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1. 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

2. The Addition of Bevacizumab to Oxaliplatin-Based Chemotherapy: Impact Upon Hepatic Sinusoidal Injury and Thrombocytopenia

Author

J.N. Vauthey, Binsah George, Kanwal Pratap Singh Raghav, Evelyn Loyer, Michael J. Overman, Scott Kopetz, Leonard B. Saltz, Paulo M. Hoff, Thibault Mazard, Brian P. Hobbs, Wei Qiao, Renata Ferrarotto, Karime Kalil Machado, 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
Male, Cancer Research, Organoplatinum Compounds, Colorectal cancer, MESH: Spleen, medicine.medical_treatment, MESH: Organ Size, Leucovorin, Gastroenterology, MESH: Chemical and Drug Induced Liver Injury, MESH: Clinical Trials, Phase III as Topic, 0302 clinical medicine, MESH: Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Multicenter Studies as Topic, Cumulative incidence, Neoplasm Metastasis, Randomized Controlled Trials as Topic, Aged, 80 and over, MESH: Aged, MESH: Middle Aged, MESH: Organoplatinum Compounds, Organ Size, Middle Aged, Chemotherapy regimen, 3. Good health, Bevacizumab, Oxaliplatin, MESH: Antineoplastic Combined Chemotherapy Protocols, Oncology, Liver, 030220 oncology & carcinogenesis, Cohort, MESH: Oxaliplatin, 030211 gastroenterology & hepatology, Female, Fluorouracil, Chemical and Drug Induced Liver Injury, Colorectal Neoplasms, medicine.drug, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, MESH: Bevacizumab, Internal medicine, medicine, Humans, MESH: Thrombocytopenia, Aged, Retrospective Studies, Chemotherapy, MESH: Humans, business.industry, Retrospective cohort study, MESH: Adult, MESH: Retrospective Studies, medicine.disease, Thrombocytopenia, MESH: Neoplasm Metastasis, MESH: Male, MESH: Randomized Controlled Trials as Topic, Clinical Trials, Phase III as Topic, NEOPLASIAS COLORRETAIS, MESH: Multicenter Studies as Topic, business, MESH: Leucovorin, MESH: Female, MESH: Fluorouracil, Spleen, MESH: Colorectal Neoplasms, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Liver
Abstract

International audience; Background:Oxaliplatin-based chemotherapy can cause hepatic sinusoidal injury (HSI), portal hypertension, and splenic sequestration of platelets. Evidence suggests that bevacizumab may protect against HSI.Methods:Two cohorts of metastatic colorectal cancer (CRC) were analyzed: a nonrandomized exploratory cohort of 184 patients treated at a single institution from 2003 to 2010 and a confirmatory cohort of 200 patients from a multi-institutional randomized trial (NO16966). All patients were treated with frontline fluoropyrimidine and oxaliplatin with or without bevacizumab. Changes in splenic volumes and platelet counts were compared by treatment, two-sided log-rank test.Results:In the exploratory cohort, the bevacizumab-treated patients (n = 138) compared with the nonbevacizumab-treated patients (n = 46) demonstrated a longer median time to splenic enlargement (≥30%, P = .02) and reduced rate of thrombocytopenia (

Published
2018

3. Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts

Author

Raquel V Mendes, Nuno Figueiredo, Rita Fior, Antonio S. Gomes, Miguel Godinho Ferreira, Vanda Póvoa, Tânia Carvalho, Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)

Subjects
0301 basic medicine, MESH: Xenograft Model Antitumor Assays, MESH: Mice, Inbred NOD, patient derived xenografts, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Pharmacology, medicine.disease_cause, Colorectal neoplasms, Metastasis, 03 medical and health sciences, Folinic acid, FOLFOX, medicine, KRAS, Chemotherapy, MESH: Animals, MESH: Irinotecan, MESH: Mice, SCID, MESH: Zebrafish, Zebrafish, MESH: Mice, Multidisciplinary, MESH: Humans, Cetuximab, fungi, MESH: Organoplatinum Compounds, chemotherapy functional screening, zebrafish xenograft, biology.organism_classification, medicine.disease, 3. Good health, Oxaliplatin, MESH: Antineoplastic Combined Chemotherapy Protocols, 030104 developmental biology, Cancer research, FOLFIRI, MESH: Oxaliplatin, MESH: Camptothecin, MESH: Leucovorin, MESH: Female, MESH: Fluorouracil, MESH: Colorectal Neoplasms, Xenograft model antitumor assays, medicine.drug
Abstract

Cancer is as unique as the person fighting it. With the exception of a few biomarker-driven therapies, patients go through rounds of trial-and-error approaches to find the best treatment. Using patient-derived cell lines, we show that zebrafish larvae xenotransplants constitute a fast and highly sensitive in vivo model for differential therapy response, with resolution to reveal intratumor functional cancer heterogeneity. We screened international colorectal cancer therapeutic guidelines and determined distinct functional tumor behaviors (proliferation, metastasis, and angiogenesis) and differential sensitivities to standard therapy. We observed a general higher sensitivity to FOLFIRI [5-fluorouracil(FU)+irinotecan+folinic acid] than to FOLFOX (5-FU+oxaliplatin+folinic acid), not only between isogenic tumors but also within the same tumor. We directly compared zebrafish xenografts with mouse xenografts and show that relative sensitivities obtained in zebrafish are maintained in the rodent model. Our data also illustrate how KRAS mutations can provide proliferation advantages in relation to KRASWT and how chemotherapy can unbalance this advantage, selecting for a minor clone resistant to chemotherapy. Zebrafish xenografts provide remarkable resolution to measure Cetuximab sensitivity. Finally, we demonstrate the feasibility of using primary patient samples to generate zebrafish patient-derived xenografts (zPDX) and provide proof-of-concept experiments that compare response to chemotherapy and biological therapies between patients and zPDX. Altogether, our results suggest that zebrafish larvae xenografts constitute a promising fast assay for precision medicine, bridging the gap between genotype and phenotype in an in vivo setting. info:eu-repo/semantics/publishedVersion

