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1. MS-CLAM: Mixed Supervision for the classification and localization of tumors in Whole Slide Images

Author

Paul Tourniaire, Marius Ilie, Paul Hofman, Nicholas Ayache, Hervé Delingette, Université Côte d'Azur (UCA), 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), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), and ANR-19-P3IA-0002,3IA@cote d'azur,3IA Côte d'Azur(2019)

Subjects
Camelyon16, Deep Learning, Radiological and Ultrasound Technology, Mixed Supervision, DigestPath2019, Digital Pathology, Health Informatics, Radiology, Nuclear Medicine and imaging, Computer Vision and Pattern Recognition, Computer Graphics and Computer-Aided Design, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI]
Abstract

International audience; Given the size of digitized Whole Slide Images (WSIs), it is generally laborious and time-consuming for pathologists to exhaustively delineate objects within them, especially with datasets containing hundreds of slides to annotate. Most of the time, only slide-level labels are available, giving rise to the development of weakly-supervised models. However, it is often difficult to obtain from such models accurate object localization, e.g., patches with tumor cells in a tumor detection task, as they are mainly designed for slide-level classification. Using the attention-based deep Multiple Instance Learning (MIL) model as our base weakly-supervised model, we propose to use mixed supervision-i.e., the use of both slide-level and patch-level labels-to improve both the classification and the localization performances of the original model, using only a limited amount of patch-level labeled slides. In addition, we propose an attention loss term to regularize the attention between key instances, and a paired batch method to create balanced batches for the model. First, we show that the changes made to the model already improve its performance and interpretability in the weakly-supervised setting. Furthermore, when using only between 12 and 62% of the total available patch-level annotations, we can reach performance close to fully-supervised models on the tumor classification datasets DigestPath2019 and Camelyon16.

Published
2023

2. Deep Learning Facilitates Distinguishing Histologic Subtypes of Pulmonary Neuroendocrine Tumors on Digital Whole-Slide Images

Author

Marius Ilié, Jonathan Benzaquen, Paul Tourniaire, Simon Heeke, Nicholas Ayache, Hervé Delingette, Elodie Long-Mira, Sandra Lassalle, Marame Hamila, Julien Fayada, Josiane Otto, Charlotte Cohen, Abel Gomez-Caro, Jean-Philippe Berthet, Charles-Hugo Marquette, Véronique Hofman, Christophe Bontoux, Paul Hofman, FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA), Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), Département Oncologie Médicale [Nice], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), 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), The University of Texas M.D. Anderson Cancer Center [Houston], UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), ANR-19-P3IA-0002,3IA@cote d'azur,3IA Côte d'Azur(2019), and ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015)

Subjects
Cancer Research, HALO-AI, lung, neuroendocrine carcinoma, deep learning, CNN, Oncology, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.CAN]Life Sciences [q-bio]/Cancer, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], respiratory tract diseases
Abstract

International audience; The histological distinction of lung neuroendocrine carcinoma, including small cell lung carcinoma (SCLC), large cell neuroendocrine carcinoma (LCNEC) and atypical carcinoid (AC), can be challenging in some cases, while bearing prognostic and therapeutic significance. To assist pathologists with the differentiation of histologic subtyping, we applied a deep learning classifier equipped with a convolutional neural network (CNN) to recognize lung neuroendocrine neoplasms. Slides of primary lung SCLC, LCNEC and AC were obtained from the Laboratory of Clinical and Experimental Pathology (University Hospital Nice, France). Three thoracic pathologists blindly established gold standard diagnoses. The HALO-AI module (Indica Labs, UK) trained with 18,752 image tiles extracted from 60 slides (SCLC = 20, LCNEC = 20, AC = 20 cases) was then tested on 90 slides (SCLC = 26, LCNEC = 22, AC = 13 and combined SCLC with LCNEC = 4 cases; NSCLC = 25 cases) by F1-score and accuracy. A HALO-AI correct area distribution (AD) cutoff of 50% or more was required to credit the CNN with the correct diagnosis. The tumor maps were false colored and displayed side by side to original hematoxylin and eosin slides with superimposed pathologist annotations. The trained HALO-AI yielded a mean F1-score of 0.99 (95% CI, 0.939–0.999) on the testing set. Our CNN model, providing further larger validation, has the potential to work side by side with the pathologist to accurately differentiate between the different lung neuroendocrine carcinoma in challenging cases.

Published
2022

3. Detection of ALK fusion transcripts in plasma of non-small cell lung cancer patients using a novel RT-PCR based assay

Author

Michel Poudenx, Radj Gervais, Juliette Thariat, Jonathan Benzaquen, Michael Lee, Charles-Hugo Marquette, Jacques Boutros, Fabrice Barlesi, Marius Ilie, Angelica Tiotiu, Véronique Hofman, Denis Moro-Sibilot, Ellen Ordinario, Julien Mazieres, Jacques Cadranel, Simon Heeke, Paul Hofman, Marc G. Denis, Virginie Tanga, Julien Fayada, Audrey Vallee, Jaya Rajamani, Maryline Allegra, Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Toulouse [Toulouse], Service de Pneumologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [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), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire [Grenoble] (CHU), Institut Gustave Roussy (IGR), Aix Marseille Université (AMU), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Université Nice Sophia Antipolis (1965 - 2019) (UNS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Pneumologie = Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], 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 Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), HAL-SU, Gestionnaire, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
circulating free RNA (cfRNA), reverse transcription PCR (RT-PCR), non-small cell lung cancer (NSCLC), Non-small cell lung cancer (NSCLC), [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Anaplastic lymphoma kinase, Multiplex, Liquid biopsy, Lung cancer, 030304 developmental biology, 0303 health sciences, liquid biopsy, business.industry, General Medicine, medicine.disease, 3. Good health, Reverse transcription polymerase chain reaction, Real-time polymerase chain reaction, anaplastic lymphoma kinase (ALK), 030220 oncology & carcinogenesis, Cancer research, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Immunohistochemistry, Original Article, business
Abstract

International audience; Background: Detection of genomic rearrangements, like anaplastic lymphoma kinase (ALK) fusions, is a pivotal requirement in non-small cell lung cancer (NSCLC) for the initiation of a targeted treatment. While tissue testing remains the gold standard, detection of these alterations using liquid biopsies is an unmet need. To enable the detection of ALK rearrangements from circulating-free RNA (cfRNA) from NSCLC patients, we have evaluated a novel reverse transcription PCR (RT-PCR) based assay.Methods: Sixty-six patients with advanced stage NSCLC were included in the study. ALK status was determined by immunohistochemistry (IHC) and/or FISH on tissue sections. For the detection of ALK rearrangements from 2ml plasma collected in EDTA or Streck BCT DNA tubes, cfRNA was extracted using a prototype cfRNA sample preparation method and tested by a novel multiplex ALK/RET RT-PCR assay (Roche).Results: Of the forty-two patients with an ALK rearrangement, 30 (71%) were included at baseline. In 10 of the baseline patients, an ALK rearrangement was detected by RT-PCR [baseline sensitivity 33.33% (95% CI: 17.29–52.81%)]. All 24 negative ALK IHC/FISH-negative patients were negative using the RT-PCR based assay (specificity =100%).Conclusions: The prototype Roche ALK/RET RT-PCR assay was able to detect ALK fusion transcripts in the plasma of NSCLC patients at baseline as well as at disease progression with limited sensitivity but high specificity. Consequently, this assay could potentially be considered to select patients for an ALK-targeting therapy when tissue samples are lacking.

