhibition in xenograft mouse models. Genetic silencing of DCC prodeath activity in a BRAFV600E mouse model increased the proportion of mice with melanoma, further supporting that DCC is a melanoma tumor suppressor. Netrin-1 expression was elevated in melanoma compared with benign melanocytic lesions. Upregulation of netrin-1 in the skin cells of a BRAFV600E-mutated murine model reduced cancer cell death and promoted melanoma progression. Therapeutic antibody blockade of netrin-1 combined with dacarbazine increased overall survival in several mouse melanoma models. Together, these data support that interfering with netrin-1 could be a viable therapeutic approach in patients with netrin-1–expressing melanoma. Significance: Netrin-1 and its receptor DCC regulate melanoma progression, suggesting therapeutic targeting of this signaling axis as a viable option for melanoma treatment.
Published: 2020

6. Lenalidomide in combination with R-CHOP (R2-CHOP) as first-line treatment of patients with high tumour burden follicular lymphoma: a single-arm, open-label, phase 2 study

Author: Steven Le Gouill, Hervé Tilly, Reda Bouabdallah, Stéphanie Becker, Thierry Lamy, Jean Gabarre, Gilles Salles, Corinne Haioun, Fabrice Jardin, José Cabeçadas, Franck Morschhauser, Pierre Feugier, Nicolas Mounier, Olivier Casasnovas, Thierry Jo Molina, Olivier Tournilhac, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biophysique, Médecine Nucléaire et Technologies Médicales (EA 1049), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Hôtel Dieu, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Instituto Português de Oncologia de Lisboa Francisco Gentil, Service de médecine nucléaire [Rouen], CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Rennes (UR)-Hôpital Pontchaillou
Subjects: Male, medicine.medical_specialty, Vincristine, Cyclophosphamide, [SDV]Life Sciences [q-bio], Follicular lymphoma, Phases of clinical research, Kaplan-Meier Estimate, CHOP, Antibodies, Monoclonal, Murine-Derived, 03 medical and health sciences, 0302 clinical medicine, Maintenance therapy, hemic and lymphatic diseases, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Lenalidomide, Lymphoma, Follicular, ComputingMilieux_MISCELLANEOUS, Aged, business.industry, Hematology, Middle Aged, medicine.disease, Thalidomide, Tumor Burden, 3. Good health, Doxorubicin, 030220 oncology & carcinogenesis, Prednisone, Female, Rituximab, business, 030215 immunology, medicine.drug
Abstract: Summary Background Immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard front-line treatment for follicular lymphoma. The combination of lenalidomide and rituximab has shown high efficacy in relapsed or refractory and untreated follicular lymphoma. We aimed to evaluate the safety and activity of the combination of lenalidomide and R-CHOP (R2-CHOP) in previously untreated patients with high burden follicular lymphoma. Methods This single-arm, open-label, multicentre, phase 2 trial was done in 16 hospitals in France, all of which were Lymphoma Study Association (LYSA) sites. Eligible patients were aged 18–70 years and had previously untreated CD20-positive follicular lymphoma of grade 1, 2, or 3a; at least one high tumour burden criterion according to Groupe d'Etude des Lymphomes Folliculaires criteria; an Eastern Cooperative Oncology Group performance status score of 2 or less; and a minimum life expectancy of more than 3 months. Patients received induction therapy with six cycles of R2-CHOP every 3 weeks (one cycle involved standard R-CHOP on days 1–5, and 25 mg oral lenalidomide per day on days 1–14), followed by two rituximab infusions at 3-week intervals. The total treatment schedule was 24 weeks. Patients who achieved a complete or partial response to induction therapy received maintenance therapy consisting of one rituximab infusion every 8 weeks for 2 years. The primary outcome was the proportion of patients who achieved a complete response (complete response and complete response unconfirmed), according to International Workshop to Standardize Response Criteria, at the end of induction treatment. Safety was assessed in all patients who completed treatment. This trial is registered with ClinicalTrials.gov , number NCT01393756 , and is closed to accrual. Findings Between Dec 21, 2010, and Jan 25, 2012, 80 patients were enrolled, and 68 (85%) completed six cycles of R2-CHOP. At the end of the induction phase, 59 patients achieved a complete response (74%, 95% CI 63–83). 55 patients achieved a complete response at 30 months from enrolment (69%, 57–78). The most frequent adverse event was grade 4 neutropenia in 52 (65%) patients. The most frequent non-haematological side-effects included grade 1–2 sensory neuropathy in 28 (35%) patients and grade 1–2 transient rash in 27 (34%) patients. Four patients died during the study period; none of these deaths were judged to be related to treatment. Interpretations Lenalidomide in combination with R-CHOP had an acceptable safety profile and showed anti-cancer activity in patients with previously untreated high burden follicular lymphoma. A future comparative study showing evidence of a survival advantage would be necessary for this combination to be proposed as a treatment for follicular lymphoma. Funding French Ministry of Health, Celgene Corporation, and Amgen France.
Published: 2018

7. Pulsed-laser irradiation of multifunctional gold nanoshells to overcome trastuzumab resistance in HER2-overexpressing breast cancer

Author: Marthe Rigal, Toni Nunes, Christophe Leboeuf, Thomas Pons, Khanh Van Do, Xue Hou, Mélanie Di Benedetto, Benoit Caron, Bruno Palpant, Guilhem Bousquet, Anne Janin, Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique (UMR 1165), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Physique et d'Etude des Matériaux (LPEM), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Photonique Quantique et Moléculaire (LPQM), École normale supérieure - Cachan (ENS Cachan)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Groupe d'Etude de la Matière Condensée (GEMAC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences de la Terre de Paris (iSTeP), Institut national des sciences de l'Univers (INSU - CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, ESPCI ParisTech-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-École normale supérieure - Cachan (ENS Cachan), Ratajczak, Philippe, Idex Paris-Saclay - - IPS2011 - ANR-11-IDEX-0003 - IDEX - VALID, Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Laboratoire de Physique et d'Etude des Matériaux (UMR 8213) (LPEM), Service de Pharmacie [Hôpital Avicenne - APHP], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de pathologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Service d'Oncologie Médicale [AP-HP Hôpital Avicenne], Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], This work received financial support from Labex LaSIPS (ANR-10-LABX0040– LaSIPS) managed by the French National Research Agency under the 'Investissements d’avenir' program (n°ANR-11-IDEX-0003–02), from the 'Plan Cancer' managed by the French ITMO Cancer (n°17CP077–00, project HEPPROS) and from the Institut d’Alembert in Ecole Normale Supérieure Paris-Saclay (FR CNRS 3242) (GESPER project)., ANR-11-IDEX-0003,IPS,Idex Paris-Saclay(2011), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut national des sciences de l'Univers (INSU - CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)
Subjects: 0301 basic medicine, Cancer Research, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Receptor, ErbB-2, Gene Dosage, Mice, Antineoplastic Agents, Immunological, 0302 clinical medicine, Trastuzumab, skin and connective tissue diseases, Trastuzumab resistance, ComputingMilieux_MISCELLANEOUS, Drug Carriers, Neovascularization, Pathologic, Chemistry, HER2-overexpressing breast cancer, Silicon Dioxide, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Magnetic Resonance Imaging, Photothermal therapy, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Oncology, Colloidal gold, 030220 oncology & carcinogenesis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Female, medicine.drug, Hyperthermia, Cell Survival, Functionalized gold nanoparticles, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Resistance reversion, 03 medical and health sciences, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cell Line, Tumor, medicine, Animals, Humans, [SPI.NANO]Engineering Sciences [physics]/Micro and nanotechnologies/Microelectronics, neoplasms, Lasers, Nanoshells, Research, Phototherapy, medicine.disease, Xenograft Model Antitumor Assays, Nanoshell, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Femtosecond laser, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, Drug Resistance, Neoplasm, Apoptosis, Cancer research, Gold
Abstract: Background HER2-overexpressing metastatic breast cancers are challenging practice in oncology when they become resistant to anti-HER2 therapies such as trastuzumab. In these clinical situations, HER2-overexpression persists in metastatic localizations, and can thus be used for active targeting using innovative therapeutic approaches. Functionalized gold nanoparticles with anti-HER2 antibody can be stimulated by near-infrared light to induce hyperthermia. Methods Here, hybrid anti-HER2 gold nanoshells were engineered for photothermal therapy to overcome trastuzumab resistance in HER2-overexpressing breast cancer xenografts. Results When gold nanoshells were administered in HER2-tumor xenografts, no toxicity was observed. A detailed pharmacokinetic study showed a time-dependent accumulation of gold nanoshells within the tumors, significantly greater with functionalized gold nanoshells at 72 h. This enabled us to optimize the treatment protocol and irradiate the mice when the anti-HER2 gold nanoshells had accumulated most in the tumors. After weekly injections of anti-HER2 gold nanoshells, and repeated irradiations with a femtosecond-pulsed laser over four weeks, tumor growth was significantly inhibited. Detailed tissue microscopic analyses showed that the tumor growth inhibition was due to an anti-angiogenic effect, coherent with a preferential distribution of the nanoshells in tumor microvessels. We also showed a direct tumor cell effect with apoptosis and inhibition of proliferation, coherent with an immune-mediated targeting of tumor cells by anti-HER2 nanoshells. Conclusion This preclinical study thus supports the use of anti-HER2 gold nanoshells and photothermal therapy to overcome trastuzumab resistance in HER2-overexpressing breast cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1305-x) contains supplementary material, which is available to authorized users.
Published: 2019

8. Germline TIM-3 Mutations Characterize Sub-Cutaneous Panniculitis T-Cell Lymphomas with Hemophagocytic Lymphohistiocytic Syndrome

Author: Simon Gravel, Sylvie Fraitag, Janie Charlebois, Jacek Majewski, Catherine Thieblemont, Rachel Conyers, Brigitte Bader-Meunier, Patrick Nitschke, Tenzin Gayden, Nada Jabado, Fernando E. Sepulveda, Paul G Ekert, Andrea Bajic, Mikko Taipale, Geneviève de Saint Basile, Daniel Schramek, Benedicte Neven, Jean-Sebastien Diana, Dong-Anh Khuong-Quang, Alain Fischer, David Michonneau, David Mitchell, Dzana Dervovic, Frank Sicheri, Maxime Battistella, Elvis Terci Valera, Alexandrine Garrigue, Stéphane Blanche, Despina Moshous, Hamid Nikbakht, Christopher McCormack, Rola Dali, Marianne Besnard, Jonathan Pratt, Nancy Hamel, Sharon Abish, Susan Kelso, H. Miles Prince, Christine Bole-Feysot, Van-Hung Nguyen, Frédéric Guerin, Leonie G. Mikael, William D. Foulkes, The University of MelbourneParkville, VIC, Australia., McGill University = Université McGill [Montréal, Canada], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Sao Paulo (Brazil), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Toronto [Canada], Canadian Centre for Computational Genomics, Montreal, Canada, Sinai Health System, Toronto, Canada, Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), McGill University and Genome Quebec Innovation Centre, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), McGill University Health Center [Montreal] (MUHC), Pediatric Hematology Oncology, Montreal Children's Hosp., Montreal, Canada, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Immunologie et Hématologie, Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley], University of California-University of California, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie pathologique [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], The Royal Children's Hospital, Melbourne, Australia, Urgences pédiatriques, Hôpital Necker Enfants Malades, Université Paris Descartes, Paris, France, parent, Peter MacCallum Cancer Centre [Melbourne, Australie], Department of Medicine, University of Melbourne, Melbourne, Australia, Centre Hospitalier de Polynésie Française, Service d'immuno-hématologie pédiatrique [CHU Necker], Murdoch Children's Research Institute (MCRI), Laboratoire d'anatomie pathologique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Human Genetics [Montréal], Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Department of Human Genetics , Department of Experimental Medicine, Radboud University Medical Center [Nijmegen], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and McGill University
Subjects: T cell, Immunology, Biochemistry, Germline, 03 medical and health sciences, 0302 clinical medicine, Immune system, Medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Hemophagocytic lymphohistiocytosis, Innate immune system, biology, business.industry, Cell Biology, Hematology, medicine.disease, Immune checkpoint, 3. Good health, Lymphoma, medicine.anatomical_structure, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, business, 030215 immunology
Abstract: Introduction Sub-cutaneous panniculitis T-cell lymphomas (SPTCL), a rare non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening activation of the immune system which adversely impacts survival. T-cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T- and innate immune cells. In this work we describe the first germline variants associated with SPTCL, which are in the TIM-3 gene. Methods We sequenced 27 SPTCL cases to identify gene variants. We performed TIM-3 functional analysis on immune cells from patients and HEK293 cells engineered to overexpress wild-type or mutant TIM-3. Results We identified homozygous, germline, loss-of-function, missense variants in highly conserved residues of TIM-3, namely p.Y82C and p.I97M in about 60% (16/27) of SPTCL cases. These samples were drawn from cases series across 3 continents. Patients with bi-allelic TIM-3 mutations were younger at diagnosis, and several had life-threatening HLH and severe disease course. TIM-3 mutations show specific geographic distribution. Y82C TIM-3 mutations occur on a founder chromosome in patients with East-Asian and Polynesian ancestry, while I97M TIM-3 is observed in Caucasians. Both variants induce protein misfolding and cytoplasmic retention of TIM-3. Loss of TIM-3 membrane expression in TIM-3 mutants abrogates the PD-1/PDL-1 checkpoint and prevents the termination of a Th1-immune response. In HEK293 cells, mutant TIM-3 was not expressed on the cell surface. Defective TIM-3 expression leads to persistent immune activation with increased production of inflammatory cytokines including TNF-alpha and IL-1beta by innate immune cells. Conclusion Our findings highlight HLH/SPTCL as a new genetic entity where loss of the TIM-3 immune checkpoint is associated with T-cell infiltration of adipose tissue and inflammasome activation. This is the first causative germline defect identified in SPTCL. While our findings indicate that TIM-3-mutant HLH/SPTCL benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint could have serious adverse consequences. Disclosures Prince: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Published: 2019

9. Radioimmunotherapy-augmented BEAM chemotherapy vs BEAM alone as the high-dose regimen for autologous stem cell transplantation (ASCT) in relapsed follicular lymphoma (FL): a retrospective study of the EBMT Lymphoma Working Party

Author: X Poire, Grant McQuaker, Ariane Boumendil, Nigel H. Russell, Charles Crawley, Francesca Bonifazi, Rachel Johnson, Emmanuel Bachy, François Guilhot, John G. Gribben, Patrice Ceballos, E. Nicolas-Virelizier, Gandhi Damaj, Silvia Montoto, David Pohlreich, S. Amorim, Kim Orchard, Anne Huynh, S. Le Gouill, Peter Dreger, Hélène Monjanel, Anette Haenel, Bernd Metzner, Giulio Rossi, H. Tilly, R. Bouabdallah, R. K. Malladi, Alessandro Rambaldi, Jacques-Olivier Bay, K Thomson, Leyre Bento, Herve Finel, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut d'Electronique du Solide et des Systèmes (InESS), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Semiconductor Photonics Research Group, Trinity College Dublin-Science Foundation Ireland-Enterprise Ireland-Higher Education Authority, Service hématologie Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers), and CHU Amiens-Picardie
Subjects: Adult, Male, Melphalan, Oncology, medicine.medical_specialty, medicine.medical_treatment, Follicular lymphoma, Transplantation, Autologous, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, Lymphoma, Follicular, ComputingMilieux_MISCELLANEOUS, Etoposide, Aged, Retrospective Studies, Transplantation, Carmustine, business.industry, Cytarabine, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, Radioimmunotherapy, medicine.disease, Combined Modality Therapy, Survival Analysis, 3. Good health, Surgery, Case-Control Studies, 030220 oncology & carcinogenesis, Female, Rituximab, business, 030215 immunology, medicine.drug
Abstract: Relapse remains the most common cause of treatment failure in patients receiving autologous stem cell transplantation (ASCT) for follicular lymphoma (FL). The aim of this study was to evaluate the effect of adding radioimmunotherapy or rituximab (R) to BEAM (carmustine, etoposide, ara-c, melphalan) high-dose therapy for ASCT in patients with relapsed FL. Using the European Society for Blood and Marrow Transplantation registry, we conducted a cohort comparison of BEAM (n=1973), Zevalin-BEAM (Z-BEAM) (n=207) and R-BEAM (n=179) and also a matched-cohort analysis of BEAM vs Z-BEAM including 282 and 154 patients, respectively. BEAM, Z-BEAM and R-BEAM groups were well balanced for age, time from diagnosis to ASCT and disease status at ASCT. The cumulative incidences of relapse (IR) at 2 years were 34, 34 and 32% for Z-BEAM, R-BEAM and BEAM, respectively. By multivariate analysis, there were no significant differences with Z-BEAM or R-BEAM compared with BEAM for IR, non-relapse mortality, event-free survival or overall survival. With the caveat that the limitations of registry analyses have to be taken into account, this study does not support adding radioimmunotherapy or R to BEAM in ASCT for relapsed FL. However, we cannot rule out the existence a particular subset of patients who could benefit from Z-BEAM conditioning that cannot be identified in our series, and this should be tested in a randomized trial.Bone Marrow Transplantation advance online publication, 22 May 2017; doi:10.1038/bmt.2017.88.
Published: 2017

10. Lésions intrarénales de coagulation intravasculaire disséminée (CIVD)

Author: Joëlle Razafimahefa, Jérôme Verine, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), and Université de Paris (UP)
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, [SDV]Life Sciences [q-bio], 030304 developmental biology, Pathology and Forensic Medicine
Published: 2019

11. Drug-resistant endothelial cells facilitate progression, EMT and chemoresistance in nasopharyngeal carcinoma via exosomes

