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1. Iatrogenic ureteral injury during colorectal surgery has a significant impact on patient outcomes: a French multicentric retrospective cohort study

Author: Sérénon, Victor, Rouanet, Philippe, Charleux-Muller, Diane, Eveno, Clarisse, Poirot, Karine, Trilling, Bertrand, Benoist, Stéphane, Manceau, Gilles, Panis, Yves, Alves, Arnaud, Kartheuser, Alex, Venara, Aurélien, Pocard, Marc, Sabbagh, Charles, Laforest, Anaïs, Lakkis, Zaher, Badic, Bogdan, Chau, Amélie, Christou, Niki, Beyer-Berjot, Laura, Dumont, Frederic, Germain, Adeline, Valverde, Alain, Duchalais, Emilie, Ouaissi, Mehdi, Benhaim, Leonor, Collard, Maxime, Tuech, Jean‐jacques, Buscail, Etienne, Mege, Diane, Régimbeau, Jean-Marc, Aix-Marseille Université - École de médecine (AMU SMPM MED), Aix-Marseille Université - Faculté des sciences médicales et paramédicales (AMU SMPM), Aix Marseille Université (AMU)-Aix Marseille Université (AMU), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications Grenoble - UMR 5525 (TIMC-IMAG), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), CHU Grenoble, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Service de Chirurgie Viscérale et Digestive [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Caen Normandie - UFR Santé (UNICAEN Santé), Normandie Université (NU)-Normandie Université (NU), Université Catholique de Louvain = Catholic University of Louvain (UCL), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), CArcinose Péritoine Paris-Technologies (ex-CART) (CAP Paris-Tech (UMR_S_1275)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Chirurgie digestive [CHU Amiens], CHU Amiens-Picardie, Simplification des soins chez les patients complexes - UR UPJV 7518 (SSPC), Université de Picardie Jules Verne (UPJV), Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire de Traitement de l'Information Medicale (LaTIM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Contrôle de l’Activation Cellulaire, Progression Tumorale et Résistance thérapeutique (CAPTuR), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Service de Chirurgie digestive, endocrinienne et générale [CHU Limoges], CHU Limoges, and The French Research Group of Rectal Cancer Surgery = Groupe de Recherche en Chirurgie du Rectum (GRECCAR)
Subjects: ureteral injury, colorectal surgery, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, chemotherapy, ureteral stent
Abstract: International audience; Aim: The long-term urological sequelae after iatrogenic ureteral injury (IUI) during colorectal surgery are not clearly known. The aims of this work were to report the incidence of IUI and to analyse the long-term consequences of urological late complications and their impact on oncological results of IUI occurring during colorectal surgery through a French multicentric experience (GRECCAR group).Method: All the patients who presented with IUI during colorectal surgery between 2010 and 2019 were retrospectively included. Patients with ureteral involvement needing en bloc resection, delayed ureteral stricture or noncolorectal surgery were not considered.Results: A total of 202 patients (93 men, mean age 63 ± 14 years) were identified in 29 centres, corresponding to 0.32% of colorectal surgeries (n = 63 562). Index colorectal surgery was mainly oncological (n = 130, 64%). IUI was diagnosed postoperatively in 112 patients (55%) after a mean delay of 11 ± 9 days. Intraoperative diagnosis of IUI was significantly associated with shorter length of stay (21 ± 22 days vs. 34 ± 22 days, p < 0.0001), lower rates of postoperative hydronephrosis (2% vs. 10%, p = 0.04), anastomotic complication (7% vs. 22.5%, p = 0.002) and thromboembolic event (0% vs. 6%, p = 0.02) than postoperative diagnosis of IUI. Delayed chemotherapy because of IUI was reported in 27% of patients. At the end of the follow-up [3 ± 2.6 years (1 month-13 years)], 72 patients presented with urological sequalae (36%). Six patients (3%) required a nephrectomy.Conclusion: IUI during colorectal surgery has few consequences for the patients if recognized early. Long-term urological sequelae can occur in a third of patients. IUI may affect oncological outcomes in colorectal surgery by delaying adjuvant chemotherapy, especially when the ureteral injury is not diagnosed peroperatively.
Published: 2023

2. Determination of biomarkers associated with neoadjuvant treatment response focusing on colibactin-producing Escherichia coli in patients with mid or low rectal cancer: a prospective clinical study protocol (MICARE)

Author: Christophe Taoum, Guillaume Carrier, Marta Jarlier, Gwenaelle Roche, Johan Gagniere, Catherine Fiess, Helene De forges, Caroline Chevarin, Pierre-Emmanuel Colombo, Nicolas Barnich, Philippe Rouanet, Mathilde Bonnet, Institut du Cancer de Montpellier (ICM), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Service de Chirurgie Digestive et Hépatobiliaire [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, and ROSSI, Sabine
Subjects: MICROBIOLOGY, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, General Medicine, GASTROENTEROLOGY, ONCOLOGY, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, RADIOTHERAPY
Abstract: IntroductionThe management of mid and low rectal cancer is based on neoadjuvant chemoradiotherapy (CRT) followed by standardised surgery. There is no biomarker in rectal cancer to aid clinicians in foreseeing treatment response. The determination of factors associated with treatment response might allow the identification of patients who require tailored strategies (eg, therapeutic de-escalation or intensification). Colibactin-producingEscherichia coli(CoPEC) has been associated with aggressive colorectal cancer and could be a poor prognostic factor. Currently, no study has evaluated the potential association between intestinal microbiota composition and tumour response to CRT in mid and low rectal cancer. The aim of this study is to assess the association between response to neoadjuvant CRT and faecal intestinal microbiota composition and/or CoPEC prevalence in patients with mid or low rectal cancer.Methods and analysisThis is a non-randomised bicentric prospective clinical study with a recruitment capacity of 200 patients. Three stool samples will be collected from participants with histological-proven adenocarcinome of mid or low rectum who meet eligibility criteria of the study protocol: one before neoadjuvant treatment start, one in the period between CRT end and surgery and one the day before surgery. In each sample, CoPEC will be detected by culture in special media and molecular (PCR) approaches. The global microbiota composition will be also assessed by the bacterial 16S rRNA gene sequencing. Neoadjuvant CRT response and tumour regression grade will be described using the Dworak system at pathological examination. Clinical data and survival outcomes will also be collected and investigated.Ethics and disseminationMICARE was approved by the local ethics committee (Comité de Protection des Personnes Sud-Est II, 18 December 2019. Reference number 2019-A02493-54 and the institutional review board. Patients will be required to provide written informed consent. Results will be published in a peer reviewed journal.Trial registration numberNCT04103567.
Published: 2022

3. Investigation of Molecular Features Involved in Clinical Responses and Survival in Advanced Endometrial Carcinoma Treated by Hormone Therapy

Author: Mathias Neron, Arnaud Guille, Lucie Allegre, Pierre-Emmanuel Colombo, Cristina Leaha, José Adelaide, Nadine Carbuccia, Frédéric Courtier, Florence Boissiere, Evelyne Crapez, Michel Fabbro, Sébastien Gouy, Emilie Mamessier, Éric Lambaudie, Daniel Birnbaum, François Bertucci, Max Chaffanet, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut du Cancer de Montpellier (ICM), 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 Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut Gustave Roussy (IGR), Pôle chirurgical et interventionnel [Gustave Roussy], and This work was supported by a grant API-K 2016 from the Groupement Interrégional deRecherche Clinique et Innovation Sud-Ouest Outre-mer Hospitalier (GIRCI SOHO).
Subjects: metastatic endometrial carcinoma, hormone therapy, predictive factors, mutations, copy number alterations, protein expression, Copy number alterations, Metastatic endometrial carcinoma, Medicine (miscellaneous), Protein expression, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Hormone therapy, Mutations, Predictive factors
Abstract: International audience; Hormone therapy (HT) is an effective treatment for metastatic endometrial carcinoma (mEC), with limited toxicity and low cost. We focused on molecular analysis of mECs treated by HT and, for the first time to date, we compared the genomic profiles of paired metastasis and primary ECs. The main objective was to identify predictive factors of the response to HT as well as specific altered signaling pathways driving mEC biology. From 1052 patients with EC treated by HT in two French cancer centers, 32 with endometrioid EC and 6 with high grade serous EC were included. We evaluated hormone receptors (HR) and mismatch repair proteins expression by immunohistochemistry and gene alterations by targeted next-generation sequencing and array-based comparative genomic hybridization. Several variables were tested in univariate and multivariate analyses to identify potential associations with (i) the clinical benefit of HT (CBHT) and (ii) a longer response (>18 months) (LRHT) and overall survival (OS). We compared the biological and genomic profiles of 11 primary/metastatic EC pairs. Thirty tumors (78.9%) were HR-positive and 6 (15.8%) showed microsatellite instability (MSI). The genomic profiles of 34 tumors showed an average altered genome of 3.26%, DNA repair homologous recombination deficiency in five tumors (14.7%), and 17 regions significantly targeted by amplification/deletion. Thirty-three tumors had 273 variants (158 genes, median of 7 mutations/sample), including 112 driver mutations. TP53, PTEN, PPP2R1A, ARID1A, FGFR2, and PIK3CA were the most frequently mutated. Based on the genomic status, nine oncogenic pathways were altered in more than 25% of primary EC. Clinically, 22 (57.9%) and 6 (15.8%) patients presented CBHT and LRHT, respectively. Neither oncogenic pathways alterations nor the variables tested were associated with CBHT and LRHT. Only patient’s age, mitotic index and the presence of at least one HR were associated with OS. Paired analysis of the primary/metastatic samples showed that among the 22 mutations acquired in the metastatic counterparts, the most frequently targeted genes were involved in pathways that might confer a selective advantage to cancer metastasis including hormone resistance. In conclusion, only patient’s age, mitotic index and the presence of at least one HR were associated with OS. The identification of gene mutations newly acquired in metastasis might help to better understand the formation of EC metastasis and select the best actionable candidates for HT-treated patients at the metastatic stage.
Published: 2022

4. Circulating Tumor DNA is Prognostic and Potentially Predictive of Eryaspase Efficacy in Second-line in Patients with Advanced Pancreatic Adenocarcinoma

Author: Pierre Laurent-Puig, Laurent Mineur, Fabienne Portales, Jean-Philippe Metges, Hélène Blons, Claire Mulot, Jason E. Cain, Jean-Baptiste Bachet, Iman El Hariry, Jérôme Cros, Camille Bourreau, Pascal Hammel, 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Cooperator Multidisciplinary Oncology Group (GERCOR), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ERYTECH Pharma, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut Sainte Catherine [Avignon], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Gestionnaire, HAL Sorbonne Université 5, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Adult, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Adenocarcinoma, law.invention, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, 0302 clinical medicine, Second line, [SDV.CAN] Life Sciences [q-bio]/Cancer, Randomized controlled trial, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Asparaginase, Humans, In patient, predictive, Objective response, Aged, Predictive biomarker, Aged, 80 and over, circulating tumor DNA, business.industry, Middle Aged, Prognosis, medicine.disease, L-asparaginase, Progression-Free Survival, Confidence interval, Pancreatic Neoplasms, Treatment Outcome, 030104 developmental biology, phase 2, Circulating tumor DNA, 030220 oncology & carcinogenesis, Mutation, Female, Tumor Suppressor Protein p53, business, prognostic
Abstract: Purpose: Eryaspase is composed of l-asparaginase encapsulated in erythrocytes and has demonstrated significant efficacy in a randomized phase II trial. We assessed the prognostic and predictive value of circulating tumor DNA (ctDNA) in patients, plasma included in this trial. Experimental Design: Samples prospectively collected pretreatment were centrally analyzed by next-generation sequencing. Prognostic values of baseline ctDNA and ctDNA early changes between day 0 and 28 were assessed in both arms combined on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS); three groups were defined: negative ctDNA (Neg), ctDNA responders (Resp), and ctDNA nonresponders (NResp). Predictive value of ctDNA for eryaspase efficacy was investigated. Results: ctDNA was positive at baseline in 77 patients of the 113 tested patients (68%). Detectable ctDNA was an independent negative prognostic factor for OS (4.6 vs. 8.8 months; P = 0.0025) and PFS (1.6 vs. 3.3 months; P = 0.00043). Early change in ctDNA levels was correlated with ORR (20%, 26%, 0%; P < 0.04), PFS (3.7, 3.4, 1.6 months; P < 0.0001), and OS (11.7, 6.5, 4.3 months; P < 0.0001) according to the three defined groups (Neg, Res, NResp, respectively). In patients with ctDNA detectable at baseline, eryaspase was associated with better PFS [HR = 0.53; 95% confidence interval (CI): 0.3–0.94)] and OS (HR = 0.52; 95% CI: 0.29–0.91). Conclusions: We confirm from a prospective randomized trial that: (i) the presence of ctDNA at baseline is a major prognostic factor, (ii) the early change of ctDNA correlates with treatment outcome, and (iii) the ctDNA could be a predictive biomarker of eryaspase efficacy.
Published: 2020

5. A single-arm multicentre phase II trial of doxorubicin in combination with trabectedin in the first-line treatment for leiomyosarcoma with long-term follow-up and impact of cytoreductive surgery

Author: Anne Floquet, Frédéric Selle, Esma Saada-Bouzid, Benjamin Lacas, Olivier Collard, Christine Chevreau, François Bertucci, Patricia Pautier, C. Delcambre, Maud Toulmonde, P Soulier, Didier Cupissol, Valerie Lebrun-Ly, Florence Duffaud, Emmanuelle Bompas, C. Guillemet, Jérôme Alexandre, N. Isambert, A. Le Cesne, Nicolas Penel, Sophie Piperno-Neumann, Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Institut Bergonié [Bordeaux], UNICANCER, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Groupe Hospitalier Diaconesses Croix Saint-Simon, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Institut Curie [Paris], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Hôpital Dupuytren [CHU Limoges], CRLCC Paul Papin, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital de la Timone [CHU - APHM] (TIMONE), Bertucci, François, 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), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: Leiomyosarcoma, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, doxorubicin plus trabectedin, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Doxorubicin, education, Trabectedin, Original Research, Chemotherapy, education.field_of_study, business.industry, Soft tissue, Cytoreduction Surgical Procedures, leiomyosarcoma, medicine.disease, Confidence interval, Surgery, first-line chemotherapy, Oncology, Female, business, Pegfilgrastim, Follow-Up Studies, medicine.drug
Abstract: Background Uterine leiomyosarcomas (U-LMSs) and soft tissue leiomyosarcomas (ST-LMSs) are rare tumours with poor prognosis when locally advanced or metastatic, and with moderate chemosensitivity. In 2015 we reported very encouraging results of the LMS-02 study (NCT02131480) with manageable toxicity. Herein, we report the updated and long-term results of progression-free survival (PFS) and overall survival (OS). Patients and methods Patients received 60 mg/m2 intravenous doxorubicin followed by trabectedin 1.1 mg/m2 as a 3-h infusion on day 1 and pegfilgrastim on day 2, every 3 weeks, up to six cycles. Surgery for residual disease was permitted. Patients were stratified into U-LMS and ST-LMS groups. Results One-hundred and eight patients were enrolled, mainly with metastatic disease (85%), and 20 patients (18.5%) had surgical resection of metastases after chemotherapy. With a median follow-up of 7.2 years [95% confidence interval (CI) 6.9-8.2 years], the median PFS was 10.1 months (95% CI 8.5-12.6 months) in the whole population, and 8.3 months (95% CI 7.4-10.3 months) and 12.9 months (95% CI 9.2-14.1 months) for U-LMSs and ST-LMSs, respectively. The median OS was 34.4 months (95% CI 26.9-42.7 months), 27.5 months (95% CI 17.9-38.2 months), and 38.7 months (95% CI 31.0-52.9 months) for the whole population, U-LMSs, and ST-LMSs, respectively. The median OS of the patients with resected metastases was not reached versus 31.6 months in the overall population without surgery (95% CI 23.9-35.4 months). Conclusions These updated results confirm the impressive efficiency of the doxorubicin plus trabectedin combination given in first-line therapy for patients with locally advanced/metastatic LMS in terms of PFS and OS. Results of the LMS04 trial (NCT02997358), a randomized phase III study comparing the doxorubicin plus trabectedin combination versus doxorubicin alone in first-line therapy in metastatic LMSs, are pending., Highlights • Long-term results on PFS and OS of doxorubicin and trabectedin in first-line treatment for advanced leiomyosarcoma. • The update confirms the impressive efficiency of the doxo+trab in terms of PFS and OS. • Results of a randomized phase-III study comparing dox+trab combination versus doxo alone in first-line therapy in metastatic LMS are pending.
Published: 2021

6. Evaluation of an aSi-EPID with flattening filter free beams: Applicability to the GLAaS algorithm for portal dosimetry and first experience for pretreatment QA of RapidArc

Author: Fenoglietto, P. [Département de Cancérologie Radiothérapie, CRLC Val d’Aurelle-Paul Lamarque, Montpellier F-34090 (France)]
Published: 2013
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7. Early MRI predictors of disease-free survival in locally advanced rectal cancer from the GRECCAR 4 trial