Published
2021

4. Comparison of Three Sequencing Panels Used for the Assessment of Tumor Mutational Burden in NSCLC Reveals Low Comparability

Author

Charles-Hugo Marquette, Véronique Hofman, Olivier Bordone, Marius Ilie, Virginie Lespinet, Hervé Delingette, Paul Hofman, Simon Heeke, Jonathan Benzaquen, Elodie Long-Mira, Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC), Department of Pulmonology and Thoracic Oncology, Centre Hospitalier Universitaire de Nice, Centre Hospitalier Universitaire de Nice (CHU Nice), 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), ANR-19-P3IA-0002,3IA@cote d'azur,3IA Côte d'Azur(2019), ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI (2016), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), and ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015)

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Oncology, medicine.medical_specialty, Optimal cutoff, Lung Neoplasms, Immune checkpoint inhibitors, Population, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Carcinoma, Non-Small-Cell Lung, medicine, Biomarkers, Tumor, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, education, ComputingMilieux_MISCELLANEOUS, Predictive biomarker, education.field_of_study, Receiver operating characteristic, business.industry, High-Throughput Nucleotide Sequencing, 3. Good health, Patient population, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, business
Abstract

Introduction Tumor mutational burden (TMB) has been proposed as a novel predictive biomarker for the stratification of patients with NSCLC undergoing immune checkpoint inhibitor (ICI) treatment. The assessment of TMB has recently been established using large targeted sequencing panels, and numerous studies are ongoing to harmonize TMB assessment. "Correlation" or the coefficient of determination has generally been used to evaluate the association between different panels. We hypothesized that these metrics might overestimate the comparability, especially for lower TMB values. Methods A total of 30 samples from patients with NSCLC undergoing ICI treatment were consecutively sequenced using the following three large, targeted sequencing panels: FoundationOne, Oncomine TML, and QiaSeq TMB. The TMB values were compared in the whole patient population and in a subset of patients in which the TMB assessed by FoundationOne was between 5 and 25 mutations/Mb. Prediction of durable clinical benefit (>6 mo with no progression) was assessed using receiver operator characteristics, and optimal cutoff values were calculated using the Youden J statistic. Results Correlation between the three targeted sequencing panels was strong in the whole patient population (R2 > 0.79) but was dramatically reduced in the subset of patients with TMB of 5 to 25 mutations/Mb. The agreement assessed using the Bland-Altman method was also very low. All panels were able to predict durable clinical benefit in the TMB-high population. Conclusions Assessment of TMB using the three targeted sequencing panels was possible and predictive of response to ICI treatment, but correlation was an inappropriate measurement to assess the association between the respective panels.

Published
2020

5. Genetic alterations of malignant pleural mesothelioma: association to tumor heterogeneity and overall survival Author names

Author

Quetel, Lisa, Meiller, Clément, Assié, Jean-Baptiste, Blum, Yuna, Imbeaud, Sandrine, Montagne, François, Tranchant, Robin, de Wolf, Julien, Caruso, Stefano, Copin, Marie-Christine, Hofman, Véronique, Gibault, Laure, Badoual, Cecile, Pintilie, Ecaterina, Hofman, Paul, Monnet, Isabelle, Scherpereel, Arnaud, Le Pimpec-Barthes, Françoise, Zucman-Rossi, Jessica, Jaurand, Marie-Claude, Jean, Didier, 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), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Genexpress, Génomique Fonctionnelle et Biologie Systémique pour la Santé, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Institut de Pathologie [CHU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC), Service d'Anatomo-cytopathologie [Hôpital Européen Georges Pompidou - APHP], 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), Service de Chirurgie Thoracique [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Pneumologie et de Pathologie Professionnelle [CHI Créteil], CHI Créteil, Réseau National Expert pour le Mésothéliome Pleural Malin [Lille] (MESOCLIN), Pneumologie et Oncologie Thoracique [CHRU de Lille], PRES Université Lille Nord de France-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Albert Calmette-Faculté de Médecine Henri Warembourg, Service de Chirurgie Thoracique (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), This work was supported by Inserm, the Ligue Contre le Cancer (Ile de France committee and national program Cartes d’Identité des Tumeurs (CIT)), the Fondation ARC pour la recherche sur le cancer, Hadassah France, and the Chancellerie des Universités de Paris (Legs POIX). LQ, JBA, FM and JdW were supported by grants from Cancéropôle Région Île-de France, from Fondation pour la Recherche Médicale (FRM), from the Institut thématique multi-organismes (ITMO) Cancer (Plan Cancer 2014-2019) and from the Fondation ARC, respectively. JdW and FM were also supported by grant of the Société Française de Chirurgie Thoracique et Cardio-Vasculaire (SFCTCV). The Inserm research unit is supported by the Labex OncoImmunology (investissement d’avenir), Coup d’Elan de la Fondation Bettencourt-Shueller, the SIRIC CARPEM, the Institut thématique multi-organismes (ITMO) Cancer (Plan Cancer 2014-2019) and Cancéropôle Île-de-France., École Pratique des Hautes Études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), PRES Université Lille Nord de France-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Faculté de Médecine Henri Warembourg - Université de Lille-Hôpital Albert Calmette, and Jean, Didier

Subjects
tumor molecular classification, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Thoracic cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], tumor heterogeneity, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], prognosis, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, gene mutations
Abstract

International audience; Development of precision medicine for malignant pleural mesothelioma (MPM) requires a deep knowledge of tumor heterogeneity. Histologic and molecular classifications and histo-molecular gradients have been proposed to describe heterogeneity, but a deeper understanding of gene mutations in the context of MPM heterogeneity is required and the associations between mutations and clinical data need to be refined. We characterized genetic alterations on one of the largest MPM series (266 tumor samples), well-annotated with histologic, molecular and clinical data of patients. Targeted next generation sequencing was performed focusing on the major MPM mutated genes and the TERT promoter. Molecular heterogeneity was characterized using predictors allowing classification of each tumor into the previously described molecular subtypes and the determination of the proportion of epithelioïd-like and sarcomatoïd-like components (E/S.scores). The mutation frequencies are consistent with literature data, but this study emphasized that TERT promoter, not considered by previous large sequencing studies, was the third locus most affected by mutations in MPM. Mutations in TERT promoter, NF2 and LATS2 were more frequent in non-epithelioid MPM and positively associated to the S.score. BAP1, NF2, TERT promoter, TP53 and SETD2 mutations were enriched in some molecular subtypes. NF2 mutation rate was higher in asbestos unexposed patient. TERT promoter, NF2 and TP53 mutations were associated with a poorer overall survival. Our findings lead to a better characterization of MPM heterogeneity by identifying new significant associations between mutational status and histologic and molecular heterogeneity. Strikingly, we highlight the strong association between new mutations and overall survival.