Author: Jing Hou, Yong Li, Zhong Xu, Yu Zhang, Chaoquan Hu, He Lu, Hui Chao, Limin Huang, Hui Chen, Hong Li, Laboratoire de Génie Electrique de Grenoble (G2ELab), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sun Yat-Sen University [Guangzhou] (SYSU), Air Force Engineering University [Xi'an] (AFEU), Xi'an Jiaotong University (Xjtu), Guizhou Medical University (贵州医科大学), Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique (UMR 1165), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Lawrence Livermore National Laboratory (LLNL)
Subjects: 0301 basic medicine, Male, Cell type, Epithelial-Mesenchymal Transition, [SDV]Life Sciences [q-bio], Mice, Nude, Cell Communication, Exosomes, Exosome, Benzylidene Compounds, 03 medical and health sciences, Mice, 0302 clinical medicine, In vivo, Cell Movement, Precursor cell, Cell Line, Tumor, medicine, Animals, Humans, Cell Proliferation, Mice, Inbred BALB C, Aniline Compounds, Nasopharyngeal Carcinoma, Human microvascular endothelial cells (HMECs), Chemistry, Endothelial Cells, Nasopharyngeal Neoplasms, Cell Biology, medicine.disease, Microvesicles, 030104 developmental biology, Nasopharyngeal carcinoma, Cytoplasm, Drug Resistance, Neoplasm, Drug resistance, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Disease Progression, [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract: International audience; Recent antitumor drug development has included investigation of a wide variety of anti-angiogenesis therapies. Because cancer cells in tumors require new blood vessels to grow and spread, they stimulate capillary proliferation from existing vessels as well as new vessel formation from endothelial precursor cells. Our previous findings suggested that drug resistance in mouse endothelial cells supported tumor growth, but the relationship between endothelial cells (ECs) and nasopharyngeal carcinoma (NPC) cells remained unclear. Exosomes are small membrane vesicles that are released by several cell types, including human microvascular ECs (HMECs). Exosomes carrying membrane and cytoplasmic constituents have been described as participants in a novel mechanism of cell-to-cell communication. In the present study, we investigated the mechanisms underlying the interactions between HMECs and NPC cells. We found that drug-resistant HMECs secreted small heterogeneous 40-100 nm vesicles, defined as exosomes. Co-incubation of NPC cells with doxorubicin-resistant (R-DOX) HMEC-derived exosomes resulted in promotion of their proliferation, migration, and chemoresistance, as well as changes in the expression of epithelial-mesenchymal transition (EMT) markers. These effects were significantly inhibited by treatment with GW4869 (an exosome inhibitor). We also found that GW4869 inhibited the stimulation of drug-resistant HMECs on NPC progression by modulating EMT in vivo. These data suggest that exosomes participate in a novel mechanism by which drug-resistant ECs enhance NPC progression.
Published: 2019

12. Recovery of central memory and naive peripheral T cells in Follicular Lymphoma patients receiving rituximab-chemotherapy based regimen

Author: Nathalie Josseaume, P. Brice, Sandy Amorim, Quentin Riller, Benoit Milcent, Sophie Sibéril, Florent Petitprez, Jean-Luc Teillaud, Catherine Thieblemont, Antoine Toubert, Pascale Loiseau, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Service d'Hémato-oncologie [CHU Saint-Louis], 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 Sorbonne Paris Cité (USPC), Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), NF-kappaB, Différenciation et Cancer (OncokappaB - EA 7324), Université Paris Descartes - Paris 5 (UPD5), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Dieu-Nosjean, Marie-Caroline, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service d'hématologie greffe [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Teillaud, Jean-Luc, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Follicular lymphoma, lcsh:Medicine, CD38, Lymphocyte Activation, 0302 clinical medicine, Immunophenotyping, immune system diseases, T-Lymphocyte Subsets, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, lcsh:Science, Lymphoma, Follicular, Immunity, Cellular, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Treatment Outcome, Vincristine, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, Female, Immunotherapy, medicine.drug, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, Adaptive immunity, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, TIGIT, medicine, Humans, Lymphocyte Count, Cyclophosphamide, Aged, Neoplasm Staging, business.industry, lcsh:R, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, 030104 developmental biology, Doxorubicin, Cancer research, Prednisone, lcsh:Q, Neoplasm Grading, business, Immunologic Memory, CD8, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomarkers
Abstract: International audience; Preclinical models and clinical studies have shown that anti-CD20-based treatment has multifaceted consequences on t-cell immunity. We have performed a prospective study of peripheral t-cell compartment in FL patients, all exhibiting high tumor burden and receiving rituximab-chemotherapy-based regimen (R-CHOP). Before treatment, FL patients harbor low amounts of peripheral naive T cells, but high levels of CD4 + t eM , CD4 + t reg and CD8 + t eMRA subsets and significant amounts of CD38 + HLA-DR + activated T cells. A portion of these activated/differentiated T cells also expressed PD-1 and/or TIGIT immune checkpoints. Hierarchical clustering of phenotyping data revealed that 5/8 patients with only a partial response to R-cHop induction therapy or with disease progression segregate into a group exhibiting a highly activated/differentiated T cell profile and a markedly low proportion of naive T cells before treatment. Rituximab-based therapy induced a shift of CD4 + and CD8 + t cells toward a central memory phenotype and of CD8 + T cells to a naive phenotype. In parallel, a decrease in the number of peripheral T cells expressing both PD-1 and TIGIT was detected. These observations suggest that the standard rituximab-based therapy partially reverts the profound alterations observed in t-cell subsets in FL patients, and that blood T-cell phenotyping could provide a better understanding of the mechanisms of rituximab-based treatment. Follicular lymphoma (FL) is the second most common form of non-Hodgkin lymphoma (NHL). Its clinical course is highly variable and survival medians are 7-15 years depending on the studies. Follicular lymphoma management is characterized by a risk-adapted therapy based on the stage of the disease and the symptoms of the patients. For high tumor burden patients, treatment options could be either rituximab plus cyclophosphamide, vincristine and prednisone with (R-CHOP) or without (R-CVP) doxorubicin or other anthracyclines, or rituxi-mab plus fludarabine for patients not eligible for anthracyclines, or rituximab plus bendamustine. Experimental therapies as well as allogeneic stem cell transplantation are rather considered for relapsed and more refractory disease 1. The addition of the anti-CD20 monoclonal antibody (mAb) rituximab to chemotherapy has resulted in a higher rate of complete remission and improved survival 2. In addition, rituximab as maintenance therapy
Published: 2019

13. Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome

Author: Fernando E. Sepulveda, Geneviève de Saint Basile, Patrick Nitschke, Stéphane Blanche, Maxime Battistella, David Michonneau, Nada Jabado, Shriya Deshmukh, David Mitchell, Christine Bole-Feysot, Janie Charlebois, Bénédicte Neven, Hamid Nikbakht, Mikko Taipale, Paul G Ekert, Christopher McCormack, William D. Foulkes, Leonie G. Mikael, Alexandrine Garrigue, Dzana Dervovic, Nancy Hamel, Andrea Bajic, Simon Gravel, Despina Moshous, Sharon Abish, Frank Sicheri, Rachel Conyers, Van-Hung Nguyen, Frédéric Guerin, Susan Kelso, Sylvie Fraitag, H. Miles Prince, Jean-Sebastien Diana, Rola Dali, Marianne Besnard, Jonathan Pratt, Elvis Terci Valera, Dong-Anh Khuong-Quang, Catherine Thieblemont, Alain Fischer, Tenzin Gayden, Jacek Majewski, Brigitte Bader-Meunier, Daniel Schramek, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Children’s Cancer Center, The Royal Children’s Hospital and Murdoch Children’s Research Institute, Parkville, Victoria, Australia, Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia, Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Genetics [Toronto], University of Toronto, Cancer Research Program, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada, Canadian Centre for Computational Genomics, Montreal, Canada, Division of Experimental Medicine [Montréal, QC, Canada] (Department of Medicine), McGill University Health Center [Montreal] (MUHC), Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], Géosciences Environnement Toulouse (GET), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), McGill University and Genome Quebec Innovation Centre, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pediatric Hematology Oncology, Montreal Children's Hosp., Montreal, Canada, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Immunologie et Hématologie, Space Sciences Laboratory [Berkeley] (SSL), University of California [Berkeley], University of California-University of California, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie pathologique [CHU Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Department of Pathology, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Quebec, Canada, Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Dermatology, St. Vincent’s Hospital, Fitzroy, Victoria, Australia, Department of Oncology [Melbourne, Australie], Peter MacCallum Cancer Centre [Melbourne, Australie], Department of Neonatology, Centre Hospitalier de Polynésie Française, Papeete, French Polynesia, Service d'immuno-hématologie pédiatrique [CHU Necker], epartment of Pediatrics, University of Melbourne, Parkville, Victoria, Australia, Laboratoire d'anatomie pathologique [CHU Necker], Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Department of Human Genetics , Department of Experimental Medicine, Radboud University Medical Center [Nijmegen], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National d'Études Spatiales [Toulouse] (CNES), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and McGill University
Subjects: 0301 basic medicine, Adult, Male, Panniculitis, Adolescent, T cell, [SDV]Life Sciences [q-bio], Biology, HAVCR2, Lymphoma, T-Cell, Lymphohistiocytosis, Hemophagocytic, Diagnosis, Differential, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Immune system, Germline mutation, Subcutaneous Panniculitis-Like T-Cell Lymphoma, Exome Sequencing, Genetics, medicine, T-cell lymphoma, Humans, Genetic Predisposition to Disease, Child, Hepatitis A Virus Cellular Receptor 2, Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Hemophagocytic lymphohistiocytosis, [SDV.GEN]Life Sciences [q-bio]/Genetics, Innate immune system, Infant, Middle Aged, medicine.disease, 3. Good health, Pedigree, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female
Abstract: Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival1,2. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3’s plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL. Our findings highlight HLH–SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH–SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.
Published: 2018

14. An open-label phase 1b study of obinutuzumab plus lenalidomide in relapsed/refractory follicular B-cell lymphoma

Author: Franck Morschhauser, Hervé Tilly, Cédric Ménard, Bettina Fabiani, Roch Houot, Catherine Thieblemont, Krimo Bouabdallah, Karin Tarte, Gilles Salles, Steven Le Gouill, Guillaume Cartron, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hémato-oncologie [CHU Saint-Louis], 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), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'hématologie et oncologie médicale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pathologie [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), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)
Subjects: Adult, Male, medicine.medical_specialty, Lymphoma, B-Cell, Maximum Tolerated Dose, Clinical Trials and Observations, Immunology, Follicular lymphoma, Administration, Oral, Angiogenesis Inhibitors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neutropenia, Antibodies, Monoclonal, Humanized, Biochemistry, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Agents, Immunological, Refractory, Obinutuzumab, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Lenalidomide, Lymphoma, Follicular, Aged, Aged, 80 and over, business.industry, Cell Biology, Hematology, Middle Aged, medicine.disease, 3. Good health, Lymphoma, chemistry, 030220 oncology & carcinogenesis, Rituximab, Female, Neoplasm Recurrence, Local, business, Febrile neutropenia, 030215 immunology, medicine.drug
Abstract: International audience; Obinutuzumab is a type II anti-CD20 monoclonal antibody that enhances antibody-dependent cellular cytotoxicity better than rituximab. Given promising results with lenalidomide and rituximab, this phase 1b study assessed the safety and efficacy of lenalidomide combined with obinutuzumab (GALEN). Patients age ≥18 years with relapsed or refractory (R/R) follicular lymphoma (FL) after rituximab-containing therapy received escalating doses (10 [n = 7], 15 [n = 3], 20 [n = 6], and 25 mg [n = 3]) of daily oral lenalidomide on days 1 to 21 of cycle 1 and on days 2 to 22 of cycles 2 to 6 (28-day cycles). Obinutuzumab 1000 mg IV was administered on days 8, 15, and 22 (cycle 1) and on day 1 (cycles 2-6). Dose was escalated in a 3 + 3 design based on dose-limiting toxicity (DLT) during cycle 1 to establish the maximum tolerated dose (MTD). We observed 164 adverse events (AEs), of which 139 were grade 1/2. The most common AEs were constipation (52.6%), neutropenia (47.4%), and asthenia (36.8%); 64.3% (9 of 14) of the grade 3/4 AEs were neutropenia/neutrophil decrease, but without any febrile neutropenia. Four DLTs occurred in 2 patients, all deemed unrelated to treatment. MTD was not reached. Twelve patients (63.2%) responded: 8 complete, 3 unconfirmed complete, and 1 partial response. Oral lenalidomide plus obinutuzumab is well tolerated and effective in R/R FL. The recommended dose of lenalidomide was established at 20 mg based on the risk of grade 3/4 neutropenia from cycle 2. This trial was registered at www.clinicaltrials.gov as #NCT01582776.
Published: 2018

15. Arterial Stiffening with Ultrafast Ultrasound Imaging Gives New Insight into Arterial Phenotype of Vascular Ehlers- Danlos Mouse Models

Author: Xavier Jeunemaitre, Mickael Tanter, Clement Papadacci, Guillaume Goudot, Véronique Baudrie, Catherine Boisson-Vidal, Tristan Mirault, Blandine Dizier, Mathieu Pernot, Emmanuel Messas, Irmine Ferreira, Institut Langevin - Ondes et Images (UMR7587) (IL), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Thrombose : Épidémiologie, Physiopathologie et Thérapeutiques Innovantes (UMR_S 765), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Innovations thérapeutiques en hémostase (IThEM - U1140), Physique des ondes pour la médecine, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Therapie Cellulaire en Pathologie Cardio-Vasculaire (UMR_S 633), Risque Thrombotique et Mecanismes de l'Hemostase (U765), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), LABEX WIFI (Laboratory of Excellence ANR-10-LABX-24) within the French Program 'Investments for the Future' under reference ANR-10- IDEX-0001-02 PSL and a grant from Shire Human Genetic Therapies. We thank Mrs Beatrice Walker for her careful proofreading of the manuscript, Boisson-Vidal, Catherine, Sorbonne Université (SU)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, MESH: collagen type III, MESH: mouse, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Blood Pressure, MESH: aorta, Pulse Wave Analysis, 030218 nuclear medicine & medical imaging, Mice, 03 medical and health sciences, Vascular Stiffness, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine.artery, medicine, Animals, Humans, MESH: pulse wave velocity, Radiology, Nuclear Medicine and imaging, Phenylephrine, Pulse wave velocity, Ultrasonography, Aorta, 030219 obstetrics & reproductive medicine, Cardiac cycle, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: arterial stiffness, medicine.disease, Pulse pressure, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Phenotype, Blood pressure, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Hypertension, Cardiology, Arterial stiffness, cardiovascular system, Ehlers-Danlos Syndrome, Aortic stiffness, business, medicine.drug, circulatory and respiratory physiology
Abstract: Vascular Ehlers-Danlos syndrome (vEDS) is associated with arterial ruptures due to a mutant gene encoding collagen type III (Col-III). To better understand the role of Col-III, we aimed at evaluating aortic stiffness and dynamic stiffening in vEDS mouse models, with either a quantitative (col3KO mice) or a qualitative Col-III defect (col3KI mice). Abdominal aortic wall pulse wave velocities (PWV) in col3KO and col3KI mice were compared to their respective wild type (WT) littermates using a 15 MHz ultrafast ultrasonic transducer. A carotid catheter continuously monitored pressure changes due to phenylephrine injections. PWV1, generated at diastolic blood pressure (DBP), and PWV2, at systolic blood pressure (SBP) were recorded. Difference between PWV2 and PWV1 (Delta-PWV) normalized by the pulse pressure (PP), corresponding to the aortic stiffening over the cardiac cycle, were compared between mutant and WT mice, as well as the regression slope of PWV as a function of pressure. Delta-PWV/PP was lower in col3KO (p = 0.033) and col3KI mice (p 0.001) vs. WT-mice regardless of the pressure level. The slope of PWV1 with DBP increase showed a lower arterial stiffness in mutant mice vs. controls in both models. This difference was amplified when evaluating stiffness at systolic blood pressure levels with PWV2. In both vEDS mouse models, aortic stiffening was reduced, mainly driven by a lower stiffness at systolic blood pressure. Defective Col-III may be responsible for this, as it is utilized when pressure rises. These pre-clinical data could explain vascular fragility observed in vEDS patients.ZIEL: Das vaskuläre Ehlers-Danlos-Syndrom (vEDS) ist mit arteriellen Rupturen assoziiert, zurückzuführen auf ein mutiertes Gen, das für Kollagen Typ III (Col-III) kodiert. Um die Rolle von Col-III besser zu verstehen, untersuchten wir die Aortensteifigkeit und die dynamische Steifigkeit in vEDS-Mausmodellen, die entweder einen quantitativen (col3KO-Mäuse) oder einen qualitativen Col-III-Defekt (col3KI-Mäuse) hatten. Die Pulswellengeschwindigkeiten der Bauchaortenwand (PWV) in col3KO- und col3KI-Mäusen wurden mit denen ihrer jeweiligen Wildtyp (WT)- Wurfgeschwister mit einem 15 MHz Ultrafast-Ultraschall-Transducer verglichen. Ein Karotiskatheter überwachte fortlaufend die durch Injektion von Phenylephrin hervorgerufenen Druckänderungen. PWV1, erzeugt bei diastolischem Blutdruck (DBP) und PWV2, bei systolischem Blutdruck (SBP) wurden aufgezeichnet. Der Unterschied zwischen PWV2 und PWV1 (Delta-PWV), normalisiert durch den Pulsdruck (PP), welcher der Aortensteifigkeit beim Herzzyklus entspricht, sowie die Regressionsneigung von PWV als Funktion des Drucks wurde zwischen Mutanten- und WT-Mäusen verglichen. Delta-PWV/PP war unabhängig vom Druckniveau niedriger in col3KO- (p = 0,033) und col3KI-Mäusen (p 0,001) im Vergleich zu WT-Mäusen. Die Neigung von PWV1 bei DBP-Anstieg zeigte bei beiden Modellen eine geringere arterielle Steifigkeit in mutierten Mäusen im Vergleich zu den Kontrollen. Dieser Unterschied wurde verstärkt, wenn die Steifigkeit mit PWV2 bei systolischem Blutdruck bewertet wurde. Beide vEDS-Mausmodelle hatten eine reduzierte Aortensteifigkeit, hauptsächlich durch die geringere Steifigkeit beim systolischen Blutdruck. Das defekte Col-III Gen könnte dafür verantwortlich sein, da es zum Einsatz kommt, wenn der Druck steigt. Diese präklinischen Daten könnten die bei Patienten mit vEDS beobachtete vaskuläre Fragilität erklären.
Published: 2018