Author: S Nougaret, F Castan, H Forges, H A Vargas, B Gallix, S Gourgou, P Rouanet, E Rullier, B Lelong, P Maingon, J-J Tuech, D Pezet, M Rivoire, B Meunier, J Loriau, A Valverde, J-M Fabre, M Prudhomme, E Cotte, G Portier, L Quero, C Lemanski, M Ychou, F Bibeau, 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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CRLCC Val d'Aurelle - Paul Lamarque, CRLC Val d'Aurelle-Paul Lamarque, and Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)
Subjects: Adult, medicine.medical_specialty, Adolescent, Colorectal cancer, Leucovorin, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Irinotecan, Gastroenterology, Disease-Free Survival, Drug Administration Schedule, Article, 030218 nuclear medicine & medical imaging, law.invention, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Robotic Surgical Procedures, Randomized controlled trial, law, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, Prospective Studies, Precision Medicine, Young adult, Infusions, Intravenous, Prospective cohort study, Aged, medicine.diagnostic_test, Rectal Neoplasms, business.industry, Induction chemotherapy, Magnetic resonance imaging, Chemoradiotherapy, Adjuvant, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Tumor Burden, 3. Good health, Oxaliplatin, Clinical trial, 030220 oncology & carcinogenesis, Laparoscopy, Surgery, Fluorouracil, Neoplasm Recurrence, Local, business, Chemoradiotherapy
Abstract: Tailored neoadjuvant treatment of locally advanced rectal cancer (LARC) may improve outcomes. The aim of this study was to determine early MRI prognostic parameters with which to stratify neoadjuvant treatment in patients with LARC.All patients from a prospective, phase II, multicentre randomized study (GRECCAR4; NCT01333709) were included, and underwent rectal MRI before treatment, 4 weeks after induction chemotherapy and after completion of chemoradiotherapy (CRT). Tumour volumetry, MRI tumour regression grade (mrTRG), T and N categories, circumferential resection margin (CRM) status and extramural vascular invasion identified by MRI (mrEMVI) were evaluated.A total of 133 randomized patients were analysed. Median follow-up was 41·4 (95 per cent c.i. 36·6 to 45·2) months. Thirty-one patients (23·3 per cent) developed tumour recurrence. In univariable analysis, mrEMVI at baseline was the only prognostic factor associated with poorer outcome (P = 0·015). After induction chemotherapy, a larger tumour volume on MRI (P = 0·019), tumour volume regression of 60 per cent or less (P = 0·002), involvement of the CRM (P = 0·037), mrEMVI (P = 0·026) and a poor mrTRG (P = 0·023) were associated with poor outcome. After completion of CRT, the absence of complete response on MRI (P = 0·004), mrEMVI (P = 0·038) and a poor mrTRG (P = 0·005) were associated with shorter disease-free survival. A final multivariable model including all significant variables (baseline, after induction, after CRT) revealed that Eastern Cooperative Oncology Group performance status (P = 0·011), sphincter involvement (P = 0·009), mrEMVI at baseline (P = 0·002) and early tumour volume regression of 60 per cent or less after induction (P = 0·007) were associated with relapse.Baseline and early post-treatment MRI parameters are associated with prognosis in LARC. Future preoperative treatment should stratify treatment according to baseline mrEMVI status and early tumour volume regression.El tratamiento neoadyuvante personalizado del cáncer de recto localmente avanzado (locally advanced rectal cancer, LARC) puede mejorar los resultados. El objetivo de este estudio fue determinar factores pronósticos precoces mediante RMN para estratificar el tratamiento neoadyuvante en pacientes con LARC. MÉTODOS: Todos los pacientes de un eensayo prospectivo de fase II, multicéntrico y aleatorizado (GRECCAR4-NCT01333709) se incluyeron en este estudio y se les realizó una RMN antes del tratamiento, 4 semanas después de la quimioterapia de inducción y después de completar la quimiorradioterapia (chemoradiation, CRT). Se evaluó la volumetría tumoral, el grado de regresión tumoral mediante RMN (MRI Tumor Regression Grade, mrTRG), la estadificación T, la estadificación N, el estado del margen de resección circunferencial (circumferential resection margin, CRM) y la presencia de invasión extramural vascular en la RMN (extramural vascular invasion, mrEMVI).Se analizaron 133 pacientes aleatorizados. La mediana de seguimiento fue de 41,4 meses (i.c. del 95%: 36,6-45,2). En 31 pacientes (23%) se diagnosticó una recidiva. En el análisis univariado de la situación basal, mrEMVI fue el único factor pronóstico asociado con un peor resultado (P = 0,0152). Después de la quimioterapia de inducción, un volumen tumoral más alto en la RMN (P = 0,019), una regresión del volumen tumoral ≤ 60% (P = 0,002), la afectación del CRM (P = 0,037), mrEMVI (P = 0,026) y un grado escaso mrTRG (P = 0,023) se asociaron con un mal resultado. Después de completar la CRT, la ausencia de respuesta completa en la RMN (P = 0,004), la presencia de mrEMVI (P = 0,04) y una insuficiente mrTRG (P = 0,005) se asociaron con una supervivencia libre de enfermedad más corta. En el modelo multivariable final en el que se incluyeron todas las variables significativas (basales, postinducción, post-CRT), el estado de ECOG (P = 0,011), la afectación esfinteriana (P = 0,009), la presencia de EMVI al inicio (P = 0,002) y una regresión precoz del volumen tumoral ≤ 60% después de la inducción (P = 0,007) se asociaron con una recidiva. CONCLUSIÓN: Los parámetros basales y post-tratamiento precoces de la RMN se asocian con el pronóstico en el LARC. La estrategia terapéutica preoperatoria futura deberá estratificar el tratamiento de acuerdo con la presencia de EMVI al inicio y la regresión precoz del volumen tumoral.
Published: 2019

8. Real‐life activity of eribulin mesylate among metastatic breast cancer patients in the multicenter national observational ESME program

Author: Audrey Mailliez, Jean-Marc Ferrero, Marie Chaix, Julien Fraisse, Mathieu Robain, Sophie Gourgou, Paul Cottu, Anthony Gonçalves, Claudia Lefeuvre, Marc Debled, Séverine Guiu, Jean-Christophe Eymard, Christelle Levy, C. Courtinard, Mario Campone, Marianne Leheurteur, Pierre-Etienne Heudel, William Jacot, Lionel Uwer, Barbara Pistilli, Florence Dalenc, Thierry Petit, Marie-Ange Mouret-Reynier, 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 du Cancer de Montpellier (ICM), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Centre Léon Bérard [Lyon], Université de Montpellier (UM), Institut Claudius Regaud, 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), Institut Gustave Roussy (IGR), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Bergonié [Bordeaux], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), CRLCC Eugène Marquis (CRLCC), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Jean Godinot [Reims], Centre Paul Strauss, CRLCC Paul Strauss, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Institut Curie [Paris], Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), and Université Lille Nord de France (COMUE)-UNICANCER
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Population, Antineoplastic Agents, Breast Neoplasms, Disease-Free Survival, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Breast cancer, real-life cohort, Randomized controlled trial, law, Internal medicine, Humans, Medicine, Furans, education, eribulin, Aged, Retrospective Studies, Chemotherapy, education.field_of_study, business.industry, Ketones, Middle Aged, medicine.disease, Metastatic breast cancer, Progression-Free Survival, 3. Good health, chemistry, 030220 oncology & carcinogenesis, Concomitant, Cohort, Female, metastatic breast cancer, business, Eribulin
Abstract: International audience; Eribulin mesylate (EM) was recently approved for metastatic breast cancer (MBC) chemotherapy (CT) in late lines by the FDA, with debated results in second line. We evaluated outcomes in breast cancer patients receiving EM as second, third and fourth line in a national real-life cohort of 16,703 consecutive MBC patients initiating their first metastatic therapeutic line between 2008 and 2014. Primary and secondary objectives were overall survival (OS) and progression-free survival (PFS). An imbalance was seen for HER2+ tumors and concomitant anti-HER2 targeted therapies use, we thus performed a subanalysis in HER2- patients. PFS and OS were significantly better in EM patients in third and fourth lines, compared to "Other chemotherapies" patients (PFS: 4.14 vs. 3.02 months, p = 0.0010; 3.61 vs. 2.53 months, p = 0.0102, third and fourth-line; OS: 11.27 vs. 7.65 months, p = 0.0001; 10.91 vs. 5.95 months, p
Published: 2019

9. Distal Pancreatectomy with Celiac Axis Resection (Modified Appleby Procedure) and Arterial Reconstruction for Locally Advanced Pancreatic Adenocarcinoma After FOLFIRINOX Chemotherapy and Chemoradiation Therapy

Author: Guillaume Carrier, Philippe Rouanet, Pierre-Emmanuel Colombo, François Quenet, A. Mourregot, Pierre Alric, Mathias Neron, Fabienne Portales, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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 National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cancer de Montpellier (ICM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département d'oncologie Médicale, Faculté de Médecine - Clermont-Auvergne (FM - UCA), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and MORNET, Dominique
Subjects: Male, medicine.medical_specialty, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, FOLFIRINOX, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Leucovorin, Locally advanced, [SDV.CAN]Life Sciences [q-bio]/Cancer, Arterial reconstruction, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Adenocarcinoma, 030230 surgery, Irinotecan, 03 medical and health sciences, Pancreatectomy, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Surgical oncology, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, Contraindication, ComputingMilieux_MISCELLANEOUS, Aged, Chemotherapy, Frozen section procedure, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Oxaliplatin, Pancreatic Neoplasms, Oncology, 030220 oncology & carcinogenesis, Surgery, Fluorouracil, Radiology, business
Abstract: Resectability of pancreatic carcinoma (PC) is directly linked to vascular extension (Tempero MA et al. in J Natl Compr Canc Netw 15(8):1028–1061, 2017. https://doi.org/10.6004/jnccn.2017.0131 ; Isaji S et al. in Pancreatology 18(1):2–11, 2018. https://doi.org/10.1016/j.pan.2017.11.011 ). Involvement of the celiac axis (CA) is typically a contraindication to surgery. High postoperative morbidity and subsequent poor prognosis have been observed in this case, especially for contact > 180° requiring arterial resection (Tempero MA et al. 2017). Recent medical advances in PC treatment, such as FOLFIRINOX-based chemotherapy eventually followed by chemoradiation therapy, offer the potential to select tumour for surgery and to obtain a negative-margin resection even in case of unresectable PC at diagnosis (Suker M et al. in Lancet Oncol 17(6):801–10, 2016. https://doi.org/10.1016/s1470-2045(16)00172-8 ; Pietrasz D et al. in Ann Surg Oncol 26(1):109–117, 2019. https://doi.org/10.1245/s10434-018-6931-6 ). A major pathologic response has been observed in more than 20% of patients after this treatment and is associated with an improved survival (Suker M et al. 2016; Pietrasz D et al. 2019). This evolution allows aggressive surgical strategies with the possibility of long-term disease control for patients showing a good response to induction treatment. This video presents the case of a 66-year-old man diagnosed with a locally advanced ductal adenocarcinoma of the pancreatic body with a 360° involvement of the CA and the hepatic artery. After eight courses of FOLFIRINOX chemotherapy and a capecitabin-based chemoradiation, a surgical exploration was planned for potential resection. The key steps of the procedure are presented, i.e. surgical exposition, assessment of resectability with frozen sections of peri-arterial tissues, en bloc resection (Strasberg SM et al. in Surgery 133(5):521–527, 2003. https://doi.org/10.1067/msy.2003.146 ), and primary end-to-end arterial reconstruction. A modified Appleby operation for locally advanced PC is a technically challenging but feasible procedure in experienced teams. It offers the possibility of en bloc R0 resection of a locally advanced PC with the potential of long-term disease local control. This video may help surgeons to perform this complex intervention.
Published: 2021

10. Implementing intensity modulated radiotherapy to the prostate bed: Dosimetric study and early clinical results

Author: Fenoglietto, Pascal [Département de Cancérologie Radiothérapie, CRLC Val d'Aurelle-Paul Lamarque, Montpellier (France)]
Published: 2013
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11. Ovarian and peritoneal psammocarcinoma: Results of a multicenter study on 25 patients

Author: Jean-Baptiste Delhorme, Jordan Ohayon, Sébastien Gouy, Gerlinde Averous, Catherine Genestie, Léopold Gaichies, Olivier Glehen, Jean-Marc Guilloit, Denis Pezet, Francois Quenet, Gwenaël Ferron, Cécile Brigand, Philippe Morice, Charles Honoré, Julio Abba, Karine Abboud, Mohammad Alyami, Catherine Arvieux, Naoual Bakrin, Gisèle Balagué, Vincent Barrau, Houda Ben Rejeb, Jean-Marc Bereder, Isabelle Berton-Rigaud, Frédéric Bibeau, Isabelle Bonnefoy, Dominique Bouzard, Ivan Bricault, Sébastien Carrère, Cécile de Chaisemartin, Madleen Chassang, Anne Chevallier, Thomas Courvoisier, Peggy Dartigues, Anthony Dohan, Julien Dubreuil, Frédéric Dumont, Clarisse Eveno, Marie Faruch-Bilfeld, Juliette Fontaine, Laure Fournier, Johan Gagniere, Delphine Geffroy, Laurent Ghouti, François-Noël Gilly, Laurence Gladieff, Diane Goéré, Aymeric Guibal, Frédéric Guyon, Bruno Heyd, Christine Hoeffel, Constance Hordonneau, Sylvie Isaac, Peggy Jourdan-Enfer, Rachid Kaci, Reza Kianmanesh, Catherine Labbé-Devilliers, Joëlle Lacroix, Bernard Lelong, Agnès Leroux-Broussier, Yoann Lherm, Réa Lo Dico, Gérard Lorimier, Caroline Malhaire, Frédéric Marchal, Pascale Mariani, Emilie Mathiotte, Pierre Meeus, Eliane Mery, Simon Msika, Cédric Nadeau, Pablo Ortega-Deballon, Guillaume Passot, Olivier Pellet, Patrice Peyrat, Nicolas Pirro, Marc Pocard, Flora Poizat, Jack Porcheron, Anaïs Poulet, François Quenet, Patrick Rat, Pierre Rousselot, Pascal Rousset, Hélène Senellart, Martine Serrano, Vincent Servois, Olivia Sgabura, Andrea Skanjeti, Magali Svrcek, Raphaël Tetreau, Emilie Thibaudeau, Yann Touchefeu, Jean-Jacques Tuech, Séverine Valmary-Degano, Delphine Vaudoyer, Stéphane Velasco, Véronique Verriele-Beurrier, Laurent Villeneuve, Romuald Wernert, Franck Zinzindohoue, Département de chirurgie générale et digestive [CHU Strasbourg], Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), Institut Gustave Roussy (IGR), Département de chirurgie gynécologique [Gustave Roussy], Service d'anatomie pathologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université de Caen Normandie - UFR Santé (UNICAEN Santé), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Hôpital Nord, Hôpital nord, Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Grenoble, Hôpitaux Universitaires de Strasbourg, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Laboratoire d'anatomo-pathologie, CRLCC Val d'Aurelle - Paul Lamarque, Département de chirurgie, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Département de biologie et pathologie médicales [Gustave Roussy], Department of Body and Interventional Imaging, Hôpital Lariboisière, Paris, France., Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Toulouse [Toulouse], Institut Claudius Regaud, 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), Chirurgie digestive et hépatobiliaire, CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Hospices Civils de Lyon (HCL), Département de chirurgie générale [Gustave Roussy], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Service de chirurgie viscérale et digestive - Unité de transplantation hépatique, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Radiologie, Service de pathologie, Service de Chirurgie Générale, Digestive et Endocrine [CHU Reims], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Service de Radiologie [CLCC Baclesse], Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de recherches (CRT), Société Lafarge, Service de Chirurgie d'Oncologie Digestive [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Paul Papin(Angers), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Centre Léon Bérard [Lyon], Institut Claudius Regaud. Department of pathology, Hôpital Louis Mourier - AP-HP [Colombes], Department of Gynecology and Obstetrics, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Service de Chirurgie Digestive (AP-HM), Université de la Méditerranée - Aix-Marseille 2, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de Biopathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Chirurgie digestive, Centre Hospitalier Universitaire de Saint-Etienne, Laboratoire Joliot Curie, École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS), CRLC Val d'Aurelle-Paul Lamarque, Service de Chirurgie Digestive, Cancérologique, Générale, Endocrinienne et Urgences (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire d'Anatomie Pathologique, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Department of Radiology, Centre René Gauducheau, CRLCC René Gauducheau, Université de Lyon, (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Institut du Cancer de Montpellier (ICM), 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), Laboratoire d'éthique médicale et médecine légale (LEM), Université Paris Descartes - Paris 5 (UPD5), Service de Pathologie, Centro de Investigaciones Oceanograficas e Hidrograficas (CIOH), DIMAR, Ministerio de Defensa Nacional, Colombie, Unité de Méthodologie en Recherche Clinique, Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL), Service de chirurgie digestive, générale et cancérologique [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), École normale supérieure de Lyon (ENS de Lyon)-Centre National de la Recherche Scientifique (CNRS), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), and Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP]
Subjects: Hyperthermic Intraperitoneal Chemotherapy, Intraperitoneal chemotherapy, chemistry.chemical_compound, 0302 clinical medicine, Infusions, Parenteral, Peritoneal Neoplasms, Ovarian Neoplasms, Univariate analysis, 030219 obstetrics & reproductive medicine, General Medicine, Cytoreduction Surgical Procedures, Middle Aged, Neoadjuvant Therapy, Progression-Free Survival, 3. Good health, Survival Rate, medicine.anatomical_structure, Oncology, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Female, France, Peritoneum, Pancreas, Adult, medicine.medical_specialty, Adolescent, Ovary, Antineoplastic Agents, Psammocarcinoma, 03 medical and health sciences, Young Adult, medicine, Humans, Aged, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Carboplatin, Surgery, chemistry, Multicenter study, Conventional PCI, Neoplasm Grading, business, Neoplasms, Cystic, Mucinous, and Serous, Rare disease
Abstract: International audience; Purpose: Psammocarcinoma (PK) is a rare disease of unknown origin. We aimed to report the characteristics, management and survival of patients operated on for PK within the French Network for Rare Peritoneal Malignancies (RENAPE) expert centers.Patients and methods: All consecutive cases of PK operated within all 26 RENAPE centers between 1997 and 2018 were retrospectively analyzed.Results: Twenty-five patients were identified. The median age was 53 years [range 17–78]. None of the patients had extra peritoneal metastases at diagnosis. A median of 6 cycles of carboplatin-based systemic chemotherapy was delivered in 52% preoperatively (n = 13) and 56% postoperatively (n = 14); associated with placlitaxel for 12 patients. All patients were operated on. The median PCI was 23 [0–33]. Eighty-four percent had a complete cytoreductive surgery through digestive (n = 7), spleen (n = 3), pancreas (n = 1) resections and/or multiple peritonectomies (n = 11). Five patients (20%) had intraperitoneal chemotherapy. Morbidity (Dindo-Clavien ≥3) was 12%. No postoperative death occurred. After a median follow-up of 42 months (range [2–194]), the median overall (OS) and progression-free (DFS) survival times were respectively 128 months and 31 months. Eighteen patients recurred (72%), mainly in the peritoneum (n = 16). Four of them (22%) were reoperated. The 5 and 10-year DFS rates were both 20.3%. The 5 and 10-year OS rates were 62% and 51.7%, respectively. A complete cytoreductive surgery was associated with a better OS and DFS in a univariate analysis.Conclusion: Complete cytoreductive surgery is the cornerstone of the PK's management as a primary treatment. Recurrence remains common and new adjuvant strategies seem needed.
Published: 2019

12. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei of appendicular and extra-appendicular origin

Author: J-B Delhorme, F Severac, G Averous, O Glehen, G Passot, N Bakrin, F Marchal, M Pocard, R Lo Dico, C Eveno, S Carrere, O Sgarbura, F Quenet, G Ferron, D Goéré, C Brigand, J Abba, K Abboud, M Alyami, C Arvieux, G Balagué, V Barrau, H Ben Rejeb, J-M Bereder, I Berton-Rigaud, F Bibeau, I Bonnefoy, D Bouzard, I Bricault, S Carrère, C de Chaisemartin, M Chassang, A Chevallier, T Courvoisier, P Dartigues, A Dohan, J Dubreuil, F Dumont, M Faruch-Bilfeld, J Fontaine, L Fournier, J Gagniere, D Geffroy, L Ghouti, F-N Gilly, L Gladieff, A Guibal, J-M Guilloit, F Guyon, B Heyd, C Hoeffel, C Hordonneau, S Isaac, P Jourdan-Enfer, R Kaci, R Kianmanesh, C Labbé-Devilliers, J Lacroix, B Lelong, A Leroux-Broussier, Y Lherm, G Lorimier, C Malhaire, P Mariani, E Mathiotte, P Meeus, E Mery, S Msika, C Nadeau, P Ortega-Deballon, O Pellet, P Peyrat, D Pezet, N Pirro, F Poizat, J Porcheron, A Poulet, P Rat, P Rousselot, P Rousset, H Senellart, M Serrano, V Servois, O Sgabura, A Skanjeti, M Svrcek, R Tetreau, E Thibaudeau, Y Touchefeu, J-J Tuech, S Valmary-Degano, D Vaudoyer, S Velasco, V Verriele-Beurrier, L Villeneuve, R Wernert, F Zinzindohoue, CHU Strasbourg, Les Hôptaux universitaires de Strasbourg (HUS), Department of Oncologic Surgery, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Department of oncologic surgery, Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique (LHEEA), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Carcinose Angiogenèse et Recherche Translationnelle, Angiogenese et recherche translationnelle (CART U965), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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), Department of Surgical Oncology Institut Claudius Regaud, Department of Surgical Oncology, Université Paris-Sud - Paris 11 (UP11), and Département de chirurgie digestive
Subjects: Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Gastroenterology, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Pseudomyxoma peritonei, Survival rate, Peritoneal Neoplasms, Survival analysis, Urachus, Retrospective Studies, business.industry, Retrospective cohort study, Cytoreduction Surgical Procedures, Hyperthermia, Induced, Middle Aged, Prognosis, Pseudomyxoma Peritonei, medicine.disease, Debulking, Survival Analysis, 3. Good health, medicine.anatomical_structure, Appendiceal Neoplasms, 030220 oncology & carcinogenesis, Peritoneal Cancer Index, Female, 030211 gastroenterology & hepatology, Surgery, Hyperthermic intraperitoneal chemotherapy, business
Abstract: BackgroundThe prognostic value of the primary neoplasm responsible for pseudomyxoma peritonei (PMP) remains poorly studied. The aim of this study was to determine the prognosis for patients with extra-appendicular PMP (EA-PMP) treated optimally with complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).MethodsAll patients treated for PMP with CCRS and HIPEC between 1994 and 2016 were selected retrospectively from a French multicentre database. Patients with EA-PMP had pathologically confirmed non-neoplastic appendices and were matched in a 1 : 4 ratio with patients treated for appendicular PMP (A-PMP), based on a propensity score.ResultsSome 726 patients were identified, of which 61 (EA-PMP group) were matched with 244 patients (A-PMP group). The origins of primary tumours in the EA-PMP group included the ovary (45 patients), colon (4), urachus (4), small bowel (1), pancreas (1) and unknown (6). The median peritoneal carcinomatosis index was comparable in EA-PMP and A-PMP groups (15·5 versus 18 respectively; P = 0·315). In-hospital mortality (3 versus 2·9 per cent; P = 1·000) and major morbidity 26 versus 25·0 per cent; P = 0·869) were also similar between the two groups. Median follow-up was 66·9 months. The 5-year overall survival rate was 87·8 (95 per cent c.i. 83·2 to 92·5) per cent in the A-PMP group and 87 (77 to 96) per cent in the EA-PMP group. The 5-year disease-free survival rate was 66·0 (58·7 to 73·4) per cent and 70 (53 to 83) per cent respectively.ConclusionOverall and disease-free survival following treatment with CCRS and HIPEC is similar in patients with pseudomyxoma peritonei of appendicular or extra-appendicular origin.
Published: 2018