Published
2020

6. Critical Assessment in Routine Clinical Practice of Liquid Biopsy for EGFR Status Testing in Non–Small-Cell Lung Cancer: A Single-Laboratory Experience (LPCE, Nice, France)

Author

Christelle Bonnetaud, Olivier Castelnau, Marius Ilie, Sylvie Leroy, Jonathan Benzaquen, Florian Cattet, Florence de Fraipont, Charles-Hugo Marquette, Simon Heeke, Fabrice Barlesi, Georges Garnier, Michel Poudenx, Charlotte Cohen, Isabelle Nanni, Lydia Ribeyre, Elodie Long-Mira, Loic Gazoppi, Carole Salacroup, Sandra Lassalle, Maryline Allegra, Paul Hofman, Marc G. Denis, Virginie Tanga, Julien Fayada, Jean-Philippe Berthet, Véronique Hofman, FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC), Centre Hospitalier Universitaire de Nice (CHU Nice), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre méditerranéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), Tumorothèque, Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire des Propriétés Mécaniques et Thermodynamiques des Matériaux (LPMTM), Centre National de la Recherche Scientifique (CNRS)-Institut Galilée-Université Paris 13 (UP13), Department of Medical Oncology, Centre Hospitalier Princesse Grasse, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSERM U823, équipe 5 (cibles diagnostiques ou thérapeutiques et vectorisation de drogues dans le cancer du poumon), CIC - Biotherapie - Lyon - Grenoble, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie thoracique et cardio-vasculaire, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve-Université de Montpellier (UM), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Canceropôle PACA, Conseil Départemental des Alpes Maritimes, ANR-11-LABX-0028-01, Agence Nationale de la Recherche, Ligue Départementale 06 contre le Cancer, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Hôpital Arnaud de Villeneuve-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Adult, Male, 0301 basic medicine, Pulmonary and Respiratory Medicine, Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Concordance, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Afatinib, 03 medical and health sciences, T790M, 0302 clinical medicine, Gefitinib, Carcinoma, Non-Small-Cell Lung, Internal medicine, Biopsy, medicine, Humans, Digital polymerase chain reaction, Osimertinib, Liquid biopsy, Lung cancer, Aged, Aged, 80 and over, medicine.diagnostic_test, Clinical Laboratory Techniques, business.industry, Liquid Biopsy, Reproducibility of Results, Middle Aged, medicine.disease, Non-invasive assay, 3. Good health, ErbB Receptors, 030104 developmental biology, Erlotinib, 030220 oncology & carcinogenesis, Mutation, Female, France, business, medicine.drug
Abstract

International audience; Background - The introduction of liquid biopsy using PCR-based assays into routine practice has had a strong impact on the treatment of EGFR-mutated lung adenocarcinoma and is now commonly used for routine testing of EGFR mutations in certain clinical settings. To assess whether the claimed benefits of PCR-based assays hold true in daily practice at a multicenter clinical institution, we assessed how treatment decisions are affected by PCR-based assays for the analysis of EGFR mutations from plasma samples in a centralized laboratory (LPCE, Nice, France). Patients and methods - A total of 345 samples were analyzed using the US Food and Drug Administration-approved Cobas EGFR Mutation Test v2 and 103 using the Therascreen EGFR Plasma RGQ PCR Kit over 3 years (395 samples from 324 patients). Eleven plasma samples were validated independently using Cobas at 3 institutions, and 130 samples were analyzed using Stilla digital PCR. Clinical data were collected for 175 (54%) of 324 patients. Results - Cobas was superior to the Therascreen assay and demonstrated 100% reproducibility. Digital PCR showed only 48%, 83%, and 58% concordance with Cobas for exon 19 deletions, L858R mutations, and T790M mutations, respectively. Liquid biopsies helped inform and change treatment when resistance occurred and enabled the detection of EGFR mutations in patients when biopsy tissue results were unavailable. Conclusion - PCR-based assays are a fast and convenient test, allowing the detection of primary and secondary EGFR mutations from plasma. Cobas proved to be a reliable test, whereas digital PCR produced too many inconclusive results to be currently recommended as a principal testing device.

Published
2020

7. Multicenter Evaluation of a Novel ROS1 Immunohistochemistry Assay (SP384) for Detection of ROS1 Rearrangements in a Large Cohort of Lung Adenocarcinoma Patients

Author

Sandra Lassalle, Jean-Christophe Sabourin, Elodie Long-Mira, Julien Mazieres, Frédéric Bibeau, Michel Poudenx, Salomé Lalvée, Jonathan Benzaquen, Charles-Hugo Marquette, Jean Michel Vignaud, Paul Hofman, Simon Heeke, Hugues Begueret, Katia Zahaf, Anne-Laure Lepage, Nicolas Piton, Emmanuel Chamorey, Clémence Yguel, Marius Ilie, Véronique Hofman, Isabelle Rouquette, FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), CHU Toulouse [Toulouse], Département de Pathologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Département de Pathologie [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), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de pathologie [Bordeaux], and Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Oncology, Lung adenocarcinoma, medicine.medical_specialty, Lung Neoplasms, Interclass correlation, Clone (cell biology), Adenocarcinoma of Lung, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Proto-Oncogene Proteins, Internal medicine, Biomarkers, Tumor, medicine, ROS1, Humans, D4D6, In Situ Hybridization, Fluorescence, Retrospective Studies, Gene Rearrangement, medicine.diagnostic_test, business.industry, Molecular pathology, Fluorescence in situ hybridization, Gold standard (test), Protein-Tyrosine Kinases, Prognosis, medicine.disease, Immunohistochemistry, SP384, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Adenocarcinoma, business, Follow-Up Studies
Abstract