Published
2017

4. PRODIGE 34-FFCD 1402-ADAGE: Adjuvant chemotherapy in elderly patients with resected stage III colon cancer: A randomized phase 3 trial

Author

Aparicio , Thomas, Francois , Eric, Cristol-Dalstein , Laurence, Carola , Elisabeth, Maillard , Emilie, Paillaud , Elena, Retornaz , Frédérique, Faroux , Roger, André , Thierry, Bedenne , Laurent, Seitz , Jean-François, Service de Gastro-entérologie [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne-Université Paris 13 ( UP13 ), Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, UNICANCER - Institut régional du Cancer [Montpellier] ( ICM ), CRLCC Val d'Aurelle - Paul Lamarque, CH Creil/Senlis, Fédération Francophone de la Cancérologie Digestive, FFCD, 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 ), Unité de médecine gériatrique ( Gériatrie - Henri Mondor ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre Gérontologique Départemental de Marseille ( CGD 13 ), Service de chirurgie digestive (CH de La Roche-sur-Yon), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Ligue Nationale Contre le Cancer, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], 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), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Unité de médecine gériatrique (Gériatrie - Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre Gérontologique Départemental de Marseille (CGD 13), 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), and Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Male, Organoplatinum Compounds, Oxaloacetates, MESH : Antineoplastic Combined Chemotherapy Protocols, Leucovorin, MESH : Aged, MESH : Leucovorin, Deoxycytidine, Activities of Daily Living, Antineoplastic Combined Chemotherapy Protocols, MESH : Neoplasm Staging, MESH : Female, Digestive System Surgical Procedures, MESH: Treatment Outcome, MESH: Digestive System Surgical Procedures, MESH: Aged, MESH: Organoplatinum Compounds, MESH : Chemotherapy, Adjuvant, MESH: Neoplasm Staging, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, MESH : Colonic Neoplasms, MESH: Chemotherapy, Adjuvant, Chemotherapy, Adjuvant, Colonic Neoplasms, MESH : Fluorouracil, MESH : Disease-Free Survival, Female, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Fluorouracil, Efficacy, MESH : Male, MESH : Treatment Outcome, MESH : Organoplatinum Compounds, MESH : Capecitabine, Disease-Free Survival, MESH : Deoxycytidine, Humans, MESH : Digestive System Surgical Procedures, Capecitabine, Aged, Neoplasm Staging, MESH: Colonic Neoplasms, MESH: Humans, MESH: Activities of Daily Living, MESH: Deoxycytidine, MESH : Humans, MESH: Capecitabine, MESH: Quality of Life, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH : Quality of Life, MESH: Male, MESH: Disease-Free Survival, Quality of Life, MESH: Leucovorin, MESH : Activities of Daily Living, MESH: Fluorouracil, MESH: Female
Abstract

IF 2.719; International audience

Published
2016

5. Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin

Author

Scott Kopetz, Cathy Eng, Tian Feng, Michael J. Overman, Sanford D. Markowitz, Michael S. Lee, Rachna T. Shroff, Helen Moinova, Stanley R. Hamilton, Bradley M. Broom, David R. Fogelman, James Lutterbaugh, Jean Pierre J. Issa, Van K. Morris, Thomas LaFramboise, Bryan K. Kee, Thibault Mazard, Joe Ensor, Ganiraju C. Manyam, The University of Texas M.D. Anderson Cancer Center [Houston], Case Western Reserve University [Cleveland], Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), University of North Carolina [Charlotte] (UNC), University of North Carolina System (UNC), 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
0301 basic medicine, Oncology, Male, Organoplatinum Compounds, Colorectal cancer, Vimentin, 0302 clinical medicine, vimentin, MESH: DNA Methylation, Antineoplastic Combined Chemotherapy Protocols, MESH: CpG Islands, MESH: Aged, Hematology, MESH: Middle Aged, biology, MESH: Organoplatinum Compounds, Middle Aged, humanities, MESH: Drug Resistance, Neoplasm, 3. Good health, Oxaliplatin, MESH: Antineoplastic Combined Chemotherapy Protocols, 030220 oncology & carcinogenesis, MESH: Oxaliplatin, Female, MESH: Biomarkers, Tumor, Colorectal Neoplasms, medicine.drug, Adult, medicine.medical_specialty, azacitidine, Azacitidine, MESH: Azacitidine, colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease-Free Survival, Capecitabine, 03 medical and health sciences, Internal medicine, medicine, Biomarkers, Tumor, Humans, neoplasms, Aged, MESH: Humans, CIMP, business.industry, MESH: Capecitabine, Cancer, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, DNA Methylation, medicine.disease, digestive system diseases, MESH: Male, Regimen, 030104 developmental biology, Drug Resistance, Neoplasm, Immunology, MESH: Disease-Free Survival, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, CpG Islands, MESH: Vimentin, methylation, Clinical Research Paper, business, MESH: Female, MESH: Colorectal Neoplasms
Abstract

// Michael J. Overman 1 , Van Morris 1 , Helen Moinova 2 , Ganiraju Manyam 6 , Joe Ensor 3 , Michael S. Lee 8 , Cathy Eng 1 , Bryan Kee 1 , David Fogelman 1 , Rachna T. Shroff 1 , Thomas LaFramboise 4 , Thibault Mazard 1 , Tian Feng 1 , Stanley Hamilton 7 , Bradley Broom 6 , James Lutterbaugh 2 , Jean-Pierre Issa 5 , Sanford D. Markowitz 2 and Scott Kopetz 1 1 Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA 2 Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH, USA 3 Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, USA 4 Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA 5 Fels Institute for Cancer and Molecular Biology, Temple University, Philadelphia, PA, USA 6 Department of Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA 7 Division of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA 8 Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA Correspondence to: Michael J. Overman, email: // Keywords : methylation, azacitidine, CIMP, colorectal cancer, vimentin Received : April 14, 2016 Accepted : August 10, 2016 Published : August 16, 2016 Abstract Purpose: Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and is implicated in the pathogenesis of a subset of colorectal cancers (CRCs) termed CIMP-high. Experimental Design: This phase I/II study in CRC (phase II portion restricted to CIMP-high CRC), treated fluoropyrimidine/oxaliplatin refractory patients with azacitidine (75 mg/m 2 /day subcutaneously D1-5) and CAPOX (capecitibine and oxaliplatin) every three weeks. Results: Twenty-six patients (pts) were enrolled in this study: 15 pts (12 treated at MTD) in phase I and 11 pts in phase II. No dose limiting toxicities were observed. A total of 14 pts were CIMP-high. No responses were seen. CIMP-high status did not correlate with efficacy endpoints [stable disease (SD) or progression-free survival (PFS)] or baseline vimentin methylation level. Changes in vimentin methylation over time did not correlate with efficacy outcomes. Baseline methylated vimentin correlated with tumor volume ( P