13. Immunohistochemical evaluation of two antibodies against PD-L1 and prognostic significance of PD-L1 expression in epithelioid peritoneal malignant mesothelioma: A RENAPE study

Author: S. Velasco, M. Chassang, Laurence Gladieff, Jean-Marc Guilloit, Frédéric Dumont, Thomas Courvoisier, Magali Svrcek, E. Mery, Jack Porcheron, Pablo Ortega-Deballon, V. Barrau, M. Serrano, Pierre Meeus, H. Senellart, Cécile Brigand, R. Kianmanesh, I. Bricault, M. Capovilla, O. Pellet, I. Bonnefoy, B. Lelong, A. Poulet, A. Chevallier, Delphine Vaudoyer, Frédéric Guyon, Julien Dubreuil, G. Ferron, S. Valmary-Degano, D. Geffroy, Franck Zinzindohoué, François-Noël Gilly, Laure Fournier, G. Lang Averous, Jean-Jacques Tuech, Catherine Arvieux, Karine Abboud, P. Rousselot, Y. Touchefeu, Guillaume Passot, R. Tetreau, Christine Hoeffel, Peggy Dartigues, Julio Abba, A. Dohan, Frédéric Bibeau, P. Peyrat, Naoual Bakrin, O. Sgabura, J.M. Bereder, Bruno Heyd, J. Lacroix, Frédéric Marchal, Johan Gagnière, Clarisse Eveno, J. Hommell-Fontaine, P. Rat, P. Jourdan-Enfer, C. Labbé-Devilliers, C. de Chaisemartin, Prudence Colpart, L. M'Hamdi, S. Carrere, Denis Pezet, D. Bouzard, R. Lo Dico, Marc Pocard, Gérard Lorimier, A. Leroux-Broussier, Cédric Nadeau, V. Verriele-Beurrier, François Quenet, Caroline Malhaire, S. Isaac, Nicolas Pirro, C. Hordonneau, Olivier Glehen, Clarisse Dromain, R. Kaci, L. Ghouti, E. Mathiotte, Vincent Servois, Mohammad Alyami, Pascale Mariani, H. Ben Rejeb, A. Guibal, S. Msika, Laurent Villeneuve, Romuald Wernert, F. Monnien, Diane Goéré, Emilie Thibaudeau, M. H. Laverrière, G. Balague, F. Poizat, M. Faruch-Bilfeld, Andrea Skanjeti, I. Berton-Rigaud, Yoann Lherm, Université Bourgogne Franche-Comté [COMUE] (UBFC), Pathology Department, CHU Besançon, Besançon, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Hospices Civils de Lyon, Departement de Neurologie (HCL), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de Hautepierre [Strasbourg], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Paul Papin(Angers), Institut Bergonié [Bordeaux], UNICANCER, Department of Oncologic Surgery, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Departement of pathology, CHU Pontchaillou [Rennes], Service central de radiologie et d'imagerie médicale, CHU Grenoble-Hôpital Michallon, Gestes Medico-chirurgicaux Assistés par Ordinateur (TIMC-IMAG-GMCAO), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département de chirurgie digestive, CHU Strasbourg, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Département de chirurgie digestive [Institut Paoli Calmettes], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Department of Radiology, Université Paris-Sud - Paris 11 (UP11), Laboratoire de Mécanique des Systèmes et des Procédés (LMSP), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Carcinose Angiogenèse et Recherche Translationnelle, Angiogenese et recherche translationnelle (CART U965), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Surgical Oncology Institut Claudius Regaud, 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), Ciblage thérapeutique en Oncologie (EA3738), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Department of Surgical Oncology, Dept. of Nucl. Med., Jean Minjoz Univ. Hosp., Besancon, Centre Hospitalier Universitaire de Reims (CHU Reims), CRLCC René Gauducheau, Service de chirurgie thoracique cardiaque et vasculaire [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Center Paul Papin, Laboratoire de physique de la matière (LPM), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique (LHEEA), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris], Université de Lyon, Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Chirurgie Digestive, Cancérologique, Générale, Endocrinienne et Urgences (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Department of oncologic surgery, Department of nuclear Imaging, CHU Clermont-Ferrand, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'hépato-gastro-entérologie, CHU Saint-Etienne, Equipe Avenir. University of Burgundy, Univers, Transport, Interfaces, Nanostructures, Atmosphère et environnement, Molécules (UMR 6213) (UTINAM), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS), Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Service d'Oncologie Médicale Thoracique et Digestive [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Médecine nucléaire, biophysique, isotopes [CHRU Besançon], Service de chirurgie thoracique cardiaque et vasculaire [Rennes] = Thoracic and Cardiovascular Surgery [Rennes], Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)
Subjects: Male, Mesothelioma, PD-L1, Pathology, medicine.medical_specialty, Survival, Antibodies, Neoplasm, [SDV]Life Sciences [q-bio], B7-H1 Antigen, Epithelioid subtype, 03 medical and health sciences, 0302 clinical medicine, Immune system, Biomarkers, Tumor, medicine, Humans, Lymphocytes, 030212 general & internal medicine, Peritoneal Neoplasms, Retrospective Studies, Immunity, Cellular, biology, business.industry, General Medicine, Middle Aged, Prognosis, medicine.disease, Immunohistochemistry, Peritoneal Malignant Mesothelioma, 3. Good health, Survival Rate, Oncology, 030220 oncology & carcinogenesis, biology.protein, Peritoneal mesothelioma, Biomarker (medicine), Female, Surgery, Hyperthermic intraperitoneal chemotherapy, France, Antibody, business, Follow-Up Studies
Abstract: Background Epithelioid peritoneal malignant mesothelioma (EPMM) is the most common subtype of this aggressive tumor. We compared two antibodies against PD-L1, a recent theranostic biomarker, and evaluated the prognostic value of PD-L1 expression by mesothelial and immune cells in EPMM. Methods Immunohistochemistry was performed on 45 EPMM. Clinical and pathological data were extracted from the RENAPE database. Using E1L3N and SP142 clones, inter-observer agreement, PD-L1 expression by mesothelial and immune cells and inter-antibody agreement were evaluated. The prognostic relevance of PD-L1 expression was evaluated in 39 EPMM by univariate and multivariate analysis of overall survival (OS) and progression-free survival (PFS). Results Inter-observer agreement on E1L3N immunostaining was moderate for mesothelial and immune cells, and fair for mesothelial and poor for immune cells using SP142. Using E1L3N, 31.1% of mesothelial and 15.6% of immune cells expressed PD-L1, and 22.2% of mesothelial and 26.7% of immune cells using SP142. Inter-antibody agreement was moderate. In most positive cases, 1–5% of tumor cells were positive. Using E1L3N, PD-L1 expression by lymphocytes was associated with better OS and PFS by both univariate and multivariate analysis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy predicted better prognosis than other treatments. Solid subtype was an independent prognostic factor for worse OS. Conclusion E1L3N appeared easier to use than SP142 to evaluate PD-L1 expression. A minority of EPMM expressed PD-L1, and only a few cells were positive. PD-L1 expression by immune cells evaluated with E1L3N was an independent prognostic factor in EPMM.
Published: 2017

14. Dynamic evaluation of circulating tumour cells in patients with advanced gastric and oesogastric junction adenocarcinoma: Prognostic value and early assessment of therapeutic effects

Author: Jaafar Bennouna, Christophe Borg, Cécile Badoual, Jean-Baptiste Bachet, Julien Taieb, François Ghiringhelli, Florence Castan, Elie Marcheteau, Sophie Gourgou, Aurélie Cazes, Christelle De La Fouchardiere, Simon Pernot, Olivier Bouché, Trevor Stanbury, Eric Francois, Emmanuelle Samalin, Magali Terme, David Malka, Michel Ducreux, Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire [AP-HP Hôpital Européen Georges Pompidou] (Service de Biochimie), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’anatomo‑pathologie [AP-HP Hôpital Européen Georges Pompidou] (Centre de Ressources biologiques), Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Cancérologie de l'Ouest, Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Centre Léon Bérard [Lyon], CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, CHU Pitié-Salpêtrière [APHP], Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC), Institut Gustave Roussy (IGR), Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), UNICANCER - Institut régional du Cancer [Montpellier] (ICM), Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire [AP-HP Hôpital Européen Georges Pompidou] ( Service de Biochimie ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Service d’anatomo‑pathologie [AP-HP Hôpital Européen Georges Pompidou] ( Centre de Ressources biologiques ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), 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 ), Centre Hospitalier Universitaire de Reims ( CHU Reims ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Institut Gustave Roussy ( IGR ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), UNICANCER - Institut régional du Cancer [Montpellier] ( ICM ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM)
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, Pathology, Esophageal Neoplasms, Organoplatinum Compounds, MESH : Antineoplastic Combined Chemotherapy Protocols, Leucovorin, Cell Count, MESH : Leucovorin, Kaplan-Meier Estimate, MESH : Cell Count, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Prostate, Circulating tumour cells, Antineoplastic Combined Chemotherapy Protocols, MESH : Stomach Neoplasms, MESH : Esophagogastric Junction, MESH : Female, MESH: Treatment Outcome, MESH : Prognosis, MESH: Organoplatinum Compounds, MESH: Stomach Neoplasms, Neoplastic Cells, Circulating, Prognosis, 3. Good health, Oxaliplatin, Clinical trial, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH: Esophageal Neoplasms, Monoclonal, Disease Progression, MESH : Fluorouracil, MESH : Disease-Free Survival, Adenocarcinoma, Female, MESH: Disease Progression, Esophagogastric Junction, Fluorouracil, MESH: Esophagogastric Junction, medicine.drug, medicine.medical_specialty, MESH : Male, Stomach neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Treatment Outcome, MESH: Neoplastic Cells, Circulating, Antibodies, Monoclonal, Humanized, MESH : Organoplatinum Compounds, Disease-Free Survival, MESH : Antibodies, Monoclonal, Humanized, MESH: Prognosis, MESH : Kaplan-Meier Estimate, 03 medical and health sciences, Internal medicine, medicine, Humans, In patient, Clinical significance, MESH: Kaplan-Meier Estimate, MESH: Humans, MESH: Cell Count, business.industry, MESH : Humans, Therapeutic effect, MESH : Disease Progression, medicine.disease, MESH: Male, 030104 developmental biology, MESH: Antibodies, Monoclonal, Humanized, MESH : Neoplastic Cells, Circulating, MESH: Disease-Free Survival, MESH : Esophageal Neoplasms, MESH: Leucovorin, business, MESH: Female, MESH: Fluorouracil, Biomarkers
Abstract: IF 6.029; International audience; Background: The identification of dynamic biomarkers in advanced gastric and oesogastric junction adenocarcinoma (GOA) could help to tailor strategies for each patient. Enumeration of circulating tumour cells (CTCs) is approved by the US Food and Drug Administration in breast, colon and prostate cancer but is not in advanced GOA. Our study aims to establish the optimal threshold and the clinical significance of CTC count in advanced GOA before and during treatment.Methods: One hundred six patients with untreated advanced GOA were included in the ancillary study of the PRODIGE 17-ACCORD 20 trial. CTCs were detected in the peripheral blood using the CellSearch system on day 0 (D0) and day 28 (D28). The prognostic value of CTCs at D0 and D28 was analysed by testing several thresholds.Results: At baseline, median CTC count was 1 (range, 0-415). While CTCs >= 1, 2 or 3 at D0 were all significantly associated with worse overall survival (OS) and progression-free survival (PFS), CTCs >2 were the optimal threshold, on D0 or D28. CTCs >2 at D28 were also predictive of disease control. Taking into account both D0 and D28 CTC count defined 3 groups (low/low, high/low and low-high/high) with significantly different PFS (p = 0.0002) and OS (p = 0.003).Conclusion: Quantification of CTCs at baseline and during treatment may be a useful prognostic tool in advanced GOA, as it is associated with worse PFS and OS. A threshold >= 2 CTCs seems to have the best discriminant value. Change in CTC count between baseline and D28 could help to tailor treatment to each individual patient. (C) 2017 Elsevier Ltd. All rights reserved.
Published: 2017

15. Atomic Force Microscopy Study of the Topography and Nanomechanics of Casein Micelles Captured by an Antibody

Author: Dominique Chevalier-Lucia, Marta Martin, Sylvie Marchesseau, Asma Bahri, Csilla Gergely, Martine Pugnière, Ingénierie des Agro-polymères et Technologies Émergentes (UMR IATE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Laboratoire Charles Coulomb (L2C), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Carboxylic acid, Analytical chemistry, Ionic bonding, 02 engineering and technology, Microscopy, Atomic Force, Antibodies, 03 medical and health sciences, Colloid, chemistry.chemical_compound, Monolayer, Electrochemistry, General Materials Science, Micelles, health care economics and organizations, Spectroscopy, Carbodiimide, chemistry.chemical_classification, Caseins, Surfaces and Interfaces, 021001 nanoscience & nanotechnology, Condensed Matter Physics, Elasticity, Characterization (materials science), 030104 developmental biology, chemistry, Chemical engineering, Covalent bond, 0210 nano-technology, Nanomechanics
Abstract: International audience; Casein micelles (CMs) are colloidal phospho-protein-mineral complexes naturally present in milk. This study used atomic force microscopy (AFM) in a liquid environment to evaluate the topography and nanomechanics of single native CMs immobilized by a novel capture method. The proposed immobilization method involves weak interactions with theantiphospho-Ser/Thr/Tyr monoclonal antibody covalently bound to a carboxylic acid self-assembled monolayer (SAM)on a gold surface. This capture strategy was compared to the commonly used covalent immobilization method of CMs viacarbodiimide chemistry. With this conventional method, CMs remained mainly mobile during AFM measurements in liquid,disturbing the evaluation of their average size and elastic properties. Conversely, when captured by the specific antibody, they were successfully immobilized and their integrity was preserved during the AFM measurement. The characterization of both CM topography and elastic properties was carried out in a liquid ionic environment at native pH 6.6. The CMs’ capture efficiency via antibody was concurrently proved by surface plasmon resonance. The calculation of casein micelles’ width, height, and contact angle was carried out from the recorded 2D AFM images. CMs were characterized by a mean width of 148 ± 8 nm and a mean height of 42 ± 1 nm. Weak forces were applied to single captured CMs. The obtained force versus indentation curves were fitted using the Hertz model in order to evaluate their elastic properties. The elasticity distribution of native CMs exhibited a unimodal trend with a peak centered at 269 ± 14 kPa.
Published: 2017

16. Outcome after pancreatectomy for neuroendocrine neoplams according to the WHO 2017 grading system: A retrospective multicentric analysis of 138 consecutive patients

Author: Jean-Michel Fabre, Stéphane Obled, Eric Assenat, Astrid Herrero, Isabelle Raingeart, Marie Dupuy, Frédéric Borie, Antoine Coignac, Benjamin Rivière, Jeanne Ramos, Michel Prudhomme, François Quenet, Regis Souche, M. Bertrand, Fabrizio Panaro, Pierre-Emmanuel Colombo, Fabienne Portales, Boris Guiu, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service Médico-Chirurgical des Maladies de l'Appareil Digestif et de Transplantation Hépatique, CHU Saint-Eloi, Département d'oncologie Médicale, CRLCC Val d'Aurelle - Paul Lamarque, Service de Biopathologie [CHRU Montpellier], 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), 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), CRLC Val d'Aurelle-Paul Lamarque, Institut de Génétique Moléculaire de Montpellier (IGMM), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Databases, Factual, Pancreatic neuroendocrine tumor, medicine.medical_treatment, World Health Organization, Disease-Free Survival, World health, Young Adult, 03 medical and health sciences, Pancreatectomy, 0302 clinical medicine, Risk Factors, medicine, Humans, Aged, Retrospective Studies, Therapeutic strategy, Hepatology, business.industry, Mortality rate, Age Factors, Gastroenterology, Margins of Excision, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Middle Aged, medicine.disease, 3. Good health, Surgery, Pancreatic Neoplasms, Neuroendocrine Tumors, Treatment Outcome, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Synchronous metastasis, Severe morbidity, Female, 030211 gastroenterology & hepatology, Neoplasm Grading, Pancreas, business
Abstract: International audience; AIM:The aim of this study was to evaluate the new World Health Organization (WHO) 2017 grading system and the others clinicopathological factors in pancreatic neuroendocrine tumor (panNET) operated patients.METHODS:Histological staging was based on the WHO 2017 grading system. Outcome after surgery and predictors of overall survival (OS) and disease free survival (DFS) were evaluated.RESULTS:A total of 138 patients underwent surgical resection with a severe morbidity and mortality rates of 14.5% and 0.7% respectively. Five years OS differed according to WHO 2017: 95% among 58 patients with NETG1, 82% in 68 patients with NETG2, 35% in 7 patients with NETG3 and 0% in 5 patients with NECG3 (P60 y.o (P=0.014), synchronous metastasis (P=0.005) and WHO 2017 with significant differences between NETG1 versus NETG2 (P=0.005), NETG3 (P
Published: 2019

17. Infiltrating and peripheral immune cell analysis in advanced gastric cancer according to the Lauren classification and its prognostic significance