Introduction The detection of a ROS1 rearrangement in advanced and metastatic lung adenocarcinoma (LUAD) led to a targeted treatment with tyrosine kinase inhibitors with favorable progression-free survival and overall survival of the patients. Thus, it is mandatory to screen for the ROS1 rearrangement in all these patients. ROS1 rearrangements can be detected using break-apart fluorescence in situ hybridization (FISH), which is the gold standard; however, ROS1 immunohistochemistry (IHC) can be used as a screening test because it is widely available, easy and rapid to perform, and cost-effective. Methods We evaluated the diagnostic accuracy and interpathologist agreement of two anti-ROS1 IHC clones, SP384 (Ventana, Tucson, Arizona) and D4D6 (Cell Signaling, Danvers, Massachusetts), in a training cohort of 51 positive ROS1 FISH LUAD cases, and then in a large validation cohort of 714 consecutive cases of LUAD from six routine molecular pathology platforms. Results In the two cohorts, the SP384 and D4D6 clones show variable sensitivity and specificity rates on the basis of two cutoff points greater than or equal to 1+ (all % tumor cells) and greater than or equal to 2+ (>30% stained tumor cells). In the validation cohort, the D4D6 yielded the best accuracy for the presence of a ROS1 rearrangement by FISH. Interpathologist agreement was moderate to good (interclass correlation 0.722–0.874) for the D4D6 clone and good to excellent (interclass correlation: 0.830–0.956) for the SP384 clone. Conclusions ROS1 IHC is an effective screening tool for the presence of ROS1 rearrangements. However, users must be acutely aware of the variable diagnostic performance of different anti-ROS1 antibodies before implementation into routine clinical practice.

Published
2019

8. The OncoAge Consortium: Linking Aging and Oncology from Bench to Bedside and Back Again

Author

Hofman, Paul, Ayache, Nicholas, Barbry, Pascal, Barlaud, Michel, Bel, Audrey, Blancou, Philippe, Checler, Frédéric, Chevillard, Sylvie, Cristofari, Gael, Demory, Mathilde, Esnault, Vincent, Falandry, Claire, Gilson, Eric, Guerin, Olivier, Glaichenhaus, Nicolas, Guigay, Joël, Ilie, Marius, Mari, Bernard, Marquette, Charles-Hugo, Paquis-Flucklinger, Véronique, Prate, Frédéric, Saintigny, Pierre, Seitz-Polsky, Barbara, Skhiri, Taycir, van Obberghen-Schilling, Ellen, Obberghen, Emmanuel, Yvan-Charvet, Laurent, Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), 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), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia-Antipolis (I3S) / Projet MEDIACODING, Signal, Images et Systèmes (Laboratoire I3S - SIS), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre d’Innovation et d’Usages en Santé (CIUS), Laboratoire de Cancérologie Expérimentale (LCE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Département de Néphrologie - Hôpital Pasteur [Nice], Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), 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), Hôpital de Cimiez, pôle Gériatrie Gérontologie, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis - Faculté de Médecine (UNS UFR Médecine), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Institut de Biologie Valrose (IBV), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de PhysioMédecine Moléculaire (LP2M), Centre méditerranéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice, Ligue Departementale des Alpes Maritimes de Lutte contre le Cancer, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), and École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
education, research, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, well-being, Perspective, aging, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, cancer, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, optimization, elderly, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation
Abstract

International audience; It is generally accepted that carcinogenesis and aging are two biological processes, which are known to be associated. Notably, the frequency of certain cancers (including lung cancer), increases significantly with the age of patients and there is now a wealth of data showing that multiple mechanisms leading to malignant transformation and to aging are interconnected, defining the so-called common biology of aging and cancer. OncoAge, a consortium launched in 2015, brings together the multidisciplinary expertise of leading public hospital services and academic laboratories to foster the transfer of scientific knowledge rapidly acquired in the fields of cancer biology and aging into innovative medical practice and silver economy development. This is achieved through the development of shared technical platforms (for research on genome stability, (epi)genetics, biobanking, immunology, metabolism, and artificial intelligence), clinical research projects, clinical trials, and education. OncoAge focuses mainly on two pilot pathologies, which benefit from the expertise of several members, namely lung and head and neck cancers. This review outlines the broad strategic directions and key advances of OncoAge and summarizes some of the issues faced by this consortium, as well as the short-and long-term perspectives.

Published
2019

9. Lung Cancer Screening, towards a Multidimensional Approach: Why and How?

Author

Jacques Boutros, Hervé Delingette, Paul Hofman, C.-H. Marquette, Jonathan Benzaquen, Centre Hospitalier Universitaire de Nice (CHU Nice), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), 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), Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
Cancer Research, medicine.medical_specialty, Context (language use), Computed tomography, Review, lcsh:RC254-282, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, law, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, 030212 general & internal medicine, Risk factor, Intensive care medicine, Lung cancer, medicine.diagnostic_test, business.industry, screening, medicine.disease, artificial intelligence, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, 3. Good health, lung cancer, Oncology, Computer-aided diagnosis, 030220 oncology & carcinogenesis, Risk assessment, business, Lung cancer screening
Abstract

International audience; Early-stage treatment improves prognosis of lung cancer and two large randomized controlled trials have shown that early detection with low-dose computed tomography (LDCT) reduces mortality. Despite this, lung cancer screening (LCS) remains challenging. In the context of a global shortage of radiologists, the high rate of false-positive LDCT results in overloading of existing lung cancer clinics and multidisciplinary teams. Thus, to provide patients with earlier access to life-saving surgical interventions, there is an urgent need to improve LDCT-based LCS and especially to reduce the false-positive rate that plagues the current detection technology. In this context, LCS can be improved in three ways: (1) by refining selection criteria (risk factor assessment), (2) by using Computer Aided Diagnosis (CAD) to make it easier to interpret chest CTs, and (3) by using biological blood signatures for early cancer detection, to both spot the optimal target population and help classify lung nodules. These three main ways of improving LCS are discussed in this review.

Published
2019

10. In-House Implementation of Tumor Mutational Burden Testing to Predict Durable Clinical Benefit in Non-Small Cell Lung Cancer and Melanoma Patients

Author

Benoît Audelan, Henri Montaudié, Jonathan Benzaquen, Simon Heeke, Hervé Delingette, Charles-Hugo Marquette, Olivier Bordone, Marius Ilie, Salomé Lalvée, Michel Poudenx, Elodie Long-Mira, Véronique Hofman, Albrecht Stenzinger, Olivier Humbert, Pierre-Michel Dugourd, Katia Zahaf, Thierry Passeron, Paul Hofman, Madleen Chassang, Virginie Lespinet, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Institute of research on Cancer and Aging (IRCAN), Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Department of Pulmonology and Thoracic Oncology, Centre Hospitalier Universitaire de Nice, Centre Hospitalier Universitaire de Nice (CHU Nice), 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), Department of Oncology, Antoine Lacassagne Comprehensive Cancer Center, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Department of Nuclear Medicine, Antoine Lacassagne Comprehensive Cancer Center, Department of Dermatology, Archet II Hospital, Centre Hospitalier Universitaire de Nice, Centre Hospitalier Universitaire de Nice (CHU de Nice), Department of Radiology, Archet 2 Hospital, Centre Hospitalier Universitaire de Nice, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institute of Pathology, University Hospital Heidelberg, University Hospital Heidelberg, Center for Personalized Oncology (DKFZ-HIPO), Deutsches Krebsforschungszentrum (DKFZ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Audelan, Benoît