Published
2016

6. Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir

Author

Bernard Weill, François Goldwasser, Christiane Chéreau, Didier Borderie, Olivier Mir, Jean-Marc Tréluyer, Romain Coriat, Hervé Lemaréchal, Joël Coste, Evelyne Benoit, Frédéric Batteux, Jérôme Alexandre, Laurent Quinquis, Carole Nicco, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Cochin [AP-HP], Laboratoire d'immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-EA1833, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Neurobiologie et Développement (N&eD), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut de Neurobiologie Alfred Fessard (INAF), Centre National de la Recherche Scientifique (CNRS), Université Paul-Valéry - Montpellier 3 (UM3), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Infections à Vih, Réservoirs, Pharmacologie des Antirétroviraux et Prévention de la Transmission Mère Enfant, Université Paris Descartes - Paris 5 (UPD5), Epidémiologie, Démographie et Sciences Sociales: santé reproductive, sexualité et infection à VIH (Inserm U569), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national d'études démographiques (INED), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-EA1833, Université Paul-Valéry - Montpellier 3 (UPVM), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d'études démographiques (INED)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Administration, Intravenous, MESH: Nociception, MESH: Muscle Contraction, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Phases of clinical research, medicine.disease_cause, Gastroenterology, 0302 clinical medicine, Mangafodipir, MESH: Animals, MESH: Action Potentials, MESH: Aged, MESH: Muscle, Skeletal, MESH: Middle Aged, MESH: Oxidative Stress, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, Cumulative dose, MESH: Organoplatinum Compounds, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, General Medicine, MESH: Motor Activity, 3. Good health, MESH: Sciatic Nerve, MESH: Hypesthesia, 030220 oncology & carcinogenesis, Anesthesia, MESH: Survival Analysis, MESH: Peripheral Nervous System Diseases, MESH: Pyridoxal Phosphate, medicine.drug, medicine.medical_specialty, MESH: Edetic Acid, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, medicine, MESH: Mice, MESH: In Vitro Techniques, MESH: Humans, business.industry, MESH: Antioxidants, Neurotoxicity, Cancer, medicine.disease, digestive system diseases, MESH: Male, Oxaliplatin, Peripheral neuropathy, MESH: Antineoplastic Agents, business, MESH: Female, 030217 neurology & neurosurgery, Oxidative stress, MESH: Colorectal Neoplasms
Abstract

Background. The majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer. Methods. The effects of mangafodipir were examined in mice following treatment with oxaliplatin. Neurotoxicity, axon myelination, and advanced oxidized protein products (AOPPs) were monitored. In addition, we enrolled 23 cancer patients with grade ≥2 oxaliplatin-induced neuropathy in a phase II study, with 22 patients receiving i.v. mangafodipir following oxaliplatin. Neuropathic effects were monitored for up to 8 cycles of oxaliplatin and mangafodipir. Results. Mangafodipir prevented motor and sensory dysfunction and demyelinating lesion formation. In mice, serum AOPPs decreased after 4 weeks of mangafodipir treatment. In 77% of patients treated with oxaliplatin and mangafodipir, neuropathy improved or stabilized after 4 cycles. After 8 cycles, neurotoxicity was downgraded to grade ≥2 in 6 of 7 patients. Prior to enrollment, patients received an average of 880 ± 239 mg/m 2 oxaliplatin. Patients treated with mangafodipir tolerated an additional dose of 458 ± 207 mg/m 2 oxaliplatin despite preexisting neuropathy. Mangafodipir responders managed a cumulative dose of 1,426 ± 204 mg/m 2 oxaliplatin. Serum AOPPs were lower in responders compared with those in nonresponders. Conclusion. Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients. Trial registration. Clinicaltrials.gov NCT00727922.

Published
2014

7. Results in the elderly with locally advanced rectal cancer from the ACCOR12/PRODIGE 2 phase III trial: Tolerance and efficacy

Author

Christophe Hennequin, Thierry Conroy, Véronique Vendrely, Pierre-Luc Etienne, Jean-François Seitz, Sophie Gourgou-Bourgade, Isabelle Martel-Laffay, Beata Juzyna, Marta Jarlier, Jean-Pierre Gerard, Eric Francois, David Azria, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CRLCC Val d'Aurelle - Paul Lamarque, Centre Léon Bérard [Lyon], Service de cancérologie et radiothérapie [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Clinique Armoricaine de Radiologie [St. Brieuc], Hôpital Saint-André, Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université Paris Descartes - Paris 5 (UPD5)-Université de Lorraine (UL), CRLCC Antoine Lacassagne, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], CHU Bordeaux [Bordeaux]-Hôpital Saint -André, Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Institut de Cancérologie de Lorraine - Alexis Vautrin ( ICL ), Maladies chroniques, santé perçue, et processus d'adaptation. Approches épidémiologiques et psychologiques. ( APEMAC - EA 4360 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Université de Lorraine ( UL ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL)

