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1. High BRAF V600 Mutation Level Associated with Worse Outcome in Metastatic Melanoma Patients Receiving BRAF and MEK Inhibitors

Author

Ariane Fizazi, Chris Serrand, Alexandre Evrard, Blanche Bergeret, Pierre-Emmanuel Stoebner, and Myriam Marque

Subjects
melanoma, BRAF V600, MAPKi, biomarker, Dermatology, RL1-803
Abstract

The prognostic value of BRAF V600 mutation level on clinical outcomes in patients with BRAF V600-mutated metastatic melanoma treated with BRAF and MEK inhibitors remains uncertain. The association was retrospectively analysed between BRAF V600 mutation level (defined as the ratio of the quantification of the BRAF V600 allele to the percentage of tumoral cells in the sample analysed) and progression-free and overall survival (PFS and OS, respectively) and 3-month response rate in a cohort of 58 patients with metastatic melanoma who harboured BRAF V600E/K mutations and received dual targeted-therapy BRAF/MEK inhibitors. The BRAF mutation level cut-off determined by the area under the receiver operating characteristic curve after internal validation by bootstrap methods was 0.44. Risk of poor PFS and OS was associated with BRAF V600 mutation level > 0.44 on multivariate analysis (p = 0.02 and p = 0.02, respectively) after adjusting for major confounding factors (age, sex, lactate dehydrogenase level, brain metastasis, and treatment line). No association was found between BRAF mutation level and 3-month response rate. Our study shows that high BRAF V600 mutation level in melanoma tissue was associated with poor prognosis in patients with metastatic melanoma treated with BRAF and MEK inhibitors.

Published
2024
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2. Cost-Effectiveness Analysis of Sequential Treatment Strategies for Advanced Melanoma in Real Life in France

Author

Marguerite Kandel, Aurélie Bardet, Stéphane Dalle, Clara Allayous, Laurent Mortier, Bernard Guillot, Caroline Dutriaux, Marie-Thérèse Leccia, Sophie Dalac, Henri Montaudie, Philippe Saiag, Delphine Legoupil, Florence Brunet-Possenti, Jean-Philippe Arnault, Julie De Quatrebarbes, Marie Beylot-Barry, Eve Maubec, Thierry Lesimple, François Aubin, Jean-Jacques Grob, Florence Granel-Brocard, Pierre-Emmanuel Stoebner, Alain Dupuy, Brigitte Dreno, Stefan Michiels, Céleste Lebbe, and Isabelle Borget

Subjects
cost-effectiveness analysis, advanced melanoma, real-life clinical practice, immunotherapy, targeted therapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Nine drugs have been marketed for 10 years for the treatment of advanced melanoma (AM). With half of patients reaching a second line, the optimal sequence of treatments remains unclear. To inform policy-makers about their efficiency, we performed a cost-effectiveness analysis of sequential strategies in clinical practice in France, for BRAF-mutated and wild-type patients. A multistate model was developed to describe treatment sequences, associated costs, and health outcomes over 10 years. Sequences, clinical outcomes, utility scores, and economic data were extracted from the prospective Melbase cohort, collecting individual data in 1518 patients since 2013, from their AM diagnosis until their death. To adjust the differences in patients’ characteristics among sequences, weighting by inverse probability was used. In the BRAF-mutated population, the MONO-targeted therapies (TT)-anti-PD1 sequence was the less expensive, whereas the anti-PD1-BI-TT sequence had an incremental cost-effectiveness ratio (ICER) of 180,441 EUR/QALY. Regarding the BRAF wild-type population, the three sequences constituted the cost-effective frontier, with ICERs ranging from 116 to 806,000 EUR/QALY. For BRAF-mutated patients, the sequence anti-PD1-BI-TT appeared to be the most efficient one in BRAF-mutated AM patients until 2018. Regarding the BRAF wild-type population until 2018, the sequence starting with IPI+NIVO appeared inefficient compared to anti-PD1, considering the extra cost for the QALY gained.

Published
2022
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3. S100-EPISPOT: A New Tool to Detect Viable Circulating Melanoma Cells

Author

Laure Cayrefourcq, Aurélie De Roeck, Caroline Garcia, Pierre-Emmanuel Stoebner, Fanny Fichel, Françoise Garima, Françoise Perriard, Jean-Pierre Daures, Laurent Meunier, and Catherine Alix-Panabières

Subjects
circulating tumor cells, melanoma, liquid biopsy, EPISPOT, CellSearch®, Cytology, QH573-671
Abstract

Metastatic melanoma is one of the most aggressive and drug-resistant cancers with very poor overall survival. Circulating melanoma cells (CMCs) were first described in 1991. However, there is no general consensus on the clinical utility of CMC detection, largely due to conflicting results linked to the use of heterogeneous patient populations and different detection methods. Here, we developed a new EPithelial ImmunoSPOT (EPISPOT) assay to detect viable CMCs based on their secretion of the S100 protein (S100-EPISPOT). Then, we compared the results obtained with the S100-EPISPOT assay and the CellSearch® CMC kit using blood samples from a homogeneous population of patients with metastatic melanoma. We found that S100-EPISPOT sensitivity was significantly higher than that of CellSearch®. Specifically, the percentage of patients with ≥2 CMCs was significantly higher using S100-EPISPOT than CellSearch® (48% and 21%, respectively; p = 0.0114). Concerning CMC prognostic value, only the CellSearch® results showed a significant association with overall survival (p = 0.006). However, due to the higher sensitivity of the new S100-EPISPOT assay, it would be interesting to determine whether this functional test could be used in patients with non-metastatic melanoma for the early detection of tumor relapse and for monitoring the treatment response.