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, tumor mutational burden, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Article, Oncomine TML assay, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, FoundationOne assay, Internal medicine, medicine, melanoma, Lung cancer, neoplasms, business.industry, Melanoma, Immunotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, lung cancer, 030104 developmental biology, 030220 oncology & carcinogenesis, Potential biomarkers, Cohort, Immunohistochemistry, Non small cell, immunotherapy, business, Progressive disease
Abstract

Tumor mutational burden (TMB) has emerged as an important potential biomarker for prediction of response to immune-checkpoint inhibitors (ICIs), notably in non-small cell lung cancer (NSCLC). However, its in-house assessment in routine clinical practice is currently challenging and validation is urgently needed. We have analyzed sixty NSCLC and thirty-six melanoma patients with ICI treatment, using the FoundationOne test (FO) in addition to in-house testing using the Oncomine TML (OTML) panel and evaluated the durable clinical benefit (DCB), defined by &gt, 6 months without progressive disease. Comparison of TMB values obtained by both tests demonstrated a high correlation in NSCLC (R2 = 0.73) and melanoma (R2 = 0.94). The association of TMB with DCB was comparable between OTML (area-under the curve (AUC) = 0.67) and FO (AUC = 0.71) in NSCLC. Median TMB was higher in the DCB cohort and progression-free survival (PFS) was prolonged in patients with high TMB (OTML HR = 0.35, FO HR = 0.45). In contrast, we detected no differences in PFS and median TMB in our melanoma cohort. Combining TMB with PD-L1 and CD8-expression by immunohistochemistry improved the predictive value. We conclude that in our cohort both approaches are equally able to assess TMB and to predict DCB in NSCLC.

Published
2019

11. Fibronectin-guided migration of carcinoma collectives

Author

Shelia M. Violette, Paul H. Weinreb, Stéphanie Beghelli-de la Forest Divonne, Marius Ilie, Stéphane Audebert, Agata Radwanska, Dominique Grall, Emilie Baudelet, Anne Sudaka, Catherine Butori, Samah Rekima, Sandeep Gopal, Ellen Van Obberghen-Schilling, Luc Camoin, Sébastien Schaub, Laurence Veracini, Paul Hofman, Audebert, Stéphane, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de signalisation, biologie du développement et cancer (ISBDC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biogen [Cambridge, USA], Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Laboratory of Clinical and Experimental Pathology, Louis Pasteur Hospital, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Pathologie Clinique et Expérimentale, Centre Hospitalier Universitaire de Nice (CHU Nice), and Human Biobank CHUN

Subjects
0301 basic medicine, Adult, Male, Integrins, Science, Cell, Integrin, General Physics and Astronomy, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Biochemistry, Genetics and Molecular Biology, Article, Extracellular matrix, 03 medical and health sciences, Stroma, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Movement, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Carcinoma, medicine, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Fibroblast, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Aged, Aged, 80 and over, Multidisciplinary, biology, Squamous Cell Carcinoma of Head and Neck, General Chemistry, Middle Aged, medicine.disease, Cell biology, Extracellular Matrix, Fibronectins, Fibronectin, Gene Expression Regulation, Neoplastic, 030104 developmental biology, medicine.anatomical_structure, Cell culture, Head and Neck Neoplasms, biology.protein, Carcinoma, Squamous Cell, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female
Abstract

Functional interplay between tumour cells and their neoplastic extracellular matrix plays a decisive role in malignant progression of carcinomas. Here we provide a comprehensive data set of the human HNSCC-associated fibroblast matrisome. Although much attention has been paid to the deposit of collagen, we identify oncofetal fibronectin (FN) as a major and obligate component of the matrix assembled by stromal fibroblasts from head and neck squamous cell carcinomas (HNSCC). FN overexpression in tumours from 435 patients corresponds to an independent unfavourable prognostic indicator. We show that migration of carcinoma collectives on fibrillar FN-rich matrices is achieved through αvβ6 and α9β1 engagement, rather than α5β1. Moreover, αvβ6-driven migration occurs independently of latent TGF-β activation and Smad-dependent signalling in tumour epithelial cells. These results provide insights into the adhesion-dependent events at the tumour–stroma interface that govern the collective mode of migration adopted by carcinoma cells to invade surrounding stroma in HNSCC., Tumour microenvironment influences the migration of cancer cells. Here the authors analyse the proteomic constitution of the extracellular matrix and identify a role for fibronectin in regulating the collective migration of squamous cell carcinoma cells.

Published
2017

12. Why and how immunohistochemistry should now be used to screen for the BRAFV600E status in metastatic melanoma? The experience of a single institution (LCEP, Nice, France)

Author

Kevin Washetine, Elodie Long, Marius Ilie, Sandra Lassalle, Paul Hofman, Philippe Bahadoran, Jérôme Mouroux, Pierre Laurent-Puig, Gilles Poissonnet, Virginie Lespinet, Véronique Hofman, Catherine Butori, Jean-Philippe Lacour, Valérie Taly, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Infection bactérienne, inflammation, et carcinogenèse digestive, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), Université Côte d'Azur (UCA)-UNICANCER, Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), Service de Dermatologie [Nice], Hôpital Archet 2 [Nice] (CHU), 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), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Clinical and Experimental Pathology, UNICANCER-Université Côte d'Azur (UCA), Centre Universitaires des Saints-Pères, Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Antoine Lacassagne, TALY, Valerie, and Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
Adult, Proto-Oncogene Proteins B-raf, Pathology, medicine.medical_specialty, Skin Neoplasms, Time Factors, Adolescent, Formalin fixed paraffin embedded, Metastatic melanoma, [SDV]Life Sciences [q-bio], Nice, Dermatology, Sensitivity and Specificity, Young Adult, Humans, Medicine, Single institution, Predictive testing, Melanoma, ComputingMilieux_MISCELLANEOUS, Aged, computer.programming_language, Aged, 80 and over, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Sequence Analysis, DNA, Gold standard (test), Middle Aged, Immunohistochemistry, 3. Good health, Staining, [SDV] Life Sciences [q-bio], Infectious Diseases, Costs and Cost Analysis, Female, France, business, computer, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Knowledge of the BRAFV600E status is mandatory in metastatic melanoma patients (MMP). Molecular biology is currently the gold standard method for status assessment. Objectives We assessed and compared the specificity, sensibility, cost-effectiveness and turnaround time (TAT) of immunohistochemistry (IHC) and molecular biology for detection of the BRAFV600E mutation in 188 MMP. Methods IHC, with the VE1 antibody, and pyrosequencing analysis were performed with formalin fixed paraffin embedded tumour samples. Results The BRAFV600E mutation was detected by pyrosequencing in 91/188 (48%) patients. IHC was strongly positive (3+) in all of these 91 cases. IHC was strongly positive in 9/188 (5%) cases in which the molecular testing failed due to non-amplifiable DNA. Weak or moderate staining was noted in 10/188 (5%) cases in which the molecular biology identified BRAF wild-type tumours. The ratio of the global cost for IHC/molecular biology testing was 1 : 2.2. The average TAT was 48 h vs. 96 h, for IHC vs. molecular biology testing, respectively. Conclusions This study showed that VE1 IHC should be a substitute for molecular biology in the initial assessment of the BRAFV600E status in MPP. This methodology needs to be set up in pathology laboratories in accordance with quality control/quality assurance accreditation procedures. Under these strict conditions the question is to know if BRAFV600E-IHC can serve not only as a prescreening tool, but also as a stand-alone test (at least in cases displaying an unequivocally staining pattern) as well as an alternative predictive test for samples for which the molecular biology failed.