Subjects
Oncology, Male, Organoplatinum Compounds, MESH : Retrospective Studies, Colorectal cancer, MESH : Antineoplastic Combined Chemotherapy Protocols, medicine.medical_treatment, MESH : Aged, Deoxycytidine, 0302 clinical medicine, Elderly, MESH: Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Rectal Adenocarcinoma, Medicine, MESH : Neoplasm Staging, MESH : Female, Stage (cooking), Rectal cancer, MESH : Rectal Neoplasms, MESH: Treatment Outcome, MESH: Chemoradiotherapy, Aged, 80 and over, MESH: Aged, MESH: Middle Aged, MESH: Organoplatinum Compounds, Age Factors, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Hematology, Chemoradiotherapy, MESH : Chemoradiotherapy, MESH: Neoplasm Staging, Middle Aged, MESH : Adult, Neoadjuvant Therapy, 3. Good health, Neoadjuvant chemoradiotherapy, Oxaliplatin, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, 030220 oncology & carcinogenesis, MESH : Fluorouracil, 030211 gastroenterology & hepatology, Female, Fluorouracil, medicine.drug, Adult, medicine.medical_specialty, MESH : Male, MESH: Neoadjuvant Therapy, MESH : Treatment Outcome, MESH : Organoplatinum Compounds, MESH : Capecitabine, Capecitabine, 03 medical and health sciences, MESH : Deoxycytidine, Internal medicine, Humans, Radiology, Nuclear Medicine and imaging, MESH : Middle Aged, MESH : Aged, 80 and over, Aged, Neoplasm Staging, Retrospective Studies, MESH: Age Factors, Chemotherapy, MESH: Humans, business.industry, Rectal Neoplasms, MESH : Humans, MESH: Deoxycytidine, MESH: Capecitabine, MESH: Rectal Neoplasms, MESH: Adult, MESH: Retrospective Studies, medicine.disease, Comorbidity, MESH: Male, Clinical trial, Exploratory analysis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH : Age Factors, business, MESH : Neoadjuvant Therapy, MESH: Female, MESH: Fluorouracil
Abstract

International audience; BACKGROUND:Rectal cancer predominantly affects the elderly. Unfortunately, this age category is under-represented in clinical trials because clinicians are loath to include patients with a high risk of comorbidity.PATIENTS AND METHODS:An exploratory analysis of the ACCORD12/PRODIGE 2 phase III trial was carried out to retrospectively compare the benefit of neoadjuvant chemotherapy between the elderly (≥70 years; n=142) and younger patients (

Published
2014

8. Impact of FOLFIRINOX Compared With Gemcitabine on Quality of Life in Patients With Metastatic Pancreatic Cancer: Results From the PRODIGE 4/ACCORD 11 Randomized Trial

Author

Jean-Luc Raoul, Rosine Guimbaud, Yves Becouarn, Thierry Conroy, Jocelyne Berille, Caroline Bascoul-Mollevi, Valérie Boige, Sophie Gourgou-Bourgade, Marc Ychou, Olivier Bouché, Françoise Desseigne, Antoine Adenis, Centre Régional de Lutte contre le Cancer Val d'Aurelle, Centre Léon Bérard [Lyon], Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), CRLCC Institut Claudius Regaud, Institut Bergonié - CRLCC Bordeaux, Centre Oscar Lambret - Centre Régional de Lutte contre le Cancer, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), UNICANCER [Paris], Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université Paris Descartes - Paris 5 (UPD5)-Université de Lorraine (UL), Institut de Cancérologie de Lorraine - Alexis Vautrin (ICL), Institut Claudius Regaud, Institut Bergonié [Bordeaux], UNICANCER, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, and Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL)

Subjects
Male, Oncology, Cancer Research, Organoplatinum Compounds, FOLFIRINOX, Leucovorin, Deoxycytidine, 0302 clinical medicine, Quality of life, Surveys and Questionnaires, Antineoplastic Combined Chemotherapy Protocols, Longitudinal Studies, Neoplasm Metastasis, MESH: Longitudinal Studies, MESH: Aged, 0303 health sciences, MESH: Antimetabolites, Antineoplastic, MESH: Middle Aged, MESH: Organoplatinum Compounds, MESH: Follow-Up Studies, MESH: Neoplasm Staging, Middle Aged, Prognosis, 3. Good health, Oxaliplatin, Survival Rate, MESH: Antineoplastic Combined Chemotherapy Protocols, 030220 oncology & carcinogenesis, MESH: Camptothecin, Female, Fluorouracil, Folfirinox Regimen, MESH: Pancreatic Neoplasms, medicine.drug, Adult, Antimetabolites, Antineoplastic, medicine.medical_specialty, MESH: Survival Rate, Adenocarcinoma, Irinotecan, MESH: Prognosis, 03 medical and health sciences, Internal medicine, medicine, Humans, MESH: Surveys and Questionnaires, Survival rate, Aged, Neoplasm Staging, 030304 developmental biology, MESH: Humans, Performance status, business.industry, MESH: Adenocarcinoma, MESH: Deoxycytidine, MESH: Quality of Life, MESH: Adult, Gemcitabine, MESH: Neoplasm Metastasis, MESH: Male, Surgery, Pancreatic Neoplasms, Quality of Life, Camptothecin, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Leucovorin, MESH: Female, MESH: Fluorouracil, Follow-Up Studies
Abstract

Purpose To compare the quality of life (QoL) of patients receiving oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) or gemcitabine as first-line chemotherapy and to assess whether pretreatment QoL predicts survival in patients with metastatic pancreatic cancer. Patients and Methods Three hundred forty-two patients with performance status 0 or 1 were randomly assigned to receive FOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 400 mg/m2 bolus followed by 2,400 mg/m2 46-hour continuous infusion, once every 2 weeks) or gemcitabine 1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. QoL was assessed using European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30 every 2 weeks. Results Improvement in global health status (GHS; P < .001) was observed in the FOLFIRINOX arm and improvement in emotional functioning (P < .001) was observed in both arms, along with a decrease in pain, insomnia, anorexia, and constipation in both arms. A significant increase in diarrhea was observed in the FOLFIRINOX arm during the first 2 months of chemotherapy. Time until definitive deterioration ≥ 20 points was significantly longer for FOLFIRINOX compared with gemcitabine for GHS, physical, role, cognitive, and social functioning, and six symptom domains (fatigue, nausea/vomiting, pain, dyspnea, anorexia, and constipation). Physical functioning, constipation, and dyspnea were independent significant prognostic factors for survival with treatment arm, age older than 65 years, and low serum albumin. Conclusion FOLFIRINOX significantly reduces QoL impairment compared with gemcitabine in patients with metastatic pancreatic cancer. Furthermore, baseline QoL scores improved estimation of survival probability when added to baseline clinical and demographic variables.