16. MicroRNA-29c Increases the Chemosensitivity of Pancreatic Cancer Cells by Inhibiting USP22 Mediated Autophagy

Author: Hong Li, Li-Min Huang, Chaoquan Hu, He Lu, Hui Chen, Hui Cao, Rongpin Wang, Xiaoliang Wu, Laboratoire de Génie Electrique de Grenoble (G2ELab), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'études en sciences sociales sur les mondes africains, américains et asiatiques (CESSMA UMRD 245), Institut de Recherche pour le Développement (IRD)-Institut National des Langues et Civilisations Orientales (Inalco)-Université Paris Diderot - Paris 7 (UPD7), Guizhou Medical University (贵州医科大学), Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique (UMR 1165), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lawrence Livermore National Laboratory (LLNL), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)
Subjects: 0301 basic medicine, Antimetabolites, Antineoplastic, Physiology, [SDV]Life Sciences [q-bio], Transplantation, Heterologous, Down-Regulation, Mice, Nude, MiR-29c, USP22, Deoxycytidine, lcsh:Physiology, Flow cytometry, lcsh:Biochemistry, 03 medical and health sciences, Mice, Annexin, Cell Line, Tumor, medicine, Autophagy, Animals, Humans, MTT assay, lcsh:QD415-436, Viability assay, RNA, Small Interfering, 3' Untranslated Regions, Chemosensitivity, medicine.diagnostic_test, lcsh:QP1-981, Chemistry, Cell growth, Antagomirs, Pancreatic cancer, Gemcitabine, 3. Good health, Blot, Pancreatic Neoplasms, MicroRNAs, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, Apoptosis, Drug Resistance, Neoplasm, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, RNA Interference, Thiolester Hydrolases, Microtubule-Associated Proteins, Ubiquitin Thiolesterase
Abstract: International audience; Background/Aims: Pancreatic cancer (PC) is an aggressive malignancy with a poor survival rate. Despite advances in the treatment of PC, the efficacy of therapy is limited by the development of chemoresistance. Here, we examined the role of microRNA-29c (miR-29c) and the involvement of autophagy and apoptosis in the chemoresistance of PC cells in vivo and in vitro. Methods: We employed qRT-PCR, western blot and immunofluorescence to examine the expression level of miR-29c, USP22 and autophagy relative protein. In addition, we used MTT assay to detect cell proliferation and transwell assay to measure migration and invasiveness. The apoptosis was determined using annexin V-FITC/PI apoptosis detection kit by flow cytometry. Luciferase reporter assays confirmed the relationship between USP22 and miR-29c.Results: miR-29c overexpression in the PC cell line PANC-1 enhanced the effect of gemcitabine on decreasing cell viability and inducing apoptosis and inhibited autophagy, as shown by western blotting, immunofluorescence staining, colony formation assays, and flow cytometry. Ubiquitin specific peptidase (USP)-22, a deubiquitinating enzyme known to induce autophagy and promote PC cell survival, was identified as a direct target of miR-29c. USP22 knockdown experiments indicated that USP22 suppresses gemcitabine-induced apoptosis by promoting autophagy, thereby increasing the chemoresistance of PC cells. Luciferase reporter assays confirmed that USP22 is a direct target of miR-29c. A xenograft mouse model demonstrated that miR-29c increases the chemosensitivity of PC in vivo by downregulating USP22, leading to the inhibition of autophagy and induction of apoptosis. Conclusions: Taken together, these findings reveal a potential mechanism underlying the chemoresistance of PC cells mediated by the regulation of USP22-mediated autophagy by miR-29c, suggesting potential targets and therapeutic strategies in PC.
Published: 2018

17. Operando Evidence for a Universal Oxygen Evolution Mechanism on Thermal and Electrochemical Iridium Oxides

Author: Elena R. Savinova, Detre Teschner, Travis Jones, Aldo Saul Gago, Robert Schlögl, K. Andreas Friedrich, Viktoriia A. Saveleva, Li Wang, Spyridon Zafeiratos, Schatz, George, Institut de chimie et procédés pour l'énergie, l'environnement et la santé (ICPEES), Université de Strasbourg (UNISTRA)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Thermodynamics and Process Engineering, University of Stuttgart, Max-Planck-Institut für Chemische Energiekonversion (MPI-CEC), and Max-Planck-Gesellschaft
Subjects: Materials science, Proton Exchange Membrane (PEM) water electrolysis, Proton exchange membrane fuel cell, chemistry.chemical_element, 02 engineering and technology, Reaction intermediate, Overpotential, 010402 general chemistry, Photochemistry, Electrochemistry, 01 natural sciences, Oxygen, Oxygen evolution reaction (OER), active sites, [CHIM]Chemical Sciences, General Materials Science, Iridium, Physical and Theoretical Chemistry, ComputingMilieux_MISCELLANEOUS, Electrolysis of water, O K-edge, Elektrochemische Energietechnik, Oxygen evolution, 021001 nanoscience & nanotechnology, 0104 chemical sciences, Near-Ambient Pressure XPS (NAP-XPS), chemistry, soft X-ray absorption spectroscopy, 0210 nano-technology
Abstract: Progress in the development of proton exchange membrane (PEM) water electrolysis technology requires decreasing the anode overpotential, where the sluggish multistep oxygen evolution reaction (OER) occurs. This calls for an understanding of the nature of the active OER sites and reaction intermediates, which are still being debated. In this work, we apply synchrotron radiation-based near-ambient pressure X-ray photoelectron and absorption spectroscopies under operando conditions in order to unveil the nature of the reaction intermediates and shed light on the OER mechanism on electrocatalysts most widely used in PEM electrolyzers—electrochemical and thermal iridium oxides. Analysis of the O K-edge and Ir 4f spectra backed by density functional calculations reveals a universal oxygen anion red–ox mechanism regardless of the nature (electrochemical or thermal) of the iridium oxide. The formation of molecular oxygen is considered to occur through a chemical step from the electrophilic OI– species, which itself is formed in an electrochemical step.
Published: 2018

18. Central nervous system relapse in patients over 80 years with diffuse large B-cell lymphoma: an analysis of two LYSA studies

Author: Cabannes‐Hamy, Aurélie, Peyrade, Frederic, Jardin, Fabrice, Emile, Jean‐François, Delwail, Vincent, Mounier, Nicolas, Haioun, Corinne, Perrot, Aurore, Fitoussi, Olivier, Lara, Diane, Delarue, Richard, André, Marc, Offner, Fritz, Ghesquières, Hervé, Pascal, Laurent, Soussain, Carole, Lazarovici, Julien, Schiano, Jean-Marc, Gaulard, Philippe, Tilly, Hervé, Thieblemont, Catherine, LYSA (LYmphoma Study Association), Bosly, André, Van Den Neste, Eric, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Oncologie Hématologique et Thérapie Cellulaire [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Polyclinique Bordeaux Nord Aquitaine, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de Recherche d'Histoire (GRHis), Normandie Université (NU)-Normandie Université (NU)-Institut de Recherche Interdisciplinaire Homme et Société (IRIHS), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Universiteit Gent = Ghent University [Belgium] (UGENT), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), CRLCC René Huguenin, Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Polyclinique Bordeaux Nord Aquitaine (PBNA), Universiteit Gent = Ghent University (UGENT), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Ghent University [Belgium] (UGENT), Université de Lille, CHU Lille, UCL - (MGD) Service d'hématologie, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique, and UCL - (SLuc) Service d'hématologie
Subjects: Male, Cancer Research, CHOP CHEMOTHERAPY, [SDV]Life Sciences [q-bio], Aggressive lymphoma, Central Nervous System Neoplasms, chemistry.chemical_compound, 0302 clinical medicine, Recurrence, Medicine and Health Sciences, SINGLE-ARM, Medicine, Cumulative incidence, ELDERLY-PATIENTS, ComputingMilieux_MISCELLANEOUS, Original Research, CNS relapse, Aged, 80 and over, education.field_of_study, Incidence (epidemiology), 3. Good health, CNS PROPHYLAXIS, Oncology, 030220 oncology & carcinogenesis, Female, Rituximab, Lymphoma, Large B-Cell, Diffuse, medicine.drug, medicine.medical_specialty, Population, PHASE-2 TRIAL, Ofatumumab, elderly, STUDY-GROUP DSHNHL, 03 medical and health sciences, Internal medicine, Humans, Radiology, Nuclear Medicine and imaging, NON-HODGKINS-LYMPHOMA, education, Aged, Retrospective Studies, AGGRESSIVE LYMPHOMA, business.industry, Clinical Cancer Research, Retrospective cohort study, medicine.disease, chemistry, Aged 80 and over, RITUXIMAB ERA, DLBCL, RISK-FACTORS, business, Diffuse large B-cell lymphoma, 030215 immunology
Abstract: CNS relapse is reported in 2–5% of diffuse large B‐cell lymphoma (DLBCL) patients, dramatically decreasing overall survival (OS). Very few studies address incidence and risk factors of CNS relapse in very elderly patients, a challenging population to treat given their commonly associated comorbidities. A retrospective analysis was performed of 270 DLBCL patients >80 years treated between 2004 and 2013 in two multicentre phase II LYSA trials (LNH03‐7B, LNH09‐7B) evaluating the addition of rituximab or ofatumumab to mini‐CHOP as front‐line therapy. No patients received CNS prophylaxis. CNS relapse was evaluated according to cumulative incidence, patient characteristics, risk factors, and survival. Median age was 83 years (range: 79–95). After a median follow‐up of 28.7 months, eight patients had CNS relapse (3.0%). Median time between inclusion and CNS relapse was 19.2 months (range: 3.2–32.6). Patients survived a median of 1.5 months after CNS relapse (range: 0.4–4.1). Median OS from relapse was significantly lower in CNS relapse patients (1.5 months, 95% CI: 0.4–3.5) compared to patients with non‐CNS relapse (6.6 months; 95% CI: 4.6–11.9). No baseline characteristics were associated with CNS relapse. The proportion of patients with CNS disease did not differ significantly between patients with low‐intermediate risk according to CNS‐IPI and patients with high risk (3% vs. 2.8%, P = 1.00). CNS relapse cumulative incidence in very elderly treatment‐naive patients is 1.8% at 2 years and is associated with poor survival. This population had a long median time to CNS relapse. Absence of prophylaxis did not strongly impact CNS relapse incidence.
Published: 2018

19. Synergistic promoting effects of pentoxifylline and simvastatin on the apoptosis of triple-negative MDA-MB-231 breast cancer cells

Author: Rémi Varin, Yessica Cristina Castellanos-Esparza, Hong Li, Anne Janin, He Lu, Berenice Sanchez-Gonzalez, Rong Shen, Limin Huang, Jean-Pierre Vannier, Olivier Boyer, Catherine Buquet, Ethel Awilda García Latorre, Shuang Wu, Jiménez-Zamudio L, Zhejiang University, Laboratoire de Génie Electrique de Grenoble (G2ELab), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Pharmacie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hemostase, Endothelium, Angiogenese (UMR_S_553)
Subjects: 0301 basic medicine, Simvastatin, Cancer Research, [SDV]Life Sciences [q-bio], Apoptosis, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Annexin, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, Autophagy, Humans, Propidium iodide, Pentoxifylline, Clonogenic assay, PI3K/AKT/mTOR pathway, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Cell growth, Drug Synergism, Cell cycle, 3. Good health, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Female
Abstract: Pentoxifylline (PTX), a xanthine family molecule and simvastatin (SIM), an anti-hypercholesterolemic agent, have recently been considered as sensitizers to chemotherapy and radiotherapy. The present in vitro study evaluated their antitumor synergistic effects on MDA‑MB‑231 breast cancer cells characterized by the triple‑negative phenotype (TNP). The anti-proliferative effects of these two agents were evaluated by MTT and clonogenic assays. Cell cycle progression was examined using propidium iodide staining. Apoptosis was investigated by Annexin V labeling, and by examining caspase 3 activity and DNA fragmentation. Autophagic vesicles and reactive oxygen species (ROS) levels were monitored by flow cytometry. Western blot analysis was performed to evaluate molecular targets. Our results revealed that when used alone, PTX and SIM exerted antitumor effects. Nevertheless, used in combination, the inhibition of cell proliferation was synergistically superior (80% vs 42%) than that observed following treatment with each agent alone after 48 h. PTX alone (0.5 mM) induced both apoptosis (25%) and autophagy (25%); however, when used in combination with SIM (0.5 µM), the balance between these processes was disrupted and the cells underwent apoptosis (>65%) as opposed to autophagy (
Published: 2018

20. Value of biomarkers for predicting immunoglobulin A vasculitis nephritis outcome in an adult prospective cohort

Author: Claire Demongeot, Manuelle Viguier, Jean-Jacques Boffa, Stéphanie Tellier, Margarita Hurtado-Nedelec, Vincent Pestre, Gérard Cheron, Guillaume Burda, Martin Flamant, Héloïse Flament, Jérôme Verine, Alexandre Seidowsky, E Bourrat, Stéphane Decramer, Mathilde de Menthon, Karine Brochard, Karim Bouchireb, Maud Bezier, Evangeline Pillebout, Fabrice Mihout, Martine Bagot, Olivier Fain, Maya Halabi-Tawil, Agnès Jamin, Philippe Remy, Sonia Azib, Vincent Audard, Monique Dehoux, Jacqueline Rivet, Quentin Raimbourg, Denis Viglietti, Alexis Mathian, Laure Champion, Guillaume Bussone, Bertrand Godeau, Eric Daugas, Anne Saussine-Hickman, Antoine Froissart, Eric Thervet, Elisa Funck-Brentano, Alain Robert, Laureline Berthelot, Nathalie Vittoz, Nicolas Limal, Denis Glotz, Georges Deschênes, Isabelle Halphen, Theresa Kwon, Laurence Vrigneaud, Pierre Housset, Sophie Georgin-Lavialle, Florence Cordoliani, Arsene Mekinian, Virginia Sauvaget, Philippe Grimbert, Jean Christophe Mercier, Philippe Vanhille, Véronique Baudouin, François Vrtovsnik, Agathe Raynaud-Simon, Renato C. Monteiro, Jean-David Bouaziz, Leila Tricot, Laurène Dehoux, Melissa Pierre, Alexandre Karras, Laure Dehen, Céline Lebas, Nathalie Bocquet, Marc Fila, Claire Dossier, Thomas Quemeneur, Maryam Piram, Coralie Bloch-Queyrat, Antoine Dossier, David Verhelst, Anne Maisin, Olivier Benveniste, Dominique Farge, Charlotte Fite, Loïc Guillevin, Rémi Salomon, Emmanuelle Vidal-Petiot, Zahir Amoura, Valérie Caudwell, Assia Smail, Philippe Bouvier, Michel Delahousse, Gentiane Monsel, Jonathan M. Chemouny, Hamza Ayari, Anne-Sophie Verhoeven, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Néphrologie [Saint-Louis], 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), Service de Néphrologie [Bichat - Claude Bernard], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), UMR 1599, Centre National de la Recherche Scientifique (CNRS), Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de néphrologie [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Service de néphrologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Sorbonne Université (SU), Hôpital Saint-Louis, Institut National de l'Environnement Industriel et des Risques (INERIS), Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Dermatologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of dermatology, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service Pédiatrique [Toulouse], CHU Toulouse [Toulouse], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Sud Francilien, Department of Dermatology, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de dermatologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service de transplantation rénale, Hôpital Foch [Suresnes], AP-HP, Service de Néphrologie Pédiatrique, Hôpital Robert Debré, Paris, Hôpital Bicêtre, Service de Médecine Interne, Centre de Recherche Saint-Antoine (UMRS893), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine interne, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de dermatologie, Service de Physiologie [Bichat-Claude Bernard], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Physiopathologie des maladies génétiques d'expression pédiatrique, Service de médecine interne [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], 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), AP-HP Hôpital universitaire Robert-Debré [Paris], Service de Néphrologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de rhumatologie [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), Service de Département de Néphrologie = Service de Néphrologie et Dialyses [CHU Tenon], CHU Tenon [AP-HP], Service de Pédiatrie Générale et Rhumatologie Pédiatrique, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, CH Valenciennes, Université Paris Descartes - Paris 5 (UPD5), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Développement et Communication Chimique chez les Insectes (DCCI), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de Référence du Sud Ouest des Maladies Rénales Rares, Service de néphrologie adultes [CHU Necker], Service de médecine interne et néphrologie, Centre Hospitalier Henri Duffaut (Avignon), Service de Néphrologie [Valenciennes], Centre Hospitalier de Valenciennes, Service d'anatomo-pathologie [Paris], Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor [Créteil], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Néphrologie et Dialyses [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), CHU Toulouse [Toulouse]-Hôpital des Enfants, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CH Evry-Corbeil, Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Hôpital Cochin [AP-HP]
Subjects: 0301 basic medicine, Immunoglobulin A, Adult, Male, medicine.medical_specialty, IgA Vasculitis, Urinary system, 030232 urology & nephrology, Antigen-Antibody Complex, Gastroenterology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, Prospective Studies, 10. No inequality, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, Aged, Transplantation, Proteinuria, Nephritis, biology, business.industry, Middle Aged, medicine.disease, Prognosis, 3. Good health, 030104 developmental biology, IgA vasculitis, ROC Curve, Nephrology, biology.protein, Female, medicine.symptom, Vasculitis, business, Biomarkers, Systemic vasculitis, Glomerular Filtration Rate
Abstract: Background Henoch-Schonlein purpura, more recently renamed immunoglobulin A vasculitis (IgAV), is a systemic vasculitis characterized by IgA deposits. The current markers used to assess IgAV inaccurately evaluate the risk of nephritis occurrence and its long-term outcomes. The current study assessed biomarkers of nephritis outcomes. Methods This French multicentre prospective study enrolled 85 adult patients at the time of disease onset. Patients were assessed for clinical and biological parameters and re-examined after 1 year. Immunoglobulins, cytokines, IgA glycosylation, IgA complexes and neutrophil gelatinase-associated lipocalin (NGAL) concentrations were assessed in blood and urine. Results We identified 60 patients with IgAV-related nephritis (IgAV-N) and 25 patients without nephritis (IgAV-woN). At the time of inclusion (Day 1), the serum levels of galactose-deficient IgA1 (Gd-IgA1) and urinary concentrations of IgA, IgG, IgM, NGAL, interleukin (IL)-1β, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were higher in the IgAV-N patients than in the IgAV-woN patients (P
Published: 2017

21. BCL2 expression but not MYC and BCL2 coexpression predicts survival in elderly patients with diffuse large B-cell lymphoma independently of cell of origin in the phase 3 LNH03-6B trial

Author: Gilles Salles, Martin Figeac, Hervé Tilly, B. Fabiani, Josette Brière, Danielle Canioni, M. Parrens, Marc André, R. Delarue, Jean-Philippe Jais, C Thieblemont, Christiane Copie-Bergman, Karen Leroy, Corinne Haioun, P. Feugier, Philippe Ruminy, Fabrice Jardin, Tony Petrella, Thierry Jo Molina, P. Gaulard, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de génomique fonctionnelle et structurelle [Lille], Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Université de Lille, Droit et Santé, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Centre d'études spatiales de la biosphère (CESBIO), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and CHU Bordeaux [Bordeaux]
Subjects: 0301 basic medicine, Oncology, Male, Pathology, [SDV]Life Sciences [q-bio], Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, International Prognostic Index, Risk Factors, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Hazard ratio, Hematology, Middle Aged, Prognosis, 3. Good health, Gene Expression Regulation, Neoplastic, Treatment Outcome, Proto-Oncogene Proteins c-bcl-2, Vincristine, 030220 oncology & carcinogenesis, Prednisolone, Rituximab, Female, Lymphoma, Large B-Cell, Diffuse, medicine.drug, medicine.medical_specialty, Disease-Free Survival, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Internal medicine, medicine, Biomarkers, Tumor, Humans, Progression-free survival, Cyclophosphamide, Aged, business.industry, medicine.disease, Lymphoma, 030104 developmental biology, Doxorubicin, Prednisone, business, Diffuse large B-cell lymphoma
Abstract: Background Our aim was to evaluate whether the cell of origin (COO) as defined by the Hans algorithm and MYC/BCL2 coexpression, which are the two main biological risk factors in elderly patients treated with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisolone (R-CHOP), maintain their prognostic value in a large prospective clinical trial. Patients and methods We evaluated 285 paraffin-embedded samples from patients (60–80years of age) enrolled in the Lymphoma Study Association trial LNH03-6B who were treated with R-CHOP. We correlated the COO defined by the transcriptome according to the Wright algorithm with that defined by the Hans algorithm in a subset of 62 tumors with available frozen tissue samples. Results The non-germinal center B-cell-like phenotype according to the Hans algorithm and BCL2 expression (but not MYC and BCL2 coexpression) predicted worse progression-free survival [hazard ratio (HR)=1.78, P = 0.003 and HR = 1.79, P = 0.003, respectively] and overall survival (HR = 1.85, P = 0.005 and HR = 1.67, P = 0.02, respectively) independently of the International Prognostic Index. The correlation between the Hans algorithm and the Wright algorithm was 91%, with an almost perfect concordance according to a kappa test (0.81). Conclusions Our results suggest that immunohistochemically defined COO remains a useful tool for predicting prognosis in diffuse large B-cell lymphoma when performed under optimized standardized conditions and that BCL2 expression may help to identify elderly patients at risk for relapse and who could potentially respond to anti-BCL2 targeted agents. In this prospective phase III trial, the coexpression of MYC and BCL2 does not appear to predict worse survival. Clinical trial Number NCT00144755
Published: 2017

22. Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study

Author: Dubois , Sydney, Viailly , J., Mareschal , Sylvain, Bohers , Elodie, Bertrand , P., Ruminy , Philippe, Maingonnat , Catherine, Jais , Jean-Philippe, Peyrouze , Pauline, Figeac , Martin, Molina , Thierry, Desmots , Fabienne, Fest , Thierry, Haioun , Corinne, Lamy , Thierry, Copie-Bergman , Christiane, Briere , J., Petrella , Tony, Canioni , Danielle, Fabiani , Bettina, Coiffier , Bertrand, Delarue , Richard, Peyrade , Frédéric, Bosly , A., Andre , M., Ketterer , Nicolas, Salles , Gilles, Tilly , Hervé, Leroy , Karen, Jardin , Fabrice, Viailly , Pierre-Julien, Bertrand , Bertrand, Brière , Josette, André , André, André , Marc, Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche des Cordeliers - Equipe 20 'ingénierie des connaissances en santé', Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculté de Médecine Henri Warembourg - Université de Lille, Plateforme de génomique fonctionnelle et structurelle [Lille], Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Université de Lille, Droit et Santé, Service d'anatomie pathologique [CHU Necker], Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), INSERM U955, équipe 9, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomo-pathologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Hôpital Maisonneuve-Rosemont, Centre de référence des mastocytoses (CEREMAST), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'anatomie et cytologie pathologiques [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'Hematologie, Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'immuno-hématologie pédiatrique [CHU Necker], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Dinant-Godinne UCL Namur, Department of Oncology, Lausanne Hospital, Lausanne Hospital, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Service de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National du Cancer (INCA), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Jonchère, Laurent, Rouen Business School, Groupe d'étude des proliférations lymphoïdes ( GPL ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Lille 2 - Faculté de Médecine, Institut pour la recherche sur le cancer de Lille [Lille] ( IRCL ) -Université de Lille, Droit et Santé, AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Microenvironment, Cell Differentiation, Immunology and Cancer ( MICMAC ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Maisonneuve-Rosemont Hospital Research Center, University of Montreal, Service de pathologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes ( LITIS ), Université Le Havre Normandie ( ULH ), Normandie Université ( NU ) -Normandie Université ( NU ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Institut national des sciences appliquées Rouen Normandie ( INSA Rouen Normandie ), Normandie Université ( NU ), Unité de Taphonomie médico-légale ( UTML ), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Microenvironnement et cancer ( MiCa ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre de référence des mastocytoses, Service d'anatomie et cytologie pathologiques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Hospices Civils de Lyon ( HCL ) -Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Laboratoire de Biologie Moléculaire de la Cellule ( LBMC ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Côte d'Azur (UCA)-UNICANCER, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (MGD) Service d'hématologie, Groupe d'étude des proliférations lymphoïdes, Université de Rouen - Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC) - École pratique des hautes études (EPHE) - Université Paris Diderot - Paris 7 (UPD7) - Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL) - Université de Lille, Droit et Santé, Université de Rennes 1 (UR1) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Henri Mondor - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Henri Mondor - Hôpital Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) - Groupe Hospitalier Saint-Louis-Lariboisière- Fernand-Widal - Université Paris Diderot - Paris 7 (UPD7), Centre de pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) - AP-HP Hôpital Necker - Enfants Malades [Paris], Université Pierre et Marie Curie - Paris 6 (UPMC) - Assistance publique - Hôpitaux de Paris (AP-HP) - CHU Saint-Antoine [APHP], Service de Radio-Oncologie [Lyon], Hospices Civils de Lyon - Centre Hospitalier Lyon Sud [Pierre Bénite], Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5) - AP-HP Hôpital Necker - Enfants Malades [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM) - IFR10 - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Le Havre Normandie (ULH) - Université de Rouen - Institut National des Sciences Appliquées - Rouen (INSA Rouen), and Institut National des Sciences Appliquées (INSA) - Institut National des Sciences Appliquées (INSA)
Subjects: 0301 basic medicine, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Cancer Research, Receptors, Cytoplasmic and Nuclear, Cell Cycle Proteins, TUMOR-SUPPRESSOR GENE, Genome, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, PROGNOSTIC-SIGNIFICANCE, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Molecular Targeted Therapy, Prospective Studies, Precision Medicine, Exome sequencing, Genetics, Oncogene Proteins, B-Lymphocytes, High-Throughput Nucleotide Sequencing, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, 3. Good health, DNA-Binding Proteins, GENOME, Phosphotransferases (Alcohol Group Acceptor), Oncology, Vincristine, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, Lymphoma, Large B-Cell, Diffuse, medicine.drug, EXPRESSION, [SDV.IMM] Life Sciences [q-bio]/Immunology, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, FREQUENT, Biology, Karyopherins, DNA sequencing, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, TARGETS, Exome Sequencing, medicine, Humans, RITUXIMAB, Cyclophosphamide, Tumor Necrosis Factor alpha-Induced Protein 3, Gene Expression Profiling, CLASSICAL HODGKIN LYMPHOMA, SOMATIC MUTATIONS, Precision medicine, medicine.disease, Lymphoma, Gene expression profiling, 030104 developmental biology, Doxorubicin, GTP-Binding Protein alpha Subunits, Gq-G11, Prednisone, BURKITT-LYMPHOMA, Diffuse large B-cell lymphoma
Abstract: Purpose: Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials. Experimental Design: A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20+de novo DLBCL in the prospective, multicenter, and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell-of-origin molecular classification was obtained through gene expression profiling with HGU133+2.0 Affymetrix GeneChip arrays. Results: The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that activated B-cell–like (ABC), germinal center B-cell like (GCB), and primary mediastinal B-cell lymphoma (PMBL) are frequently affected by mutations in NF-κB, epigenetic, and JAK–STAT pathways, respectively. Novel truncating immunity pathway, ITPKB, MFHAS1, and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with R-CHOP were associated with significantly less favorable prognoses. Conclusions: This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting the molecular heterogeneity of subtypes and identifying somatic mutations with therapeutic and prognostic impact. Clin Cancer Res; 22(12); 2919–28. ©2016 AACR. See related commentary by Lim and Elenitoba-Johnson, p. 2829
Published: 2016

23. La résistance aux traitements antiangiogéniques Une actualité clinique et scientifique

Author: Yuchen Gu, Anne Janin, Mélanie Di Benedetto, Hong Li, He Lu, Catherine Boisson-Vidal, Guilhem Bousquet, Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique (UMR 1165), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Innovations thérapeutiques en hémostase (IThEM - U1140), and Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, medicine.medical_treatment, Resistance, [SDV.CAN]Life Sciences [q-bio]/Cancer, Drug resistance, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Tumor growth, Cancer, Toxicity, business.industry, General Medicine, Immunotherapy, medicine.disease, 3. Good health, Bioavailability, Clinical trial, 030104 developmental biology, 030220 oncology & carcinogenesis, Antiangiogenic, Therapeutic, business
Abstract: International audience; Although the use of anti-angiogenic agents has been considered a promising strategy to block tumor growth and improve the bioavailabilityof drugs into the tumor, the use of most of them in clinical trials is limited. The development of resistance to some anti-angiogenic agentsand their high toxicity are currently under investigations. However, the approach is still valid since this therapeutic tool has lengthenedsurvival of patients with colon, breast, kidney, lungs and liver cancers. The identification of biomarkers in response to this family of drugs is animportant area of investigation.; Bien que l’utilisation des agents antiangiogéniques ait été considérée comme une stratégie prometteuse qui permet de bloquer la croissance tumorale et d’améliorer la biodisponibilité des médicaments jusqu’à la tumeur, l’utilisation en clinique de la plupart de ces agents s’avère limitée du fait du développement de la résistance à certains de ces antiangiogéniques et de leur importante toxicité. L’approche reste toutefois valable puisque cet outil thérapeutique a permis d’allonger la survie des patients sans progression pour ceux atteints de cancers coliques, mammaires, rénaux, pulmonaires et hépatiques. L’identification de marqueurs biologiques de réponse à cette famille de médicaments représente donc un domaine important d’investigation.
Published: 2016

24. Pediatric-Like Acute Lymphoblastic Leukemia Therapy in Adults With Lymphoblastic Lymphoma: The GRAALL-LYSA LL03 Study

Author: Patrice Chevallier, Carlos Graux, Vahid Asnafi, Anne Moreau, Thomas Vermeulin, Jacques Benichou, Gilles Salles, Stephanie Seris, Josette Brière, Norbert Ifrah, Aline Tanguy-Schmidt, Stéphane Leprêtre, Elizabeth Macintyre, Marie-Christine Béné, Jean-Michel Picquenot, Aurore Touzart, Serge Bologna, Reda Bouabdallah, Valérie Tallon-Simon, Françoise Huguet, Emmanuel Raffoux, Thierry Lamy, Hervé Dombret, Groupe d'étude des proliférations lymphoïdes ( GPL ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Charles Nicolle [Tunis], Pharmacoepidemiologie et évaluation de l'impact des produits de santé sur les populations, Université Bordeaux Segalen - Bordeaux 2-Université de Rouen Normandie ( UNIROUEN ), HEMATOLOGIE, CRLCC Henri Becquerel, Service d'Hématologie Clinique [Nantes], Hôpital Hôtel Dieu-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, Laboratoire de Biologie Moléculaire de la Cellule ( LBMC ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'hématologie clinique, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou, Service d'Hématologie [Nantes], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre Hospitalier Universitaire de Purpan ( CHU Purpan ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Département d'Hematologie, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'anatomo-pathologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Cliniques Universitaires UCL de Mont-Godinne, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), The study was supported by a grant from the French Ministry of Health (Projet Hospitalier de Recherche Clinique of France [PHRC 2003 No. 13-2]). The Macintyre laboratory was supported by the Fondation de France, the Association de Recherche sur le Cancer, Cent pour Sang la Vie, and the Société Française des Cancers de l’Enfant. CHUGAI PHARMA France provided technical and financialsupport., Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Pontchaillou [Rennes], Centre hospitalier universitaire de Nantes (CHU Nantes), 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), Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Unité de biostatistiques [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Bordeaux Segalen - Bordeaux 2-Université de Rouen Normandie (UNIROUEN), Hôpital Hôtel Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Hôpital Pontchaillou, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Unité de biostatistiques [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), 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)-CHU Necker - Enfants Malades [AP-HP], Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Centre Hospitalier Universitaire de Purpan (CHU Purpan), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire d'Angers ( CHU Angers ), PRES Université Nantes Angers Le Mans ( UNAM ), Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Université Toulouse III - Paul Sabatier ( UPS ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], IFR105-Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Bernardo, Elizabeth
Subjects: Male, Cancer Research, F-Box-WD Repeat-Containing Protein 7, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Phases of clinical research, Cell Cycle Proteins, Hematopoietic stem cell transplantation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Gastroenterology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Central Nervous System Diseases, Recurrence, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, Young adult, Receptor, Notch1, Prospective cohort study, Hematopoietic Stem Cell Transplantation, Induction Chemotherapy, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma, 3. Good health, Survival Rate, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Female, medicine.drug, Adult, medicine.medical_specialty, Cyclophosphamide, Adolescent, Ubiquitin-Protein Ligases, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease-Free Survival, Maintenance Chemotherapy, 03 medical and health sciences, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, medicine, Humans, Survival rate, [ SDV ] Life Sciences [q-bio], L-Lactate Dehydrogenase, business.industry, F-Box Proteins, Lymphoblastic lymphoma, PTEN Phosphohydrolase, Induction chemotherapy, medicine.disease, Surgery, Consolidation Chemotherapy, ras Proteins, business, 030215 immunology
Abstract: Purpose This study evaluated the efficacy of pediatric-like acute lymphoblastic leukemia (ALL) therapy in adults with lymphoblastic lymphoma (LL). Patients and Methods This was a prospective phase II study in adults 18 to 59 years old with previously untreated LL. Patients were treated with an adapted pediatric-like ALL protocol, which included a corticosteroid prephase, a five-drug induction reinforced by sequential cyclophosphamide administration, dose-dense consolidation, late intensification, CNS prophylaxis, and a 2-year maintenance phase. Treatment response was assessed by computed tomography and optional positron emission tomography. Allogeneic hematopoietic stem cell transplant was offered to selected patients in first complete remission (CR) or unconfirmed CR. Results The study enrolled 148 patients (131 with T-lineage LL [T-LL] and 17 with B-lineage LL [B-LL]). A total of 119 patients with T-LL (90.8%) and 13 with B-LL (76.5%) reached CR/unconfirmed CR, including 26 with T-LL and two with B-LL who needed a second induction salvage course. Relapse occurred in 34 patients with T-LL and four with B-LL. In patients with T-LL, 3-year event-free survival was 63.3% (95% CI, 54.2% to 71.0%), disease-free survival was 72.4% (95% CI, 63.0% to 79.7%), and overall survival was 69.2% (95% CI, 60.0% to 76.7%). Multivariate analysis identified serum lactate dehydrogenase level and the NOTCH1/FBXW7/RAS/PTEN oncogene (a four-gene oncogenetic classifier) status but not positron emission tomography or hematopoietic stem cell transplant as independent prognostic factors for outcome in T-LL. Conclusion In adults with LL, an intensive pediatric-like ALL treatment protocol was associated with a good response rate and outcome. In patients with T-LL, the four-gene oncogenetic classifier and lactate dehydrogenase level were independent prognostic indicators.
Published: 2016

25. Intrathecal Trastuzumab Halts Progression of CNS Metastases in Breast Cancer

Author: Gilles Paintaud, Stéphane Culine, David Ternant, Anne Janin, Emmanuel Barranger, François Darrouzain, Marc Polivka, Jean-Baptiste Thiebaut, Guilhem Bousquet, Sabine Winterman, Cédric de Bazelaire, Isabelle Madelaine-Chambin, Ratajczak, Philippe, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Service de gynécologie-obstétrique [CHU Rothschild], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Avicenne [AP-HP], Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Fondation Ophtalmologique Adolphe de Rothschild [Paris], Service de gynécologie-obstétrique [Hôpital Rothschild], Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université de Tours-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, MEDLINE, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Intrathecal, Central Nervous System Neoplasms, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Text mining, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Trastuzumab, Internal medicine, medicine, Humans, Injections, Spinal, ComputingMilieux_MISCELLANEOUS, business.industry, medicine.disease, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, [SDV.TOX] Life Sciences [q-bio]/Toxicology, 030104 developmental biology, 030220 oncology & carcinogenesis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Female, business, medicine.drug
Abstract: International audience; no abstract
Published: 2016

26. BCL2 expression in CD105 positive neoangiogenic cells and tumor progression in angioimmunoblastic T-cell lymphoma

Author: Wei-Li Zhao, Philippe Ratajczak, Christophe Leboeuf, Irmine Loisel-Ferreira, Anne Janin, Josette Brière, Catherine Thieblemont, Li Wang, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Pathogenesis of Leukemia, Shanghai Jiao Tong University School of Medicine-Shanghai Rui Jin Hospital-Shanghai Institute for Biological Sciences Chinese Academy of Sciences, Service d'anatomo-pathologie [Paris], 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), Service d'hématologie-oncologie adultes, and Ratajczak, Philippe
Subjects: Male, Vascular Endothelial Growth Factor A, Pathology, Time Factors, Angiogenesis, CD34, Fluorescent Antibody Technique, Antigens, CD34, Kaplan-Meier Estimate, 0302 clinical medicine, Risk Factors, immune system diseases, hemic and lymphatic diseases, Tumor Microenvironment, Aged, 80 and over, 0303 health sciences, Neovascularization, Pathologic, Endoglin, Middle Aged, VEGF, CD105, Vascular endothelial growth factor A, Treatment Outcome, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, 030220 oncology & carcinogenesis, Disease Progression, endothelial cell, Female, Adult, Paris, BCL2, neoangiogenesis, Angioimmunoblastic T-cell lymphoma, medicine.medical_specialty, Receptors, Cell Surface, [SDV.CAN]Life Sciences [q-bio]/Cancer, Laser Capture Microdissection, Angioimmunolbastic T-Cell Lyphoma, Biology, Lymphoma, T-Cell, Real-Time Polymerase Chain Reaction, Risk Assessment, Disease-Free Survival, Article, Pathology and Forensic Medicine, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, CD, Biomarkers, Tumor, medicine, Humans, RNA, Messenger, Aged, Proportional Hazards Models, 030304 developmental biology, Tumor microenvironment, Chi-Square Distribution, Endothelial Cells, medicine.disease, Lymphoma, Tumor progression, Case-Control Studies, Immunoblastic Lymphadenopathy, Microvessels, Multivariate Analysis, Lymph Nodes, Bone marrow
Abstract: International audience; The angiogenic microenvironment has been known to be a component of angioimmunoblastic T-cell lymphoma since its initial characterization. We have shown that angioimmunoblastic T-cell lymphoma endothelial cells produce vascular endothelial growth factor-A (VEGFA), and participate in lymphoma progression. In squamous cell carcinoma, endothelial BCL2 expression induces a crosstalk with tumor cells through VEGFA, a major mediator of tumoral angiogenesis. In the present study, we analyzed BCL2 and VEGFA in 30 angioimmunoblastic T-cell lymphomas, using triple immunofluorescence to identify protein coexpression in well-characterized lymphoma cells and microenvironment neoangiogenic endothelial cells. Using quantitative real-time PCR, we assessed mRNA expression levels in laser-microdissected endothelial and lymphoma cells. In lymphoma cells, as in endothelial cells, BCL2 and VEGFA proteins were coexpressed. BCL2 was expressed only in neoangiogenic CD34(+)CD105(+) endothelial cells. In laser-microdissected cells, mRNA studies showed a significant relationship between BCL2 and VEGFA levels in CD34(+) endothelial cells, but not in CD3(+)CD10(+)lymphoma cells, or in CD34(+) endothelial cells from lymph node hyperplasia. Further study showed that, in AITL, BCL2 mRNA levels in CD34(+)CD105(+) neoangiogenic endothelial cells also correlated with microvessel density, International Prognostic Index, Ann Arbor stage, bone marrow involvement and elevated LDH. BCL2 expression by CD105(+) neoangiogenic endothelial cells is related to tumor progression in angioimmunoblastic T-cell lymphoma.
Published: 2012