Published
2019
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4. Extracellular 20S proteasome secreted via microvesicles can degrade poorly folded proteins and inhibit Galectin-3 agglutination activity

Author

Anne Bonhoure, Laurent Henry, Claudia Bich, Lionel Blanc, Blanche Bergeret, Marie‐Pierre Bousquet, Olivier Coux, Pierre‐Emmanuel Stoebner, and Michel Vidal

Subjects
Agglutination, Cytoplasm, Proteasome Endopeptidase Complex, Structural Biology, Galectin 3, Proteolysis, Genetics, Humans, Cell Biology, Molecular Biology, Biochemistry
Abstract

Proteasomes are major non-lysosomal proteolytic complexes localized in the cytoplasm and in the nucleus of eukaryotic cells. Strikingly, high levels of extracellular proteasome have also been evidenced in the plasma (p-proteasome) of patients with specific diseases. Here, we examined the process by which proteasomes are secreted, as well as their structural and functional features once in the extracellular space. We demonstrate that assembled 20S core particles are secreted by cells within microvesicles budding from the plasma membrane. Part of the extracellular proteasome pool is also free of membranes in the supernatant of cultured cells, and likely originates from microvesicles leakage. We further demonstrate that this free proteasome released by cells (cc-proteasome for cell culture proteasome) possesses latent proteolytic activity and can degrade various extracellular proteins. Both standard (no immune-subunits) and intermediate (containing some immune-subunits) forms of 20S are observed. Moreover, we show that galectin-3, which displays a highly disordered N-terminal region, is efficiently cleaved by purified cc-proteasome, without SDS activation, likely after its binding to PSMA3 (α7) subunit through its intrinsically disordered region. As a consequence, galectin-3 is unable to induce red blood cells agglutination when preincubated with cc-proteasome. These results highlight potential novel physio- and pathologic functions for the extracellular proteasome.

Published
2022

5. Cemiplimab for locally advanced and metastatic cutaneous squamous-cell carcinomas: Real-life experience from the French CAREPI study group

Author

Pierre-Emmanuel Stoebner, Christophe Bedane, A. Jannic, Marc Dumas, Marie Moncourier, Sandrine Mansard, Anne-Bénédicte Duval-Modeste, David Solub, Sophie Darras, Suzanne Devaux, Julia Sanchez, Nicolas Meyer, Laurent Misery, Valentine Heidelberger, Raoul Triller, Ingrid Kupfer-Bessaguet, Nathalie Beneton, Florence Brunet-Possenti, Gaëlle Quéreux, E. Maubec, Sophie Dalac, François Skowron, Safia Abed, Caroline Gaudy-Marqueste, Laurent Mortier, Monica Dinulescu, F. Herms, Lucie Peuvrel, Marouane Boubaya, Candice Hober, Pierre Guillet, Mahtab Samimi, Yves Reguerre, Nicolas Poulalhon, Anne Pham-Ledard, Stéphanie Catala, Eve-Marie Neidhardt, Romain Lesbazeilles, Jean-Philippe Arnault, Brigitte Dréno, Olivier Collard, Philippe Celerier, Julie De Quatrebarbes, Youssef Tazi, Pierre Combe, Caroline Jacobzone, Élodie Archier, F. Aubin, Dominique Spaeth, Clémence Berthin, Nora Kramkimel, Florent Grange, Candice Lesage, Lisa Fredeau, A. Schoeffler, Marc Pracht, Bertille Bonniaud, Laure Cesaire, Maxime Etienne, Olivier Lauche, CHU Lille, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Bordeaux [Bordeaux], Université de Bordeaux (UB), Hopital Saint-Louis [AP-HP] (AP-HP), Hôpital Saint-Louis de La Rochelle (CH La Rochelle), Université de Bourgogne (UB), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Le Mans (CH Le Mans), Hôpital Pontchaillou, Hôpital Henri Mondor, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Léon Bérard [Lyon], Hôpital Saint-Joseph [Marseille], Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Cochin [AP-HP], Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier de Valence (CH DE VALENCE), Centre hospitalier de Valence, CH Annecy Genevois, CHU de Nîmes, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Amiens-Picardie, Hopital d'instruction des armées Sainte-Anne [Toulon] (HIA), CH Boulogne sur Mer, Hôpital Robert Ballanger [Aulnay-sous-Bois], Centre Hospitalier de la Côte Basque (CHCB), Centre Hospitalier Universitaire [Grenoble] (CHU), Université de Bretagne Occidentale, CHU Clermont-Ferrand, Centre Hospitalier Intercommunal de Cornouaille (CHIC), Centre Hospitalier Intercommunal de Cornouaille [Quimper] (CHI Cornouaille [Quimper]), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Clinique Saint Pierre, Perpignan, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Clinique Sainte Anne [Strasbourg], Centre d'Oncologie de Gentilly, Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Institut hospitalier Franco-Britannique [Levallois-Perret], CH René Dubos, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Pôle Santé Léonard de Vinci, Partenaires INRAE, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), CHU Limoges, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), UFR Santé, Médecine et Biologie Humaine (UFR SMBH), Université Sorbonne Paris Nord, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Toulouse [Toulouse]-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 hospitalier universitaire de Toulouse - CHU Toulouse, 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 Universitaire de Montpellier (CHU Montpellier ), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Le CHCB, Centre Hospitalier de la Côte Basque, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Cancer Research, medicine.medical_specialty, cutaneous squamous cell carcinoma, Locally advanced, Best Overall Response, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, Article, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Overall survival, Medicine, Adverse effect, Group performance, RC254-282, Immune status, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Mean age, medicine.disease, chronic dermatosis, Toxic epidermal necrolysis, 3. Good health, immunocompromised, real-life setting, Oncology, 030220 oncology & carcinogenesis, PD-1–blocking antibody, cemiplimab, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

Although cemiplimab has been approved for locally advanced (la) and metastatic (m) cutaneous squamous-cell carcinomas (CSCCs), its real-life value has not yet been demonstrated. An early-access program enrolled patients with la/mCSCCs to receive cemiplimab. Endpoints were best overall response rate (BOR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. The 245 patients (mean age 77 years, 73% male, 49% prior systemic treatment, 24% immunocompromised, 27% Eastern Cooperative Oncology Group performance status (PS) ≥ 2) had laCSCCs (35%) or mCSCCs (65%). For the 240 recipients of ≥1 infusion(s), the BOR was 50.4% (complete, 21%, partial, 29%). With median follow-up at 12.6 months, median PFS was 7.9 months, and median OS and DOR were not reached. One-year OS was 73% versus 36%, respectively, for patients with PS &lt, 2 versus ≥ 2. Multivariate analysis retained PS ≥ 2 as being associated during the first 6 months with PFS and OS. Head-and-neck location was associated with longer PFS. Immune status had no impact. Severe treatment-related adverse events occurred in 9% of the patients, including one death from toxic epidermal necrolysis. Cemiplimab real-life safety and efficacy support its use for la/mCSCCs. Patients with PS ≥ 2 benefited less from cemiplimab, but it might represent an option for immunocompromised patients.