Published
2013

9. High pressure enhances the effect of hyperthermia in intraperitoneal chemotherapy with oxaliplatin: an experimental study

Author

Bruno Chauffert, Olivier Facy, François Ghiringhelli, Patrick Rat, Pablo Ortega-Deballon, Guy Magnin, Sylvain Ladoire, Sophie Al Samman, 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, Cancérologique, Générale, Endocrinienne et Urgences (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service d'anesthésie réanimation, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), CHU Amiens-Picardie, Ortega Deballon, Pablo, 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), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement

Subjects
MESH : Hyperthermia, Induced, MESH: Combined Modality Therapy, Organoplatinum Compounds, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Swine, 030230 surgery, MESH : Pressure, 0302 clinical medicine, Medicine, MESH: Peritoneal Neoplasms, MESH: Animals, MESH : Female, [ SDV.MHEP.CHI ] Life Sciences [q-bio]/Human health and pathology/Surgery, MESH: Swine, Peritoneal Neoplasms, MESH: Organoplatinum Compounds, MESH: Peritoneum, Intraperitoneal chemotherapy, Combined Modality Therapy, Peritoneal carcinomatosis, Oxaliplatin, MESH : Antineoplastic Agents, Chemotherapy Drugs, 030220 oncology & carcinogenesis, High pressure, Anesthesia, Female, Hyperthermic intraperitoneal chemotherapy, Peritoneum, Cytoreductive surgery, MESH: Pressure, medicine.drug, Hyperthermia, medicine.medical_specialty, Antineoplastic Agents, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, MESH : Organoplatinum Compounds, 03 medical and health sciences, MESH : Peritoneal Neoplasms, Pressure, Animals, MESH : Peritoneum, MESH: Hyperthermia, Induced, business.industry, Hyperthermia, Induced, MESH : Chemotherapy, Cancer, Regional Perfusion, MESH : Swine, medicine.disease, digestive system diseases, Surgery, Chemotherapy, Cancer, Regional Perfusion, MESH: Antineoplastic Agents, MESH: Chemotherapy, Cancer, Regional Perfusion, MESH : Animals, business, MESH : Combined Modality Therapy, MESH: Female
Abstract

International audience; BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) achieve good results in selected patients with peritoneal carcinomatosis. High intra-abdominal pressure could enhance the penetration of chemotherapy drugs. The aim of this study was to compare the effects of high pressure and hyperthermia when used separately and when combined in terms of blood and tissue absorption of oxaliplatin in a swine model of intraperitoneal chemotherapy. METHODS: Four groups of 5 pigs each underwent laparotomy and open intraperitoneal chemotherapy with oxaliplatin at a constant concentration (150 mg/L) for 30 minutes in normothermia and atmospheric pressure (group 1), or hyperthermia (42°C) and atmospheric pressure (group 2), or normothermia and high pressure (25 cm H2O) (group 3), or hyperthermia and high pressure (group 4). High pressure was achieved thorough a water column over the abdomen. Systemic absorption and abdominal tissue mapping of the penetration of oxaliplatin in each group were studied. RESULTS: Blood concentrations of oxaliplatin were similar in the different groups. Hyperthermia achieved higher concentrations in visceral surfaces (P = 0.0014), but not in parietal surfaces. High pressure enhanced diffusion of the drug in both the visceral and parietal peritoneum (P = 0.0058 and P = 0.0044, respectively). The combination of hyperthermia and high pressure significantly increased the penetration of oxaliplatin and achieved the highest tissue concentrations (10.39 mg/kg vs 5.48 mg/kg; P = 0.00001 in the visceral peritoneum, and 66.16 mg/kg vs 35.62 mg/kg; P = 0.0003 in the parietal peritoneum). CONCLUSIONS: Open high-pressure HIPEC with oxaliplatin is feasible in the pig. Hyperthermia enhances diffusion in the visceral peritoneum, whereas high pressure is effective in the visceral and parietal peritoneum. The combination of the two achieves the highest tissue concentrations of oxaliplatin.

Published
2012

10. Bevacizumab combined with chemotherapy in the second-line treatment of metastatic colorectal cancer: results from the phase II BEVACOLOR study

Author

Jaafar Bennouna, Roger Faroux, Eric Francois, Véronique Trillet-Lenoir, François Goldwasser, Hélène Senellart, F. Husseini, Sandrine Kraemer, Christophe Borg, Jean-Yves Douillard, Marc Ychou, Olivier Bouché, Jean-Pierre Delord, Centre René Gauducheau, CRLCC René Gauducheau, 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]), Institut Claudius Regaud, Hôpital pasteur [Colmar], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Départemental La Roche sur Yon, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU de Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Roche France, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (HOTE GREFFON), Université de Franche-Comté (UFC) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté]), CRLCC Institut Claudius Regaud, Hospices Civils de Lyon / Centre hospitalier Lyon Sud (HCL), Hospices Civils de Lyon, Centre Antoine Lacassagne, CRLCC Antoine Lacassagne, CHU Cochin [APHP], Hôpital Robert Debré - CHU Reims, Roche, Saas, Philippe, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
Oncology, Male, Organoplatinum Compounds, MESH: Lymphatic Metastasis, Leucovorin, Deoxycytidine, 0302 clinical medicine, MESH: Aged, 80 and over, FOLFOX, MESH: Liver Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, MESH: Treatment Outcome, Aged, 80 and over, MESH: Aged, MESH: Middle Aged, Liver Neoplasms, MESH: Organoplatinum Compounds, Gastroenterology, MESH: Follow-Up Studies, MESH: Neoplasm Staging, Middle Aged, 3. Good health, MESH: Salvage Therapy, Bevacizumab, Oxaliplatin, Survival Rate, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, 030220 oncology & carcinogenesis, Lymphatic Metastasis, FOLFIRI, MESH: Camptothecin, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030211 gastroenterology & hepatology, Female, Fluorouracil, Colorectal Neoplasms, medicine.drug, Adult, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Survival Rate, Antibodies, Monoclonal, Humanized, Irinotecan, 03 medical and health sciences, Folinic acid, Internal medicine, medicine, Humans, Survival rate, Capecitabine, Aged, Neoplasm Staging, Salvage Therapy, XELIRI, MESH: Humans, business.industry, MESH: Deoxycytidine, MESH: Adult, digestive system diseases, MESH: Male, MESH: Prospective Studies, MESH: Antibodies, Monoclonal, Humanized, Camptothecin, business, MESH: Leucovorin, MESH: Female, MESH: Fluorouracil, MESH: Colorectal Neoplasms, Follow-Up Studies
Abstract