Published
2015

13. BRAFV600E mutation analysis by immunohistochemistry in patients with thoracic metastases from colorectal cancer

Author

Marius Ilie, Elodie Long-Mira, Xavier Hébuterne, Paul Hofman, Jean-Philippe Merlio, Jean-François Emile, Guillaume Gauchotte, Jean-Michel Vignaud, Hugues Begueret, Jérôme Mouroux, Véronique Hofman, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Human Biobank CHUN, Hôpital Pasteur [Nice] (CHU), Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], L'Association pour la Recherche contre le Cancer (ARC), Service de Chirurgie thoracique, Centre Hospitalier Universitaire de Nice (CHU Nice), Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Département de pathologie [Hôpital Haut Lévêque], Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux]-CHU Bordeaux [Bordeaux], Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Service de gastroentérologie, and Hôpital l'Archet

Subjects
Oncology, Male, Proto-Oncogene Proteins B-raf, medicine.medical_specialty, endocrine system diseases, Colorectal cancer, [SDV]Life Sciences [q-bio], Population, DNA Mutational Analysis, Adenocarcinoma, medicine.disease_cause, Sensitivity and Specificity, Pathology and Forensic Medicine, symbols.namesake, BRAFV600E mutation, Internal medicine, medicine, Biomarkers, Tumor, Humans, skin and connective tissue diseases, education, neoplasms, Aged, Sanger sequencing, Aged, 80 and over, education.field_of_study, business.industry, Antibodies, Monoclonal, Middle Aged, Thoracic Neoplasms, medicine.disease, Prognosis, targeted therapy, digestive system diseases, 3. Good health, enzymes and coenzymes (carbohydrates), Monoclonal, immunohistochemistry, Cancer research, Mutation testing, symbols, Immunohistochemistry, Female, KRAS, business, Colorectal Neoplasms, V600E, metastatic colorectal carcinoma
Abstract

The BRAF(V600E) mutation confers worse prognosis to metastatic colorectal cancer (mCRC) patients. In addition, this mutation has a negative predictive value for response to treatment with monoclonal antibodies against EGFR in patients with KRAS wild-type (wt) mCRC. The utility of immunohistochemistry (IHC) as an alternative approach for detection of BRAF(V600E) in the thoracic metastases of sporadic mCRC patients has not been evaluated until now. The purpose of this study was to compare BRAF(V600E) IHC staining with molecular biology methods and to define the diagnostic value of the VE1 antibody for the detection of BRAF(V600E) in this population. BRAF mutations were analysed by two DNA sequencing methods (pyrosequencing and Sanger sequencing) in a Caucasian population of 310 sporadic mCRC with thoracic metastases patients expressing KRAS wt. Detection of the BRAF(V600E) mutation was performed in the corresponding tumours by IHC using the VE1 antibody and compared to results of the DNA-based assays. Thirty-nine out of 310 (13%) of tumours harboured a BRAF mutation, which corresponded to either a BRAF(V600E) in 34 of 310 (11%) cases or a non-BRAF(V600E) mutation in 5 of 310 (2%) cases. IHC with VE1 was strongly positive in 32 of 34 (88%) BRAF(V600E) mutated tumours and negative in non-BRAF(V600E) mutated tumours. IHC using the VE1 clone is a specific and sensitive method for the detection of BRAF(V600E) and may be either a complementary or an alternative method to molecular testing in mCRC patients.

Published
2014

14. 'Sentinel' Circulating Tumor Cells Allow Early Diagnosis of Lung Cancer in Patients with Chronic Obstructive Pulmonary Disease

Author

Marius Ilie, Elodie Long-Mira, Eric Selva, Jean-Michel Vignaud, Bernard Padovani, Véronique Hofman, Paul Hofman, Charles-Hugo Marquette, Jérôme Mouroux, Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), Human Biobank CHUN, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Imagerie Médicale, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Hôpital Pasteur [Nice] (CHU), Service de Chirurgie Thoracique [Pasteur-Nice], Service de Pneumologie [Pasteur-Nice], UL, NGERE, and Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
Male, Oncology, Pathology, Lung Neoplasms, Pulmonology, Respiratory System, lcsh:Medicine, medicine.disease_cause, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Lung and Intrathoracic Tumors, Metastasis, Pulmonary Disease, Chronic Obstructive, Circulating tumor cell, Invasion, Medicine and Health Sciences, lcsh:Science, Early Detection of Cancer, Aged, 80 and over, COPD, Multidisciplinary, Statistics, Middle Aged, Neoplastic Cells, Circulating, Immunohistochemistry, 3. Good health, medicine.anatomical_structure, Blood, Female, Anatomy, Research Article, Adult, Risk, medicine.medical_specialty, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.CAN]Life Sciences [q-bio]/Cancer, Interstitial Lung Diseases, Senescence, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Risk factor, Mortality, Lung cancer, Aged, Lung, business.industry, lcsh:R, Biology and Life Sciences, Cancers and Neoplasms, Cancer, medicine.disease, Molecular Insights, respiratory tract diseases, Tumorigenesis, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, lcsh:Q, Lungs, Carcinogenesis, business
Abstract

International audience; Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. Migration of circulating tumor cells (CTCs) into the blood stream is an early event that occurs during carcinogenesis. We aimed to examine the presence of CTCs in complement to CT-scan in COPD patients without clinically detectable lung cancer as a first step to identify a new marker for early lung cancer diagnosis. The presence of CTCs was examined by an ISET filtration-enrichment technique, for 245 subjects without cancer, including 168 (68.6%) COPD patients, and 77 subjects without COPD (31.4%), including 42 control smokers and 35 non-smoking healthy individuals. CTCs were identified by cytomorphological analysis and characterized by studying their expression of epithelial and mesenchymal markers. COPD patients were monitored annually by low-dose spiral CT. CTCs were detected in 3% of COPD patients (5 out of 168 patients). The annual surveillance of the CTC-positive COPD patients by CT-scan screening detected lung nodules 1 to 4 years after CTC detection, leading to prompt surgical resection and histopathological diagnosis of early-stage lung cancer. Follow-up of the 5 patients by CT-scan and ISET 12 month after surgery showed no tumor recurrence. CTCs detected in COPD patients had a heterogeneous expression of epithelial and mesenchymal markers, which was similar to the corresponding lung tumor phenotype. No CTCs were detected in control smoking and non-smoking healthy individuals. CTCs can be detected in patients with COPD without clinically detectable lung cancer. Monitoring ''sentinel'' CTC-positive COPD patients may allow early diagnosis of lung cancer.