27. TP53 Status and Response to Treatment in Breast Cancers

Author: Louis-François Plassa, Philippe Bertheau, Anne Janin, Mariana Varna, Guilhem Bousquet, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie, 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), Service d'anatomo-pathologie [Paris], This work was supported by grants from Canceropole Ile de France. M. Varna and G. Bousquet were equally contributed, and Ratajczak, Philippe
Subjects: Oncology, medicine.medical_specialty, Poor prognosis, MESH: Mutation, Article Subject, lcsh:Biotechnology, Health, Toxicology and Mutagenesis, MESH: Genes, p53, lcsh:Medicine, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review Article, Biology, medicine.disease_cause, Tp53 mutation, MESH: Prognosis, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, lcsh:TP248.13-248.65, Internal medicine, Genetics, medicine, Animals, Humans, MESH: Animals, MESH: Mice, Molecular Biology, Gene, 030304 developmental biology, 0303 health sciences, Mutation, MESH: Humans, lcsh:R, General Medicine, Genes, p53, Prognosis, Response to treatment, 3. Good health, 030220 oncology & carcinogenesis, Molecular Medicine, Female, Good prognosis, MESH: Female, MESH: Breast Neoplasms, Biotechnology
Abstract: The p53 wild-type protein plays an important role in cells as is shown by its fine regulation at different levels. Since its discovery, numerous mutations have been described. In breast cancers, p53 is mutated in almost 30% of cases, with a higher frequency in some tumor subtypes.TP53mutation is reported to be a factor for good prognosis in some studies, while in others it is a factor for poor prognosis. The explanation for these different results could be linked to the fact that the studies were performed on different tumor types and with different therapy regimens.
Published: 2011

28. Highly directive ISM band cavity antenna using a bi-layered metasurface reflector

Author: Philippe Ratajczak, Jean-Pierre Daniel, Shah Nawaz Burokur, Abdelwaheb Ourir, André de Lustrac, Laboratoire Energétique Mécanique Electromagnétisme (LEME), Université Paris Nanterre (UPN), Institut Langevin - Ondes et Images (UMR7587) (IL), Sorbonne Université (SU)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale de l'Aviation Civile (ENAC), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), IEF, Université Paris-Sud - Paris 11 (UP11), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Patch antenna, Engineering, Coaxial antenna, business.industry, Antenna measurement, 020206 networking & telecommunications, 02 engineering and technology, 021001 nanoscience & nanotechnology, Condensed Matter Physics, Atomic and Molecular Physics, and Optics, Electronic, Optical and Magnetic Materials, Radiation pattern, law.invention, [SPI]Engineering Sciences [physics], Microstrip antenna, Optics, law, 0202 electrical engineering, electronic engineering, information engineering, Dipole antenna, Electrical and Electronic Engineering, 0210 nano-technology, business, Monopole antenna, ComputingMilieux_MISCELLANEOUS, Metamaterial antenna
Abstract: The design of a highly directive metamaterial-based cav- ity antenna for a 2.46 GHz application is reported. The proposed struc- ture is evolved from a Fabry-Perot (FP) cavity with a patch antenna acting as the feed and four metallic walls on the lateral sides. One of the two reflectors is the antenna's ground plane and the other is made from a bilayered metamaterial-based partially reflecting surface (PRS) constituted by a capacitive and an inductive grid. Calculations together with experimental results obtained from the fabricated prototype are presented. The results show a high directivity and low levels for the sec- ondary lobes compared to a 2 2 patch antenna array. © 2009 Wiley Periodicals, Inc. Microwave Opt Technol Lett 51: 1393-1396, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.24391
Published: 2009

29. A phase II, single-arm, multicentre study of coltuximab ravtansine (SAR3419) and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma

Author: Roch Houot, Robert Navarro, Florence Broussais, Catherine Thieblemont, Jehan Dupuis, Olivier Casasnovas, Hervé Tilly, Corinne Haioun, Thierry Lamy, Sophie de Guibert, Franck Morschhauser, Laurence Hatteville, Harald Holte, Vincent Ribrag, Reda Bouabdallah, Bertrand Coiffier, Sandrine Payrard, Steven Le Gouill, Service d'Hematologie, Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Laboratoire de recherche translationnelle, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département d'Hematologie, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'hématologie, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'hématologie et oncologie médicale, Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'étude des proliférations lymphoïdes (GPL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Sanofi, Adelphi Communications Ltd, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou, Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Lymphoma, Gastrointestinal Diseases, [SDV]Life Sciences [q-bio], Antibodies, Monoclonal, Humanized, Gastroenterology, Drug Administration Schedule, resistance, 03 medical and health sciences, 0302 clinical medicine, Refractory, Pharmacokinetics, Recurrence, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Medicine, Refractory Diffuse Large B-Cell Lymphoma, Humans, maytansinoid, Maytansine, Adverse effect, Aged, Aged, 80 and over, Salvage Therapy, CD19, business.industry, antibody–drug conjugate, Hematology, Middle Aged, medicine.disease, Survival Analysis, Confidence interval, 3. Good health, 030104 developmental biology, Treatment Outcome, 030220 oncology & carcinogenesis, Asthenia, Immunology, Rituximab, Female, Lymphoma, Large B-Cell, Diffuse, business, medicine.drug
Abstract: International audience; In this phase II, multicentre, single-arm study, 52 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) received the anti-CD19 antibody–drug conjugate coltuximab ravtansine (55 mg/m2) and rituximab (375 mg/m2) weekly for 4 weeks, then every 2 weeks for 8 weeks. The primary endpoint was objective response rate (ORR) by International Working Group Criteria. The primary objective was to reject the null hypothesis of an ORR of ≤40%. Among 45 evaluable patients, the ORR was 31·1% (80% confidence interval [CI]: 22·0–41·6%) and the primary objective was not met. The ORR appeared higher in patients with relapsed disease (58·3% [80% CI: 36·2–78·1%]) versus those refractory to their last (42·9% [80% CI: 17·0–72·1%]) or first-line therapy (15·4% [80% CI: 6·9–28·4%]). Median progression-free survival, overall survival and duration of response were 3·9 [80% CI: 3·22–3·98], 9·0 [80% CI: 6·47–13·67] and 8·6 (range: 0–18) months, respectively. The pharmacokinetics of both drugs were unaffected by co-administration. Common adverse events included gastrointestinal disorders (52%) and asthenia (25%). No patients discontinued due to adverse events. In conclusion, coltuximab ravtansine with rituximab was well tolerated and yielded clinical responses in a subset of patients with relapsed/refractory DLBCL
Published: 2015

30. 292 Lymphomas in dogs: spontaneous models to decipher the genetics of lymphomagenesis and new therapeutic options in dogs and humans

Author: Ulvé, R., Hédan, B., Bahin, M., Derrien, Thomas, Brito, C. De, Nguyen, F., Hennuy, B., Abadie, J., Coppieters, W., Guillaudeux, T., Thieblemont, C., André, C., Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Animaux modèles pour la recherche en oncologie comparée (AMaROC), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), Université de Liège, Microenvironnement et cancer (MiCa), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; Background and Aim: There are over 400 genetically distinct breeds of dogs, each corresponding to a genetic isolate. The consequence of breeding practices is that most breeds naturally develop specific cancer types, reflecting the presence of predisposing alleles. This is interesting for lymphomas, as most human lymphoma subtypes are encountered in dogs, with some subtypes over-represented in specific breeds (Pastor et al., 2009; Rowell et al., 2011; Marconato et al., 2013). We focused on lymphoma occurring in large families of Bernese Mountain Dogs (BMDs) with the objectives to identify predisposing genetic regions and somatic alterations involved in lymphomagenesis.Materials and Methods: We collected blood and tumour samples, clinical and genealogical information of affected BMDs, using the French CaniDNA biobank at CNRS, Rennes. Histopathological diagnosis was performed from formalin-fixed paraffin-embedded tumour samples by veterinary pathologists F. N. and J. A. DNA and RNA were extracted using Macherey-Nagel® kits. Dog DNAs were genotyped on the canine Illumina®, and 170 000 single-nucleotide polymorphism (SNP) arrays and RNA of matched tumour and healthy tissues were sequenced (RNAseq) using Illumina technology, by the GIGA genomic facility, University of Liege. Data were analysed by the software crac/ chimCT (Philippe et al., 2013) to identify translocations. The fusion point was validated on tumour DNA and cDNA, by Sanger sequencing.Results: First, we demonstrated a familial segregation of lymphoma in a pedigree of BMDs. We performed a genome-wide association study using 63 lymphoma cases and 164 controls with the high-density SNP chips. Preliminary data showed a significant locus, associated with predisposition to lymphoma, on canine chromosome CFA 23. This locus does not correspond to any known locus for human lymphomas and thus represents an interesting candidate region. Second, while many chromosomal translocations are known to drive lymphomagenesis in humans, only little genetic data are available in dogs. We thus investigated somatic alterations through RNAseq on five lymphoma-affected dogs and identified a relevant translocation involving an immunoglobulin gene and a gene involved in cell cycle. Interestingly, this gene is known to be involved in translocations in human lymphomas, showing that similar genes are involved in both human and dog lymphomas.Conclusions: Based on the collection of different types of canine lymphomas in several predisposed breeds, we first identified a potential novel locus predisposing to lymphomas. We are exploring and reducing the region of interest by using other canine breeds. Second, we discovered a novel chromosomal translocation in dogs, homologous to a translocation in the same human lymphoma type. These data clearly showed that the same key pathways are involved in lymphomas in dogs and humans, justifying the setting up of clinical trials in dogs for the benefit of both humans and dogs.
Published: 2015

31. Cross-drug resistance to sunitinib induced by doxorubicin in endothelial cells

Author: Li Wang, Mélanie Di Benedetto, Anne Janin, Rémi Varin, Chaoquan Hu, Jian Jin, Hong Li, Li-Min Huang, Jielin Liu, Jean Pierre Vannier, He Lu, Laboratoire de Génie Electrique de Grenoble (G2ELab), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Guizhou Medical University (贵州医科大学), Cancer et Transplantation : Physiopathologie et Réponse Thérapeutique (UMR 1165), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Pharmacie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Laboratoire de génie des procédés - environnement - agroalimentaire (GEPEA), Mines Nantes (Mines Nantes)-Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des signaux et systèmes (L2S), Centre National de la Recherche Scientifique (CNRS)-CentraleSupélec-Université Paris-Sud - Paris 11 (UP11), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Microenvironnement et régulation cellulaire intégrés (MERCI), Li, Hong, Mines Nantes (Mines Nantes)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre National de la Recherche Scientifique (CNRS), Hemostase, Endothelium, Angiogenese (UMR_S_553), Beijing National Laboratory for Condensed Matter Physics and Institute of Physics (IoP/CAS), Chinese Academy of Sciences [Changchun Branch] (CAS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), and Normandie Université (NU)-Normandie Université (NU)-CHU Rouen
Subjects: Cancer Research, Abcg2, sunitinib, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Drug resistance, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Pharmacology, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Cytotoxic T cell, Doxorubicin, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, ABC family, 0303 health sciences, drug resistance, biology, Sunitinib, business.industry, Articles, Cell cycle, endothelial cells, 3. Good health, Multiple drug resistance, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, biology.protein, cancer therapy, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, medicine.drug
Abstract: International audience; Multiple drug resistance remains an unsolved problem in cancer therapy. A previous study has demonstrated that the chemotherapeutic drug doxorubicin (Dox) induced upregulation of P-glycoprotein in endothelial cells, resulting in a 20-fold increase in drug resistance and reduced efficiency of doxorubicin treatment in a mouse tumor model. In the present study, the cross-resistance and sensitivity of HMECd1 and HMECd2 established cell lines to anti-angiogenic drugs, particularly sunitinib, was explored. The results revealed that Dox treatment induced a significant increase in the breast cancer resistance protein (ABCG2) gene transcription and protein expression. This increase gave rise to a 4- to 5-fold increase in the half maximal inhibitory concentration of the HMECd1 and HMECd2 cells in response to sunitinib treatment in vitro. Functionally, the role of ABCG2 in the resistance to sunitinib was confirmed by the use of the ABCG2 inhibitors fumitremorgin C and diethylstilbestrol, which blocked cell resistance. The present study indicates that endothelial cells exhibit cross-resistance between cytotoxic drugs and anti-angiogenic drugs. This suggests that multiple drug resistance induced by chemotherapy in endothelial cells may affect the efficiency of anti-angiogenic drugs.
Published: 2015

32. Peripheral and Local Human Papillomavirus 16–Specific CD8 + T-Cell Expansions Characterize Erosive Oral Lichen Planus

Author: Jérémy Kagan, Hervé Bachelez, Manuelle Viguier, Béatrice Poirier, Camille Francès, Maxime Battistella, François Aubin, Marie-Lise Gougeon, Nicolas Fazilleau, Antoine Touzé, Maryvonnick Carmagnat, Immunité Anti-virale, Biothérapie et Vaccins (IABV), Institut Pasteur [Paris], Université Paris Diderot - Paris 7 (UPD7), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de dermatologie et allergologie [CHU Tenon], CHU Tenon [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), This work was supported by Institut Pasteur, the Société Française de Dermatologie, AVENIR INSERM (NF), Association pour la Recherche sur le Cancer (ARC AO 2009, NF), la Ligue Nationale Contre le Cancer (NF), Conseil Régional Midi-Pyrénées (NF), Institut National contre le Cancer (PLBIO10-195 and INCA-6530, NF), Collery Grant from Académie Nationale de Médecine (MB), and International Re-integration Grant Marie Curie., We are indebted to Laure Buisson for her help in sequencing analyses (UDEAR, CNRS, France), Pierre-Henri Commère for cell sorting (Flow Cytometry Facility, Pasteur Institute), Nathalie Parquet (Saint-Louis Hospital, Paris, France) and Claire Rabian (Saint-Louis Hospital, Paris, France) for their help in cell collection and cell preparation, and to Tarik Gheit (International Agency for Research in Cancer, Lyon, France) for HPV genotyping., Institut Pasteur [Paris] (IP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Université de Tours, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Fazilleau, Nicolas
Subjects: Adult, Male, MESH: Human papillomavirus 16/immunology, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Lichen Planus, Oral/virology, Mucocutaneous zone, MESH: Genes, T-Cell Receptor beta, Dermatology, Biology, CD8-Positive T-Lymphocytes, Biochemistry, MESH: CD8-Positive T-Lymphocytes/immunology, Epitope, Pathogenesis, Immune system, stomatognathic system, Cytotoxic T cell, Humans, Molecular Biology, Aged, MESH: Aged, Human papillomavirus 16, MESH: Middle Aged, MESH: Humans, T-cell receptor, MESH: Adult, Cell Biology, Middle Aged, MESH: Male, 3. Good health, CTL, stomatognathic diseases, Immunology, Genes, T-Cell Receptor beta, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Lichen Planus, Oral/immunology, MESH: Female, CD8, Lichen Planus, Oral
Abstract: International audience; Erosive oral lichen planus (OLP) is a chronic, disabling mucocutaneous dysimmune rare disease characterized by mucosal inflammatory erosive lesions with pathological evidence for a marked CD8+ cytotoxic T-lymphocyte (CTL) infiltration. However, the specificity of lesional CTL in OLP has never been analyzed. To investigate the molecular mechanisms underlying dysregulation of T-cell immune responses in patients with OLP, we studied the diversity and antigen specificity of the TCR expressed by CD8+ T cells using dextramer staining, spectratyping, and TCR sequencing in 10 OLP patients undergoing extracorporeal photochemotherapy. Expansions of TCRVβ3-bearing CD8+ T cells were found in peripheral blood and in lesional tissues of OLP patients. Spectratyping and sequencing studies identified specific clonotypes in each patient. These expansions were enriched with human papillomavirus 16 (HPV16)-specific CD8+ T cells in HLA-A*0201+ patients as shown by their immune recognition of the E711-20 immunodominant epitope. Under treatment with extracorporeal photochemotherapy, clonotypic CD8+ T-cell expansions decreased in parallel with clinical remission. Altogether, these data establish a link between HPV infection and OLP pathogenesis by identifying a massive clonal expansion of CD8+ T cells with increased frequency of HPV 16-specific CD8+ T cells in OLP patients.
Published: 2015

33. Clinical, cytogenetic and molecular characteristics of 14 T-ALL patients carrying the TCRβ-HOXA rearrangement: a study of the Groupe Francophone de Cytogénétique Hématologique