International audience; BACKGROUND: This prospective phase II study assessed the efficacy and safety of bevacizumab plus chemotherapy regimens commonly used in the second-line treatment of metastatic colorectal cancer (mCRC). METHODS: Patients with mCRC who progressed or relapsed after first-line oxaliplatin-based or irinotecan-based treatment received bevacizumab 2.5 mg/kg/week plus chemotherapy until disease progression. The primary endpoint was disease-control rate (DCR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety. RESULTS: Fifty-three patients (66% men; median age, 62 years old) received second-line bevacizumab plus folinic acid, fluorouracil, and irinotecan (FOLFIRI; 57%), folinic acid, fluorouracil, oxaliplatin (FOLFOX; 26%), irinotecan (15%), or capecitabine plus irinotecan (XELIRI; 2%). The DCR was 87% (95% CI, 77%-97%); ORR was 32% (95% CI, 19%-46%). Median PFS was 6.5 months (95% CI, 5.8-7.8 months) and median OS 19.3 months, (95% CI, 14.2-25.1 months).The most frequent grade 3/4 adverse events included neutropenia (21%), diarrhea (15%), asthenia, and vomiting (9% each). Five patients (9%) had grade 3/4 targeted toxicities: grade 3 hypertension (n = 2), grade 3 venous thromboembolism (n = 2), and grade 4 arterial thromboembolism (n = 1). None of these events led to death during the study. CONCLUSION: Bevacizumab plus standard second-line chemotherapy is highly active in patients with mCRC and has an acceptable safety profile.

Published
2012

11. Expression of p53 and DR5 in normal and malignant tissues of colorectal cancer: correlation with advanced stages

Author

Hussein Akil, Marie-Odile Jauberteau, François Labrousse, Michelle Nouaille, Daniel Petit, Muriel Mathonnet, Aurélie Perraud, Department of Chemistry, Faculty of Science, Université libre de Bruxelles (ULB), Université de Limoges (UNILIM), Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Service d'Immunologie et immunogénétique [CHU Limoges], Service de Chirurgie digestive, endocrinienne et générale [CHU Limoges], Authors gratefully acknowledge the University of Limoges, La Ligue contre le Cancer and the région Limousin for financial support given by the COrC (Comité Orientation Recherche Cancer)., and Faculté des Sciences et Techniques de Limoges

Subjects
Male, Cancer Research, Pathology, Organoplatinum Compounds, Colorectal cancer, [SDV]Life Sciences [q-bio], Leucovorin, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, MESH: In Situ Nick-End Labeling, MESH: Tumor Suppressor Protein p53, In Situ Hybridization, ComputingMilieux_MISCELLANEOUS, MESH: Aged, 0303 health sciences, MESH: Organoplatinum Compounds, apoptosis, General Medicine, MESH: Neoplasm Staging, Cell cycle, Prognosis, Immunohistochemistry, 3. Good health, Survival Rate, MESH: Antineoplastic Combined Chemotherapy Protocols, Oncology, 030220 oncology & carcinogenesis, Female, Fluorouracil, Colorectal Neoplasms, medicine.medical_specialty, MESH: Survival Rate, [SDV.CAN]Life Sciences [q-bio]/Cancer, colorectal cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, MESH: Prognosis, 03 medical and health sciences, MESH: In Situ Hybridization, medicine, In Situ Nick-End Labeling, Humans, MESH: Receptors, TNF-Related Apoptosis-Inducing Ligand, Survival rate, 030304 developmental biology, Aged, Neoplasm Staging, MESH: Humans, Oncogene, MESH: Apoptosis, Cancer, MESH: Immunohistochemistry, medicine.disease, Molecular medicine, MESH: Male, MESH: Prospective Studies, protein, Receptors, TNF-Related Apoptosis-Inducing Ligand, Tumor progression, Tumor Suppressor Protein p53, MESH: Leucovorin, MESH: Female, MESH: Fluorouracil, MESH: Colorectal Neoplasms
Abstract

Chantier qualité GA; International audience; Apoptosis has to be drastically controlled in organs with important cell turnover such as the colon. Deregulation of this process is often present in tumor progression. Tissues of 82 patients treated for colorectal cancer (CRC) were analyzed using antibodies against AIF, p53, DR4, DR5, cleaved caspase-3 and the TUNEL method to detect apoptosis; whereas staining of Ki-67 was used as a proliferation marker. In situ immunohistochemical analyses were compared in non-tumor (NT) cells from normal adjacent mucous membranes with tumor (T) cells from patients with Stage I (n=6), Stage II (n=35), Stage III (n=27) and Stage IV (n=14) CRC. Results were correlated with the tumor stages and the treatment response of patients to improve the understanding of CRC development. p53 and DR5 expression decreased progressively with CRC stage, suggesting that these proteins are important markers of advanced tumor stages. Moreover, p53 appears as a prognostic factor to predict recurrence-free survival. Including the detection of p53 and DR5 for establishing the diagnosis of CRC and adapting the treatment to each patient is strongly suggested by our work.