Published
2021
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6. Quality‐of‐life assessment in French patients with metastatic melanoma in real life

Author

Florence Granel-Brocard, Alain Dupuy, D. Legoupil, Jean-Jacques Grob, Marie Beylot-Barry, Marie-Thérèse Leccia, Jean-Philippe Arnault, Florence Brunet-Possenti, A. Bardet, Pierre-Emmanuel Stoebner, Céleste Lebbe, Stéphane Dalle, Eve Maubec, Clara Allayous, Isabelle Borget, Bernard Guillot, Brigitte Dréno, Julie DeQuatrebarbes, Philippe Saiag, Laurent Mortier, Marguerite Kandel, Sophie Dalac, Caroline Dutriaux, Thierry Lesimple, Stefan Michiels, Henri Montaudié, François Aubin, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Gustave Roussy (IGR), 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 de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Groupe hospitalier Saint-André, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Ambroise Paré [AP-HP], Centre Hospitalier Universitaire de Nice (CHU Nice), Service de dermatologie [CHU d'Amiens-Picardie], CHU Amiens-Picardie, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Service de dermatologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], CRLCC Eugène Marquis (CRLCC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Avicennes University Hospital, Service de Dermatologie et Allergologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Dermatologie [Rennes] = Dermatology [Rennes], CHU Pontchaillou [Rennes], Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Léon Bérard [Lyon], AP-HP. Université Paris Saclay, Amgen Pfizer Merck Novartis Roche Janssen Biotech Meso Scale Diagnostics, MSD Array BioPharma Takeda Pharmaceutical Company Sanofi Pasteur British Microcirculation Society, BMS Institut National Du Cancer, INCa: DOC 16‐009, This work was supported by the French National Cancer Institute (DOC 16‐009)., Stéphane Dalle reports institutional research funding Roche, institutional research funding and nonfinancial support from Bristol‐Myers Squibb (BMS), and an immediate family member who is employed by Sanofi and owns stock or other ownership interest in the company. Aurélie Bardet was employed by Roche and held stock and other ownership interest in the company until March of 2018. Clara Allayous reports nonfinancial support from BMS, Amgen, and Roche outside the submitted work. Laurent Mortier reports personal fees and nonfinancial support from Roche, Novartis, BMS, and Merck Sharp & Dohme (MSD) outside the submitted work. Caroline Dutriaux reports personal fees from Roche, BMS, Novartis, MSD, and Pierre Fabre Laboratories outside the submitted work. Philippe Saiag reports research funding and personal fees from Roche, grants, personal fees, and nonfinancial support from BMS, MSD, Novartis, and Pierre Fabre Laboratories, and personal fees from Array, Sanofi, and Merck, all outside the submitted work. Henri Montaudié reports institutional research funding from LeoPharma, institutional research funding, personal fees, and nonfinancial support from BMS, personal fees from Pierre Fabre Laboratories and MSD, and nonfinancial support from Novartis, all outside the submitted work. Jean‐Phillipe Arnault reports institutional research funding and personal fees from BMS and institutional research funding from Novartis outside the submitted work. Jean‐Jacques Grob reports personal fees and nonfinancial support from BMS, Roche, MSD, Novartis, Merck, Amgen, Pierre Fabre Laboratories, Sanofi, and Pfizer and nonfinancial support from Amgen, all outside the submitted work. Julie De Quatrebarbes reports nonfinancial support from BMS, MSD, and Janssen outside the submitted work. Thierry Lesimple reports research funding and personal fees from Roche and personal fees from BMS, MSD, Novartis, Pierre Fabre Laboratories, and Incyte, all outside the submitted work. François Aubin reports personal fees and nonfinancial support from Novartis, MSD, and Roche outside the submitted work. Eve Maubec reports grants, personal fees, and nonfinancial support from MSD, personal fees from Sanofi and Novartis, personal fees and nonfinancial support from BMS, and nonfinancial support from Pierre Fabre Laboratories, all outside the submitted work. Stefan Michiels reports personal fees from IDDI Belgium, Janssen Cilag France, Hexal, Johnson & Johnson, Ipsen, Genticel, Mabxience, Steba, IQVIA, Roche, Sensorion, Biophytis, and Servier, all outside the submitted work. Céleste Lebbe reports institutional research funding, personal fees, and nonfinancial support from BMS, institutional funding and personal fees from Roche, personal fees and nonfinancial support from MSD, and personal fees from Aventis, Novartis, Amgen, Pierre Fabre Laboratories, Pfizer, and Incyte, all outside the submitted work. Isabelle Borget reports research funding from the BMS Foundation during the course of the study and personal fees from Roche, Janssen, CSC Behring, Novartis, and Takeda outside the submitted work. The remaining authors made no disclosures., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)

Subjects
Male, Cancer Research, MESH: Adolescent, Adult, Aged, 80 and over, Cohort Studies, Disease Progression, Female, France / epidemiology, Humans, Disease, Clinical practice, Targeted therapy, 0302 clinical medicine, Second line, Quality of life, Advanced disease, Medicine, Molecular Targeted Therapy, Prospective Studies, 030212 general & internal medicine, Neoplasm Metastasis, Melanoma, MESH: Immunotherapy, Melanoma / epidemiology, Melanoma / immunology, Melanoma / pathology, Melanoma / therapy, MESH: Middle Aged, Neoplasms, Second Primary / epidemiology, Young Adult, Real-life, Neoplasms, Second Primary, Middle Aged, 3. Good health, Survival Rate, Oncology, 030220 oncology & carcinogenesis, Cohort, France, Immunotherapy, medicine.medical_specialty, Adolescent, Metastatic melanoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Internal medicine, In real life, Survival rate, Aged, business.industry, MESH: Neoplasms, Second Primary / immunology, Neoplasms, Second Primary / pathology, Quality of Life, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