Author: Jaafar Bennouna, Christelle De La Fouchardiere, Simon Pernot, Trevor Stanbury, Jean-Baptiste Bachet, Thibault Voron, Florence Castan, Emmanuelle Samalin, Olivier Bouché, Christophe Borg, Cécile Badoual, Sophie Gourgou, Nina Radosevic-Robin, Eric Tartour, Frédérique Penault-Llorca, Magali Terme, François Ghiringhelli, David Malka, Valérie Boige, Eric Francois, Julien Taieb, Elie Marcheteau, Unité Fonctionnelle de Pharmacogénétique et Oncologie Moléculaire [AP-HP Hôpital Européen Georges Pompidou] (Service de Biochimie), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Rôle des cellules dendritiques dans la régulation des effecteurs de l'immunité antitumorale, Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'anatomopathologie, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER-UNICANCER-UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER, Centre Hospitalier Universitaire de Reims (CHU Reims), Service de pneumologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de signalisation, biologie du développement et cancer (ISBDC), 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), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut Gustave Roussy (IGR), Service de chirurgie générale et digestive [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de biostatistiques en Oncologie, CRLC Val d'Aurelle, Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service de gastroenterologie [CHU HEGP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), 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), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Kaplan-Meier Estimate, Peripheral blood mononuclear cell, Gastroenterology, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Immune system, Stomach Neoplasms, Surgical oncology, Internal medicine, medicine, Humans, Pathological, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, business.industry, FOXP3, General Medicine, Middle Aged, Prognosis, 3. Good health, Killer Cells, Natural, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Leukocytes, Mononuclear, Biomarker (medicine), Female, 030211 gastroenterology & hepatology, business, CD8
Abstract: The correlation between immune cells and the Lauren classification subtypes and their prognostic impact in advanced gastric cancer (AGC) are unknown. Circulating natural killer (NK) cells, CD4+ and CD8+ T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were quantified in peripheral blood mononuclear cells (PBMCs) from 67 patients with untreated AGC enrolled in the PRODIGE 17-ACCORD 20 trial. CD56+ cells (NK), CD8+, and FoxP3+ (Treg) tumor-infiltrating lymphocytes (TILs) were assessed in tumor samples. Circulating NK and Treg proportions were significantly lower in patients with diffuse/mixed-type AGC (n = 27) than those with intestinal type (n = 40; median 6.3% vs 11.5%; p = 0.02 and median 3.3% vs 5.2%; p = 0.03, respectively). Proportions of circulating MDSC, CD4+ and CD8+ T cells were not associated with one pathological type. Among tumor-infiltrating cells, CD8+ T cells, but not NK or FoxP3+ cells, were significantly lower in diffuse/mixed-type AGC (median 21 vs 59 cells/field; p = 0.009). Patients with high circulating NK cell counts (> 17%) had a better overall survival than those with 31 cells/field) had significantly longer overall survival (HR 0.44; 95% CI [0.21–0.92]; p = 0.02). The prognostic value of CD8+ TILs was maintained after adjustment for confounding factors, including the Lauren classification (HR = 0.42; 95% CI [0.18–0.96]; p = 0.039). Diffuse/mixed-type AGC has lower rates of CD8+ TILs and circulating NK cells and Tregs than the intestinal type. This “cold tumor” phenotype may be associated with a worse outcome.
Published: 2019

18. Head and neck carcinoma of unknown primary

Author: Renaud Garrel, P. Boisselier, Valérie Costes, Valentin Favier, Louis Crampette, T. Kennel, Service d'ORL et chirurgie cervico-faciale, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cancer de Montpellier (ICM), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, and Université de Montpellier (UM)
Subjects: Adult, Herpesvirus 4, Human, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Adenocarcinoma, medicine.disease_cause, Malignancy, Metastasis, Head and neck tumor, Thyroid carcinoma, 03 medical and health sciences, Metastasis of unknown primary, 0302 clinical medicine, medicine, Carcinoma, Humans, Thyroid Neoplasms, 030223 otorhinolaryngology, Papillomaviridae, Lymph node, business.industry, Nasopharyngeal Neoplasms, medicine.disease, Epstein–Barr virus, Carcinoma, Neuroendocrine, 3. Good health, Oropharyngeal Neoplasms, medicine.anatomical_structure, Otorhinolaryngology, Head and Neck Neoplasms, Lymph-node metastasis, Lymphatic Metastasis, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Neoplasms, Unknown Primary, Surgery, Radiology, Presentation (obstetrics), business, Neck
Abstract: International audience; In adult cervicofacial pathology, carcinoma of unknown primary is defined as lymph-node metastasis the anatomic origin of which is not known at the time of initial management. It constitutes up to 5% of head and neck cancers. Presentation may suggest benign pathology, delaying and confusing oncologic treatment. Diagnostic strategy in cervical lymph node with suspicion of neoplasia requires exhaustive work-up to diagnose malignancy and, in 45% to 80% of cases, depending on the series, to identify the primary site. Histologic types comprise squamous cell carcinoma, thyroid carcinoma, adenocarcinoma, neuroendocrine carcinoma and undifferentiated carcinoma. Association is sometimes found with human papilloma virus or Epstein Barr virus, guiding treatment. The objective of the present study was to provide clinicians with the necessary diagnostic tools, based on the current state of clinical, imaging and pathologic knowledge, and to detail treatment options.
Published: 2019

19. Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study

Author: Stefano Kim, Nabil Baba-Hamed, Denis Smith, Dewi Vernerey, Marine Jary, Aurélia Meurisse, Olivier Adotevi, Olivier Bouché, Nicolas Badet, Thierry André, Amélie Anota, François Ghiringhelli, Julien Taieb, Eric Francois, Emmanuelle Samalin, Aurélie Parzy, Mélanie Deberne, Laurie Spehner, Véronique Vendrely, Christelle De La Fouchardiere, Simon Pernot, Jérôme Desramé, Mustapha Zoubir, Bruno Buecher, Marie-Christine Kaminsky, Christophe Borg, Farid El Hajbi, Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fédération Francophone de la Cancérologie Digestive, FFCD, Service d'oncologie médicale (Centre Antoine Lacassagne, Nice), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Groupe Hospitalier Paris Saint Joseph, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Département d'oncologie médicale (CHU Robert Debré, Reims), Centre Hospitalier Universitaire de Reims (CHU Reims), Center Jean Mermoz, Hôpital privé des Peupliers (Paris), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre Léon Bérard [Lyon], Département d'Oncologie [CHU Bordeaux] (Cancérologie/Oncologie/Digestive), GH Sud Haut-Lévêque [CHU Hôpitaux de Bordeaux] (Centre médico chirurgical Magellan)-Hôpital Saint-André [CHU de Bordeaux], Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Clinique Saint Vincent [Besançon], Plateforme Qualité de vie et cancer, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Département d'Oncologie Médicale [Institut Curie, Paris], Institut Curie [Paris], Cooperator Multidisciplinary Oncology Group (GERCOR), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université de Lille-UNICANCER, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), and Hôpital Haut-Lévêque - CHU de Bordeaux (Centre médico chirurgical Magellan)-Hôpital Saint-André [CHU de Bordeaux]
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Docetaxel, Neutropenia, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Squamous cell carcinoma, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Progression-free survival, Neoplasm Metastasis, education, Aged, education.field_of_study, Performance status, business.industry, Anal Squamous Cell Carcinoma, Middle Aged, Anus Neoplasms, medicine.disease, Progression-Free Survival, 3. Good health, 030104 developmental biology, Oncology, Fluorouracil, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Female, Cisplatin, Neoplasm Recurrence, Local, business, Febrile neutropenia, medicine.drug
Abstract: Summary Background The incidence of anal squamous cell carcinoma has been increasing markedly in the past few decades. Currently, there is no validated treatment for advanced-stage anal squamous cell carcinoma. Therefore, we aimed to validate the clinical activity and safety of docetaxel, cisplatin, and fluorouracil (DCF) chemotherapy in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma. Methods We did a multicentre, single-arm, phase 2 study. We recruited patients from 25 academic hospitals, cancer research centres, and community hospitals in France who were aged 18 years or older with histologically confirmed anal squamous cell carcinoma, with metastatic disease or with unresectable local recurrence; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and with at least one evaluable lesion according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Chemotherapy-naive patients received either six cycles of standard DCF (75 mg/m 2 docetaxel and 75 mg/m 2 cisplatin on day 1 and 750 mg/m 2 per day of fluorouracil for 5 days, every 3 weeks) or eight cycles of modified DCF (40 mg/m 2 docetaxel and 40 mg/m 2 cisplatin on day 1 and 1200 mg/m 2 per day of fluorouracil for 2 days, every 2 weeks), which were administered intravenously. The choice between the standard versus modified regimens was recommended based on, but not limited to, age (≤75 years vs >75 years) and ECOG performance status (0 vs 1). The primary endpoint was investigator-assessed progression-free survival at 12 months from the first DCF cycle; for the primary endpoint to be met, at least 11 (17%) of 66 enrolled patients had to be alive without disease progression at 12 months. Efficacy and safety analyses were done in a modified intention-to-treat population, defined as all patients who were evaluable for progression at 12 months who received at least one cycle of DCF. This trial is registered at ClinicalTrials.gov, number NCT02402842, and the final results are presented here. Findings Between Sept 17, 2014, and Dec 7, 2016, we enrolled 69 patients. Of these patients, three did not receive DCF. Of the 66 patients who received treatment, 36 received the standard DCF regimen and 30 received modified DCF. The primary endpoint was met: 31 (47%) of 66 patients were alive and progression free at 12 months. 22 (61%) of 36 patients who received the standard DCF regimen and 18 (60%) of 30 patients who received the modified DCF regimen had disease progression at data cutoff. 46 (70%) of 66 patients had at least one grade 3–4 adverse event (30 [83%] of 36 in the standard DCF regimen and 16 [53%] of 30 in the modified DCF regimen). The most common grade 3–4 adverse events were neutropenia (15 [23%]; eight [22%] for standard DCF vs seven [23%] for modified DCF), diarrhoea (12 [18%]; nine [25%] vs three [10%]), asthenia (ten [15%]; eight [22%] vs two [7%]), anaemia (ten [15%]; six [17%] vs four [13%]), lymphopenia (eight [12%]; three [8%] vs five [17%]), mucositis (seven [11%]; seven [19%] vs none), and vomiting (seven [11%]; five [14%] vs two [7%]). No grade 4 non-haematological adverse events and febrile neutropenia were observed with modified DCF, whereas three (8%) grade 4 non-haematological adverse events and five (14%) cases of febrile neutropenia were reported with standard DCF. 97 serious adverse events were reported (69 in patients who received the standard DCF regimen [61 drug-related] and 28 in those given the modified DCF regimen [14 drug-related]). No treatment-related deaths were recorded. Interpretation Compared with standard DCF, modified DCF provided long-lasting response with good tolerability in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma with ECOG performance status of 0–1 in the first-line setting, and therefore could be considered as a new standard of care for these patients. Regarding the elevated risk of high-grade and serious adverse events and febrile neutropenia, standard DCF cannot be recommended in this situation. Funding Besancon University Hospital and Ligue contre le cancer Grand-Est.
Published: 2018

20. Prognostic value of androgen receptor and FOXA1 co-expression in non-metastatic triple negative breast cancer and correlation with other biomarkers

Author: Céline Charon-Barra, William Jacot, Marian Gutowski, Florence Boissière, Caroline Mollevi, Céline Bourgier, Gilles Romieu, Pierre-Jean Lamy, Evelyne Crapez, Elodie Chartron, Séverine Guiu, Joelle Simony-Lafontaine, Département d'oncologie Médicale, CRLCC Val d'Aurelle - Paul Lamarque, 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), CRLC Val d'Aurelle-Paul Lamarque, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Département de chirurgie, and Herrada, Anthony
Subjects: 0301 basic medicine, Hepatocyte Nuclear Factor 3-alpha, Cancer Research, Class I Phosphatidylinositol 3-Kinases, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, B7-H1 Antigen, Disease-Free Survival, Correlation, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Risk Factors, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biomarkers, Tumor, Non metastatic, PTEN, Medicine, Humans, PI3K/AKT/mTOR pathway, Triple-negative breast cancer, Aged, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, business.industry, BRCA1 Protein, Middle Aged, Prognosis, 3. Good health, Androgen receptor, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Oncology, Receptors, Androgen, 030220 oncology & carcinogenesis, Mutation, biology.protein, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Immunohistochemistry, Female, FOXA1, Neoplasm Recurrence, Local, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; BACKGROUND: In luminal androgen receptor (AR) tumours, FOXA1 may direct AR to sites occupied by ER in luminal tumours, thus stimulating proliferation.METHODS: AR and FOXA1 expression were evaluated by immunohistochemistry in 333 non-metastatic triple-negative breast cancers (TNBC). Positivity threshold was set at ≥ 1% staining. Lymphocytic infiltration, PD-L1expression, PIK3CA mutations, PTEN defects and BRCA1 promoter methylation were assessed.RESULTS: AR + /FOXA1 + tumours (42.4%) were more frequently: found in older patients, lobular, of lower nuclear grade, with more frequently PIK3CA mutations; exhibited less frequently BRCA1 promoter methylation, defects of PTEN and PD-L1 expression than others. Recurrence-free and overall survivals were significantly lower for AR + /FOXA1 + TNBC (median follow-up: 7.8 years).CONCLUSIONS: AR + /FOXA1 + expression defines a luminal-like TNBC subgroup affected with a worse outcome compared to other TNBC and a higher risk of late recurrences. This subgroup appears enriched in PIK3CA mutations, suggesting a role for PI3K inhibitors in this subgroup.
Published: 2018

21. Development of parallel reaction monitoring (PRM)-based quantitative proteomics applied to HER2-Positive breast cancer

Author: Guérin, Mathilde, Gonçalves, Anthony, Toiron, Yves, Baudelet, Emilie, Pophillat, Matthieu, Granjeaud, Samuel, Fourquet, Patrick, Jacot, William, Tarpin, Carole, Sabatier, Renaud, Agavnian, Emilie, Finetti, Pascal, Adelaïde, José, Birnbaum, Daniel, Ginestier, Christophe, Charafe-Jauffret, Emmanuelle, Viens, Patrice, Bertucci, François, Borg, Jean-Paul, Camoin, Luc, Centre interuniversitaire de recherche et d'ingenierie des matériaux (CIRIMAT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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 d'Oncologie Médicale, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), 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)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Bidaut, Ghislain, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées
Subjects: [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, HER2-positive, [SDV] Life Sciences [q-bio], parallel reaction monitoring, proteomics, breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, skin and connective tissue diseases, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, neoplasms, Research Paper, mass spectrometry
Abstract: Introduction treatments targeting the Human Epidermal Growth Factor Receptor 2 (HER2/ERBB2) have improved the natural history of HER2-positive breast cancer. However, except HER2 protein expression and gene amplification, there is no predictive biomarker to guide the HER2-targeted therapies. We developed Parallel reaction monitoring (PRM) a powerful approach, to quantify and evaluate key proteins involved in the HER2 pathway and/or anti-HER2 treatment sensitivity. Results in BCLs, PRM measurements correlated with western blot immunocytochemistry and transcriptomic data. At baseline, higher expression of HER2, EGFR, PTEN and HER3 but lower expression of phospho-HER2 correlated with trastuzumab sensitivity. Under trastuzumab, PRM demonstrated a decrease in HER2 and an increase in phospho-HER2, which correlated with drug sensitivity. The opposite was observed under lapatinib. HER2 quantification was also correlated with immunohistochemistry in PDXs and clinical breast cancer samples. Discussion in conclusion, PRM-based assay, developed to quantify proteins of the HER2 pathway in breast cancer samples revealed a large magnitude of expression, which may have relevance in terms of treatment sensitivity. Materials and Methods we first evaluated PRM in term of sensitivity, linearity and reproducibility. PRM was then applied to breast cancer cell lines (BCLs) including BCLs exposed to anti-HER2 agents, patient-derived xenografts (PDXs) and frozen breast cancer samples.
Published: 2018

22. Time trends of overall survival among metastatic breast cancer patients in the real-life ESME cohort

Author: Laurence Vanlemmens, Marc Debled, Christian Cailliot, Elisa Gobbini, Thomas Bachelot, Monia Ezzalfani, Christelle Jouannaud, Suzette Delaloge, Magali Lacroix-Triki, Anne Patsouris, Thierry Petit, Simone Mathoulin-Pélissier, Veronique Lorgis, William Jacot, Marie Ange Mouret-Reynier, Mathieu Robain, C. Lefeuvre-Plesse, Florence Dalenc, Audrey Lardy Cleaud, Etienne Brain, Christelle Levy, David Pérol, C. Courtinard, Véronique Diéras, Marianne Leheurteur, Lionel Uwer, Anthony Gonçalves, Jean Marc Ferrero, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute Curie, Centre Léon Bérard [Lyon], Institut Curie [Saint-Cloud], Service d'Oncologie Médicale, CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), École nationale supérieure d'architecture de Toulouse (ENSA Toulouse), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Service d'Oncologie médicale [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Department of Medical Oncology, CRLCC Eugène Marquis (CRLCC), Centre d'Investigation Clinique - Epidemiologie Clinique / Essais Cliniques Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Jean Godinot, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Département de biologie et pathologie médicales [Gustave Roussy], Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Haute Normandie-CRLCC Henri Becquerel, CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut de cancérologie de l'Ouest - Paul Papin (ICO - Paul Papin), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Center Oscar Lambret, CRLCC Oscar Lambret, Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie - Saint Cloud (ICSC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-UNICANCER
Subjects: Adult, Cancer Research, medicine.medical_specialty, Multivariate analysis, Time Factors, Receptor, ErbB-2, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Triple Negative Breast Neoplasms, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Cancer Survivors, Risk Factors, HER2, Internal medicine, polycyclic compounds, Overall survival, Biomarkers, Tumor, Medicine, Humans, 030212 general & internal medicine, Neoplasm Metastasis, skin and connective tissue diseases, Aged, Retrospective Studies, Subtypes, Aged, 80 and over, business.industry, Time trends, Hazard ratio, Middle Aged, Metastatic breast cancer, medicine.disease, Confidence interval, 3. Good health, Treatment Outcome, Oncology, Receptors, Estrogen, 030220 oncology & carcinogenesis, Cohort, Observational study, Female, France, business, Receptors, Progesterone
Abstract: Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort.ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008-31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor-positive and HER2-negative (HR+/HER2-, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR-/HER2-, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts.Median OS of the whole cohort was 37.22 months (95% confidence interval [CI], 36.3-38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 [95% CI, 0.97-1.00], P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2-, HER2+ and HR-/HER2- subcohorts was, respectively, 42.12 (95% CI, 40.90-43.10), 44.91 (95% CI, 42.51-47.90) and 14.52 (95% CI, 13.70-15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 [95% CI, 0.88-0.94], P .001), but not in HR+/HER2- nor HR-/HER2- subcohorts (hazard ratio 1.00 [95% CI, 0.98-1.01], P = .80 and 1.00 [95% CI, 0.97-1.02], P = .90, respectively).The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes.
Published: 2018

23. Quantification of uPA in breast tumour tissue extracts by microarray immunoassay: Comparison with ELISA technology

Author: Liu Shi, Thomas Gehin, William Jacot, Yann Chevolot, Pierre-Jean Lamy, Emmanuelle Laurenceau, INL - Chimie et Nanobiotechnologies (INL - C&N), Institut des Nanotechnologies de Lyon (INL), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École supérieure de Chimie Physique Electronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut médical d'anayse génomique (IMAGENOME), and Labosud
Subjects: 0301 basic medicine, Antibody microarray, Microarray, Health, Toxicology and Mutagenesis, Population, Biomedical Engineering, Nano level techniques, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Tumour tissue, 0302 clinical medicine, Breast cancer, Artificial Intelligence, medicine, General Pharmacology, Toxicology and Pharmaceutics, education, education.field_of_study, General Immunology and Microbiology, medicine.diagnostic_test, business.industry, General Neuroscience, Cell migration, General Medicine, Immunological approaches, [CHIM.MATE]Chemical Sciences/Material chemistry, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunoassay, uPA quantification, Cancer research, General Agricultural and Biological Sciences, business, [CHIM.OTHE]Chemical Sciences/Other, Plasminogen activator
Abstract: International audience; The urokinase-type plasminogen activator (uPA) and PA inhibitor 1 (PAI-1) play important roles in breast cancer metastasis through cell migration and invasion. They are clinically applicable prognostic and predictive markers. High levels of uPA and PAI-1 are associated with high risk of recurrence and adjuvant chemotherapy provides substantial benefit for this breast cancer population. The current sole validated method for quantifying uPA level in breast tumour tissue is ELISA assay. It requires 50-300 mg of fresh or frozen tissue, which is the main limitation for routine use. In this study, we evaluated the performances of customized antibody microarray to quantify uPA concentration from reduced extraction solution of breast tumour tissue and compared it with standard ELISA kit. We firstly optimized the elaboration of customized antibody microarray in order to sensitively detect and quantify uPA standard solutions. In the best conditions, we analysed uPA concentration in 16 cytosolic extracts from breast tumour tissue. Results showed that our customized antibody microarray could correctly quantify uPA concentration while consuming 100 times less volume of tumour tissue extraction solution than ELISA. Our antibody microarray is a powerful and promising tool for the miniaturization of the immunoassay quantification of uPA from breast tumour tissue extracts.
Published: 2018