Published
2011

12. [Preoperative radiochemotherapy for rectal cancer: forecasting the next steps through ongoing and forthcoming studies]

Author

G, Créhange, J-F, Bosset, P, Maingon, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), and Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC )

Subjects
MESH: Radiation-Sensitizing Agents, Radiation-Sensitizing Agents, MESH: Combined Modality Therapy, Time Factors, Organoplatinum Compounds, MESH : Radiation-Sensitizing Agents, MESH : Antineoplastic Combined Chemotherapy Protocols, Leucovorin, Cetuximab, MESH : Camptothecin, MESH : Leucovorin, MESH : Randomized Controlled Trials as Topic, Deoxycytidine, MESH : Multicenter Studies as Topic, MESH : Radiotherapy, Conformal, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Antibodies, Monoclonal, MESH : Clinical Trials, Phase II as Topic, MESH : Adenocarcinoma, MESH: Clinical Trials, Phase III as Topic, Antineoplastic Combined Chemotherapy Protocols, Multicenter Studies as Topic, MESH : Rectal Neoplasms, Randomized Controlled Trials as Topic, MESH: Treatment Outcome, MESH: Antimetabolites, Antineoplastic, MESH : Antimetabolites, Antineoplastic, MESH: Organoplatinum Compounds, Antibodies, Monoclonal, MESH : Chemotherapy, Adjuvant, Combined Modality Therapy, Neoadjuvant Therapy, Oxaliplatin, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, Chemotherapy, Adjuvant, MESH: Chemotherapy, Adjuvant, MESH : Antibodies, Monoclonal, MESH: Radiotherapy, Conformal, MESH : Fluorouracil, MESH: Camptothecin, Fluorouracil, MESH: Clinical Trials, Phase II as Topic, MESH : Time Factors, MESH: Forecasting, Antimetabolites, Antineoplastic, MESH: Neoadjuvant Therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Treatment Outcome, Adenocarcinoma, Antibodies, Monoclonal, Humanized, Irinotecan, MESH : Organoplatinum Compounds, Clinical Trials, Phase II as Topic, MESH : Deoxycytidine, Humans, MESH : Forecasting, MESH : Clinical Trials, Phase III as Topic, Capecitabine, MESH: Humans, Rectal Neoplasms, MESH : Humans, MESH: Adenocarcinoma, MESH: Time Factors, MESH: Deoxycytidine, MESH: Rectal Neoplasms, MESH: Randomized Controlled Trials as Topic, Clinical Trials, Phase III as Topic, MESH: Multicenter Studies as Topic, Camptothecin, Radiotherapy, Conformal, MESH : Combined Modality Therapy, MESH: Leucovorin, MESH : Neoadjuvant Therapy, MESH: Fluorouracil, Forecasting
Abstract

International audience; Protracted preoperative radiochemotherapy with a 5-FU-based scheme, or a short course of preoperative radiotherapy without chemotherapy, are the standard neoadjuvant treatments for resectable stage II-III rectal cancer. Local failure rates are low and reproducible, between 6 and 15% when followed with a "Total Mesorectal Excision". Nevertheless, the therapeutic strategy needs to be improved: distant metastatic recurrence rates remain stable around 30 to 35%, while both sphincter and sexual sequels are still significant. The aim of the present paper was to analyse the ongoing trials listed on the following search engines: the Institut National du Cancer in France, the National Cancer Institute and the National Institute of Health in the United States, and the major cooperative groups. Keywords for the search were: "rectal cancer", "preoperative radiotherapy", "phase II-III", "preoperative chemotherapy", "adjuvant chemotherapy" and "surgery". Twenty-three trials were selected and classified in different groups, each of them addressing a question of strategy: (1) place of adjuvant chemotherapy; (2) optimization of preoperative radiotherapy; (3) evaluation of new radiosensitization protocols and/or neoadjuvant chemotherapy; (4) optimization of techniques and timing of surgery; (5) place of radiotherapy for non resectable or metastatic tumors.

Published
2011

13. Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability

Author

René Adam, Mohamed Bouchahda, Catherine Guettier, Francis Lévi, Raphaël Saffroy, Sylvie Giacchetti, Lee Gorden, Pasquale F. Innominato, Abdoulaye Karaboué, Dominique Hauteville, Rythmes Biologiques et Cancers, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie pathologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Unité de chronothérapie, Departments of Surgery and Cancer Biology, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville]-Vanderbilt University [Nashville], and Karaboué, Abdoulaye

Subjects
Male, Oncology, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, MESH: Catherine Guettier MD, PhD, Toxicology, MESH: Gene Amplification, MESH: Antibodies, Monoclonal, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Pharmacology (medical), Neoplasm Metastasis, MESH: René Adam MD, PhD, MESH: Treatment Outcome, Aged, 80 and over, 0303 health sciences, MESH: Middle Aged, Cetuximab, Antibodies, Monoclonal, MESH: Raphael Saffroy PhD, Prognosis, Chronotherapy (treatment scheduling), 3. Good health, ErbB Receptors, Oxaliplatin, Survival Rate, MESH: Antineoplastic Combined Chemotherapy Protocols, 030220 oncology & carcinogenesis, liver resection, MESH: Camptothecin, circadian clocks, neoadjuvant chemotherapy, medicine.medical_specialty, Antineoplastic Agents, MESH: Receptor, Epidermal Growth Factor, Irinotecan, Disease-Free Survival, MESH: Prognosis, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, MESH: Francis Lévi MD, PhD, Humans, MESH: Dominique Hauteville MD, Aged, Pharmacology, MESH: Humans, chronotherapy, Gene Amplification, MESH: Adult, medicine.disease, MESH: Neoplasm Metastasis, digestive system diseases, MESH: Mohamed Bouchahda MD, Drug Chronotherapy, MESH: Genes, ras, MESH: Disease-Free Survival, MESH: Antineoplastic Agents, MESH: Female, MESH: Fluorouracil, Cancer Research, Leucovorin, MESH: Abdoulaye Karaboué MD, MESH: Aged, 80 and over, cetuximab, Epidermal growth factor receptor, MESH: Aged, biology, metastatic colorectal cancer, MESH: Organoplatinum Compounds, Middle Aged, MESH: Sylvie Giacchetti MD, PhD, MESH: Salvage Therapy, Treatment Outcome, Female, Fluorouracil, Colorectal Neoplasms, medicine.drug, Adult, MESH: Drug Chronotherapy, MESH: Survival Rate, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antibodies, Monoclonal, Humanized, MESH: Lee Gorden MD, Internal medicine, medicine, Survival rate, 030304 developmental biology, Salvage Therapy, MESH: Pasquale Fabio Innominato MD, business.industry, MESH: Male, Genes, ras, biology.protein, Camptothecin, business, MESH: Leucovorin, MESH: Colorectal Neoplasms
Abstract