International audience; Background: Significant progress was recently observed in the treatment of metastatic melanoma (MM). With >50% of patients now reaching a second line of treatment and a significant improvement in the survival rate, an assessment of quality of life (QoL) during the whole course of the disease becomes necessary. The objective of this study was to describe the QoL of patients with MM in France, from their diagnosis of advanced disease to their death, in real life. Methods: QoL data were collected through MelBase, a prospective, French, multicentric cohort dedicated to the follow-up of adults with MM. QoL was assessed using the EuroQoL-5D questionnaire and the Functional Assessment of Cancer Treatment (FACT)-Melanoma questionnaire at the time of study inclusion, every 3 months, and at the time of each treatment change until death. To assess longitudinal changes from baseline to death, mixed-effect models for repeated-measures analyses were used to control for baseline covariates. Results: QoL was assessed in 1435 patients who were included in the study between 2013 and 2018. The median follow-up was 9.4 months, and 47% of patients died during follow-up. During first-line treatment, the model-based, mean utility score was 0.830 (95% CI, 0.818-0.843), the mean FACT-General score was 77.22 (95% CI, 76.23-78.22), and the mean FACT-Melanoma score was 129.46 (95% CI, 128.02-130.90). At the time of a change in treatment line, there was a decrease of −0.027 (95% CI, −0.03, −0.02) in the utility score, −1.82 (95% CI, −1.88, −1.76) in the FACT-General score, and −2.98 (95% CI, −3.05, −2.91) in the FACT-Melanoma score compared with first-line treatment. Conclusions: In the MelBase cohort, the QoL among patients with MM seems to be fairly stable over the whole disease course, although a small but significant decrease at time therapy is changed is observed.

Published
2019
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7. Proteasome 19S RP and translation preinitiation complexes are secreted within exosomes upon serum starvation

Author

Pierre-Emmanuel Stoebner, Olivier Coux, Laurence Berry, Nicole Bec, Christian Larroque, Anne Bonhoure, Laurent Henry, Michel Vidal, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Biologie Cellulaire (CRBM), and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Ribosomal Proteins, Proteasome Endopeptidase Complex, Proteome, Translation preinitiation complex, Endosome, Vesicular Transport Proteins, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Cytoplasmic Granules, Exosomes, Biochemistry, Exosome, Culture Media, Serum-Free, Autophagy-Related Protein 5, 03 medical and health sciences, 0302 clinical medicine, Structural Biology, Cell Line, Tumor, Autophagy, Genetics, Extracellular, Humans, Secretion, Eukaryotic Initiation Factors, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Vesicle, Cell Biology, Microvesicles, Cell biology, Protein Transport, 030217 neurology & neurosurgery, Intracellular
Abstract

The aim of our study was to investigate the impact of macroautophagy on exosome secretion. Exosomes are small membrane vesicles released in the extracellular space upon fusion of multivesicular endosomes with the plasma membrane. They were initially discovered as a way to remodel the reticulocyte plasma membrane before entering the blood circulation (Current Opinion in Hematology 2010, 17:177-183) and are now essentially studied as mediators of intercellular communication. Using iTRAQ proteomics, we compared the protein composition of purified exosomes secreted by cells impaired or not for macroautophagy by Atg5 depletion, during serum starvation conditions or complete medium culture. We show that the absence of serum modifies exosomal content, especially inducing secretion of two cytoplasmic protein complexes, namely proteasomal 19S regulatory particle (RP) and components of noncanonical translation preinitiation complex (PIC). This process is enhanced when autophagy is impaired by Atg5 depletion. Moreover, we show that the proteasome 20S core particle (CP) is released in the extracellular space. However, in striking contrast to what seen for its 19S RP regulator, release is independent of the exosomal vesicles, Atg5 expression and cell culture conditions. Exosome secretion can thus be considered as a cell process that participates in and reflects cell homeostasis, and care must be taken when studying potential extracellular function of exosomes due to the possible copurification of proteasome 20S CP.

Published
2019
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8. Que retenir de notre expérience d’enseignement « virtuel » au cours de la période épidémique? Enquête nationale du CEDEF auprès des enseignants et des internes de dermatologie

Author

Marie-Aleth Richard, Caroline Gaudy-Marqueste, Mahtab Samimi, et Cedef, and Pierre-Emmanuel Stoebner

Subjects
Pédagogie, COVID-19, Ocean Engineering, Safety, Risk, Reliability and Quality, Enseignement, P274
Abstract

Introduction L’epidemie COVID-19 a contraint enseignants et etudiants a s’adapter rapidement a des modes d’enseignements « distanciels ». Le format « visioconference » s’est generalise a tous les enseignements, de la formation initiale jusqu’aux congres virtuels. Ces roues de secours, que nous pensions transitoires, ont modifie nos pratiques pendant plus d’un an : que faut-il en retenir pour notre enseignement ? Notre objectif etait d’evaluer aupres des enseignants et des internes de dermatologie, leur experience numerique au cours de l’epidemie. Materiel et methodes Entre le 10 et le 21/05/2021, une enquete par questionnaires, destinee aux enseignants et aux internes, a porte sur les thematiques suivantes: experiences en enseignement « visio »; aspects techniques; ressenti pedagogique. Les questionnaires ont ete envoyes par un lien GoogleForm aux mailing-listes « enseignants » et « internes » du CEDEF; les reponses etaient anonymes. Resultats Les taux de participation etaient de 50 repondants/106 enseignants (47 %) et de 120 repondants/453 internes (26 %). La majorite des enseignants avait participe a de multiples enseignements en « visio » (cours DFASM 96%, congres 84 %, reunion DES 70 %, cours DES 58 %, DU/DIU 56 %, EPU 60 %) et etait autonome pour la “visio” (cours DFASM et DES 78 %, reunion DES 58 %, EPU 56 %). Le logiciel Zoom etait utilise par la majorite (90 %) des enseignants et des internes. La connexion restait problematique au CHU pour plus de 80 % des repondants. La « simplicite d’utilisation » etait la qualite prioritaire d’un logiciel « visio ». Une majorite des enseignants estimait que les cours de DES (54 %) et les reunions de DES (52 %) pourraient etre perennises en distanciel, tandis que les internes estimaient que les DU/DIU (56 %), les cours de DES (57 %), les reunions de DES (56 %) et les seminaires du CEDEF (61 %) pourraient etre maintenues « en visio » apres la pandemie. Seuls 3% des internes estimaient qu’aucun cours ne devrait etre maintenu en “visio” contre 14% des enseignants (p = 0,03). Le format « hybride » des futurs congres etait plebiscite par la majorite (> 70 %) des repondants. Discussion L’experience COVID a servi de catalyseur a un nouveau mode d’enseignement, pour lequel les enseignants ont acquis une experience diversifiee et une certaine autonomie. Les enseignants sont plus reticents que les etudiants au maintien de formats « visio » en post-COVID, ces derniers privilegiant le format « visio » pour de nombreuses formes d’enseignements. Ainsi, la digitalisation de certains seminaires du CEDEF permet une accessibilite a un plus grand nombre et un suivi personnalise du parcours de l’etudiant. Le presentiel reste privilegie pour les formations post-universitaires, les solutions « hybrides » permettant de combiner les avantages des deux formats.