Published
2014

15. EBV Infection Is Common in Gingival Epithelial Cells of the Periodontium and Worsens during Chronic Periodontitis

Author

Alain Doglio, Isabelle Prêcheur, Caroline C. Mouline, Patrick Mahler, Janet L. Maryanski, Séverine Vincent-Bugnas, Yves Charbit, Paul Hofman, Wafa Khaali, Sébastien Vitale, Microbiologie Orale, Immunothérapie et Santé (MICORALIS), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), Unité de Thérapie Cellulaire et Génique [CHU Nice] (UTCG), Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), Centre population et développement (CEPED - UMR_D 196), Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5), Université Henri Poincaré - Nancy 1 (UHP), Université Nice Sophia Antipolis - Faculté de Chirurgie Dentaire (UNS UFR Odontologie), This work was supported in part by the Centre Hospitalier de Nice [AOI N°2010-A01119-30 to SVB] and the Agence Nationale de Recherche contre le SIDA [ANRS N° 10338 to AD]. SV was the recipient of a fellowship from Sidaction, and CCM was the recipient of a fellowship from the Agence Nationale de Recherche [ANR-2010-RFCS-007-02 to AD]., The authors aknowledge the IRCAN Cellular and Molecular Imaging (PICMI) platform, the Institut Fédératif de Recherche (IFR50), the GEPITO laboratory, and the Laboratoire d'Anatomie Cytologie Pathologique du CHU de Nice for helpful access to facilities and equipment for confocal microscopy, microscopy, qPCR and cytocentrifugation, respectively. We thank the statistical department from the CHU de Nice (Eric Fontas) for helpful guidance and interpretation of statistical analysis. We are very grateful to S. Gottshalk and C.Rooney for gift of recombinant Ad5F35 vectors and for helpful discussion., and Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)

Subjects
Male, Periodontium, Chemokine, Epstein-Barr Virus Infections, MESH: Epithelial Cells/virology, [SDV]Life Sciences [q-bio], Gingiva, Apoptosis, Epithelial cells, medicine.disease_cause, Epithelium, 0302 clinical medicine, hemic and lymphatic diseases, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Aged, 0303 health sciences, Multidisciplinary, MESH: Middle Aged, biology, Reverse Transcriptase Polymerase Chain Reaction, Middle Aged, MESH: Chronic Periodontitis/virology, Cell staining, 3. Good health, MESH: Gingiva/virology, MESH: Epstein-Barr Virus Infections/virology, Medicine, Female, Research Article, Science, In Vitro Techniques, 03 medical and health sciences, medicine, Humans, Epstein-Barr virus, Viral shedding, Periodontitis, Epstein–Barr virus infection, 030304 developmental biology, Aged, MESH: In Vitro Techniques, B cells, Reverse transcriptase-polymerase chain reaction, MESH: Humans, 030206 dentistry, medicine.disease, Epstein–Barr virus, Chronic periodontitis, MESH: Male, CCL20, Immunology, Chronic Periodontitis, biology.protein, MESH: Female, MESH: Periodontium/virology
Abstract

International audience; An amplifying role for oral epithelial cells (ECs) in Epstein-Barr Virus (EBV) infection has been postulated to explain oral viral shedding. However, while lytic or latent EBV infections of oro/nasopharyngeal ECs are commonly detected under pathological conditions, detection of EBV-infected ECs in healthy conditions is very rare. In this study, a simple non-surgical tissue sampling procedure was used to investigate EBV infection in the periodontal epithelium that surrounds and attaches teeth to the gingiva. Surprisingly, we observed that the gingival ECs of the periodontium (pECs) are commonly infected with EBV and may serve as an important oral reservoir of latently EBV-infected cells. We also found that the basal level of epithelial EBV-infection is significantly increased in chronic periodontitis, a common inflammatory disease that undermines the integrity of tooth-supporting tissues. Moreover, the level of EBV infection was found to correlate with disease severity. In inflamed tissues, EBV-infected pECs appear to be prone to apoptosis and to produce larger amounts of CCL20, a pivotal inflammatory chemokine that controls tissue infiltration by immune cells. Our discovery that the periodontal epithelium is a major site of latent EBV infection sheds a new light on EBV persistence in healthy carriers and on the role of this ubiquitous virus in periodontitis. Moreover, the identification of this easily accessible site of latent infection may encourage new approaches to investigate and monitor other EBV-associated disorders.

Published
2013

16. Measuring the contribution of tumor biobanks to research in oncology: Surrogate indicators and bibliographic output

Author

Anne Cambon-Thomsen, Véronique Hofman, Marius Ilie, Christian Chabannon, Paul Hofman, Bruno Clément, Barbara Parodi, Laurence Mabile, Georges Dagher, Dominique Figarella-Branger, Elodie Long, Robert Hewitt, Pascal Boucher, Kevin Washetine, Hospital-Integrated Tumor Biobank [Hôpital Pasteur, Sophia Antipolis], Pasteur Hospital, Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), Centre de Ressources Biologiques en Oncologie, Biobank [Paoli-Calmettes Institute, Marseille], Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de pathologie [AP-HM Hôpital La Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Foie, métabolismes et cancer, 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 ), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-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), Institut National du Cancer [Boulogne Billancourt] (INC), European, Middle Eastern and African Society, Biopreservation and Biobanking, IRCCS Azienda Ospedaliera Universitaria Integrata San Martino (IRCCS AOU San Martino), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), 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 Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Infrastructure Nationale des Biobanques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Mabile, Laurence