Author: C. Charrin, Anne Hagemeijer, Carole Barin, M J Mozzicconacci, Barbara Cauwelier, Christine Lefebvre, Bruno Verhasselt, Isabelle Luquet, M.J. Gregoire, Philippe Jonveaux, Hélène Cavé, Barbara De Moerloose, Christine Terré, Kim De Keersmaecker, Anne De Paepe, G Plessis, F Sigaux, Nicole Dastugue, Bruce Poppe, Michel Lessard, B Laurence, Laurent Mauvieux, Hélène Antoine-Poirel, Marina Lafage-Pochitaloff, Francine Mugneret, Emmanuelle Clappier, J van den Akker, J Soulier, C Graux, Yves Benoit, Jan Cools, Carine Gervais, Franki Speleman, Pascale Cornillet-Lefebvre, Marie-Pierre Pages, C Chalas, Dominique Leroux, N. Van Roy, Christine Perot, Pierre Heimann, Roland Berger, Center for Medical Genetics [Ghent], Ghent University Hospital, Laboratoire de Biochimie Génétique, Hôpital Robert Debré, Laboratoire d'Hématologie, CHU Strasbourg, CHU Bretonneau, 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), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire Central d'Anatomie et de Cytologie Pathologiques [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier de Versailles André Mignot (CHV), Hôpital Maison Blanche, Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Génétique [CHU Caen], 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), Bases moléculaires de la progression tumorale -Groupe de Recherche sur les Lymphomes, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR73, Centre for Medical genetics, Hôpital UCL-St Luc, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Genetics, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre for Molecular Diagnostics, Department of Pediatric Hematology/Oncology, Department of Human Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre for Human Genetics, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre for Medical Genetics, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC) - Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon (CHU Dijon), Laboratoire de Cytopathologie, Hôpital Edouard Herriot, Laboratoire de Génétique, CHU Nancy, Institut Paoli Calmettes, CHU Versailles, Centre Hospitalier de Versailles (CHV), CHU Reims, Hôpital Robert Debré - CHU Reims, Service de génétique, CHU Caen - Hôpital Clémenceau, Université Joseph Fourier - Grenoble 1 (UJF) - Institut National de la Santé et de la Recherche Médicale (INSERM) - IFR73, Université Paris Diderot - Paris 7 (UP7) - Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Erasme, Hôpital Necker - Enfants malades, Assistance publique - Hôpitaux de Paris (AP-HP) - Université Paris Descartes - Paris 5 (UPD5), Hôpital Purpan, and Duley, Samuel
Subjects: Male, Cancer Research, Receptors, Antigen, T-Cell, alpha-beta, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Receptor, Notch1, Translocation, Genetic, 0302 clinical medicine, Immunophenotyping, MESH: Child, Leukemia-Lymphoma, Adult T-Cell, MESH: Leukemia-Lymphoma, Adult T-Cell, Receptor, Notch1, Child, Chromosomal inversion, 0303 health sciences, MESH: Middle Aged, MESH: Receptors, Antigen, T-Cell, alpha-beta, hemic and immune systems, Hematology, Middle Aged, MESH: Gene Rearrangement, T-Lymphocyte, MESH: Translocation, Genetic, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Female, Chromosome Deletion, Adult, Transcriptional Activation, medicine.medical_specialty, Adolescent, MESH: Immunophenotyping, MESH: Chromosome Deletion, chemical and pharmacologic phenomena, Chromosomal rearrangement, Biology, Gene Rearrangement, T-Lymphocyte, 03 medical and health sciences, Acute lymphocytic leukemia, MESH: Homeodomain Proteins, medicine, Humans, 030304 developmental biology, Homeodomain Proteins, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, T-cell receptor, Cytogenetics, MESH: Adult, Gene rearrangement, medicine.disease, Molecular biology, MESH: Male, Homeobox A10 Proteins, Chromosome Inversion, MESH: Inversion, Chromosome, MESH: Transcriptional Activation, MESH: Female, Comparative genomic hybridization
Abstract: International audience; Recently, we and others described a new chromosomal rearrangement, that is, inv(7)(p15q34) and t(7;7)(p15;q34) involving the T-cell receptor beta (TCRbeta) (7q34) and the HOXA gene locus (7p15) in 5% of T-cell acute lymphoblastic leukemia (T-ALL) patients leading to transcriptional activation of especially HOXA10. To further address the clinical, immunophenotypical and molecular genetic findings of this chromosomal aberration, we studied 330 additional T-ALLs. This revealed TCRbeta-HOXA rearrangements in five additional patients, which brings the total to 14 cases in 424 patients (3.3%). Real-time quantitative PCR analysis for HOXA10 gene expression was performed in 170 T-ALL patients and detected HOXA10 overexpression in 25.2% of cases including all the cases with a TCRbeta-HOXA rearrangement (8.2%). In contrast, expression of the short HOXA10 transcript, HOXA10b, was almost exclusively found in the TCRbeta-HOXA rearranged cases, suggesting a specific role for the HOXA10b short transcript in TCRbeta-HOXA-mediated oncogenesis. Other molecular and/or cytogenetic aberrations frequently found in subtypes of T-ALL (SIL-TAL1, CALM-AF10, HOX11, HOX11L2) were not detected in the TCRbeta-HOXA rearranged cases except for deletion 9p21 and NOTCH1 activating mutations, which were present in 64 and 67%, respectively. In conclusion, this study defines TCRbeta-HOXA rearranged T-ALLs as a distinct cytogenetic subgroup by clinical, immunophenotypical and molecular genetic characteristics.
Published: 2006

34. Inhibition of Hedgehog signaling for the treatment of lymphoma and CLL: a phase II study from the LYSA

Author: Kamal Bouabdallah, Tony Marchand, Roch Houot, Sylvain Choquet, Céline Pangault, T. Lamy, Gilles Salles, Catherine Thieblemont, S. Le Gouill, Corinne Haioun, Camille Laurent, H. Tilly, Olivier Casasnovas, Carole Soussain, Khê Hoang-Xuan, Franck Morschhauser, Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'hématologie clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'hématologie, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), OncoNeuroTek [Paris], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Service d'Hématologie clinique [CHU Pitié-Salpêtrière], 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), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Roche, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), 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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, business.industry, [SDV]Life Sciences [q-bio], Phases of clinical research, Hematology, medicine.disease, Hedgehog signaling pathway, 3. Good health, Lymphoma, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Cancer research, Medicine, Signal transduction, business, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; no abstract
Published: 2016

35. Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours

Author: Annie Renier, Céline Lecomte, Marie-Claude Jaurand, Marco Giovannini, Anne Janin, Jocelyne Fleury-Feith, Laurence Kheuang, Mireille Matrat, Vincent Abramowski, Françoise Levy, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Oncogenèse des tumeurs respiratoires et urogénitales, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Fondation Jean Dausset CEPH, Genetique des Tumeurs, Institut National de la Santé et de la Recherche Médicale (INSERM), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Division of Clinical and Translational Research, and House Research Institute
Subjects: Mesothelioma, congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, Ratón, [SDE.MCG]Environmental Sciences/Global Changes, Mice, Nude, Hemizygosity, Biology, medicine.disease_cause, Asbestos, Mice, 03 medical and health sciences, NF2 Gene Mutation, [SDV.EE.ECO]Life Sciences [q-bio]/Ecology, environment/Ecosystems, 0302 clinical medicine, Genes, Neurofibromatosis 2, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], otorhinolaryngologic diseases, Genetics, medicine, Animals, Genetic Predisposition to Disease, Allele, Molecular Biology, Peritoneal Neoplasms, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Asbestos, Crocidolite, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, 3. Good health, Cell culture, 030220 oncology & carcinogenesis, Immunology, Cancer research, [SDV.TOX.ECO]Life Sciences [q-bio]/Toxicology/Ecotoxicology, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, Carcinogenesis
Abstract: Biallelic NF2 gene inactivation is frequently found in human malignant mesothelioma. In order to assess whether NF2 hemizygosity may enhance susceptibility to asbestos fibres, we investigated the Nf2 status in mesothelioma developed in mice presenting a heterozygous mutation of the Nf2 gene (Nf2(KO3/+)), after intraperitoneal inoculation of crocidolite fibres. Asbestos-exposed Nf2(KO3/+) mice developed tumoural ascites and mesothelioma at a higher frequency than their wild-type (WT) counterparts (P&
Published: 2003

36. Association of both Langerhans cell histiocytosis and Erdheim-Chester disease linked to the BRAFV600E mutation

Author: Laurent Arnaud, Stéphane Barete, Jean Donadieu, Antoine Néel, Valérie Taly, Baptiste Hervier, Julien Haroche, Karine Cury, Zahir Amoura, Jean-François Emile, Jean-Marie Michot, Maud Bézier, Camille Roubille, Aude Rigolet, Véronique Meignin, Eric Hachulla, Bruno Graffin, Laurence Marie, Olivier Hermine, Marie Conrad, Elise Kostrzewa, Frédéric Charlotte, François Lifermann, Thierry Carmoi, Carles Villabona, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunité et Infection, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR113-Sorbonne Université (SU), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], 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 de référence des Histiocytoses [HU Saint-Louis, Lariboisière, Fernand-Widal - APHP], Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand-Widal, Service de médecine interne [Nantes], Université de Nantes (UN)-Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Médecine Interne [Dax], Centre Hospitalier de Dax, Department of Endocrinology [Barcelona, Spain], L’Hospitalet de Llobregat [Barcelona, Spain]-Hospital de Bellvitge [Barcelona, Spain], Service de Médecine Interne [HI des Armées Legouest, Metz], Hôpital d’Instruction des Armées Legouest [Metz], Service d'hématologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service de Médecine Interne [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital d'Instruction des Armées du Val de Grâce, Service de Santé des Armées, Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Raincy-Montfermeil, CHU Bordeaux [Bordeaux], Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de dermatologie et allergologie [CHU Tenon], CHU Tenon [AP-HP], Bases moléculaires de la réponse aux xénobiotiques (U775 (IFR95)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'anatomie pathologique [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], French Histiocytoses Study Group : Bulifon S, Brousse N, Tazi A, Girerd X, de Gennes C, de Lassale E, Leclair F, Rieu P, De Wazière B, Ory JP, Lambotte O, Meekel P, Cohen-Aubart F, Hélias-Rodzewicz Z, Rousselet-Chapeau MC, Vital-Durand D, Hamidou MA., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de médecine interne et d'immunologie clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Sorbonne Université (SU), Laboratoire Géomatériaux (DGCB-LGM), École Nationale des Travaux Publics de l'État (ENTPE)-Centre National de la Recherche Scientifique (CNRS), Service d’anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Rhumatologie[Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Service de médecine interne, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), service de Médecine Interne et d'Immunologie Clinique [AP-HP Hôpital Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Hôpital Bicêtre, Assistance Publique - Hôpitaux de Paris (AP-HP), CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Dermatologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [APHP], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), TALY, Valerie, and Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP)
Subjects: Adult, Male, Proto-Oncogene Proteins B-raf, Pathology, medicine.medical_specialty, Erdheim-Chester Disease, Adolescent, genetic structures, [SDV]Life Sciences [q-bio], Immunology, DNA Mutational Analysis, Mutation, Missense, Kaplan-Meier Estimate, Biology, medicine.disease_cause, Biochemistry, Young Adult, Langerhans cell histiocytosis, Inside BLOOD Commentary, Biopsy, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Child, ComputingMilieux_MISCELLANEOUS, Aged, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, Cell Biology, Hematology, Middle Aged, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Histiocytosis, Histiocytosis, Langerhans-Cell, Treatment Outcome, Histiocytoses, Child, Preschool, Erdheim–Chester disease, Female, V600E, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Comment in "A common progenitor cell in LCH and ECD. [Blood. 2014]"; International audience; Histiocytoses are a group of heterogeneous diseases that mostly comprise Langerhans cell histiocytosis (LCH) and non-LCH. The association of LCH with non-LCH is exceptional. We report 23 patients with biopsy-proven LCH associated with Erdheim-Chester disease (ECD) (mixed histiocytosis) and discuss the significance of this association. We compare the clinical phenotypes of these patients with those of 56 patients with isolated LCH and 53 patients with isolated ECD. The average age at diagnosis was 43 years. ECD followed (n = 12) or was diagnosed simultaneously with (n = 11) but never preceded LCH. Although heterogeneous, the phenotype of patients with mixed histiocytosis was closer to that of isolated ECD than to that of isolated LCH (principal component analysis). LCH and ECD improved in response to interferon alpha-2a treatment in only 50% of patients (8 of 16). We found the BRAF(V600E) mutation in 11 (69%) of 16 LCH lesions and in 9 (82%) of 11 ECD lesions. Eight patients had mutations in both ECD and LCH biopsies. Our findings indicate that the association of LCH and ECD is not fortuitous and suggest a link between these diseases involving the BRAF(V600E) mutation.
Published: 2014

37. Syringotropic mycosis fungoides: Clinical and histologic features, response to treatment, and outcome in 19 patients

Author: Jean-David Bouaziz, F. Mouly, François Le Gall, Adèle de Masson, Antoine Petit, Anne Saussine, Alexiane Dallot, Pascal Joly, Jacqueline Rivet, Marie-Dominique Vignon-Pennamen, Martine Bagot, Philippe Assouly, Olivier Dereure, S. Ronceray, Alain Dupuy, Anne Janin, Isabelle Moulonguet, Maxime Battistella, Bénédicte Cavelier-Balloy, Michel Rybojad, Caroline Ram-Wolff, Céleste Lebbé, Service de dermatologie [Paris], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'anatomo-pathologie [Paris], 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), Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service de Dermatologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Dermatologie [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service de Dermatologie [Aulnay-sous-Bois], Hôpital Robert Ballanger [Aulnay-sous-Bois], Service de Dermatologie [Rennes], CHU Pontchaillou [Rennes], Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), 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), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Hôpital Charles Nicolle [Rouen], Service de Dermatologie [Rennes] = Dermatology [Rennes], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Charles Nicolle [Rouen], and Normandie Université (NU)-Normandie Université (NU)-CHU Rouen
Subjects: Adult, Male, medicine.medical_specialty, Skin Neoplasms, Dermatology, Syringotropic mycosis fungoides, Eccrine Glands, Tropism, Lymphocytic Infiltrate, 030207 dermatology & venereal diseases, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Mycosis Fungoides, Follicular phase, medicine, Humans, Lymphocytes, Aged, Retrospective Studies, Aged, 80 and over, Mycosis fungoides, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Cutaneous T-cell lymphoma, Retrospective cohort study, Alopecia, Middle Aged, medicine.disease, Confidence interval, 3. Good health, Natural history, Survival Rate, Treatment Outcome, 030220 oncology & carcinogenesis, Female, business, Hair Follicle
Abstract: International audience; BACKGROUND: A rare variant of mycosis fungoides (MF), syringotropic MF (STMF) is characterized by a particular tropism of the lymphocytic infiltrate for the eccrine structures, and included in the follicular subtype of MF in the World Health Organization-European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas. OBJECTIVE: We sought to determine the clinicopathologic features and disease course of patients with STMF. METHODS: A retrospective study was conducted to identify patients with STMF from 1998 to 2013. RESULTS: Nineteen patients were included: 15 men and 4 women, mean age 55 years (range, 24-86). Most had multiple lesions (n = 16, 84%) with associated alopecia (n = 12, 63%) and/or punctuated aspect (n = 12, 63%). Palms or soles were involved in 10 cases (53%). Folliculotropism was found in 13 cases (68%). After a median follow-up of 70 months (range, 2-140), 3 patients died, 1 from disease-related death. The 5-year overall and disease-specific survival were 100%. The disease-specific survival was significantly higher than in 54 patients with folliculotropic MF without syringotropism (5-year disease-specific survival, 74%; 95% confidence interval, 58%-94%, P = .02). LIMITATIONS: Retrospective setting is a limitation. CONCLUSIONS: In the spectrum of adnexotropic MF, STMF appears as a distinct entity from follicular MF, with peculiar clinical characteristics and natural history.
Published: 2014

38. In vivo uptake and cellular distribution of gold nanoshells in a preclinical model of xenografted human renal cancer

Author: Joel Poupon, Philippe Ratajczak, Guilhem Bousquet, Bruno Palpant, Raphaël Boisgard, Christophe Leboeuf, Irmine Ferreira, Emmanuel Bossy, Anne Janin, Mariana Pannerec-Varna, Eric Doris, Emmanuel Fort, Guillaume Gapihan, Jérôme Verine, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Sino-Français de Recherches en Sciences du Vivant et Génomique, Shanghai Jiao Tong University School of Medicine-Ruijin Hospital-Shanghai Institute for Biological Sciences-Chinese National Human Genome Center-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Imagerie Moléculaire Expérimentale (LIME), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service d'anatomo-pathologie [Paris], 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 de Photonique Quantique et Moléculaire (LPQM), École normale supérieure - Cachan (ENS Cachan)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Imagerie Paramétrique (LIP), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Centre National de la Recherche Scientifique (CNRS), Service de Chimie Bio-Organique et de Marquage (SCBM), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Toxicologie Biologique, Hôpital Lariboisière, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Langevin - Ondes et Images (UMR7587) (IL), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Palpant, Bruno, Centre National de la Recherche Scientifique (CNRS)-Chinese National Human Genome Center-Shanghai Institute for Biological Sciences-Ruijin Hospital-Shanghai Jiao Tong University School of Medicine, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: [PHYS.PHYS.PHYS-OPTICS] Physics [physics]/Physics [physics]/Optics [physics.optics], Pathology, medicine.medical_specialty, Materials science, Nanotechnology, Spleen, 02 engineering and technology, [PHYS] Physics [physics], Inorganic Chemistry, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, In vivo, medicine, General Materials Science, [PHYS.COND]Physics [physics]/Condensed Matter [cond-mat], ComputingMilieux_MISCELLANEOUS, [PHYS]Physics [physics], Kidney, [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics], Cancer, 021001 nanoscience & nanotechnology, medicine.disease, Nanoshell, 3. Good health, medicine.anatomical_structure, Colloidal gold, 030220 oncology & carcinogenesis, Bone marrow, 0210 nano-technology, [PHYS.COND] Physics [physics]/Condensed Matter [cond-mat]
Abstract: Large-sized gold nanoparticles, promising imaging and therapeutic tools in human cancer, need long-term studies evaluating tissue bio-distribution in blood, organs and tumor. In a preclinical model of mouse xenografted with human renal cancer, we analysed the bio-distribution of a single dose (160 μg/kg) intravenously injected of poly-ethylene glycol (PEG)ylated gold nanoshells (~150 nm), in blood, normal and tumoral tissues. Using inductively coupled plasma mass spectrometry (ICP-MS), dark field and electron microscopy, we performed a sequential study of nanoshell uptake and distribution in the tumor. We also studied microscopically the organs most sensitive to efficient anticancer drugs to detect a possible long-term toxicity. Gold quantities significantly decreased in blood between early and late time points, whereas they significantly increased in liver and spleen. In addition, gold nanoshells did not induce any tissue damage, such as necrosis, inflammatory infiltrate or fibrosis in mouse liver, spleen, kidney or bone marrow after 6 months. In human renal cancer xenografts, ICP-MS showed an early decrease of gold, with 1-week stability before decrease at Day 15. Dark field microscopy showed gold particles within the vessel lumen 5 to 30 min after nanoshell injection, while 24 h later, gold particle distribution was mainly intracellular. Electron microscopy identified nanoshells within blood vessels at 5 and 30 min, within endothelial cells at 3 and 6 h and within cytoplasms of macrophages in the tumoral tissue after 24 h. In conclusion, no toxicity was observed in mice 6 months after administration of PEGylated gold nanoshells and the distribution kinetics progressed from intravascular flow at 30 min to intratumoral cells 24 h later.
Published: 2013

39. Crohn's disease of the vulva

Author: Vincent de Parades, Nicolas Lemarchand, Maximilien Barret, Philippe Marteau, Harry Sokol, Maxime Battistella, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), gastroenterology, Lariboisière hospital, Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: medicine.medical_specialty, Azathioprine, Disease, Vulva, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, Biopsy, medicine, Humans, 030212 general & internal medicine, Prospective cohort study, Ulcer, Crohn's disease, medicine.diagnostic_test, business.industry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Gastroenterology, General Medicine, Hypertrophy, medicine.disease, Infliximab, Abscess, 3. Good health, Surgery, Metronidazole, medicine.anatomical_structure, Female, Vulvar Diseases, business, medicine.drug
Abstract: International audience; : Crohn's disease (CD) of the vulva is a rare, yet under recognized condition. Fistulae arising from the digestive tract account for the greater part of genital lesions in CD. However, cutaneous so-called metastatic lesions of the vulva have been reported in the literature. They are clinically challenging for gastroenterologists as well as for gynecologists, with numerous differential diagnoses, especially among venereal diseases, and require a multidisciplinary approach. The most frequently observed features of the disease are labial swelling, vulvar ulcers, and hypertrophic lesions. Biopsy samples for histological study are mandatory, in order to establish the diagnosis of vulvar CD. Treatment options include oral prolonged courses of metronidazole and systemic immunosuppressive therapy such as corticosteroids and azathioprine, with promising data published on the efficacy of infliximab. Surgery remains restricted to medical treatment failures or resection of unsightly lesions. Prospective studies or case series with long follow-up data are still missing to guide the treatment of this condition.
Published: 2013