Published
2021

9. S100-EPISPOT: A New Tool to Detect Viable Circulating Melanoma Cells

Author

Aurélie De Roeck, Françoise Garima, Jean-Pierre Daurès, Laurent Meunier, Laure Cayrefourcq, Françoise Perriard, Pierre-Emmanuel Stoebner, C. Garcia, F. Fichel, Catherine Alix-Panabières, Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Service de Dermatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de l'Environnement Industriel et des Risques (INERIS), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Oncology, Treatment response, medicine.medical_specialty, Population, CellSearch®, [SDV.CAN]Life Sciences [q-bio]/Cancer, circulating tumor cells, S100 protein, Article, 03 medical and health sciences, 0302 clinical medicine, Circulating tumor cell, Internal medicine, Biomarkers, Tumor, melanoma, Humans, Medicine, EPISPOT, In patient, Liquid biopsy, education, lcsh:QH301-705.5, Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, education.field_of_study, liquid biopsy, business.industry, Melanoma, S100 Proteins, General Medicine, Middle Aged, Neoplastic Cells, Circulating, medicine.disease, 3. Good health, Molecular Diagnostic Techniques, lcsh:Biology (General), Homogeneous, 030220 oncology & carcinogenesis, Female, business, Software
Abstract

Metastatic melanoma is one of the most aggressive and drug-resistant cancers with very poor overall survival. Circulating melanoma cells (CMCs) were first described in 1991. However, there is no general consensus on the clinical utility of CMC detection, largely due to conflicting results linked to the use of heterogeneous patient populations and different detection methods. Here, we developed a new EPithelial ImmunoSPOT (EPISPOT) assay to detect viable CMCs based on their secretion of the S100 protein (S100-EPISPOT). Then, we compared the results obtained with the S100-EPISPOT assay and the CellSearch&reg, CMC kit using blood samples from a homogeneous population of patients with metastatic melanoma. We found that S100-EPISPOT sensitivity was significantly higher than that of CellSearch&reg, Specifically, the percentage of patients with &ge, 2 CMCs was significantly higher using S100-EPISPOT than CellSearch&reg, (48% and 21%, respectively, p = 0.0114). Concerning CMC prognostic value, only the CellSearch&reg, results showed a significant association with overall survival (p = 0.006). However, due to the higher sensitivity of the new S100-EPISPOT assay, it would be interesting to determine whether this functional test could be used in patients with non-metastatic melanoma for the early detection of tumor relapse and for monitoring the treatment response.

Published
2019
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10. Association of Time From Primary Diagnosis to First Distant Relapse of Metastatic Melanoma With Progression of Disease and Survival

Author

Céleste Lebbé, Anais Vallet, Raphaël Porcher, D. Legoupil, Thierry Lesimple, Bernard Guillot, Philippe Saiag, Jean-Philippe Lacour, Eve Maubec, Caroline Dutriaux, Florence Brunet-Possenti, Marie-Thérèse Leccia, Brigitte Dréno, Julie De Quatrebarbes, Bastien Oriano, Florence Granel-Brocard, Jean-Philippe Arnault, for MelBase, Laurent Mortier, Pierre-Emmanuel Stoebner, Clara Allayous, Stéphane Dalle, Sophie Dalac, François Aubin, 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), Centre de Diagnostic et de Thérapeutique, Hôpital de l’Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Institut National du Cancer [Boulogne Billancourt] (INC), Service de Dermatologie [Nice], Hôpital Archet 2 [Nice] (CHU), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Département d'oncologie médicale [Rennes], CRLCC Eugène Marquis (CRLCC), Service de dermatologie [CHU d'Amiens-Picardie], CHU Amiens-Picardie, Département de dermatologie, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Hôpital Saint-Jacques-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Dermatologie et Allergologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de dermatologie [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, 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), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire Dynamique des Protéines et Modélisation (LDPM), Université des Antilles et de la Guyane (UAG), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Hôpital Hôtel-Dieu [Paris], Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), and Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Oncology, medicine.medical_specialty, Skin Neoplasms, Time Factors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, Cohort Studies, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, medicine, Humans, Prospective Studies, Progression-free survival, Neoplasm Metastasis, Stage (cooking), Prospective cohort study, Melanoma, Aged, Original Investigation, business.industry, Hazard ratio, MESH: Cohort studies, Melanoma/diagnosis, Middle aged, Skin neoplasms/diagnosis, Survival rate, Progression-Free survival, Middle Aged, Prognosis, Chemotherapy regimen, Progression-Free Survival, 3. Good health, Survival Rate, 030220 oncology & carcinogenesis, Localized disease, Cohort, Disease Progression, Female, France, Neoplasm Recurrence, Local, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

International audience; The prognosis of advanced melanoma has been greatly improved by new therapeutic agents and clinicians rely on dynamic signals to drive their therapeutic choices. Although the kinetics of metastatic disease seem to be correlated with survival, progression of the localized disease is not predictable.Objective: To assess whether progression of metastatic disease is associated with the time to the first distant recurrence of melanoma.Design, Setting, and Participants: This study was conducted from March 1, 2013, to September 1, 2017, among 638 adults with unresectable stage III or IV melanoma within the French multicentric prospective cohort MelBase. Patients treated with first-line immunotherapies, targeted therapies, or chemotherapy were included. Patients with unknown primary or de novo metastatic melanoma were not included. Data were analyzed from March 1, 2013, to December 1, 2017.Main Outcomes and Measures: The date of primary excision and time to first distant recurrence, progression-free survival, and overall survival were collected. Cox proportional hazards regression models were planned to assess the association between time to first distant recurrence and progression-free survival or overall survival, which was evaluated in terms of hazard ratio (HR). Time to recurrence was analyzed both as a continuous and categorical variable (24 months).Results: A total of 638 patients (272 women and 366 men; median age, 64 years [interquartile range, 52-73 years]) were included in the study. The median time from primary excision to first distant recurrence was 25 months (interquartile range, 12-55 months). There was no evidence of association of the time to recurrence with progression-free survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.99-1.01) or after categorization (12-24 months: HR, 0.75; 95% CI, 0.56-1.02; >24 months: HR, 0.62; 95% CI; 0.47-1.01). There was no evidence of association of the time to recurrence with overall survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.98-1.02) or after categorization (12-24 months: HR, 0.76; 95% CI, 0.54-1.07; >24 months: HR, 0.61; 95% CI, 0.54-1.03). Those results remained nonsignificant after stratification by treatment.Conclusions and Relevance: In the MelBase cohort, time to recurrence of metastatic melanoma appears not to be associated with progression-free survival or overall survival.