Subjects
Quality Control, Resource (biology), [SDV]Life Sciences [q-bio], Medicine (miscellaneous), [SDV.CAN]Life Sciences [q-bio]/Cancer, Tissue Banks, General Biochemistry, Genetics and Molecular Biology, Translational Research, Biomedical, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Humans, Medicine, 030304 developmental biology, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Cell Biology, General Medicine, Biobank, Data science, Hospitals, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Journal Impact Factor, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; The number of biobanks, in particular hospital-integrated tumor biobanks (HITB), is increasing all around the world. This is the consequence of an increase in the need for human biological resources for scientific projects and more specifically, for translational and clinical research. The robustness and reproducibility of the results obtained depend greatly on the quality of the biospecimens and the associated clinical data. They also depend on the number of patients studied and on the expertise of the biobank that supplied the biospecimens. The quality of a research biobank is undoubtedly reflected in the number and overall quality of the research projects conducted with biospecimens provided by the biobank. Since the quality of a research project can be measured from the impact factor of resulting publications, this also provides some indication of the quality of a research biobank. It is necessary for the biobank community to define "surrogate" quality indicators, and to establish systems of evaluation in relation to current and future resource requirements. These indicators will help in the realistic assessment of biobanks by institutions and funding bodies, and they will help biobanks demonstrate their value, raise their quality standards, and compete for funding. Given that biobanks are expensive structures to maintain, funding issues are particularly important, especially in the current economic climate. Use of performance indicators may also contribute to the development of a biobank impact factor or "bioresource research impact factor" (BRIF). Here we review four major categories of indicators that appear to be useful for the evaluation of a(m) HITB (quality, activity, scientific productivity, and "visibility"). In addition, we propose a scoring system to measure the chosen indicators.

Published
2013

17. Autophagy : Moving benchside promises to patient bedsides

Author

Harilaos Filippakis, Baharia Mograbi, Patrick Brest, Paul Hofman, Yacine Graba, Papa Diogop Ndiaye, Jérémie Roux, Amine Belaid, Eric Rottinger, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Infection bactérienne, inflammation, et carcinogenèse digestive, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR50-Université Côte d'Azur (UCA), Laboratoire de Pathologie Clinique et Expérimentale. Hôpital Pasteur [Nice], Hôpital Pasteur [Nice] (CHU), Human Tissue Biobank Unit [CHU Nice], Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), and Röttinger, Eric

Subjects
Cancer Research, tumor dormancy, Cancer therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Tumor initiation, Biology, Metastasis, law.invention, 03 medical and health sciences, 0302 clinical medicine, translational medicine, Drug Delivery Systems, [SDV.CAN] Life Sciences [q-bio]/Cancer, law, Signaling proteins, Neoplasms, Drug Discovery, medicine, Autophagy, autophagy addiction/KRAS/BRAF-driven cancers, Humans, Neoplasm Metastasis, 030304 developmental biology, Pharmacology, 0303 health sciences, tumor metastasis, tumor relapse, Cancer, medicine.disease, tumor resistance, 3. Good health, Oncology, Point-of-Care Testing, 030220 oncology & carcinogenesis, Immunology, Cancer research, Suppressor, tumor metabolism, Neoplasm Recurrence, Local, Antineoplastic agents/drug effects/autophagy targeted therapy
Abstract

International audience; Survival rates of patients with metastatic or recurrent cancers have remained virtually unchanged during the past 30 years. This fact makes the need for new therapeutic options even more urgent. An attractive option would be to target autophagy, an essential quality control process that degrades toxic aggregates, damaged organelles, and signaling proteins, and acts as a tumor suppressor pathway of tumor initiation. Conversely, other fascinating observations suggest that autophagy supports cancer progression, relapse, metastasis, dormancy and resistance to therapy. This review provides an overview of the contradictory roles that autophagy plays in cancer initiation and progression and discusses the promises and challenges of current strategies that target autophagy for cancer therapy.

19. [Antiretroviral treatments-related lipodystrophy syndrome: clinico-pathological findings].

Author

Lassalle S, Cervera P, Hofman V, Mari M, Dellamonica P, and Hofman P

Subjects
Acquired Immunodeficiency Syndrome pathology, Adipocytes drug effects, Adipocytes pathology, HIV Infections drug therapy, HIV Protease Inhibitors adverse effects, HIV Seropositivity pathology, HIV-Associated Lipodystrophy Syndrome chemically induced, Humans, Reverse Transcriptase Inhibitors adverse effects, Acquired Immunodeficiency Syndrome drug therapy, Antiretroviral Therapy, Highly Active adverse effects, HIV-Associated Lipodystrophy Syndrome pathology
Abstract

Effective therapies are available that can stop or slow down the progression of HIV infection. Highly active antiretroviral therapy (HAART) is a combination of antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors. Among the side effects due to these drugs, lipodystrophy is a pathology characterized by fat wasting in face and limbs, accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia (hypertriglyceridemia and hypercholesterolemia), insulin resistance, and lactic acidemia. The main clinical features include peripheral fat loss (presumed lipoatrophy in the face, limbs, and buttocks) and central fat accumulation (within the abdomen, breasts, and over the dorsocervical spine, so-called "buffalo hump"). Histopathological features disclose a peculiar type of involutional lipodystrophy. Skin biopsies generally show thinning of the subcutaneous fat, associated with fibrosis, lipogranuloma and sometimes vessel proliferation. There is still an open debate concerning the precise responsibility of HAART as well as the metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. There is no proven therapy for any component of lipodystrophy syndrome.

Published
2005
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20. [Disseminated pulmonary infection due to Cryptococcus neoformans in a non immunocompromised patient].

Author

Hofman V, Venissac N, Mouroux C, Butori C, Mouroux J, and Hofman P

Subjects
Adult, Amphotericin B therapeutic use, Antifungal Agents therapeutic use, Biopsy, Cryptococcosis diagnostic imaging, Cryptococcosis drug therapy, Cryptococcosis immunology, Diagnosis, Differential, Humans, Immunocompetence, Lung microbiology, Lung ultrastructure, Lung Diseases, Fungal diagnostic imaging, Lung Diseases, Fungal drug therapy, Male, Radiography, Treatment Outcome, Cryptococcosis pathology, Cryptococcus neoformans isolation & purification, Lung pathology, Lung Diseases, Fungal pathology
Abstract

We report a case of a primary pulmonary infection due to Cryptococcus neoformans developed in a 40 Year old immunocompetent and HIV negative man. Radiologic findings consisted in diffuse, bilateral reticular and nodular opacities. Bronchoscopy was normal and bronchoalveolar lavage showed numerous macrophages without associated pathogens. A thoracovideoscopy with an open lung biopsy showed numerous cryptococci, free in the alveoli or located within the macrophages. They were associated with an inflammatory infiltrate in the interalveolar spaces, predominantly composed of mononuclear cells. Ultrastructural study showed yeasts with numerous intracytoplasmic organites, a nucleus, a wall and a thick capsule. Pulmonary cryptococcosis is rare in immunocompetent hosts and can be difficult to diagnose since clinicoradiologic features observed in this cryptococcal infection mimic other infectious or neoplastic diseases.

Published
2004
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