24. IL-21 promotes the development of a CD73-positive Vγ9Vδ2 T cell regulatory population

Author: Jean-François Eliaou, Cécile Dejou, Virginie Lafont, Françoise Sanchez, Henri-Alexandre Michaud, Angeline Fages, Alexandre Zampieri, Laetitia They, Aurelie Gennetier, Nathalie Bonnefoy, Clément Barjon, Laurent Gros, 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), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CEntre Technique des Industries Mécaniques (CETIM), CEntre Technique des Industries Mécaniques - Cetim (FRANCE), Centre de génétique moléculaire (CGM), Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), St-Eloi University Hospital, Department of Oncology, 34000 Montpellier, France., Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Salvy-Córdoba, Nathalie
Subjects: 0301 basic medicine, lcsh:Immunologic diseases. Allergy, T cell, Immunology, cd73, il-10, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, lcsh:RC254-282, 03 medical and health sciences, Interleukin 21, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Immunology and Allergy, Cytotoxic T cell, tumor microenvironment, IL-2 receptor, Antigen-presenting cell, Original Research, ZAP70, γδ t cells, il-21, CD28, regulatory functions, Natural killer T cell, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Oncology, adenosine, 030220 oncology & carcinogenesis, lcsh:RC581-607
Abstract: International audience; Vγ9Vδ2 T cells contribute to the immune response against many tumor types through their direct cytotoxic activity and capacity to regulate the biological functions of other immune cells, such as dendritic cells and IFN-γ-producing CD8+ T cells. However, their presence in the tumor microenvironment has also been associated with poor prognosis in breast, colon and pancreatic cancers. Additionally, recent studies demonstrated that cytokines can confer some plasticity to Vγ9Vδ2 T cells and promote their differentiation into cells with regulatory functions. Here, we demonstrated that activation of Vγ9Vδ2 T cells isolated from healthy donors and cultured in the presence of IL-21 favors the emergence of a subpopulation of Vγ9Vδ2 T cells that express the ectonucleotidase CD73 and inhibits T cell proliferation in a CD73/adenosine-dependent manner. This subpopulation produces IL-10 and IL-8 and displays lower effector functions and cytotoxic activity than CD73-negative Vγ9Vδ2 T cells. We also showed, in a syngeneic mouse tumor model, the existence of a tumor-infiltrating γδ T cell subpopulation that produces IL-10 and strongly expresses CD73. Moreover, maturation, IL-12 production and induction of antigen-specific T cell proliferation are impaired in DC co-cultured with IL-21-amplified Vγ9Vδ2 T cells. Altogether, these data indicate that IL-21 promotes Vγ9Vδ2 T cell regulatory functions by favoring the development of an immunosuppressive CD73+ subpopulation. Thus, when present in the tumor microenvironment, IL-21 might negatively impact γδ T cell anti-tumor functions.
Published: 2018

25. The IL-17B-IL-17 receptor B pathway promotes resistance to paclitaxel in breast tumors through activation of the ERK1/2 pathway

Author: Stanislas du Manoir, Jérôme Giustiniani, Pierre-Emmanuel Colombo, Henri-Alexandre Michaud, Jean-François Eliaou, Cécile Dejou, Jérémy Bastid, Nathalie Bonnefoy, Marion Philippe, Andrew James Sanders, Marion Lapierre, Kathryn A. Frewer, Armand Bensussan, Emilie Laprevotte, Gilles Alberici, Wen Guo Jiang, Stéphanie Cochaud, 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), OREGA Biotech, Immunodermatologie, Cytokines, Cancer - EA 7319 (ICA), Université de Reims Champagne-Ardenne (URCA), Université Paris Diderot - Paris 7 (UPD7), Cardiff University, Cardiff Metropolitan University, School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Oncogénèse et progression tumorale, 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), Salvy-Córdoba, Nathalie, and Institute of Medical Genetics [Cardiff]-Cardiff University
Subjects: 0301 basic medicine, MAPK/ERK pathway, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, interleukin-17B, interleukin-17, 03 medical and health sciences, chemistry.chemical_compound, paclitaxel, Breast cancer chemotherapy, Breast cancer, breast cancer, Downregulation and upregulation, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Receptor, business.industry, chemoresistance, medicine.disease, R1, 3. Good health, 030104 developmental biology, Cytokine, Oncology, Paclitaxel, chemistry, Cancer research, Signal transduction, business, Research Paper
Abstract: International audience; Interleukin 17B (IL-17B) is a pro-inflammatory cytokine that belongs to the IL-17 cytokines family and binds to IL-17 receptor B (IL-17RB). Here we found that high expression of IL-17B and IL-17RB is associated with poor prognosis in patients with breast cancer and that IL-17B expression upregulation is specifically associated with poorer survival in patients with basal-like breast cancer. We thus focused on IL-17B role in breast cancer by using luminal and triple negative (TN)/basal-like tumor cell lines. We found that IL-17B induces resistance to conventional chemotherapeutic agents. In vivo, IL-17B induced resistance to paclitaxel and treatment with an anti-IL-17RB neutralizing antibody completely restored breast tumor chemosensitivity, leading to tumor shrinkage. We next focused on the signaling pathways activated in human breast cancer cell lines upon incubation with IL-17B. We observed that IL-17B induces ERK1/2 pathway activation, leading to upregulation of anti-apoptotic proteins of the BCL-2 family. IL-17B-induced chemoresistance was completely abolished by incubation with PD98059, an inhibitor of the MAPK/ERK pathway, indicating that the ERK pathway plays a crucial role. Altogether our results emphasize the role of the IL-17B/IL-17RB signaling pathway in breast tumors and identify IL-17B and its receptor as attractive therapeutic targets for potentiating breast cancer chemotherapy.
Published: 2017

26. Inhibition of CD39 Enzymatic Function at the Surface of Tumor Cells Alleviates Their Immunosuppressive Activity

Author: Nathalie Bonnefoy, Armand Bensussan, Nicole Bec, Jérémy Bastid, Stéphanie Cochaud, Caroline Laheurte, Jean-François Eliaou, Cécile Dejou, Laurent Gros, Anne Regairaz, Jérôme Giustiniani, Christian Larroque, Patrice Hemon, Emilie Laprevotte, Gilles Alberici, Elisa Funck-Brentano, OREGA Biotech, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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), Immunodermatologie, Cytokines, Cancer - EA 7319 (ICA), Université de Reims Champagne-Ardenne (URCA), Immunologie, dermatologie, oncologie, Oncodermatologie, immunologie et cellules souches cutanées (IDO (U976 / UMR_S 976)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)
Subjects: Cancer Research, Adenosine, Regulatory T cell, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, CD8-Positive T-Lymphocytes, Biology, T-Lymphocytes, Regulatory, Immune tolerance, 03 medical and health sciences, chemistry.chemical_compound, Adenosine Triphosphate, 0302 clinical medicine, Antigens, CD, Cell Line, Tumor, Immune Tolerance, medicine, Humans, Cytotoxic T cell, 5'-Nucleotidase, 030304 developmental biology, Adenosine Triphosphatases, 0303 health sciences, Lymphokine-activated killer cell, Apyrase, Receptors, Purinergic P1, Adenosine receptor, 3. Good health, Cell biology, Killer Cells, Natural, Adenosine diphosphate, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Cancer cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.drug
Abstract: The ectonucleotidases CD39 and CD73 hydrolyze extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to generate adenosine, which binds to adenosine receptors and inhibits T-cell and natural killer (NK)–cell responses, thereby suppressing the immune system. The generation of adenosine via the CD39/CD73 pathway is recognized as a major mechanism of regulatory T cell (Treg) immunosuppressive function. The number of CD39+ Tregs is increased in some human cancers, and the importance of CD39+ Tregs in promoting tumor growth and metastasis has been demonstrated using several in vivo models. Here, we addressed whether CD39 is expressed by tumor cells and whether CD39+ tumor cells mediate immunosuppression via the adenosine pathway. Immunohistochemical staining of normal and tumor tissues revealed that CD39 expression is significantly higher in several types of human cancer than in normal tissues. In cancer specimens, CD39 is expressed by infiltrating lymphocytes, the tumor stroma, and tumor cells. Furthermore, the expression of CD39 at the cell surface of tumor cells was directly demonstrated via flow cytometry of human cancer cell lines. CD39 in cancer cells displays ATPase activity and, together with CD73, generates adenosine. CD39+CD73+ cancer cells inhibited the proliferation of CD4 and CD8 T cells and the generation of cytotoxic effector CD8 T cells (CTL) in a CD39- and adenosine-dependent manner. Treatment with a CD39 inhibitor or blocking antibody alleviated the tumor-induced inhibition of CD4 and CD8 T-cell proliferation and increased CTL- and NK cell–mediated cytotoxicity. In conclusion, interfering with the CD39–adenosine pathway may represent a novel immunotherapeutic strategy for inhibiting tumor cell–mediated immunosuppression. Cancer Immunol Res; 3(3); 254–65. ©2014 AACR.
Published: 2015

27. FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial

Author: M. Hebbar, B. Chibaudel, T. André, L. Mineur, D. Smith, C. Louvet, J.L. Dutel, M. Ychou, J.L. Legoux, M. Mabro, R. Faroux, D. Auby, D. Brusquant, A. Khalil, S. Truant, A. Hadengue, C. Dalban, B. Gayet, F. Paye, F.R. Pruvot, F. Bonnetain, J. Taieb, P. Brucker, B. Landi, M. Flesch, E. Carola, P. Martin, E. Vaillant, A. de Gramont, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Sainte Catherine [Avignon], Hôpital Saint-André, Institut Mutualiste de Montsouris (IMM), Institut du Cancer de Montpellier (ICM), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Foch [Suresnes], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Centre Hospitalier Libourne, Cooperator Multidisciplinary Oncology Group (GERCOR), Univ Cadi Ayyad, Fac Sci & Tech Cueliz, Lab Matiere Condensee & Nanostruct, Marrakech, Morocco, Université Cadi Ayyad [Marrakech] (UCA), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)
Subjects: Adult, Male, Oncology, medicine.medical_specialty, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, Leucovorin, [SDV.CAN]Life Sciences [q-bio]/Cancer, Kaplan-Meier Estimate, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, ComputingMilieux_MISCELLANEOUS, Aged, Proportional Hazards Models, Chemotherapy, business.industry, 030503 health policy & services, Hazard ratio, Hematology, Perioperative, Middle Aged, medicine.disease, Chemotherapy regimen, 3. Good health, Oxaliplatin, Irinotecan, 030220 oncology & carcinogenesis, FOLFIRI, Camptothecin, Female, Fluorouracil, Colorectal Neoplasms, 0305 other medical science, business, medicine.drug
Abstract: The sequential FOLFOX7–FOLFIRI combination is not superior to FOLFOX4 in colorectal cancer patients with resectable metastases. Patients with synchronous metastases preferably received perioperative chemotherapy, while patients with metachronous metastases were given postoperative chemotherapy in preference. We observed the highest long-term survival rates ever reported in this setting. Background Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative. Patients and methods In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m2) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m2) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m2). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS). Results A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7–FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7–FOLFIRI. Conclusions FOLFOX7–FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing. Clinical trials number NCT00268398.
Published: 2015

28. Combined cetuximab and trastuzumab are superior to gemcitabine in the treatment of human pancreatic carcinoma xenografts

Author: Caroline Bascoul-Mollevi, Alexandre Ho-Pun-Cheung, Bruno Robert, Frédérique Penault-Llorca, Christelle Larbouret, Isabelle Navarro-Teulon, Jean-Pierre Mach, David Azria, André Pèlegrin, Sébastien Morisseau, Le Ster, Yves, 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), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Département de biochimie, Université de Lausanne = University of Lausanne (UNIL), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), and Université de Lausanne (UNIL)
Subjects: Pancreatic disease, Receptor, ErbB-2, Cetuximab, Deoxycytidine, MESH: Antibodies, Monoclonal, Mice, 0302 clinical medicine, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols, MESH: Animals, Epidermal growth factor receptor, 0303 health sciences, biology, gemcitabine, Antibodies, Monoclonal, Hematology, Immunohistochemistry, 3. Good health, ErbB Receptors, MESH: Antineoplastic Combined Chemotherapy Protocols, Oncology, MESH: Receptor, erbB-2, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, CA19-9, monoclonal antibodies, MESH: Pancreatic Neoplasms, medicine.drug, MESH: Xenograft Model Antitumor Assays, MESH: Cell Line, Tumor, [SDV.IMM] Life Sciences [q-bio]/Immunology, EGFR, Blotting, Western, HER2, pancreatic carcinoma, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Receptor, Epidermal Growth Factor, Antibodies, Monoclonal, Humanized, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Pancreatic cancer, medicine, MESH: Mice, Nude, Animals, Humans, MESH: Blotting, Western, MESH: Mice, 030304 developmental biology, MESH: Humans, business.industry, MESH: Deoxycytidine, Cancer, MESH: Immunohistochemistry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Xenograft Model Antitumor Assays, Gemcitabine, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Pancreatic Neoplasms, MESH: Antibodies, Monoclonal, Humanized, Cancer research, biology.protein, business, MESH: Female
Abstract: International audience; BACKGROUND: Pancreatic carcinoma remains a treatment-refractory cancer with a poor prognosis. Here, we compared anti-epidermal growth factor receptor (EGFR) and anti-HER2 monoclonal antibodies (2mAbs) injections with standard gemcitabine treatment on human pancreatic carcinoma xenografts. MATERIALS AND METHODS: Nude mice, bearing human pancreatic carcinoma xenografts, were treated with either combined anti-EGFR (cetuximab) and anti-HER2 (trastuzumab) or gemcitabine, and tumor growth was observed. RESULTS AND CONCLUSION: In first-line therapy, mice survival was significantly longer in the 2mAbs group compared with gemcitabine (P < 0.0001 for BxPC-3, P = 0.0679 for MiaPaCa-2 and P = 0.0019 for Capan-1) and with controls (P < 0.0001). In second-line therapy, tumor regressions were observed after replacing gemcitabine by 2mAbs treatment, resulting in significantly longer animal survival compared with mice receiving continuous gemcitabine injections (P = 0.008 for BxPC-3, P = 0.05 for MiaPaCa-2 and P < 0.001 for Capan-1). Therapeutic benefit of 2mAbs was observed despite K-Ras mutation. Interestingly, concerning the mechanism of action, coinjection of F(ab')(2) fragments from 2mAbs induced significant tumor growth inhibition, compared with controls (P = 0.001), indicating that the 2mAbs had an Fc fragment-independent direct action on tumor cells. This preclinical study demonstrated a significant improvement of survival and tumor regression in mice treated with anti-EGFR/anti-HER2 2mAbs in first- and second-line treatments, compared with gemcitabine, independently of the K-Ras status.
Published: 2017

29. Iron homeostasis and anemia markers in early breast cancer

Author: Anna Durigova, William Jacot, Pierre-Jean Lamy, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), and 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)
Subjects: Anemia, Iron, Clinical Biochemistry, Ferroportin, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Biochemistry, Breast cancer, Hepcidin, medicine, Homeostasis, Humans, chemistry.chemical_classification, Anemia, Iron-Deficiency, biology, Iron/*metabolism, Breast Neoplasms/*metabolism, Biochemistry (medical), General Medicine, medicine.disease, Homeostasis/*physiology, 3. Good health, Ferritin, Gene Expression Regulation, chemistry, Transferrin, Iron-Deficiency/*blood/metabolism, Cancer cell, Immunology, Cancer research, biology.protein, Female
Abstract: Iron plays a fundamental role in cell life and its concentration in living organisms is precisely regulated. Different molecules for iron storage and transport are used to maintain its intracellular homeostasis which is often altered in cancer cells. Specifically, recent studies have demonstrated that in breast cancer cells, the expression/activity of several iron-related proteins, such as ferritin, hepcidin and ferroportin, is deregulated and that these alterations may have a prognostic impact in patients with breast cancer. Moreover, molecules that regulate iron metabolism could become therapeutic targets. This review focuses on recent findings on iron metabolism particularly in breast cancer and on the development of new biomarkers that may be used in the clinical routine for the diagnosis, prognosis and management of cancer-associated anemia as well as for monitoring personalized treatments.
Published: 2014

30. Sorafenib and irinotecan (NEXIRI) as second- or later-line treatment for patients with metastatic colorectal cancer and KRAS-mutated tumours: a multicentre Phase I/II trial

Author: Pierre Laurent-Puig, Sylvain Poujol, Françoise Desseigne, S. Thezenas, Thibault Mazard, Evelyne Crapez, Emmanuelle Samalin, E. Francois, Antoine Adenis, T. Conroy, J.F. Seitz, Julien Taieb, M.P. Galais, Jaafar Bennouna, F. Boissière, Marc Ychou, Eric Assenat, O. Bouche, Frédéric Bibeau, CRLCC Val d'Aurelle - Paul Lamarque, Hôpital universitaire Robert Debré [Reims], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, CIC - HEGP (CIC 1418), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), 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), CRLC Val d'Aurelle-Paul Lamarque, 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), Université Lille Nord de France (COMUE)-UNICANCER, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1), 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), Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, CRLCC Oscar Lambret, Institut de Cancérologie de l'Ouest, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), and Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: Male, Cancer Research, Colorectal cancer, medicine.medical_treatment, Camptothecin/administration & dosage/analogs & derivatives, Gastroenterology, tyrosine kinase inhibitor, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, 80 and over, clinic, Aged, 80 and over, education.field_of_study, metastatic colorectal cancer, ras Proteins/*genetics, Mutation, Middle Aged, Sorafenib, 3. Good health, Oncology, Disease Progression, Female, Colorectal Neoplasms, medicine.drug, Adult, Niacinamide, medicine.medical_specialty, Niacinamide/administration & dosage/analogs & derivatives, Population, Colorectal Neoplasms/*drug therapy/genetics, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neutropenia, Irinotecan, Disease-Free Survival, Proto-Oncogene Proteins p21(ras), Internal medicine, Proto-Oncogene Proteins, medicine, Humans, Antineoplastic Combined Chemotherapy Protocols/*therapeutic use, education, neoplasms, Aged, Chemotherapy, business.industry, Phenylurea Compounds, medicine.disease, digestive system diseases, Surgery, KRAS gene mutation, Regimen, Phenylurea Compounds/administration & dosage, Clinical Study, ras Proteins, Proto-Oncogene Proteins/*genetics, Camptothecin, business
Abstract: IMPACT: 5.922; International audience; BACKGROUND: This trial evaluated the feasibility and efficacy of combined sorafenib and irinotecan (NEXIRI) as second- or later-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC), who had progressed after irinotecan-based chemotherapy. METHODS: In Phase I, in a 3+3 dose escalation schedule, patients received irinotecan (125, 150 or 180 mg m(-2) every 2 weeks), in combination with 400 mg sorafenib b.d. The primary end point was the maximum-tolerated dose of irinotecan. In Phase II, the primary end point was disease control rate (DCR). Secondary end points were progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Phase I included 10 patients (median age 63 (49-73)); no dose-limiting toxicity was seen. In Phase II, 54 patients (median age 60 (43-80) years) received irinotecan 180 mg m(-)(2) every 2 weeks with sorafenib 400 mg b.d. Nine patients (17%) remained on full-dose sorafenib. The DCR was 64.9% (95% CI, 51-77). Median PFS and OS were 3.7 (95% CI, 3.2-4.7) and 8.0 (95% CI, 4.8-9.7) months, respectively. Toxicities included Grade 3 diarrhoea (37%), neutropenia (18%), hand-foot syndrome (13%) and Grade 4 neutropenia (17%). CONCLUSION: The NEXIRI regimen showed promising activity as second- or later-line treatment in this heavily pretreated mCRC population (ClinicalTrials.gov NCT00989469).
Published: 2014