Published
2019
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11. Impact of radiotherapy administered simultaneously with systemic treatment in patients with melanoma brain metastases within MelBase, a French multicentric prospective cohort

Author

Stéphane Dalle, Raphaël Porcher, Thierry Lesimple, Marie-Thérèse Leccia, Jean-Philippe Lacour, Sophie Dalac, D. Legoupil, Pauline Tétu, Sameh Mohamed, A. Ballon, Florence Brunet-Possenti, Céleste Lebbé, Clara Allayous, Laurent Mortier, François Aubin, Julie De Quatrebarbes, Pierre-Emmanuel Stoebner, Caroline Dutriaux, Bastien Oriano, Brigitte Dréno, Bernard Guillot, Philippe Saiag, Marie Beylot-Barry, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre de Diagnostic et de Thérapeutique, Hôpital de l’Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Dermatologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Bordeaux [Bordeaux], Service de Dermatologie [Nice], Hôpital Archet 2 [Nice] (CHU), Hôpital Ambroise Paré [AP-HP], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Centre Eugène Marquis (CRLCC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-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)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), and CCSD, Accord Elsevier

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, genetic structures, Propensity score, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Systemic therapy, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Prospective Studies, cardiovascular diseases, Stage (cooking), Prospective cohort study, Melanoma, Aged, Proportional Hazards Models, Radiotherapy, Brain Neoplasms, business.industry, MESH: Brain Neoplasms/radiotherapy, Melanoma/drug therapy, Melanoma/radiotherapy, Middle Aged, Brain metastases, medicine.disease, equipment and supplies, Advanced melanoma, Combined Modality Therapy, Confidence interval, 3. Good health, Radiation therapy, 030104 developmental biology, 030220 oncology & carcinogenesis, Propensity score matching, cardiovascular system, Female, Immunotherapy, business, circulatory and respiratory physiology
Abstract

International audience; Background: Melanoma brain metastases (MBMs) are historically associated with poor prognosis. Radiation therapy is conventionally associated with a high local control rate. Development of targeted therapy and immunotherapy has improved overall survival (OS) and intracranial response rate, but about 50% of patients failed to respond to these novel therapies. The objective of this study was to assess the impact of combined radiotherapy (cRT) on overall survival in a large multicenter real-life prospective cohort of patients with MBM treated with immunotherapy or targeted therapy.Patients and methods: Clinical data from 262 patients with MBM were collected via MelBase, a French multicentric biobank prospectively enrolling unresectable stage III or IV melanoma. Two groups were defined: patients receiving cRT (cRT group) or not receiving cRT (no-cRT group). Primary end-point was OS. Propensity score weighting was used to correct for indication bias.Results: Among the 262 patients, 93 (35%) received cRT (cRT group). The patients were treated with immunotherapy in 69% and 60% and with targeted therapy in 31% and 40% of the cRT and no-cRT groups, respectively. With a median follow-up of 6.9 months, median OS was 16.8 months and 6.9 months in the cRT and no-cRT groups, respectively. After propensity score weighting, cRT was associated with longer OS (hazard ratio = 0.6, 95% confidence interval: 0.4-0.8; p=0.007). Median OS after ponderation was 15.3 months and 6.2 months in the cRT and no-cRT groups, respectively.Conclusion: This study shows that cRT may be associated with a significant decrease of 40% in the risk of death in patients with MBM treated with systemic therapy.

Published
2019
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12. ILDS Newsletter No. 31

Author

Camille Fleuret, Felipe L.S. Ferreira, Shirli Israeli, Marianna Shvartsbeyn, Margarita Indelman, P.H. Itin, C. Garcia, G. Lamblin, C. Röcken, M. Dandurand, Laurent Misery, Simone Cazzaniga, Jehanne Morvan, Josep Malvehy, Ilknur Balta, Giovanni Lo Scocco, Laurent Meunier, Yanhua Liu, Cem Nazli, Yaoyin Li, Biao Cheng, E. Haneke, Yan Peng, Ben Zion Garty, Laure Aurelian, Cristina Carrera, Ranjit Joseph, A.L. Breton, Guy Le Toux, Görgün Akpek, L. Borradori, Annarosa Virgili, D. Koumaki, Santo Raffaele Mercuri, Sergio Chimenti, Eli Sprecher, Ofer Sarig, Alex Zvulunov, Xiao Cui, D. Jullien, Evangelos J. Giamarellos-Bourboulis, S. Giatrakou, Kaisa Tasanen, Luigi Naldi, G. Avgerinou, Dan Ben Amitai, T. Renker, Cengiz Ozturk, H. Beltraminelli, Zehra Ilke Akyildiz, Pascal Roger, D. Rigopoulos, Moshe Lapidoth, Georgia Damoraki, D. Ferra, Lior Sagi, Jean-Marie Joujoux, Satz Mengensatzproduktion, Sait Demirkol, Mustafa Demir, Sevket Balta, N. Stavrianeas, Giulia Toni, Ilan Goldberg, Canan Günay, I. Alarcon, Sara Minghetti, Reuven Bergman, Laura Huilaja, Monica Corazza, N. Ruzza, Alessandro Borghi, E. Papadavid, Aila Immonen, C. Pariset, Pierre-Emmanuel Stoebner, Ioanna Grech, Rosita Saraceno, P. Loumou, S. Gregoriou, Riitta Riekki, E. Toumbis-Ioannou, K. Theodoropoulos, Sophia Giatrakos, Gérard Guillet, Philippos Kaldrimidis, Werner Druck Medien Ag, A. Katoulis, Emiliano Schincaglia, M. Dalamaga, Myriam Chastaing, Dimitrios Rigopoulos, C. Stamou, Susana Puig, and Jian Liu