40. Lymphoma occurring in patients over 90 years of age: characteristics, outcomes, and prognostic factors. A retrospective analysis of 234 cases from the LYSA

Author: Alain Monnereau, Yann Guillermin, Ghandi Damaj, T. Marchand, Xavier Troussard, Delphine Rossille, Gilles Salles, Pascal Godmer, Florence Broussais-Guillaumot, S. Le Gouill, Richard Lemal, Marc Maynadié, Catherine Thieblemont, Thierry Lamy, Adrien Trebouet, Emmanuel Gyan, Christophe Fruchart, Roch Houot, Hélène Monjanel, P. Feugier, Microenvironnement et cancer ( MiCa ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'hématologie, CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I ( UdA ), CIC - Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHRU Tours, CIC - Tours, CHRU Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Paoli Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Léon Bérard [Lyon], Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier de Bretagne Atlantique, Centre François Baclesse, Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Département d'oncologie médicale, Institut Bergonié - CRLCC Bordeaux, CHU Caen, Pôle Biologie, Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Microenvironnement et cancer (MiCa), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I (UdA), Centre d'Investigation Clinique [CHU Clermont-Ferrand] (CIC 1405), Institut National de la Santé et de la Recherche Médicale (INSERM)-Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut Bergonié [Bordeaux], Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Martin, Clémence, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)
Subjects: Male, medicine.medical_specialty, Palliative care, Survival, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, lymphoma, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, immune system diseases, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Hypoalbuminemia, education, Serum Albumin, 030304 developmental biology, Cause of death, Retrospective Studies, Aged, 80 and over, 0303 health sciences, education.field_of_study, palliative care, business.industry, Incidence (epidemiology), Incidence, Lymphoma, Non-Hodgkin, Hematology, medicine.disease, Prognosis, Comorbidity, 3. Good health, Lymphoma, Surgery, aged 80 and over, comorbidity, Oncology, 030220 oncology & carcinogenesis, Female, Lymphoma, Large B-Cell, Diffuse, business, Diffuse large B-cell lymphoma
Abstract: International audience; BACKGROUND: Lymphoma occurring in patients aged 90 or older is not uncommon, and its incidence is expected to increase over time. Management of these patients is difficult given their underlying fragility and the lack of information regarding this population. PATIENTS AND METHODS: We retrospectively analyzed 234 patients diagnosed with lymphoma at the age of 90 years or older (90+) between 1990 and 2012 to describe their characteristics, management, outcomes and prognostic factors. RESULTS: The median age was 92 years; 88% were B-cell lymphomas consisting mainly in diffuse large B-cell lymphoma. The median overall survival (OS) was 7.2 months (range, 0-92 months) for the 227 patients with non-Hodgkin Lymphoma (NHL), with a significant difference between aggressive and indolent NHL (5.2 months versus 19.4 months, respectively). We further analyzed 166 NHL patients for whom detailed characteristics were available. Among these patients, 63.5% received a treatment, either local (7.5%) or systemic (56%). Lymphoma was reported as the main cause of death (40%). Treatment administration was associated with improved OS in patients with aggressive (P < 0.001) but not indolent NHL (P = 0.96). In patients with aggressive NHL, hypoalbuminemia appeared as a strong and independent negative prognostic factor. CONCLUSIONS: The median OS is short in 90+ patients diagnosed with lymphoma but some patients experience prolonged survival. Lymphoma represents the main cause of death in these patients. Treatment may improve survival of selected patients with aggressive but not indolent NHL. Management of these patients may be guided by prognostic factors identified in this study, notably serum albumin.
Published: 2013

41. Analyzing huge pathology images with open source software

Author: Alexandre Granier, David Ameisen, Chloé Gerin, Marc Lartaud, Mathilde Badoual, Christophe Deroulers, Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC (UMR_8165)), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme d'histocytologie et d'imagerie cellulaire végétale (PHIV), Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), BMC, Ed., Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)
Subjects: business.product_category, Histology, Gigabyte, Computer science, computer.software_genre, Quantitative Biology - Quantitative Methods, NDPI, Pathology and Forensic Medicine, User-Computer Interface, 03 medical and health sciences, 0302 clinical medicine, Software, Image processing, Predictive Value of Tests, Computer graphics (images), Computer cluster, Image Interpretation, Computer-Assisted, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Pathology, Humans, Digital pathology, Plug-in, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Quantitative Methods (q-bio.QM), 030304 developmental biology, Microscopy, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, General Medicine, computer.file_format, Modular design, JPEG, ImageJ, C30 - Documentation et information, Virtual slides, 030220 oncology & carcinogenesis, Laptop, FOS: Biological sciences, S50 - Santé humaine, business, Systems biology, computer, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; BACKGROUND: Digital pathology images are increasingly used both for diagnosis and research, because slide scanners are nowadays broadly available and because the quantitative study of these images yields new insights in systems biology. However, such virtual slides build up a technical challenge since the images occupy often several gigabytes and cannot be fully opened in a computer¿s memory. Moreover, there is no standard format. Therefore, most common open source tools such as ImageJ fail at treating them, and the others require expensive hardware while still being prohibitively slow. RESULTS: We have developed several cross-platform open source software tools to overcome these limitations. The NDPITools provide a way to transform microscopy images initially in the loosely supported NDPI format into one or several standard TIFF files, and to create mosaics (division of huge images into small ones, with or without overlap) in various TIFF and JPEG formats. They can be driven through ImageJ plugins. The LargeTIFFTools achieve similar functionality for huge TIFF images which do not fit into RAM. We test the performance of these tools on several digital slides and compare them, when applicable, to standard software. A statistical study of the cells in a tissue sample from an oligodendroglioma was performed on an average laptop computer to demonstrate the efficiency of the tools. CONCLUSIONS: Our open source software enables dealing with huge images with standard software on average computers. They are cross-platform, independent of proprietary libraries and very modular, allowing them to be used in other open source projects. They have excellent performance in terms of execution speed and RAM requirements. They open promising perspectives both to the clinician who wants to study a single slide and to the research team or data centre who do image analysis of many slides on a computer cluster.Virtual slides The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/5955513929846272.
Published: 2013

42. Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15

Author: Cédric de Bazelaire, Anne de Roquancourt, Marcela Albiter, Solenne Leman-Detours, Patricia de Cremoux, Jacqueline Lehmann-Che, Anne Janin, Marc Espié, E. Bourstyn, Raphaël Porcher, Anne-Sophie Hamy, Laurence Cahen-Doidy, Fatiha Bouhidel, Caroline Cuvier, Hanadi Habuellelah, Sylvie Giacchetti, Marc Barritault, Philippe Bertheau, Laboratoire de biochimie, 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), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre des maladies du sein, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service de Biostatistiques, Service d'anatomo-pathologie [Paris], Service de chirurgie, Service de radiologie [Saint-Louis], Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), BMC, Ed., and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
Subjects: Oncology, Receptor, ErbB-2, Estrogen receptor, basal-like, 0302 clinical medicine, Surgical oncology, breast carcinoma, Medicine(all), Aged, 80 and over, 0303 health sciences, Apocrine, Middle Aged, Neoplasm Proteins, 3. Good health, Gene Expression Regulation, Neoplastic, Apocrine Glands, Receptors, Estrogen, Receptors, Androgen, 030220 oncology & carcinogenesis, Immunohistochemistry, Female, Research Article, estrogen receptor, Adult, medicine.medical_specialty, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, GCDFP15, triple negative, molecular apocrine, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, HER2, Biomarkers, Tumor, medicine, Humans, cancer, Estrogen receptor beta, Aged, Glycoproteins, 030304 developmental biology, Membrane Transport Proteins, Cancer, medicine.disease, Androgen receptor, Cancer research, Carrier Proteins, Estrogen receptor alpha
Abstract: International audience; INTRODUCTION: Molecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analyzed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors. METHODS: We performed quantitative reverse transcription PCR (qRT-PCR) for ESR1, AR, FOXA1 and AR-related genes, and immunohistochemistry (IHC) for ER, PR, Human Epidermal Growth Factor Receptor 2 (HER2), CK5/6, CK17, EGFR, Ki67, AR, FOXA1 and GCDFP15 and we analyzed clinical features. RESULTS: MA tumors were all characterized by ESR1(-) AR(+) FOXA1(+) and AR-related genes positive mRNA profile. IHC staining on these tumors showed 93% ER(-), only 58% AR(+) and 90% FOXA1(+). 67% and 57% MA tumors were HER2(3+) and GCDFP15(+), respectively. Almost all MA tumors (94%) had the IHC signature HER2(3+) or GCDFP15(+) but none of the 13 control basal-like (BL) tumors did. Clinically, MA tumors were rather aggressive, with poor prognostic factors. CONCLUSION: MA tumors could be better defined by their qRT-PCR-AR profile than by AR IHC. In addition, we found that HER2 or GCDFP15 protein overexpression is a sensitive and specific tool to differentiate MA from BL in the context of ER negative tumors. A composite molecular and IHC signature could, therefore, help to identify MA tumors in daily practice.
Published: 2013

43. Clinicopathological study of glomerular diseases associated with sarcoidosis : A multicenter study

Author: Philippe Vanhille, Laurent Mesnard, Matthieu Mahévas, Dominique Desvaux, Jean Jacques Boffa, Maxime Hoffmann, Dil Sahali, Philippe Grimbert, Jérôme Verine, Dominique Joly, Philippe Remy, Gabriel Choukroun, Philippe Lang, Thomas Stehlé, Vincent Audard, Francine Walker, François Vrtovsnik, Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre de recherche Croissance et signalisation ( UMR_S 845 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Néphrologie, CH de Valenciennes, Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Urgences Néphrologiques & Transplantation Rénale, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Néphrologie Hémodialyse, Hôpital Privé La Louvière, Service de Néphrologie [Amiens], CHU Amiens-Picardie-Hôpital Sud, Service de Néphrologie [Bichat - Claude Bernard], Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Pathologie [Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Institut Francilien de recherche en Néphrologie et Transplantation (IFRNT)-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service d'Anatomopathologie [Bichat - Claude Bernard], Service de Médecine Interne [Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Centre de référence maladie rare des cytopénies auto-immunes de l'adulte-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de recherche Croissance et signalisation (UMR_S 845), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Amiens-Picardie-hôpital Sud, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut Francilien de recherche en Néphrologie et Transplantation (IFRNT)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Centre de référence maladie rare des cytopénies auto-immunes de l'adulte-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and BMC, Ed.
Subjects: Adult, Male, medicine.medical_specialty, Sarcoidosis, 030232 urology & nephrology, Lupus nephritis, Nephrotic syndrome, Kidney biopsy, Context (language use), [SDV.GEN] Life Sciences [q-bio]/Genetics, Gastroenterology, Nephropathy, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Focal segmental glomerulosclerosis, Membranous nephropathy, Glomerulopathy, Internal medicine, medicine, Humans, Genetics(clinical), Pharmacology (medical), 030212 general & internal medicine, Genetics (clinical), Retrospective Studies, Medicine(all), Glomerular disease, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Glomerulosclerosis, Focal Segmental, Research, General Medicine, Middle Aged, medicine.disease, 3. Good health, Endocrinology, Female, Kidney Diseases, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics
Abstract: Background The association between sarcoidosis and glomerular diseases has not been extensively investigated in a large series and the potential features of this uncommon association remain to be determined. Methods We retrospectively identified 26 patients with biopsy-proven glomerular lesions that occurred in a sarcoidosis context. Potential remission of glomerular disease and sarcoidosis under specific treatment (steroid and/or immunosuppressive agents) was recorded for all patients. Demographic, clinical and biological characteristics were assessed at the time of kidney biopsy for each patient. Therapeutic data were analyzed for all patients. Results Glomerular disease occurred after the diagnosis of sarcoidosis in 11 of 26 cases (42%) (mean delay of 9.7 years). In six patients (23%), the glomerulopathy preceded the sarcoidosis diagnosis (mean delay 8 years). In the last nine patients (35%), both conditions occurred simultaneously. The most frequent glomerular disease occurring in sarcoidosis patients was membranous nephropathy in eleven cases. Other glomerular lesions included IgA nephropathy in six cases, focal segmental glomerulosclerosis in four patients, minimal change nephrotic syndrome for three patients and proliferative lupus nephritis in two patients. Granulomatous interstitial nephritis was associated with glomerular disease in six patients and was exclusively found in patients in whom the both disease occurred simultaneously. In nine patients with simultaneous glomerular and sarcoidosis diseases, we observed a strong dissociation between glomerular disease and sarcoidosis in terms of steroid responsiveness. At the end of the follow-up (mean of 8.4 years), six patients had reached end-stage renal disease and three patients had died. Conclusions A wide spectrum of glomerular lesions is associated with sarcoidosis. The close temporal relationship observed in some patients suggests common causative molecular mechanisms of glomerular injury but complete remission of both diseases in response to exclusive steroid therapy is infrequent.
Published: 2013

44. Rac3 induces a molecular pathway triggering breast cancer cell aggressiveness: differences in MDA-MB-231 and MCF-7 breast cancer cell lines

Author: Lionel Cazin, Françoise Fauvel-Lafève, Linda-Louise Pritchard, He Lu, Rémi Varin, Marc Laurent, Claudine Soria, Ulrich Joimel, Catherine Buquet, Jean-Pierre Vannier, Caroline Gest, Hong Li, P. Mirshahi, Jeannette Soria, Limin Huang, Charlène Dulong, Alexandre Petit, Chaoquan Hu, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique moléculaire et destin cellulaire (FRE 3377), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hemostase, Endothelium, Angiogenese (UMR_S_553), Unité Fonctionnelle d' oncologie médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, This work was supported by the Groupement des Entreprises Francaises dans la Lutte contre le Cancer de Rouen (GEFLUC of Rouen), and the Ligue Regionale de Haute Normandie de Lutte contre le Cancer. Caroline Gest is a recipient of grant from Ministère de l'enseignement supérieur et de la recherche., BMC, Ed., Départment d'onco-hématologie, Université Paris Descartes - Paris 5 (UPD5)-UMRS 872-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Micro-Environnement et Régulation Cellulaire Intégrée ( MERCI ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Génétique moléculaire et destin cellulaire ( FRE 3377 ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ) -UMRS 872-Centre National de la Recherche Scientifique ( CNRS ), Hemostase, Endothelium, Angiogenese, and Assistance publique - Hôpitaux de Paris (AP-HP)-Hôtel-Dieu
Subjects: Cancer Research, RHOA, Time Factors, Apoptosis, NF-κB, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Breast cancer, Cell Movement, Extracellular Signal-Regulated MAP Kinases, Rac3 GTPases, 0303 health sciences, biology, NF-kappa B, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, rac GTP-Binding Proteins, ERK, Oncology, Matrix Metalloproteinase 9, 030220 oncology & carcinogenesis, MCF-7 Cells, Cytokines, Female, RNA Interference, Collagen, Research Article, Signal Transduction, Cell signaling, Cell Survival, RAC1, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transfection, lcsh:RC254-282, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Genetics, Cell Adhesion, Humans, Neoplasm Invasiveness, Cell Shape, 030304 developmental biology, Tumor Necrosis Factor-alpha, Cancer, medicine.disease, MCF-7, Cancer cell, biology.protein, Cancer research, Cancer aggressiveness, Cytokine secretion, rhoA GTP-Binding Protein
Abstract: Background Rho GTPases are involved in cellular functions relevant to cancer. The roles of RhoA and Rac1 have already been established. However, the role of Rac3 in cancer aggressiveness is less well understood. Methods This work was conducted to analyze the implication of Rac3 in the aggressiveness of two breast cancer cell lines, MDA-MB-231 and MCF-7: both express Rac3, but MDA-MB-231 expresses more activated RhoA. The effect of Rac3 in cancer cells was also compared with its effect on the non-tumorigenic mammary epithelial cells MCF-10A. We analyzed the consequences of Rac3 depletion by anti-Rac3 siRNA. Results Firstly, we analyzed the effects of Rac3 depletion on the breast cancer cells’ aggressiveness. In the invasive MDA-MB-231 cells, Rac3 inhibition caused a marked reduction of both invasion (40%) and cell adhesion to collagen (84%), accompanied by an increase in TNF-induced apoptosis (72%). This indicates that Rac3 is involved in the cancer cells’ aggressiveness. Secondly, we investigated the effects of Rac3 inhibition on the expression and activation of related signaling molecules, including NF-κB and ERK. Cytokine secretion profiles were also analyzed. In the non-invasive MCF-7 line; Rac3 did not influence any of the parameters of aggressiveness. Conclusions This discrepancy between the effects of Rac3 knockdown in the two cell lines could be explained as follows: in the MDA-MB-231 line, the Rac3-dependent aggressiveness of the cancer cells is due to the Rac3/ERK-2/NF-κB signaling pathway, which is responsible for MMP-9, interleukin-6, -8 and GRO secretion, as well as the resistance to TNF-induced apoptosis, whereas in the MCF-7 line, this pathway is not functional because of the low expression of NF-κB subunits in these cells. Rac3 may be a potent target for inhibiting aggressive breast cancer.
Published: 2013

45. Donor-derived keratinocytes in actinic keratosis and squamous cell carcinoma in patients with kidney transplant

Author: Louis François Plassa, Anne Janin, Fatiha Bouhidel, Mariana Varna, Marie-Noëlle Peraldi, Philippe Ratajczak, Morad Elbouchtaoui, Christophe Leboeuf, Irmine Loisel-Ferreira, Céleste Lebbé, Laurence Verneuil, Université Sorbonne Paris Cité (USPC), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Dermatologie [CHU Caen], 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), Service de Pathologie [AP-HP Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 (UPD7)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Biochimie [AP-HP Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service de Néphrologie [AP-HP Hôpital Saint-Louis, Paris], Service de Dermatologie [AP-HP Hôpital Saint Louis, Paris], Grants were received from Région-Ile-de-France, Cancéropôle Ile-de-France, INCa, and ANR., 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), and Ratajczak, Philippe
Subjects: Adult, Keratinocytes, Male, medicine.medical_specialty, Skin Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, Kidney transplant, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Medicine, Humans, Basal cell, Donor derived, In patient, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Transplantation Chimera, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Histocompatibility Testing, Actinic keratosis, Cell Biology, Middle Aged, medicine.disease, Kidney Transplantation, 3. Good health, Keratosis, Actinic, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; No abstract
Published: 2012