31. Versatile UCST-based thermoresponsive hydrogels for loco-regional sustained drug delivery

Author: Michel Vert, Sebastien Lenglet, Pierre-Emmanuel Colombo, Mahfoud Boustta, Sylvain Poujol, 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), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Laboratoire de Bioingénierie et NanoSciences (LBN), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), and 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)
Subjects: Diffusion, Acrylic Resins, Coloring Agents/administration & dosage/chemistry/pharmacokinetics, Pharmaceutical Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, Acetates, 010402 general chemistry, 01 natural sciences, Tartrazine/chemistry, Mice, chemistry.chemical_compound, Drug Delivery Systems, Methylene Blue/administration & dosage/chemistry/pharmacokinetics, Upper critical solution temperature, Albumins, Acrylic Resins/*chemistry, Albumins/chemistry, Animals, Acetates/chemistry, clinic, Coloring Agents, Peritoneal Cavity, Tartrazine, Inbred BALB C, chemistry.chemical_classification, Mice, Inbred BALB C, Molar mass, Chromatography, Delayed-Action Preparations/administration & dosage/chemistry/pharmacokinetics, Chemistry, Temperature, Hydrogels, Cobalt, Polymer, 021001 nanoscience & nanotechnology, 0104 chemical sciences, Methylene Blue, Cobalt/chemistry, Delayed-Action Preparations, Self-healing hydrogels, Drug delivery, Female, 0210 nano-technology, Methylene blue
Abstract: IMPACT: 7.877; International audience; Poly(N-acryloyl glycinamide) is a neutral polymer that can form gel-sol thermoresponsive systems with upper critical solution temperature in aqueous media. The temperature of the reversible gel-sol transition depends on the molar mass and the concentration of macromolecules. These parameters were combined to adjust the transition temperature slightly above body temperature for the sake of respecting living tissues during the sol form injection using a classical syringe. On contact with local tissues, the injected sol turned rapidly to a gel. The simplicity of the process makes it exploitable to administrate and deliver neutral or ionic drug and especially those that are soluble in aqueous media. The versatility was exemplified from formulations with cobalt acetate, small polymers (MW~2000g/mol), tartrazine and methylene blue dyes and albumin. The model compounds were allowed to diffuse in an isotonic pH=7.4 buffered medium at 37 degrees C. All the release profiles were typical of diffusion control with 100% release within 2 to 3weeks and no obvious burst. The in vitro release of methylene blue from a gel formulation was checked prior to injection in the peritoneal cavity of mice where the release of the dye was monitored visually through tissue and organ colorations. A comparable polymer-free dye solution was used as control. Coloration appeared rapidly in tissues and organs and it was still detectable 52h post injection of the gel whereas it was no longer present at 24h in control mice.
Published: 2014

32. Prognostic value of health‐related quality of life for death risk stratification in patients with unresectable glioblastoma

Author: Marc Frenay, Jérome Skrzypski, Michel Fabbro, Luc Taillandier, Bruno Chauffert, Chantal Campello, Brice Paquette, Roland Schott, Dewi Vernerey, Isabelle Tennevet, Loïc Feuvret, Sandrine Dabakuyo, Olivier Chinot, Daniel Castera, Franck Bonnetain, Amélie Anota, François Ghiringhelli, H. Taillia, Jean-Sébastien Guillamo, C. Dalban, Xavier Durando, François Ducray, Didier Frappaz, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Léon Bérard [Lyon], Service d'Oncologie (HIA VAL DE GRACE - Oncologie), HIA VAL DE GRACE, Centre Paul Strauss, CRLCC Paul Strauss, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service de Neurologie [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), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Clinique Saint Pierre, Perpignan, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), and Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: Oncology, Male, Cancer Research, Psychometrics, [SDV]Life Sciences [q-bio], risk stratification, Kaplan-Meier Estimate, 0302 clinical medicine, Quality of life, Antineoplastic Combined Chemotherapy Protocols, Original Research, Brain Neoplasms, Hazard ratio, Chemoradiotherapy, Middle Aged, Prognosis, prognostic score, humanities, 3. Good health, Bevacizumab, Dacarbazine, Health‐related quality of life, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, unresectable glioblastoma, Female, medicine.drug, medicine.medical_specialty, overall survival, [SDV.CAN]Life Sciences [q-bio]/Cancer, Irinotecan, 03 medical and health sciences, Internal medicine, medicine, Temozolomide, Humans, Radiology, Nuclear Medicine and imaging, Karnofsky Performance Status, Aged, business.industry, Clinical Cancer Research, Clinical trial, Physical therapy, Quality of Life, Camptothecin, business, Glioblastoma, 030217 neurology & neurosurgery
Abstract: International audience; Glioblastoma is the most common malignant brain tumor in adults. Baseline health‐related quality of life (HRQoL) is a major subject of concern for these patients. We aimed to assess the independent prognostic value of HRQoL in unresectable glioblastoma (UGB) patients for death risk stratification. One hundred and thirty‐four patients with UGB were enrolled from the TEMAVIR trial. HRQoL was evaluated at baseline using the EORTC QLQ‐C30 and BN20 brain cancer module. Clinical and HRQoL parameters were evaluated in univariable and multivariable Cox analysis as prognostic factors for overall survival (OS). Performance assessment and internal validation of the final model were evaluated with Harrel's C‐index, calibration plot, and bootstrap sample procedure. Two OS independent predictors were identified: future uncertainty and sensitivity deficit. The final model exhibited good calibration and acceptable discrimination (C statistic = 0.63). The internal validity of the model was verified with robust uncertainties around the hazard ratio. The prognostic score identified three groups of patients with distinctly different risk profiles with median OS estimated at 16.2, 9.2, and 4.5 months. We demonstrated the additional prognostic value of HRQoL in UGB for death risk stratification and provided a score that may help to guide clinical management and stratification in future clinical trials.
Published: 2016

33. Impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients: a randomized phase III study

Author: Anna Durigova, L. Roca, Nelly Firmin, Pierre-Jean Lamy, William Jacot, Véronique D'Hondt, S. Gallet, Stéphane Pouderoux, L. Abach, Jean-Pierre Bleuse, Gilles Romieu, Delphine Topart, S. Mirr, 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), Département d'oncologie Médicale, CRLCC Val d'Aurelle - Paul Lamarque, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CRLC Val d'Aurelle-Paul Lamarque, and Herrada, Anthony
Subjects: 0301 basic medicine, vitamin D, MESH: Dietary Supplements, chemotherapy, Gastroenterology, 0302 clinical medicine, MESH: Vitamin D, Clinical endpoint, Medicine, MESH: Aged, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Middle Aged, Hematology, MESH: Neoplasm Staging, Middle Aged, Chemotherapy regimen, MESH: Drug-Related Side Effects and Adverse Reactions, 3. Good health, Oncology, 030220 oncology & carcinogenesis, MESH: Vitamin D Deficiency, Female, Adult, medicine.medical_specialty, Drug-Related Side Effects and Adverse Reactions, Population, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, vitamin D deficiency, 03 medical and health sciences, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Vitamin D and neurology, Humans, early breast cancer, education, Aged, Neoplasm Staging, MESH: Humans, business.industry, MESH: Quality of Life, MESH: Adult, Vitamin D Deficiency, medicine.disease, Surgery, Clinical trial, Regimen, 030104 developmental biology, Dietary Supplements, Quality of Life, business, MESH: Female, MESH: Breast Neoplasms, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background A minority of early breast cancer (EBC) patients treated with adjuvant or neoadjuvant chemotherapy have sufficient baseline vitamin D (vitD) level. This randomized phase III study assessed the safety and efficacy of a tailored, high-dose, oral vitD supplementation in restoring a normal 25-hydroxy vitD (25OHD) level in this population. Patients and methods Participants received a 6-month conventional (C) vitD and calcium supplementation or a 6-month high-dose oral vitD regimen tailored on the deficiency (T) and a conventional calcium supplementation. The primary end point was the 6-month percentage of 25OHD serum level normalization. Results A total of 215 patients including 197 patients with vitD deficiency were recruited, and 195 patients were randomized (T, 100; C, 95). Compliance to the daily oral supplementation was 68.4% and 67% in the C and T arms, respectively. Discontinuous high-dose vitD compliance appeared higher in the T arm (77%). At 6 months, more patients presented with a normalized vitD level in the T arm (30% versus 12.6%; P = 0.003). Supplementation was well tolerated, and no significant difference in the treatment-related toxicity between the two arms was reported. Fifty-two patients without vitD normalization from the C arm switched to the T arm after 6 months. At 12 months, 44% of these patients achieved vitD normalization. Conclusion A tailored high-dose oral vitD supplementation safely allows a higher percentage of the serum 25OHD level normalization compared with a conventional regimen in chemotherapy-treated EBC patients. As compliance to a daily oral supplementation remains poor in this setting, an adaptation of the treatment schedule is warranted. Clinical trial number NCT01480869.
Published: 2016

34. Reproductive Decision-Making in MMR Mutation Carriers After Results Disclosure: Impact of Psychological Status in Childbearing Options

Author: Frédéric Bibeau, L. Roca, Evelyne Crapez, Hélène de Forges, Julie Courraud, Marc Ychou, Jacqueline Duffour, Florence Boissière-Michot, Audrey Combes, Pierre Senesse, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), and Laboratoire d'anatomo-pathologie
Subjects: Male, MESH: Decision Making, Prenatal diagnosis, MESH: Reproduction, DNA Mismatch Repair, Stress Disorders, Post-Traumatic, 0302 clinical medicine, Surveys and Questionnaires, Genetic carrier detection, Medicine, Young adult, Genetics (clinical), 030219 obstetrics & reproductive medicine, MESH: Middle Aged, Reproduction, Preimplantation genetic diagnosis, MESH: Colorectal Neoplasms, Hereditary Nonpolyposis, Middle Aged, 16. Peace & justice, Lynch syndrome, 3. Good health, Distress, MESH: Stress Disorders, Post-Traumatic, MESH: DNA Mismatch Repair, MESH: Young Adult, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Female, France, MESH: Disclosure, Adult, medicine.medical_specialty, MESH: Mutation, Genetic counseling, Decision Making, Disclosure, Hereditary non-polyposis, Post-traumatic stress disorders, Colorectal neoplasms, Young Adult, 03 medical and health sciences, Humans, MESH: Preimplantation Diagnosis, MESH: Prenatal Diagnosis, MESH: Surveys and Questionnaires, Psychiatry, Preimplantation Diagnosis, MESH: Humans, business.industry, Public health, MESH: Adult, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, MESH: Male, MESH: France, Mutation, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Demography
Abstract: International audience; Reproductive techniques such as prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD), although debated, are legally forbidden in France in case of Lynch syndrome. The preference of mutation carriers about their reproductive options is not systematically considered in France. We aimed to prospectively assess the reproductive preferences of mismatch repair mutation carriers consulting in our institution (2003-2010, n = 100). We also considered the short- and long-term post-disclosure psychological impact using the Impact of Events Scale-Revised questionnaire to measure the prevalence of posttraumatic stress disorder (PTSD) in those patients. Complete data were obtained for 34 respondents (17 males, 17 females, median age of 33.5 years [22-59]). Seventeen respondents (57 %) preferred spontaneous natural conception versus 28 % and 35 % choosing PND and PGD, respectively. At results disclosure, respondents mainly explained their distress by fear of premature death (43 %) and transmitting mutated genes (42 %). One year later, this last fear remained predominant in 55 % of subjects. None of the main socio-demographical, psychological or medical variables (including fear of transmitting mutations) was significantly associated with the reproductive preferences. Results disclosure had a real and time-decreasing psychological impact on mutation carriers. Reproductive techniques, expected to decrease the hereditary risk, were not significantly preferred to natural conception.
Published: 2016

35. Clinical relevance of 8q23, 15q13 and 18q21 SNP genotyping to evaluate colorectal cancer risk

Author: Delphine Bonnet, Rosine Guimbaud, Pascaline Berthet, Anne-Françoise Cailleux, Marie-Pierre Buisine, Jacques Mauillon, Paul Gesta, David Malka, Stéphanie Baert-Desurmont, Estelle Cauchin, Estelle Houivet, Marine Lebrun, Caroline Abadie, Salima El Chehadeh, Isabelle Coupier, Lorena Ippolito, Julie Tinat, Philippe Jonveaux, Qing Wang, Marie Agnès Collonge-Rame, Françoise Desseigne, Sylvie Manouvrier, Jean-Christophe Saurin, Marion Gauthier-Villars, Jean-Marc Rey, Catherine Dugast, Laurence Brugières, Christine Toulas, Brigitte Bressac-de Paillerets, Pierre Laurent-Puig, Pascal Pujol, Sophie Giraud, Fabienne Prieur, Florence Polycarpe-Osaer, Jean Chiesa, Jacques Benichou, Dominique Leroux, Bruno Buecher, Ludovic Mansuy, Marie-Emmanuelle Morin-Meschin, Joanna Sokolowska, Marion Bougeard, Sophie Lejeune, Myriam Bronner, Jacqueline Duffour, Agnès Hardouin, Hakim Sebaoui, Valérie Bonadona, Julien Blot, Chrystelle Colas, Aziz Zaanan, Olivier Caron, Françoise Charbonnier, François Duhoux, Thierry Frebourg, Laurence Faivre, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Cancéropole Nord-Ouest, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Eugène Marquis (CRLCC), Oncologie thoracique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Centre Léon Bérard [Lyon], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique, Institut Curie Paris, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Service de génétique médicale CHU Grenoble Hôpital Couple Enfant, CHU Grenoble, Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Institut Claudius Regaud, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de Génétique [CHU HEGP], 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), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique Clinique [CHRU Nïmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Onco-génétique, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de génétique [Cliniques Universitaires Saint-Luc, Bruxelles], Cliniques Universitaires Saint-Luc [Bruxelles], Génétique biologique histologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'Hépatologie et de Gastroentérologie [Lyon], Unité de recherche clinique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU), and UL, NGERE
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Genotyping Techniques, [SDV]Life Sciences [q-bio], Single-nucleotide polymorphism, Bioinformatics, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Gene Frequency, Risk Factors, Internal medicine, Odds Ratio, Genetics, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Prospective cohort study, Alleles, Genetics (clinical), Chromosomes, Human, Pair 15, business.industry, Case-control study, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Lynch syndrome, 3. Good health, SNP genotyping, [SDV] Life Sciences [q-bio], 030104 developmental biology, Genetic Loci, Case-Control Studies, Female, Chromosomes, Human, Pair 18, Colorectal Neoplasms, business, Chromosomes, Human, Pair 8, Genome-Wide Association Study
Abstract: International audience; To determine if the at-risk single-nucleotide polymorphism (SNP) alleles for colorectal cancer (CRC) could contribute to clinical situations suggestive of an increased genetic risk for CRC, we performed a prospective national case-control study based on highly selected patients (CRC in two first-degree relatives, one before 61 years of age; or CRC diagnosed before 51 years of age; or multiple primary CRCs, the first before 61 years of age; exclusion of Lynch syndrome and polyposes) and controls without personal or familial history of CRC. SNPs were genotyped using SNaPshot, and statistical analyses were performed using Pearson's chi(2) test, Cochran-Armitage test of trend and logistic regression. We included 1029 patients and 350 controls. We confirmed the association of CRC risk with four SNPs, with odds ratio (OR) higher than previously reported: rs16892766 on 8q23.3 (OR: 1.88, 95% confidence interval (CI): 1.30-2.72; P=0.0007); rs4779584 on 15q13.3 (OR: 1.42, CI: 1.11-1.83; P=0.0061) and rs4939827 and rs58920878/Novel 1 on 18q21.1 (OR: 1.49, CI: 1.13-1.98; P=0.007 and OR: 1.49, CI: 1.14-1.95; P=0.0035). We found a significant (P
Published: 2016

36. Essential requirement for β-arrestin2 in mouse intestinal tumors with elevated Wnt signaling

Author: Bonnans, Caroline, Flacelière, Maud, Grillet, Fanny, Dantec, Christelle, Desvignes, Jean-Pierre, Pannequin, Julie, Severac, Dany, Dubois, Emeric, Bibeau, Frédéric, Escriou, Virginie, Crespy, Philippe, Journot, Laurent, Hollande, Frédéric, Joubert, Dominique, Flaceliere, M., Desvignes, P., 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), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), 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), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Unité de pharmacologie chimique et génétique et d'imagerie (UPCGI - UMR 8151 / UMR_S 1022 ), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC), Laboratoire des Amino-acides Peptides et Protéines (LAPP), Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Small interfering RNA, Arrestins, Adenomatous Polyposis Coli Protein, Down-Regulation, Cell Separation, Tumor initiation, Biology, medicine.disease_cause, Mice, 03 medical and health sciences, Transcription Factor 4, 0302 clinical medicine, Intestinal Neoplasms, medicine, Animals, Humans, Wnt Signaling Pathway, Tumor Stem Cell Assay, beta-Arrestins, Cell Proliferation, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell growth, Beta-Arrestins, Wnt signaling pathway, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, LRP5, Biological Sciences, beta-Arrestin 2, Molecular biology, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Cell Transformation, Neoplastic, beta-Arrestin 1, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Cancer research, Signal transduction, Carcinogenesis
Abstract: β-Arrestins (Arrb) participate in the regulation of multiple signaling pathways, including Wnt/β-catenin, the major actor in human colorectal cancer initiation. To better understand the roles of Arrb in intestinal tumorigenesis, a reverse genetic approach ( Arrb −/− ) and in vivo siRNA treatment were used in Apc Δ14/+ mice. Mice with Arrb2 depletion (knockout and siRNA) developed only 33% of the tumors detected in their Arrb2 -WT littermates, whereas Arrb1 depletion remained without significant effect. These remaining tumors grow normally and are essentially Arrb2–independent. Unsupervised hierarchical clustering analysis showed that they clustered with 25% of Apc Δ14/+ ;Arrb 2 +/+ tumors. Genes overexpressed in this subset reflect a high interaction with the immune system, whereas those overexpressed in Arrb2–dependent tumors are predominantly involved in Wnt signaling, cell adhesion, migration, and extracellular matrix remodeling. The involvement of Arrb2 in intestinal tumor development via the regulation of the Wnt pathway is supported by ex vivo and in vitro experiments using either tumors from Apc Δ14/+ mice or murine Apc Min/+ cells. Indeed, Arrb2 siRNAs decreased the expression of Wnt target genes in cells isolated from 12 of 18 tumors from Apc Δ14/+ mice. In Apc Min/+ cells, Arrb2 siRNAs completely reversed the increased Wnt activity and colony formation in soft agar induced by Apc siRNA treatment, whereas they did not affect these parameters in basal conditions or in cells expressing constitutively active β-catenin. We demonstrate that Arrb2 is essential for the initiation and growth of intestinal tumors displaying elevated Wnt pathway activity and identify a previously unsuspected molecular heterogeneity among tumors induced by truncating Apc mutations.
Published: 2012

37. High EGFR protein expression and exon 9 PIK3CA mutations are independent prognostic factors in triple negative breast cancers