Subjects
Dermatology
Published
2014
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13. Clinical use of p-proteasome in discriminating metastatic melanoma patients: Comparative study with LDH, MIA and S100B protein

Author

Jean Martinez, Isabelle Guiraud, Cécile Fabre, Thierry Lavabre-Bertrand, Pascale Fabbro-Peray, Sophie Bastide, Laurent Henry, Pierre-Emmanuel Stoebner, and Laurent Meunier

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Univariate analysis, Pathology, Proportional hazards model, business.industry, Melanoma, Circulating Proteasome, medicine.disease, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, Predictive value of tests, Lactate dehydrogenase, Internal medicine, medicine, Stage (cooking), business, Lymph node
Abstract

Plasmatic proteasome (p-proteasome) has recently been described as a new marker for metastatic melanoma. The objective of this study was to compare the diagnostic and prognostic values of p-proteasome with three other melanoma serological markers: S100B protein, melanoma inhibitory activity protein (MIA) and lactate dehydrogenase (LDH) in the plasma of 121 stage I-IV melanoma patients. Laboratory analyses were performed by standardized ELISA (p-proteasome, MIA), immunoluminometric assay (S100B) and colorimetry (LDH). We found that all markers were relevant for discriminating metastatic from nonmetastatic patients but p-proteasome displayed the highest diagnostic accuracy. P-proteasome and S100B were the most sensitive (58.1%) and p-proteasome and MIA the most specific (98.7 and 100%) in detecting metastatic disease. P-proteasome and S100B had the highest area under receiver operating characteristics curve, 0.811 (95% CI: 0.725-0.897) and 0.822 (95% CI: 0.738-0.906), respectively. These two markers were the best in detecting patients with lymph node metastases. S100B, MIA and LDH diagnostic accuracy was increased when these markers were combined with p-proteasome. As shown with univariate analysis, shorter progression-free and overall survival rates were significantly associated with elevated plasma levels of each markers. The multivariate Cox regression analysis identified p-proteasome as the only independent predictor of a poorer progression-free survival (p = 0.030). In conclusion, this comparative study established that p-proteasome quantification in combination with other melanoma biomarkers is an attractive approach for the biological follow-up of melanoma patients.

Published
2013
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14. AMPK/HuR-Driven IL-20 Post-Transcriptional Regulation in Psoriatic Skin

Author

Stéphanie Rialle, Lionel Le Gallic, Thierry Lavabre-Bertrand, Jean-Marie Joujoux, Matthieu Lacroix, Geneviève Garcin, Pierre-Emmanuel Stoebner, Clémence Genthon, Isabelle Guiraud, Laurent Meunier, Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), 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), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), BioCampus Montpellier (BCM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Herrada, Anthony, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), BioCampus (BCM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Keratinocytes, Immunoprecipitation, Dermatology, AMP-Activated Protein Kinases, Biology, Real-Time Polymerase Chain Reaction, Biochemistry, Statistics, Nonparametric, ELAV-Like Protein 1, Mice, Random Allocation, Interleukin 20, Downregulation and upregulation, Psoriasis, medicine, Animals, Humans, RNA, Messenger, Protein kinase A, Molecular Biology, Post-transcriptional regulation, Cells, Cultured, Skin, Epidermis (botany), Interleukins, Biopsy, Needle, AMPK, Cell Biology, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, medicine.disease, Immunohistochemistry, Up-Regulation, Cell biology, Mice, Inbred C57BL, Disease Models, Animal, Gene Expression Regulation, Immunology, RNA Interference, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

International audience; IL-20 is involved in the development of skin psoriasis. The molecular mechanisms underlying IL-20 overexpression in psoriatic epidermis remain to be elucidated. We showed that IL-20 was primarily upregulated in psoriatic skin at the post-transcriptional level. The RNA-binding protein HuR relocalized to the cytoplasm of keratinocytes (KCs) of psoriatic patients, suggesting that it stabilizes numerous transcripts, as observed in the human KC cell lines used to assess IL-20 mRNA. We characterized epidermal HuR RNA targets in psoriatic skin using ribonucleoprotein immunoprecipitation analyzed via high-throughput sequencing. Numerous transcripts that are upregulated in psoriasis were targeted by HuR, supporting the participation of HuR in pathogenic processes such as morphological changes, innate and adaptive immune responses, and metabolic inflammatory responses. Finally, we identified the metabolic sensor AMP-activated protein kinase (AMPK) as being responsible for HuR cytoplasmic relocalization because its activity was severely impaired in human psoriatic epidermis, and in vivo drug-mediated AMPK inhibition in mouse epidermis promoted HuR cytoplasmic localization, IL-20 overproduction, acanthosis, and hyperkeratosis. These results provide insights into the molecular links between metabolism and post-transcriptional networks during chronic inflammation.

Published
2015
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15. Koebnerizing Kaposi's sarcoma mimics a laparotomic hypertrophic scar in a liver transplant recipient

Author

Pierre Emmanuel, Stoebner, Cécile, Fabre, Nelly, El Kabbaj, Michael, Bismuth, Georges Philippe, Pageaux, and Laurent, Meunier

Subjects
Risk, Laparotomy, Liver Diseases, Herpesviridae Infections, Hypertrophy, Middle Aged, Liver Transplantation, Diagnosis, Differential, Cicatrix, Risk Factors, Herpesvirus 8, Human, Humans, Female, Sarcoma, Kaposi, Immunosuppressive Agents
Published
2009

16. Treatment with taxanes of refractory or life-threatening Kaposi sarcoma not associated with human immunodeficiency virus infection

Author

Vincent Descamps, Laurent Meunier, M. Dandurand, Céleste Lebbé, Delphine Kerob, Hervé Bachelez, Pierre-Emmanuel Stoebner, Laurence Fardet, and Patrice Morel