46. Molecular features of hepatosplenic T-cell lymphoma unravels potential novel therapeutic targets.: Molecular Signature of Hepatosplenic T-cell Lymphoma

Author: Travert, Marion, Huang, Yenlin, De Leval, Laurence, Martin-Garcia, Nadine, Delfau-Larue, Marie-Helene, Berger, Françoise, Bosq, Jacques, Brière, Josette, Soulier, Jean, Macintyre, Elizabeth, Marafioti, Teresa, De Reyniès, Aurélien, Gaulard, Philippe, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of Anatomic Pathology, Chang Gung Memorial Hospital [Taipei] (CGMH), Service de Pathologie Clinique, Université de Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)-Institut Universitaire de Pathologie, Service d'immunologie biologique, Centre de Biologie et de Pathologie, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Hôpital Renée Sabran [CHU - HCL], Hospices Civils de Lyon (HCL), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomo-pathologie [Paris], 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), Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Service hématologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Department of histopathology, University College Hospital, (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), This work is part of the Carte d'Identité des Tumeurs (CIT) program (http://cit.liguecancer.net/index.php/en) from the Ligue Nationale Contre le Cancer and of the Tenomic project inserm-00730464, version 1 - 10 Sep 2012 supported by a Programme Hospitalier de Recherche Clinique and the Institut National du Cancer (INCa). This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Institut National du Cancer (INCa), the Plan cancer of the Belgian government, and the Association pour la Recherche Thérapeutique, Génétique et Immunologique dans les Lymphomes (ARTGIL). M.T. was supported by the Fondation pour la Recherche Médicale (DEQ 2010/0318253), Université de Lausanne = University of Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)-Institut Universitaire de Pathologie, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
Subjects: MESH: Base Sequence, MESH: Protein-Tyrosine Kinases, MESH: Gene Expression Profiling, MESH: Isochromosomes, MESH: Liver Neoplasms, MESH: Receptors, Antigen, T-Cell, gamma-delta, MESH: Intracellular Signaling Peptides and Proteins, MESH: Molecular Targeted Therapy, MESH: Chromosome Aberrations, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Genes, Neoplasm, MESH: Aged, MESH: Humans, MESH: Middle Aged, MESH: Molecular Sequence Data, MESH: Receptors, Antigen, T-Cell, alpha-beta, MESH: Adult, MESH: Gene Expression Regulation, Neoplastic, MESH: Cell Lineage, MESH: Splenic Neoplasms, MESH: Cluster Analysis, MESH: Male, MESH: Drug Resistance, Neoplasm, MESH: Crystallins, MESH: Young Adult, MESH: Tumor Markers, Biological, MESH: Lymphoma, T-Cell, MESH: Membrane Proteins, MESH: Female
Abstract: International audience; The pathogenesis of hepatosplenic T-cell lymphoma (HSTL), a rare entity mostly derived from γδ T cells and usually with a fatal outcome, remains largely unknown. In this study, HSTL samples (7γδ and 2αβ) and the DERL2 HSTL cell line were subjected to combined gene-expression profiling and array-based comparative genomic hybridization. Compared with other T-cell lymphomas, HSTL had a distinct molecular signature irrespective of TCR cell lineage. Compared with peripheral T-cell lymphoma, not otherwise specified and normal γδ T cells, HSTL overexpressed genes encoding NK-cell-associated molecules, oncogenes (FOS and VAV3), the sphingosine-1-phosphatase receptor 5 involved in cell trafficking, and the tyrosine kinase SYK, whereas the tumor-suppressor gene AIM1 (absent in melanoma 1) was among the most down-expressed. We found highly methylated CpG islands of AIM1 in DERL2 cells, and decitabine treatment induced a significant increase in AIM1 transcripts. Syk was present in HSTL cells and DERL2 cells contained phosphorylated Syk and were sensitive to a Syk inhibitor in vitro. Genomic profiles confirmed recurrent isochromosome 7q (n = 6/9) without alterations at the SYK and AIM1 loci. Our results identify a distinct molecular signature for HSTL and highlight oncogenic pathways that offer rationale for exploring new therapeutic options such as Syk inhibitors and demethylating agents.
Published: 2012

47. Ten-Year Relative Survival and Causes of Death in Elderly Patients Treated With R-CHOP or CHOP in the GELA LNH-985 Trial

Author: Reda Bouabdallah, Hervé Tilly, Bertrand Coiffier, Catherine Thieblemont, Nicolas Mounier, Hervé Ghesquières, Philippe Gaulard, Violaine Safar, Natacha Heutte, Josette Brière, Eric Van Den Neste, Pierre Feugier, Daniela Robu, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d’études des transformations des activités physiques et sportives (CETAPS), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut de Recherche Interdisciplinaire Homme et Société (IRIHS), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'anatomo-pathologie [Paris], 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), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Département Hématologie (FNCLCC), Centre Léon Bérard [Lyon], Cliniques Universitaires Saint-Luc [Bruxelles], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), College of Information and Electrical Engineering [Beijing] (CIEE), China Agricultural University (CAU), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), 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), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Régional d'Etudes sur le CANcer (GRECAN), Normandie Université (NU)-Normandie Université (NU)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-IFR146, Service de biochimie [CHU Caen], Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire d'informatique de l'École polytechnique [Palaiseau] (LIX), Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X), Centre de Recherche et d'Etude en Droit et Science Politique [Dijon] (CREDESPO), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and Institut de Recherche Interdisciplinaire Homme et Société (IRIHS)
Subjects: Male, Cancer Research, [SDV]Life Sciences [q-bio], CHOP, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, Cause of Death, Antineoplastic Combined Chemotherapy Protocols, MESH: Peritoneal Neoplasms, Glycolysis, MESH: Animals, MESH: Oxygen Consumption, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, MESH: Energy Metabolism, Hematology, Middle Aged, Warburg effect, 3. Good health, Oncology, Vincristine, MESH: Enzyme Inhibitors, 030220 oncology & carcinogenesis, Female, Lymphoma, Large B-Cell, Diffuse, Rituximab, medicine.medical_specialty, MESH: Mitochondria, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Pleural Neoplasms, 03 medical and health sciences, MESH: Pyruvate Dehydrogenase Complex, medicine, MESH: Mice, Nude, Humans, Secretion, MESH: Tumor Cells, Cultured, Cyclophosphamide, MESH: Mice, MESH: Pyruvates, Aged, Neoplasm Staging, MESH: Humans, MESH: Mesothelioma, business.industry, Metabolism, Surgery, Metabolic pathway, MESH: Cisplatin, Doxorubicin, Anaerobic glycolysis, Cancer cell, Cancer research, Prednisone, business, MESH: Female, Follow-Up Studies, 030215 immunology
Abstract: International audience; Most cancer cells exhibit increased anaerobic glycolysis and use this metabolic pathway for the generation of ATP as a main source of energy. This impaired metabolism of glucose, leading to the secretion of lactic acid even in the presence of oxygen, is named the Warburg effect. Because cancer cells are partly or mainly dependent on such a pathway to generate ATP, inhibition of glycolysis may slow down the proliferation or kill cells.
Published: 2012

48. Opposite regulation by PI3K/Akt and MAPK/ERK pathways of tissue factor expression, cell-associated procoagulant activity and invasiveness in MDA-MB-231 cells

Author: Anne Janin, Caroline Gest, Chaoquan Hu, Xiaodong Xi, Hong Li, He-Lin Lu, Limin Huang, Claudine Soria, Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Shanghai Institute of Hematology, Shanghai Jiao Tong University School of Medicine-Shanghai Rui Jin Hospital, Service d'anatomo-pathologie [Paris], 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), Support from the institute of cancer (INCA, PL06_130), the Association pour la Recherche sur le Cancer (ARC), the Ligue Nationale contre le Cancer (Ligue) and the Fondation de France., and BMC, Ed.
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, MAPK/ERK pathway, Cancer Research, Small interfering RNA, Transcription, Genetic, Wortmannin, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, Breast cancer, 0302 clinical medicine, Cell Movement, Tumor Cells, Cultured, LY294002, Tumor invasiveness, Enzyme Inhibitors, Phosphorylation, Promoter Regions, Genetic, Phosphoinositide-3 Kinase Inhibitors, Ovarian Neoplasms, Gene expression regulation, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, lcsh:Diseases of the blood and blood-forming organs, Hematology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, ErbB Receptors, Gene Expression Regulation, Neoplastic, Drug Combinations, Oncology, PI3K/Akt pathway, 030220 oncology & carcinogenesis, Female, Proteoglycans, Collagen, Mitogen-Activated Protein Kinases, Signal transduction, Signal Transduction, MAP Kinase Signaling System, Blotting, Western, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Real-Time Polymerase Chain Reaction, lcsh:RC254-282, Thromboplastin, Pro-coagulation activity, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Humans, Neoplasm Invasiveness, RNA, Messenger, Blood Coagulation, Molecular Biology, Protein kinase B, PI3K/AKT/mTOR pathway, Cell Proliferation, 030304 developmental biology, lcsh:RC633-647.5, Research, Tissue factor, Molecular biology, chemistry, Cancer cell, Cancer research, Laminin, Proto-Oncogene Proteins c-akt
Abstract: Background Tissue factor (TF), an initiator of blood coagulation, participates in cancer progression and metastasis. We recently found that inhibition of MAPK/ERK upregulated both full length TF (flTF) and soluble isoform TF (asTF) gene expression and cell-associated TF activity in breast cancer MDA-MB-231 cells. We explored the possible mechanisms, especially the possible interaction with EGFR and PI3K/Akt pathways. Methods A plasmid containing TF promoter −2174 ~ +128 plus luciferase reporter gene was introduced into MDA-MB-231 cells to evaluate TF promoter activity. In order to study the interaction of these pathways, ERK inhibitor (PD98059), PI3K inhibitors (LY294002, wortmannin), Akt inhibitor (A6730), and EGFR inhibitor (erlotinib) as well as the corresponding siRNAs were used to treat MDA-MB-231 cells, and ovarian cancer OVCAR-3 and SKOV-3 cells. Quantitative PCR and western blot were used to determine TF expression. One stage clotting assays were used to measure pro-coagulation activity of the MDA-MB-231 cells. Results We show that PI3K inhibitors LY294002, wortmannin and A6730 significantly inhibited TF promoter activity, and reduced TF mRNA and protein levels due to the inhibition of Akt phosphorylation. In contrast, ERK inhibitor PD98059 and ERK siRNA enhanced TF promoter activity by 2.5 fold and induced an increase in TF mRNA and protein levels in a dose dependent manner in these cells. The PI3K/Akt pathway was shown to be involved in PD98059-induced TF expression because the induction was inhibited by PI3K/Akt inhibitors. Most interestingly, the EGFR inhibitor erlotinib and EGFR siRNA also significantly suppressed PD98059- or ERK siRNA-induced TF promoter activity and TF protein expression. Similar results were found with ovarian cancer cells SKOV-3 and OVCAR-3. Furthermore, in MDA-MB-231, mRNA levels of asTF were regulated in a similar way to that of TF in response to the cell treatment. Conclusions This study showed a regulatory mechanism in which MAPK/ERK signals inhibit EGFR/PI3K/Akt-mediated TF expression in breast cancer MDA-MB-231 cells. The same regulation was observed in ovarian cancer OVCAR-3 and SKOV-3 cells. Interestingly, we observed that both flTF and asTF could be regulated in a parallel manner in MDA-MB-231. As the PI3K/Akt pathway and EGFR regulate TF expression in cancer cells, targeting these signaling components is expected to potentially inhibit TF expression-associated tumor progression.
Published: 2012

49. MYC+ diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation

Author: Sergio Cogliatti, Wendy Cuccuini, Andreas Rosenwald, Nicolas Mounier, Hans-Ullrich Voelker, Jean Soulier, Christian Gisselbrecht, Rémi Houlgatte, Dominique Bron, Josette Brière, Christer Sundström, Catherine Thieblemont, Loic Ysebaert, Philippe Gaulard, Edouard Hirchaud, Centre de Biologie et de Pathologie, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Hôpital Renée Sabran [CHU - HCL], Hospices Civils de Lyon (HCL), Service d'hématologie biologique, 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), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomo-pathologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service d'onco-hématologie, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital l'Archet, Institute of Pathology, University of Würzburg = Universität Würzburg, Pathology, Uppsala University Hospital, St Gallen Hospital (for Schweizerische Arbeitgeminschaft für Klinische Krebsforchnung [SAKK]), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hématologie [Purpan], CHU Toulouse [Toulouse], Service Hématologie, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), GELA, Groupe d'Etude des Lymphomes de l'Adulte, This work was supported by the Program Hospitalier de Recherche Clinique 2009, INCa, Institut National du Cancer, France (grant PHRC AOM09271), and F. Hoffmann-La Roche Ltd. S.C. was sponsored by the SAKK (Schweizerische Arbeitgeminschaft für Klinische Krebsforchnung)., Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Guellaen, Georges, Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Male, Genes, myc, Salvage therapy, Biochemistry, Dexamethasone, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, Autologous stem-cell transplantation, International Prognostic Index, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Treatment Failure, Melphalan, Etoposide, Podophyllotoxin, Cytarabine, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, BCL6, Combined Modality Therapy, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Female, Immunotherapy, Lymphoma, Large B-Cell, Diffuse, Rituximab, medicine.drug, Adult, Immunology, Transplantation, Autologous, Article, 03 medical and health sciences, Young Adult, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Ifosfamide, neoplasms, Aged, Salvage Therapy, business.industry, Cell Biology, medicine.disease, Carmustine, Lymphoma, Transplantation, Cancer research, Cisplatin, business, Diffuse large B-cell lymphoma, 030215 immunology
Abstract: Approximately 5-10% of diffuse large B-cell lymphomas (DLBCL) harbor a 8q24/MYC rearrangement (MYC+). We determined the prognostic significance of MYC rearrangement in patients with relapsed/refractory DLBCL prospectively treated by R-ICE or R-DHAP followed by high-dose therapy and autologous stem cell transplantation. Twenty-eight (17%) of the 161 patients analyzed presented a MYC+ rearrangement, targeted as either simple hit (25%) or complex hits (n=75%) including MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6. Results were statistically highly concordant in matched primary and relapsed biopsies (n = 45). Compared to the MYC− DLBCL patients, the MYC+ DLBCL patients presented with a more elevated lactico-deshydrogenase level (P = .0006) and a more advanced age adjusted international prognostic index (P = .0039). The 4-year PFS and OS were significantly lower in the MYC+ DLBCL patients than those in the MYC− DLBCL patients, with rates of 18% vs 42% (P = .0322), and of 29% vs 62% (P = .0113), respectively. Type of treatment, R-DHAP or R-ICE, had no impact on survivals, with 4-year PFS rates of 17% vs 19% and 4-year OS rates of 26% vs 31%. In conclusion, MYC rearrangement is an early event in DLBCL. MYC+ DLBCL patients have a significant inferior prognosis than MYC− DLBCL patients. Their outcome was not influenced by the proposed salvage therapy.
Published: 2012

50. The strategy for the diagnosis of invasive pulmonary aspergillosis should depend on both the underlying condition and the leukocyte count of patients with hematologic malignancies

Author: Jean Louis Poirot, Benoit Brethon, Raphaël Porcher, Anne Vekhoff, Patricia Ribaud, Françoise Isnard, Anne Bergeron, Cédric de Bazelaire, Muriel Cornet, Claire Lacroix, Emmanuel Raffoux, Abdellatif Tazi, Annie Sulahian, Claire Bouges, Karine Chagnon, Francis Derouin, Service de pneumologie, Université Paris Diderot - Paris 7 (UPD7)-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), Biostatistique et épidemiologie clinique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gvh et Gvl : Physiopathologie Chez l'Homme et Chez l'Animal, Incidence et Role Therapeutique, Service de radiologie [Saint-Louis], 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), Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Thérapeutique Recombinante Expérimentale (TIMC-IMAG-TheREx), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des Matériaux Polymères - Laboratoire des Matériaux Macromoléculaires (IMP-LMM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie [Saint-Louis], Service d'hématologie greffe [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
Subjects: Male, MESH: Logistic Models, Disease, Logistic regression, Biochemistry, Gastroenterology, Leukocyte Count, 0302 clinical medicine, MESH: Child, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Child, Lung, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Invasive Pulmonary Aspergillosis, MESH: Aged, 0303 health sciences, Leukemia, MESH: Middle Aged, Hematology, Middle Aged, 3. Good health, Aspergillus, MESH: Young Adult, Hematologic Neoplasms, MESH: Aspergillus, Acute Disease, MESH: Acute Disease, Female, MESH: Tomography, X-Ray Computed, Adult, medicine.medical_specialty, MESH: Invasive Pulmonary Aspergillosis, Adolescent, Immunology, Sensitivity and Specificity, 03 medical and health sciences, Young Adult, Internal medicine, Bronchoscopy, MESH: Leukemia, medicine, Humans, MESH: Lung, MESH: Bronchoscopy, Aged, MESH: Adolescent, MESH: Humans, 030306 microbiology, business.industry, MESH: Adult, Cell Biology, Odds ratio, Invasive pulmonary aspergillosis, medicine.disease, Confidence interval, MESH: Sensitivity and Specificity, MESH: Male, MESH: Prospective Studies, Surgery, Logistic Models, Concomitant, MESH: Leukocyte Count, business, Tomography, X-Ray Computed, MESH: Female, MESH: Hematologic Neoplasms
Abstract: The identification of the causative organism in invasive pulmonary aspergillosis (IPA) is recommended. We investigated whether a mycologic diagnostic strategy could be optimized based on patient characteristics. Fifty-five patients were enrolled in a prospective study. The presence of Aspergillus in respiratory samples occurred more frequently in non-acute leukemia (AL) patients than in AL patients (P = .0003), and in patients with leukocyte counts more than 100/mm3 (P = .002). In a logistic regression model, these 2 factors appeared to be independent, with an adjusted odds ratio of 7.14 (95% confidence interval, 1.40-36.5) for non-AL patients and an adjusted odds ratio of 6.97 (95% confidence interval, 1.33-36.5) for patients with leukocyte counts more than 100/mm3. A positive mycologic result was also more frequent among patients with lung CT scan signs of airway-invasive disease than among other patients (P = .043). Airway-invasive signs were more frequent among non-AL patients (P = .049), whereas angioinvasive disease was more frequent among both AL patients (P = .01) and patients with leukocyte counts less than 100/mm3 (P = .001). A concomitant pulmonary infection was identified more frequently among non-AL patients (P = .005 vs allogeneic hematopoietic stem cell transplant and P = .048 vs others). Our results suggest that different strategies for diagnosing IPA should be considered based on the underlying condition.
Published: 2012

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