Author: Caroline Mollevi, Evelyne Lopez-Crapez, Pierre-Emmanuel Colombo, Pierre-Jean Lamy, Frédéric Bibeau, Pierre-Marie Martin, William Jacot, Gilles Romieu, Frédéric Fina, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Département d'oncologie Médicale, Lab-STICC_UBO_MOM_DIM, Laboratoire des sciences et techniques de l'information, de la communication et de la connaissance (Lab-STICC), École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Laboratoire d'anatomo-pathologie, Clinique Beau Soleil [Montpellier], KARLI, Mélanie, Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)-Université européenne de Bretagne - European University of Brittany (UEB)-École Nationale d'Ingénieurs de Brest (ENIB)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Télécom Bretagne-Institut Brestois du Numérique et des Mathématiques (IBNM), and Université de Brest (UBO)-École Nationale Supérieure de Techniques Avancées Bretagne (ENSTA Bretagne)-Institut Mines-Télécom [Paris] (IMT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Oncology, CA15-3, PTEN, Cancer Research, Triple Negative Breast Neoplasms, PI3K, Phosphatidylinositol 3-Kinases, Exon, Breast cancer, Surgical oncology, Medicine, Aged, 80 and over, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, Exons, Middle Aged, Prognosis, 3. Good health, ErbB Receptors, Gene Expression Regulation, Neoplastic, Female, Research Article, Adult, medicine.medical_specialty, Class I Phosphatidylinositol 3-Kinases, EGFR, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Genetics, Humans, EGFR Gene Amplification, education, Aged, Gene amplification, business.industry, PTEN Phosphohydrolase, medicine.disease, Mutation, Cancer research, biology.protein, Triple negative, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background Triple negative breast cancers (TNBC) are a more aggressive subset of breast cancer. A better understanding of its biology could allow the rational development of targeted therapies. Methods We extensively analyzed the EGFR/PI3K/PTEN axis in a large, homogeneous population of TNBC to help defining the putative role of anti-EGFR and -PI3K targeted therapies in this setting. EGFR gene amplification, EGFR protein expression, PIK3CA and PTEN gene alterations (two members of EGFR downstream pathways) and their clinicopathological and prognostic implications were analyzed in 204 TNBC samples from European patients. Results EGFR amplification was detected in 18 of the 204 TNBC specimens (8.9 %) and was significantly associated with higher EGFR protein levels. Fourteen PIK3CA mutations were identified in exon 9 (6.7 %), and 17 in exon 20 (8.3 %). PIK3CA mutations, especially in exon 9, were significantly associated with grade I-II tumors. PTEN deletions were detected in 43 samples (21.50 %) and were significantly associated with grade III tumors (p
Published: 2015

38. Immunohistochemical staining for p16 and BRAFV600E is useful to distinguish between sporadic and hereditary (Lynch syndrome-related) microsatellite instable colorectal carcinomas

Author: Hélène Frugier, Florence Boissière-Michot, Frédéric Bibeau, Alexandre Ho-Pun-Cheung, Jacqueline Duffour, Evelyne Lopez-Crapez, 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), CRLC Val d'Aurelle-Paul Lamarque, and CRLCC Val d'Aurelle - Paul Lamarque
Subjects: 0301 basic medicine, MESH: Genes, p16, MESH: Genotype, 0302 clinical medicine, MESH: DNA Methylation, MESH: Germ-Line Mutation, Promoter Regions, Genetic, General Medicine, Methylation, MESH: Colorectal Neoplasms, Hereditary Nonpolyposis, Immunohistochemistry, Lynch syndrome, 3. Good health, MESH: Staining and Labeling, 030220 oncology & carcinogenesis, DNA methylation, DNA mismatch repair, Microsatellite Instability, Proto-Oncogene Proteins B-raf, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, Genotype, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MLH1, Pathology and Forensic Medicine, 03 medical and health sciences, Germline mutation, MESH: Promoter Regions, Genetic, medicine, Humans, Molecular Biology, Genotyping, neoplasms, MSI, Germ-Line Mutation, Surrogate markers, MESH: Proto-Oncogene Proteins B-raf, MESH: Humans, Staining and Labeling, Genes, p16, Microsatellite instability, nutritional and metabolic diseases, MESH: Immunohistochemistry, Cell Biology, DNA Methylation, medicine.disease, Promoter methylation, Molecular biology, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, 030104 developmental biology, Mutation, Cancer research, MESH: Microsatellite Repeats, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Microsatellite Instability, Microsatellite Repeats
Abstract: International audience; DNA mismatch repair (MMR) protein analysis by immunohistochemistry (IHC) can identify colorectal cancer (CRC) with microsatellite instability (MSI). As MLH1-deficient CRC can be hereditary or sporadic, markers to distinguish between them are needed. MLH1 promoter methylation assay is the reference method; however, sometimes, it is challenging on formalin-fixed paraffin-embedded tissue samples. We assessed by IHC the expression of BRAFV600E, p16, MGMT, and CDX2 in 55 MLH1-deficient MSI CRC samples (of which 8 had a germline MLH1 mutation) to determine whether this panel differentiates between sporadic and hereditary CRCs. We also analyzed MLH1 promoter methylation by methylation-specific PCR and pyrosequencing and BRAF status by genotyping. None of the hereditary CRCs showed MLH1 methylation, BRAF mutation, BRAFV600E-positive immunostaining, or loss of p16 expression. We detected MLH1 promoter methylation in 67 % and a BRAF mutation in 42 % of CRC, all showing MLH1 promoter methylation. BRAFV600E IHC and BRAF genotyping gave concordant results in all but two samples. Loss of expression of p16 was found in 30 % of CRC with methylation of the MLH1 promoter, but its expression was retained in all non-methylated and part of MLH1-methylated tumors (100 % specificity, 30 % sensitivity). CDX2 and MGMT expression was not associated with MLH1 status. Thus, BRAFV600E and p16 IHC may help in differentiating sporadic from hereditary MLH1-deficient CRC with MSI. Specifically, p16 IHC might be used as a surrogate marker for MLH1 promoter methylation, because all p16-negative CRCs displayed MLH1 methylation, whereas hereditary CRCs were all p16-positive.
Published: 2015

39. What type of hypofractionated radiotherapy of primary tumours in palliative care ?

Author: C, Bourgier, M, Charissoux, P, Boisselier, A, Ducteil, D, Azria, 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 du Cancer de Montpellier (ICM), CRLC Val d'Aurelle-Paul Lamarque, and CRLCC Val d'Aurelle - Paul Lamarque
Subjects: Otorhinolaryngologic Neoplasms, Tumeur primitive, Radiotherapy, Brain Neoplasms, Neoplasms, Palliative Care, Palliative radiotherapy, Humans, Primary tumour, Radiothérapie palliative, Radiation Dose Hypofractionation, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Palliative radiation therapy is well-known in the setting of metastatic lesions (haemostatic, analgesic, anti-inflammatory aims, etc.). Palliative primary tumour radiotherapy is less studied. Here we propose a review of palliative indications of primary tumours, the most studied in the literature, and their radiotherapy modalities (target volumes and fractionation).; La prise en charge palliative en radiothérapie est largement connue comme traitement métastatique à visée symptomatique (hémostatique, antalgique, anti-inflammatoire, etc.). Elle est moins étudiée dans le cadre de la prise en charge de tumeur primitive localement évoluée qui requiert un traitement palliatif. Nous proposons de détailler dans cette revue les différentes indications, les volumes d’irradiation et les fractionnements adaptés concernant les types de tumeur primitive les plus décrits dans la littérature.
Published: 2015

40. 36th San Antonio Breast Cancer Symposium: focus on clinical trial results

Author: William Jacot, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), and 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)
Subjects: Oncology, Cancer Research, medicine.medical_specialty, endocrine system diseases, Cancer therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, Humans, Breast Neoplasms/prevention & control/*therapy, 030304 developmental biology, Clinical Trials as Topic, 0303 health sciences, business.industry, General Medicine, medicine.disease, 3. Good health, Clinical trial, Clinical Practice, 030220 oncology & carcinogenesis, Family medicine, Female, business, Research center
Abstract: The 2013 San Antonio Breast Cancer Symposium, held under the auspices of the San Antonio Cancer Therapy & Research Center, the AACR, and Baylor College of Medicine, took place in San Antonio (TX, USA) on 10-14 December 2013. This international Symposium was attended by more than 7000 academic and private physicians and researchers from more than 90 countries, involved in all the fields of breast cancer (BC) research and treatment, including basic, translational and clinical research. Topics of discussion covered all aspects of BC research, from basic science to clinical practice, from prevention to targeted therapies. This report will focus on some of the most important results that were presented during the meeting.
Published: 2014

41. Hyperthermic intra-peritoneal chemotherapy using Oxaliplatin as consolidation therapy for advanced epithelial ovarian carcinoma. Results of a phase II prospective multicentre trial. CHIPOVAC study

Author: Philippe Morice, Frédéric Marchal, Pierre Meeus, Jean-Marc Classe, Gwenael Ferron, Dominique Elias, Christophe Pomel, Catherine Lhommé, Annie Rey, J.M. Bereder, Gérard Lorimier, François Quenet, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Institut Claudius Regaud, Centre Paul Papin(Angers), Institut Gustave Roussy (IGR), Centre René Gauducheau(Nantes), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Centre Léon Bérard [Lyon], Centre Alexis Vautrin (CAV), Centre René Gauducheau, CRLCC René Gauducheau, Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique de Lorraine (INPL)-Université Henri Poincaré - Nancy 1 (UHP), and Université Henri Poincaré - Nancy 1 (UHP)-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Reoperation, Hyperthermia, medicine.medical_specialty, Adolescent, Organoplatinum Compounds, medicine.medical_treatment, FIGO Stage IIIC, Antineoplastic Agents, Hemorrhage, Gastroenterology, Consolidation therapy, 03 medical and health sciences, 0302 clinical medicine, Laparotomy, Internal medicine, medicine, Humans, Infusions, Parenteral, Prospective Studies, Aged, Neoplasm Staging, Ovarian Neoplasms, Chemotherapy, HIPEC, business.industry, Mortality rate, Hyperthermia, Induced, Ovarian epithelial carcinomatosis, General Medicine, Middle Aged, medicine.disease, 3. Good health, Oxaliplatin, Surgery, Survival Rate, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Treatment Outcome, Oncology, Epithelial ovarian carcinoma, 030220 oncology & carcinogenesis, Medicine, Female, 030211 gastroenterology & hepatology, business, medicine.drug
Abstract: Presented at the 16th International Meeting of the European Society for Gynaecological Oncology (ESGO 16) Belgrade, Serbia, October 11–14, 2009.; International audience; INTRODUCTION: The aim of the present study was to prospectively evaluate morbidity of intra-peritoneal hyperthermic chemotherapy (HIPEC) using Oxaliplatin as consolidation therapy for advanced epithelial ovarian carcinoma and, secondly, to study peritoneal recurrence. METHODS: Between 2004 and 2007, 31 patients from 18 to 65 years with FIGO stage IIIC epithelial ovarian carcinoma were treated by surgery and a total of 6 cycles of platinum based chemotherapy. Those patients were eligible for consolidation therapy. We performed a second look laparotomy operation with intra-peritoneal hyperthermic chemotherapy. We used Oxaliplatin 460 mg/m(2) with 2 l/m(2) of dextrose in an open medial laparotomy for a total of 30 min at a temperature of 42-44 degrees C. RESULTS: The grade 3 morbidity rate was 29% (95 CI: 14-45%). Nine patients experienced a total of 13 exploratory laparotomies for intra-abdominal bleeding after HIPEC. Two-year disease free and overall survival were 27% and 67% respectively. As a result of this high level of morbidity the trial was closed. CONCLUSION: Using intra-peritoneal Oxaliplatin associated with hyperthermia as consolidation therapy for advanced ovarian cancer results in a high risk of grade 3 morbidities with only a small benefit on survival
Published: 2010

42. Endoscopic ultrasound-guided fine-needle aspiration biopsy coupled withKRASmutation assay to distinguish pancreatic cancer from pseudotumoral chronic pancreatitis

Author: Ariane Aubert, Barbara Bournet, Eric Assenat, Pierre Senesse, Jean Escourrou, Pierre Cordelier, Marc Barthet, M. Bouisson, Philippe Lévy, Louis Buscail, Philippe Ruszniewski, Pascal Hammel, Dermot O'Toole, Anny Souque, N. Lesavre, Service de Gastro-entérologie et Nutrition[Rangueil], CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Department of Gastroenterology, Hôpital Nord [CHU - APHM], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pôle Maladies de l'appareil digestif [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Simon, Marie Francoise
Subjects: Male, Pathology, medicine.medical_specialty, Pancreatic disease, Biopsy, Fine-Needle, medicine.disease_cause, Gastroenterology, Endosonography, Diagnosis, Differential, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, 0302 clinical medicine, Pancreatitis, Chronic, Proto-Oncogene Proteins, Internal medicine, Pancreatic cancer, medicine, Pancreatic mass, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 10. No inequality, Pancreas, Aged, medicine.diagnostic_test, business.industry, Middle Aged, medicine.disease, digestive system diseases, 3. Good health, Pancreatic Neoplasms, KRAS Mutation Analysis, Fine-needle aspiration, Cytopathology, 030220 oncology & carcinogenesis, Mutation, ras Proteins, Pancreatitis, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030211 gastroenterology & hepatology, KRAS, business
Abstract: International audience; BACKGROUND AND STUDY AIMS: Differential diagnosis between pancreatic adenocarcinoma (PADC) and pseudotumoral forms of chronic pancreatitis remains difficult. Mutation of KRAS oncogene is present in 75% to 95% of PADC. This study aimed to evaluate whether the combined analysis of KRAS mutation with cytopathological findings from endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) might improve discrimination between PADC and chronic pancreatitis. PATIENTS AND METHODS: This prospective multicenter study included 178 patients with solid pancreatic masses (men 104, women 74; mean age 64.5 years). Cytopathological examination and KRAS mutation analysis (codon-12 and codon-13, restriction fragment length polymorphism [RFLP] and direct sequencing) were performed on EUS-FNAB material. Final diagnoses were obtained on EUS-FNAB analysis and/or a second biopsy and/or clinical follow-up and/or surgery: PADC, n = 129; chronic pancreatitis, n = 27; other pancreatic neoplasms, n = 16; and benign lesions, n = 6. RESULTS: KRAS status analysis was successful in all EUS-FNAB samples. Codon-12 KRAS point mutation was found in 66% of PADC samples. No case of chronic pancreatitis displayed KRAS mutation. Sensitivity, specificity, positive and negative predictive values, and overall accuracy of cytopathology alone for diagnosis of PADC versus chronic pancreatitis were 83%, 100%, 100%, 56% and 86%, respectively. When KRAS mutation analysis was combined with cytopathology, these values reached 88%, 100%, 100%, 63% and 90% respectively. CONCLUSION: Although the value of KRAS analysis in addition to EUS-FNAB is limited for distinguishing pancreatic mass lesions, when chronic pancreatitis presented as a pseudotumor a negative finding (wild-type KRAS), was useful in strongly suggesting a benign lesion.
Published: 2009

43. Prognostic Factors for Survival in Noncastrate Metastatic Prostate Cancer: Validation of the Glass Model and Development of a Novel Simplified Prognostic Model

Author: Claude El Kouri, Marjorie Baciuchka, Gael Deplanque, Michel Soulié, Loic Mourey, Jean-Pascal Machiels, Brigitte Laguerre, Jochen Walz, Jean-Marie Boher, Patricia Marino, Jean-Marc Ferrero, Guilhem Bousquet, Jérôme Dauba, Stéphane Oudard, Philippe Beuzeboc, Claude Linassier, Christine Theodore, Florence Joly, Ivan Krakowski, Frederic Rolland, Jean-François Berdah, Alain Ravaud, Karim Fizazi, Remy Delva, Gwenaelle Gravis, Muriel Habibian, Igor Latorzeff, Ali Hasbini, Damien Pouessel, Sylvie Zanetta, Christian Platini, Jean-Christophe Eymard, Jean-Luc Labourey, Etienne Suc, Franck Priou, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Université Paris-Sud - Paris 11 (UP11), Oncologie génito-urinaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), 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 Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Clinique Pasteur [Toulouse], Centre Paul Papin, CRLCC Paul Papin, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Centre Eugène Marquis (CRLCC), CRLCC René Gauducheau, Hôpital Foch [Suresnes], Centre hospitalier Saint-Joseph [Paris], 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), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut Claudius Regaud, Institut Curie [Paris], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Hôpital de Toulon/Hyères - Sainte Marguerite [Hyères] (HTH-SM), Centre Hospitalier Layné, Hôpital de la Timone [CHU - APHM] (TIMONE), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Dupuytren [CHU Limoges], Université Catholique de Louvain = Catholic University of Louvain (UCL), Centre Catherine-de-Sienne [Nantes] (CCS), Hôpital Saint-André, Clinique Saint-Jean Languedoc [Toulouse] (CSJL), Institut Jean Godinot [Reims], Clinique Armoricaine de Radiologie [St. Brieuc], Hopital Saint-Louis [AP-HP] (AP-HP), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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), Université Paris Descartes - Paris 5 (UPD5), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), CHD Vendée - Hôpital Les Oudairies [La Roche sur Yon], Centre Alexis Vautrin [Vandoeuvre-lès-Nancy], Université Côte d'Azur (UCA)-UNICANCER, Hôpital de Rangueil, CHU Toulouse [Toulouse], UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Unité d'oncologie médicale, and Malbec, Odile
Subjects: Male, Oncology, Time Factors, [SDV]Life Sciences [q-bio], Kaplan-Meier Estimate, Docetaxel, Androgen deprivation therapy, Prostate cancer, Risk Factors, Antineoplastic Combined Chemotherapy Protocols, Medicine, Prospective Studies, 10. No inequality, 2. Zero hunger, education.field_of_study, Univariate analysis, Hazard ratio, Noncastrate, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Treatment Outcome, Lymphatic Metastasis, Metastatic, Taxoids, France, medicine.drug, medicine.medical_specialty, Antineoplastic Agents, Hormonal, Urology, Population, Bone Neoplasms, Adenocarcinoma, Prognostic factors, Risk Assessment, Decision Support Techniques, Predictive Value of Tests, Internal medicine, Alkaline phosphatase, Biomarkers, Tumor, Humans, education, Aged, Proportional Hazards Models, Performance status, business.industry, Prostatic Neoplasms, Reproducibility of Results, Androgen Antagonists, medicine.disease, Confidence interval, Surgery, Nomograms, business, Orchiectomy
Abstract: BACKGROUND: The Glass model developed in 2003 uses prognostic factors for noncastrate metastatic prostate cancer (NCMPC) to define subgroups with good, intermediate, and poor prognosis. OBJECTIVE: To validate NCMPC risk groups in a more recently diagnosed population and to develop a more sensitive prognostic model. DESIGN, SETTING, AND PARTICIPANTS: NCMPC patients were randomized to receive continuous androgen deprivation therapy (ADT) with or without docetaxel in the GETUG-15 phase 3 trial. Potential prognostic factors were recorded: age, performance status, Gleason score, hemoglobin (Hb), prostate-specific antigen, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), metastatic localization, body mass index, and pain. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: These factors were used to develop a new prognostic model using a recursive partitioning method. Before analysis, the data were split into learning and validation sets. The outcome was overall survival (OS). RESULTS AND LIMITATIONS: For the 385 patients included, those with good (49%), intermediate (29%), and poor (22%) prognosis had median OS of 69.0, 46.5 and 36.6 mo (p=0.001), and 5-yr survival estimates of 60.7%, 39.4%, and 32.1%, respectively (p=0.001). The most discriminatory variables in univariate analysis were ALP, pain intensity, Hb, LDH, and bone metastases. ALP was the strongest prognostic factor in discriminating patients with good or poor prognosis. In the learning set, median OS in patients with normal and abnormal ALP was 69.1 and 33.6 mo, and 5-yr survival estimates were 62.1% and 23.2%, respectively. The hazard ratio for ALP was 3.11 and 3.13 in the learning and validation sets, respectively. The discriminatory ability of ALP (concordance [C] index 0.64, 95% confidence interval [CI] 0.58-0.71) was superior to that of the Glass risk model (C-index 0.59, 95% CI 0.52-0.66). The study limitations include the limited number of patients and low values for the C-index. CONCLUSION: A new and simple prognostic model was developed for patients with NCMPC, underlying the role of normal or abnormal ALP. PATIENT SUMMARY: We analyzed clinical and biological factors that could affect overall survival in noncastrate metastatic prostate cancer. We showed that normal or abnormal alkaline phosphatase at baseline might be useful in predicting survival.
Published: 2015