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Skin Neoplasms, Paclitaxel, medicine.medical_treatment, Angiogenesis Inhibitors, Docetaxel, Neutropenia, Gastroenterology, Asymptomatic, chemistry.chemical_compound, Internal medicine, HIV Seronegativity, Medicine, Humans, Sarcoma, Kaposi, Aged, Aged, 80 and over, Chemotherapy, business.industry, Cancer, Middle Aged, medicine.disease, Antineoplastic Agents, Phytogenic, Surgery, Lymphedema, Oncology, chemistry, Female, Taxoids, Sarcoma, medicine.symptom, business, medicine.drug
Abstract

BACKGROUND Kaposi sarcoma (KS) is an angioproliferative disease that may represent a difficult therapeutic challenge in disseminated stages. The efficacy of taxanes (paclitaxel and docetaxel), as agents with antiangiogenic properties, has been described previously in the treatment of patients with acquired immunodeficiency syndrome (AIDS)-associated KS but remains unknown in the treatment of patients with refractory or life-threatening KS without human immunodeficiency (HIV) infection. METHODS During the past 6 years, 12 non-HIV-infected patients with refractory KS were treated with paclitaxel (175 mg/m2 every 3 wks) or docetaxel (60 mg/m2 every 3 wks). RESULTS All patients improved dramatically after chemotherapy. Partial desinfiltration (n = 6) or complete desinfiltration (n = 6) of all papulonodular skin lesions was observed with marked improvement of lymphedema in 6 patients. According to the AIDS Clinical Trials Group criteria, response was partial in 100% of patients. A major response was obtained among patients who had visceral lesions (n = 3 patients), with rapid and complete remission of digestive or respiratory symptoms. The mean delay to response was 2 courses. Treatment was sustained for 3 patients. For the remaining 9 patients who received a median of 7 courses (range, 2-14 courses), the mean time to recurrence or follow-up without recurrence was 13 months. Tolerance was good except for 3 episodes of Grade 3 or 4 asymptomatic neutropenia and 1 episode of moderate myositis. CONCLUSIONS The results of this study showed that taxanes are beneficial in the treatment of patients with refractory or life-threatening Kaposi sarcoma. Cancer 2006. © 2006 American Cancer Society.

Published
2006

17. Ross Syndrome with Sweating Anomaly Associated with Sjögren Syndrome: An Infrared Thermo­graphic Case Study

Author

Laurent Jomir, Minh Son Luong, M. Dandurand, Pierre-Emmanuel Stoebner, Pierre Labauge, and Laurent Meunier

Subjects
Pathology, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Hyperhidrosis, Magnetic resonance imaging, Dermatology, General Medicine, Hyporeflexia, Thermoregulation, Spinal cord, Constriction, medicine.anatomical_structure, Nerve conduction study, medicine, medicine.symptom, Anhidrosis, business
Abstract

Ross syndrome is a rare partial dysautonomic syndrome of unknown aetiology, characterized by a one-sided or bi-lateral anhidrosis associated with Holmes-Adie syndrome (defined by tonic pupil and hyporeflexia of deep tendons) (1). Since it was first described in 1958 (2), approxima-tely 50 cases have been described in the literature (3). Dermatologists may be confronted with this disorder of thermoregulation, which is often revealed by a segmental “compensatory” hyperhidrosis. We describe here a case of Ross syndrome associated with Sjogren syndrome (SS) and discuss the potential relationship between these two entities. Thermography imaging exploration with an in-frared camera performed in different ambient temperature settings allowed better definition of the thermoregulatory sweating abnormalities in our patient. Moreover, to our knowledge, this examination showed, for the first time, an unexpected body “thermal pattern”, which may be characteristic of Ross syndrome. CASe RepoRTWe present here a case of a 35-year-old woman with a 10-year medical history of localized hyperhidrosis. Her medical history revealed autoimmune thyroid disease and SS. The hyperhidrosis appeared at an ambient tem-perature of approximately 25–27°C and was localized on the left side of her lower back, extending belt-like towards the side and in the controlateral lower back on the right side, as well as on the nape of her neck and shoulders. The rest of the skin was anhidrotic. She was also heat intolerant, with lack of sweating, abnormal increase in body temperature and generalized fati-gability when exposed to high ambient temperatures (32–34°C). Both pupils showed a slow reaction to light and a normal constriction to a near target, and deep tendon jerks were absent without motor deficits (Holmes-Adie syndrome). There were no other signs of autonomic dysfunction. punch biopsies obtained from hyperhidrotic and hypohidrotic skin areas were normal. The skin direct immunofluorescence test was negative. Blood explorations showed an isolated presence of anti-SSA, anti-SSB antibodies and anti-thyroid antibodies. Serum ganglionic (AChR) antibody was negative. Oral and conjunctival Sicca were objectively confirmed by Schirmer’s test. Salivary gland biopsy revealed lympho-cytic infiltration in both periglandular and perivascular regions. All of these Sicca findings fulfilled the diag-nostic criteria for primary SS (4). Brain and spinal cord magnetic resonance imaging (MRI), as well as thoracic and abdominal computed tomography scan findings, were normal. Electrophysiological explorations of both hands and forearms showed an absence or collapse of the sympathetic skin responses. Nerve conduction study findings, EEG and cardiac tilt-test (reflecting the adren-ergic sympathetic and parasympathetic functions) were normal. Thermographic explorations with an infrared camera (A320, FLIRsystems, Inc., Issy Les Moulineaux, France) allowed for evaluating the body’s surface tem-perature at 22°C and after a 20 min exposure to 32°C ambient temperature (Fig. 1). This examination was significantly more efficient than the Minor Starch Test and clearly delimited the skin thermoregulation abnor-malities associated with Ross syndrome. Hyperhidrotic and anhidrotic areas were also clearly visualized as the lowest and highest estimated skin surface temperature. This examination showed large dermatomal-like pat-terns in hyperhidrotic areas (lower back and shoulder regions), but also detected unexpected smaller patch

Published
2011
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18. Possible Drug-induced Sweet's Syndrome due to Trimethoprim-sulfamethoxazole

Author

Pierre-Emmanuel Stoebner, Mechel Dandurand, Laurent Meunier, Nicolas Kluger, and M. Marque

Subjects
Sweet's syndrome, Drug, business.industry, Sulfamethoxazole, media_common.quotation_subject, Dermatology, General Medicine, Pharmacology, medicine.disease, Trimethoprim, medicine, business, medicine.drug, media_common
Abstract

This article does not have an abstract

Published
2008
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