44. Neoadjuvant therapy for gastroesophageal adenocarcinoma

Author: Emmanuelle Samalin, Marc Ychou, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), and CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Oncology, medicine.medical_specialty, Neoadjuvant treatment, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroesophageal Junction Adenocarcinoma, Gastroesophageal junction adenocarcinoma, 03 medical and health sciences, Gastric adenocarcinoma, 0302 clinical medicine, Internal medicine, medicine, 030212 general & internal medicine, Survival rate, Preoperative treatment, Neoadjuvant therapy, Gastroesophageal adenocarcinoma, business.industry, Incidence (epidemiology), Induction chemotherapy, Minireviews, Esophageal cancer, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Lower esophagus adenocarcinoma
Abstract: International audience; Gastric and esophageal adenocarcinomas are one of the main causes of cancer-related death worldwide. While the incidence of gastric adenocarcinoma is decreasing, the incidence of gastroesophageal junction adenocarcinoma is rising rapidly in Western countries. Considering that surgical resection is currently the major curative treatment, and that the 5-year survival rate highly depends on the pTNM stage at diagnosis, gastroesophageal adenocarcinoma management is very challenging for oncologists. Several treatment strategies are being evaluated, and among them systemic chemotherapy, to decrease recurrences and improve overall survival. The MAGIC and FNCLCC-FFCD trials showed a survival benefit of perioperative chemotherapy in patients with operable gastric and lower esophageal cancer, and these results had an impact on the European clinical practice. New strategies, including induction chemotherapy followed by preoperative chemoradiotherapy, targeted therapies in combination with perioperative chemotherapy and the new cytotoxic regimens, are currently assessed to improve current standards and help developing patient-tailored therapeutic interventions.
Published: 2015

45. Late side-effects after curative intent radiotherapy: Identification of hypersensitive patients for personalized strategy

Author: Alain Mangé, André Pèlegrin, Mahmut Ozsahin, Jerome Lacombe, Jérôme Solassol, D. Azria, Céline Bourgier, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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), Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV)
Subjects: medicine.medical_specialty, Time Factors, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Predictive markers, Radiation Tolerance, 03 medical and health sciences, 0302 clinical medicine, Quality of life (healthcare), Risk Factors, Neoplasms, Overall survival, Medicine, Survivors, Precision Medicine, Radiation Injuries, Intensive care medicine, 030304 developmental biology, Curative intent, 0303 health sciences, Radiotherapy, business.industry, Radiotherapy outcome, Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Prognosis, medicine.disease, 3. Good health, Radiation therapy, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Physical therapy, business, Biomarkers
Abstract: International audience; Radiation therapy undeniably enhances local control and thus improves overall survival in cancer patients. However, some long-term cancer survivors (less than 10%) develop severe late radio-induced toxicities altering their quality of life. Therefore, there is a need to identify patients who are sensitive to those toxicities and who could benefit from adapted care. In this review, we address all available techniques aiming to detect patients' hyper-radiosensitivity and present the scientific rationales these techniques are based on.
Published: 2015

46. Targeting triple-negative breast cancer and high-grade ovarian carcinoma: refining BRCAness beyond BRCA1/2 mutations?

Author: Charles Theillet, Pierre-Jean Lamy, William Jacot, Séverine Guiu, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, and Clinique Beau Soleil [Montpellier]
Subjects: CA15-3, Oncology, Cancer Research, medicine.medical_specialty, Genes, BRCA2, Genes, BRCA1, Antineoplastic Agents, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Poly(ADP-ribose) Polymerase Inhibitors, Genomic Instability, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, Ovarian carcinoma, Internal medicine, medicine, Humans, Molecular Targeted Therapy, Triple-negative breast cancer, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Ovarian Neoplasms, 0303 health sciences, business.industry, Cancer, General Medicine, medicine.disease, BRCA1, 53BP1, targeted therapies, 3. Good health, ovarian cancer, 030220 oncology & carcinogenesis, Mutation, Female, methylation, Neoplasm Grading, Ovarian cancer, business, DNA Damage
Abstract: Department of Medical Oncology, Institut regional du Cancer de Montpellier (ICM) Val d’Aurelle, 208 rue des Apothicaires, 34298 Montpellier Cedex 5, France Translational Research Unit, Institut regional du Cancer de Montpellier (ICM) Val d’Aurelle, 208 rue des Apothicaires, 34298 Montpellier Cedex 5, France INSERM U896, Institut de Recherche en Cancerologie de Montpellier, Universite Montpellier 1, Institut regional du Cancer de Montpellier (ICM) Val d’Aurelle, 208 rue des Apothicaires, 34298 Montpellier Cedex 5, France Department of Biology & Oncogenetic, Institut regional du Cancer de Montpellier (ICM) Val d’Aurelle, 208 rue des Apothicaires, 34298 Montpellier Cedex 5, France *Author for correspondence: Tel.: +33 467 612 339; Fax: +33 467 613 706; william.jacot@icm.unicancer.fr
Published: 2015

47. Bone metastases in gastrointestinal cancer

Author: Eric Assenat, Thibault Mazard, Fabienne Portales, Marc Ychou, Emmanuelle Samalin, Simon Thezenas, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), and CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Colorectal cancer, Pain, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, Gastrointestinal cancer, Prospective cohort study, Aged, Gastrointestinal Neoplasms, Neoplasm Staging, Retrospective Studies, Aged, 80 and over, Univariate analysis, business.industry, Bone metastasis, General Medicine, Esophageal cancer, Middle Aged, medicine.disease, 3. Good health, Treatment Outcome, Epidermoid carcinoma, 030220 oncology & carcinogenesis, Female, business
Abstract: International audience; Colorectal (CRC) and gastroesophageal (GEC) cancers unusually spread to the bone. However, bone metastases (BM) are responsible for skeletal-related events (SREs) associated with an altered quality of life. Aiming to describe the characteristics and prognostic influence of BM from gastro-intestinal cancers, we performed a retrospective analysis of prospectively collected data in patients treated in our institution (1996-2006). 189 patients (5.5 %) developed BM: 79 with GEC and 110 with CRC. 57 patients had bone-exclusive metastases. In univariate analyses, the median time to BM occurrence was correlated with the primary tumour (PT) localisation, surgery, histology and TNM staging. However, in multivariate analyses, the occurrence delay was significantly shorter only for patients with GEC (HR 2.1), N1-2 status (HR 1.9), M1 status (HR 2.4), and epidermoid carcinoma (HR 6.0). Pain was the most frequent clinical sign leading to BM diagnosis (77.2 %). SRE occurred in 55 % of patients. Median overall survivals (OSs) of patients with CRC and GEC were 9.4 months [95 % confidence interval (95 % CI) 6.4-11.1] and 3.4 months (95 % CI 2.5-9.0), respectively. In univariate analyses, OS was correlated with PT surgery and NM staging, and the number of BM. In multivariate analyses, only the PT surgery and the number of BM remained correlated with OS. Our results suggest that there may be a subset of patients associated with a quicker development of BM. Given their higher risk of SRE, they could benefit from an early screening, calling for further prospective studies encompassing patients with and without BM.
Published: 2015

48. Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)dagger

Author: Roger A'Hern, Stefan Michiels, Robert E. Coleman, D. Azria, F. Bonnetain, Gaëtan MacGrogan, Henri Roché, William Jacot, Carine Bellera, Bernard Asselain, David Cameron, Simone Mathoulin-Pélissier, Tanja Cufer, Michael Untch, Hans Wildiers, I. Negreiros, V. Servent, F. Penault Llorca, Suzette Delaloge, G. van Tienhoven, Thomas Filleron, Marc Debled, John Yarnold, Hervé Bonnefoi, P.M. Poortmans, Fernando Schmitt, Nicola S. Russell, Birgitte Vrou Offersen, Judith M Bliss, Joseph Gligorov, Etienne Brain, Florence Dalenc, Fatima Cardoso, E. de Azambuja, Maciej Gutowski, Jan Bogaerts, Sophie Gourgou-Bourgade, L. Dal Lago, Maria João Cardoso, T. S. Dabakuyo-yonli, C. Kirkove, Benoist Chibaudel, J.A. van der Hage, Giancarlo Pruneri, Beat Thürlimann, Institut du Cancer de Montpellier (ICM), University of Edinburgh, Radiation Oncology Department, Dr. B. Verbeeten Institute, Institut Curie [Paris], CRLCC Val d'Aurelle - Paul Lamarque, 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), European School of Oncology & Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal, Champalimaud Clinical Center, The institute of cancer research [London], European Organisation for Research and Treatment of Cancer [Bruxelles] (EORTC), European Cancer Organisation [Bruxelles] (ECCO), Institut Bergonié [Bordeaux], UNICANCER, Hôpital René HUGUENIN (Saint-Cloud), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut Claudius Regaud, Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], CHU Tenon [AP-HP], CRLC Val d'Aurelle-Paul Lamarque, Département de pathologie, UNICANCER-UNICANCER, Equipe de recherche sur les traitements individualisés des cancers (ERTICa), Université d'Auvergne - Clermont-Ferrand I (UdA), Division of Pathology, European Institute of Oncology [Milan] (ESMO), Institut de Recherche sur la Fusion par confinement Magnétique (IRFM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Unité de neurophysiologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), UCL - SSS/IREC - Institut de recherche expérimentale et clinique, and UCL - (SLuc) Service de radiothérapie oncologique
Subjects: Oncology, Research design, Time Factors, Delphi Technique, Event (relativity), Delphi method, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Medicine, Treatment Failure, guidelines, Randomized Controlled Trials as Topic, 0303 health sciences, Hematology, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Research Design, 030220 oncology & carcinogenesis, Disease Progression, Female, medicine.medical_specialty, Consensus, Endpoint Determination, Comparative effectiveness research, MEDLINE, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease-Free Survival, 03 medical and health sciences, Breast cancer, breast cancer, Terminology as Topic, Internal medicine, Humans, Medical physics, time-to-event end point, 030304 developmental biology, End point, Surrogate endpoint, business.industry, efficacy measure, Cancer, controlled trial, medicine.disease, Clinical trial, randomized, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: Item does not contain fulltext BACKGROUND: Using surrogate end points for overall survival, such as disease-free survival, is increasingly common in randomized controlled trials. However, the definitions of several of these time-to-event (TTE) end points are imprecisely which limits interpretation and cross-trial comparisons. The estimation of treatment effects may be directly affected by the definitions of end points. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for randomized cancer clinical trials (RCTs) in breast cancer. PATIENTS AND METHODS: A literature review was carried out to identify TTE end points (primary or secondary) reported in publications of randomized trials or guidelines. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points based on a validated consensus method that formalize the degree of agreement among experts. RESULTS: Recommended guidelines for the definitions of TTE end points commonly used in RCTs for breast cancer are provided for non-metastatic and metastatic settings. CONCLUSION: The use of standardized definitions should facilitate comparisons of trial results and improve the quality of trial design and reporting. These guidelines could be of particular interest to those involved in the design, conducting, reporting, or assessment of RCT.
Published: 2015

49. Neoadjuvant treatment with docetaxel plus lapatinib, trastuzumab, or both followed by an anthracycline-based chemotherapy in HER2-positive breast cancer: results of the randomised phase II EORTC 10054 study

Author: C. Moldovan, David Cameron, Guy Jerusalem, Olivier Tredan, Mahasti Saghatchian, N. Quenel-tueux, William Jacot, Laurence Venat-Bouvet, Etienne Brain, Thierry Petit, Leen Slaets, Khalil Zaman, Camille Chakiba, Alexandre Bodmer, Erika Matos, Peter Vuylsteke, Hervé Bonnefoi, Carlo Messina, Institut Bergonié [Bordeaux], UNICANCER, CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, 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), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CHU Limoges, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Centre Paul Strauss, CRLCC Paul Strauss, Hôpitaux Universitaires de Genève (HUG), Department of Oncology, Sint-Elisabeth Hospital, Hôpital René HUGUENIN (Saint-Cloud), 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), European Organisation for Research and Treatment of Cancer [Bruxelles] (EORTC), European Cancer Organisation [Bruxelles] (ECCO), Western General Hospital, and University of Edinburgh
Subjects: Oncology, Receptor, ErbB-2, medicine.medical_treatment, Docetaxel, 0302 clinical medicine, Trastuzumab, Antineoplastic Combined Chemotherapy Protocols, Anthracyclines, skin and connective tissue diseases, 0303 health sciences, Hematology, Middle Aged, Chemotherapy regimen, Neoadjuvant Therapy, 3. Good health, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Female, Taxoids, Fluorouracil, pathological response, neoadjuvant chemotherapy, medicine.drug, Epirubicin, Adult, medicine.medical_specialty, Anthracycline, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Lapatinib, 03 medical and health sciences, breast cancer, HER2, Internal medicine, medicine, Humans, neoplasms, Cyclophosphamide, 030304 developmental biology, Aged, Chemotherapy, business.industry, Original Articles, medicine.disease, Quinazolines, business, Febrile neutropenia
Abstract: Five trials assessed lapatinib and trastuzumab (L+T) combined with paclitaxel-containing chemotherapy regimens. They showed high pathological complete response rates, but at the cost of toxicity. This trial assesses L+T combined with docetaxel. The use of docetaxel rather than paclitaxel does not avoid much of the toxicity. Regarding efficacy our results are very consistent with NSABP-B41 trial. Background Neoadjuvant trials conducted using a double HER2 blockade with lapatinib and trastuzumab, combined with different paclitaxel-containing chemotherapy regimens, have shown high pathological complete response (pCR) rates, but at the cost of important toxicity. We hypothesised that this toxicity might be due to a specific interaction between paclitaxel and lapatinib. This trial assesses the toxicity and activity of the combination of docetaxel with lapatinib and trastuzumab. Patients and methods Patients with stage IIA to IIIC HER2-positive breast cancer received six cycles of chemotherapy (three cycles of docetaxel followed by three cycles of fluorouracil, epirubicin, cyclophosphamide). They were randomised 1 : 1 : 1 to receive during the first three cycles either lapatinib (1000 mg orally daily), trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), or trastuzumab + lapatinib at the same dose. The primary end point was pCR rate defined as ypT0/is. Secondary end points included safety and toxicity. pCR rate defined as ypT0/is ypN0 was assessed as an exploratory analysis. In June 2012, arm A was closed for futility based on the results from other studies. Results From October 2010 to January 2013, 128 patients were included in 14 centres. The percentage of the 122 assessable patients with pCR in the breast, and pCR in the breast and nodes, was numerically highest in the lapatinib + trastuzumab group (60% and 56%, respectively), intermediate in the trastuzumab group (52% and 52%), and lowest in the lapatinib group (46% and 36%). Frequency (%) of the most common grade 3–4 toxicities in the lapatinib /trastuzumab/lapatinib + trastuzumab arms were: febrile neutropenia 23/15/10, diarrhoea 9/2/18, infection (other) 9/4/8, and hepatic toxicity 0/2/8. Conclusions This study demonstrates a numerically modest pCR rate increase with double anti-HER2 blockade plus chemotherapy, but suggests that the use of docetaxel rather than paclitaxel may not reduce toxicity. ClinicalTrials.gov NCT00450892.
Published: 2014

50. Clinical validation of the detection of KRAS and BRAF mutations from circulating tumor DNA

Author: Bruno Robert, Michelle Nouaille, Virginie Loriot, Frédéric Bibeau, Safia El Messaoudi, Denis Pezet, Maguy Del Rio, Anne Sophie Jarrousse, Pierre-Jean Lamy, Alain R. Thierry, Céline Gongora, Marc Ychou, Fanny Rolet, Evelyne Lopez-Crapez, Muriel Mathonnet, Caroline Mollevi, Franck Molina, Brigitte Gillet, Pierre Déchelotte, Florent Mouliere, Défenses antivirales et antitumorales (DAA), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), 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), 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), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Département d'oncologie Médicale, Imagerie par Résonance Magnétique Médicale et MultiModalité, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'anatomo-pathologie, Centre d'Investigation Clinique de Limoges (CIC1435), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Limoges, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Sys2Diag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (Sys2Diag), Centre National de la Recherche Scientifique (CNRS)-Alcediag, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA), Pathology, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLC Val d'Aurelle-Paul Lamarque, Sysdiag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (SysDiag ), BIO-RAD-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, CHU Limoges, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte - Clermont Auvergne (M2iSH), Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Laboratoire des Défenses Antivirales et Antitumorales, Université Montpellier 2 - Sciences et Techniques (UM2), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER - Institut régional du Cancer [Montpellier] (ICM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-CHU Limoges, and CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)
Subjects: Male, Oncology, Pathology, Colorectal cancer, medicine.medical_treatment, [SDV]Life Sciences [q-bio], medicine.disease_cause, Targeted therapy, Cohort Studies, 0302 clinical medicine, 80 and over, Prospective Studies, Neoplasm Metastasis, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, ras Proteins/*genetics, DNA, Neoplasm, General Medicine, Middle Aged, 3. Good health, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, Female, original, Proto-Oncogene Proteins B-raf/*genetics, KRAS, Colorectal Neoplasms, Neoplasm/*analysis, Sequence Analysis, Proto-Oncogene Proteins B-raf, Adult, medicine.medical_specialty, Point Mutation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Sensitivity and Specificity, General Biochemistry, Genetics and Molecular Biology, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Proto-Oncogene Proteins, Internal medicine, medicine, Humans, Matrix-Assisted Laser Desorption-Ionization, Liquid biopsy, Aged, 030304 developmental biology, Spectrometry, business.industry, Point mutation, Colorectal Neoplasms/*diagnosis/genetics, Cancer, Sequence Analysis, DNA, DNA, Mass, medicine.disease, Humans, Female, Middle Aged, Adult, Male, Aged, Prospective Studies, Cohort Studies, Case-Control Studies, 80 and over, Sensitivity and Specificity, Proto-Oncogene Proteins/*genetics, ras Proteins/*genetics, Neoplasm Metastasis, original, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Reverse Transcriptase Polymerase Chain Reaction, *Point Mutation, Colorectal Neoplasms/*diagnosis/genetics, DNA, Neoplasm/*analysis, Proto-Oncogene Proteins B-raf/*genetics, Sequence Analysis, digestive system diseases, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Case-Control Studies, ras Proteins, Proto-Oncogene Proteins/*genetics, Personalized medicine, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Assessment of KRAS status is mandatory in patients with metastatic colorectal cancer (mCRC) before applying targeted therapy. We describe here a blinded prospective study to compare KRAS and BRAF mutation status data obtained from the analysis of tumor tissue by routine gold-standard methods and of plasma DNA using a quantitative PCR-based method specifically designed to analyze circulating cell-free DNA (cfDNA). The mutation status was determined by both methods from 106 patient samples. cfDNA analysis showed 100% specificity and sensitivity for the BRAF V600E mutation. For the seven tested KRAS point mutations, the method exhibited 98% specificity and 92% sensitivity with a concordance value of 96%. Mutation load, expressed as the proportion of mutant alleles in cfDNA, was highly variable (0.5-64.1%, median 10.5%) among mutated samples. CfDNA was detected in 100% of patients with mCRC. This study shows that liquid biopsy through cfDNA analysis could advantageously replace tumor-section analysis and expand the scope of personalized medicine for patients with cancer.
Published: 2014

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