Dix pages; International audience; BACKGROUND: Circadian rhythm disruption was linked to high serum levels of Transforming Growth Factor Receptor α, an Epidermal Growth Factor Receptor (EGFR) ligand and poor survival in patients with metastatic colorectal cancer (mCRC). We hypothesized that EGFR blockade with cetuximab would enhance the activity of chronotherapy as a result of improved circadian coordination. METHODS: All the patients with mCRC referred to our unit for progression on prior chemotherapy over a 30-month-period received weekly cetuximab and fortnightly chronotherapy. RESULTS: Fifty-six patients were treated with a median of six courses of fluoropyrimidine-based chemotherapy and irinotecan (61%), oxaliplatin (25%) or both (14%) after a median of three prior regimens. We found no EFGR amplification by FISH in the tumor of 27 consecutive patients. Acneiform rash and diarrhea were the most common toxicities. Objective response rate was 32.1% and positively correlated with rash grade (p = 0.025). None of the responders had K-Ras mutation in their tumor. Median progression-free and overall survival were 4.6 and 13.7 months, respectively. Complete macroscopic resections of metastases in liver, lung or other abdominopelvic sites were performed following tumor downstaging by the treatment regimen in 11 patients (21%), 8 of whom being alive at 3 years. These figures are twice as high as those reported for first-line combination of cetuximab with conventional chemotherapy or for third line chronotherapy. CONCLUSIONS: The addition of cetuximab to chronotherapy allowed safe and effective therapeutic control of metastases, including their complete resection, despite previous failure of several treatment regimens.

Published
2011

14. Oxaliplatin‐induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors

Author

Emmanuel Bourinet, Anne Pizzoccaro, Nicolas Authier, Michel Lazdunski, Christine Courteix, Violette Maffre, Brigitte Couette, Jacques Noël, Bing Ling, Amaury François, Alain Eschalier, Juliette Descoeur, Jérôme Busserolles, Vanessa Pereira, Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pharmacologie fondamentale et clinique de la douleur, Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), 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 National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Potassium Channels, Organoplatinum Compounds, MESH: Cold Temperature, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Pharmacology, Mice, 0302 clinical medicine, MESH: Animals, MESH: Nociceptors, Research Articles, 0303 health sciences, MESH: Organoplatinum Compounds, Nociceptors, MESH: Potassium Channels, Potassium channel, chemotherapy-induced neuropathy, Cold Temperature, Oxaliplatin, medicine.anatomical_structure, Hyperalgesia, Nociceptor, Molecular Medicine, medicine.symptom, Ivabradine, hyperpolarization activated channels, medicine.drug, TRPM8, background potassium channels, TRPM Cation Channels, Antineoplastic Agents, 03 medical and health sciences, medicine, Animals, Humans, MESH: Mice, 030304 developmental biology, cold pain, MESH: Humans, business.industry, MESH: TRPM Cation Channels, MESH: Hyperalgesia, Sensory neuron, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Thermoreceptor, MESH: Antineoplastic Agents, business, 030217 neurology & neurosurgery
Abstract

International audience; Cold hypersensitivity is the hallmark of oxaliplatin-induced neuropathy, which develops in nearly all patients under this chemotherapy. To date, pain management strategies have failed to alleviate these symptoms, hence development of adapted analgesics is needed. Here, we report that oxaliplatin exaggerates cold perception in mice as well as in patients. These symptoms are mediated by primary afferent sensory neurons expressing the thermoreceptor TRPM8. Mechanistically, oxaliplatin promotes over-excitability by drastically lowering the expression of distinct potassium channels (TREK1, TRAAK) and by increasing the expression of pro-excitatory channels such as the hyperpolarization-activated channels (HCNs). These findings are corroborated by the analysis of TREK1-TRAAK null mice and use of the specific HCN inhibitor ivabradine, which abolishes the oxaliplatin-induced cold hypersensibility. These results suggest that oxali-platin exacerbates cold perception by modulating the transcription of distinct ionic conductances that together shape sensory neuron responses to cold. The translational and clinical implication of these findings would be that ivabradine may represent a tailored treatment for oxaliplatin-induced neuropathy.

Published
2011

15. 18F-FDG PET/CT in primary non-Hodgkin's lymphoma of the sinonasal tract

Author

Sylvie Boisramé, Christian Berthou, Gerald Valette, Solène Querellou, Adrian Tempescul, Jean-Christophe Ianotto, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Department of Nuclear Medicine, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service Hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Department of Odontology, Department of ORL, Université européenne de Bretagne - European University of Brittany (UEB), and Michel, Geneviève

Subjects
medicine.medical_specialty, Pathology, MESH: Remission Induction, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Tomography, Emission-Computed, MESH: Vincristine, MESH: Prognosis, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, MESH: Doxorubicin, 0302 clinical medicine, MESH: Lymphoma, Non-Hodgkin, MESH: Fluorodeoxyglucose F18, Internal medicine, medicine, MESH: Cytarabine, ComputingMilieux_MISCELLANEOUS, MESH: Aged, MESH: Paranasal Sinus Neoplasms, Hematology, MESH: Humans, MESH: Middle Aged, business.industry, MESH: Organoplatinum Compounds, MESH: Cyclophosphamide, General Medicine, Sinonasal Tract, medicine.disease, MESH: Positron-Emission Tomography, Non-Hodgkin's lymphoma, MESH: Antineoplastic Combined Chemotherapy Protocols, 030220 oncology & carcinogenesis, MESH: Dexamethasone, [SDV.IMM]Life Sciences [q-bio]/Immunology, Fdg pet ct, Radiology, business, MESH: Paranasal Sinuses, MESH: Prednisone
Abstract

International audience

Published
2010

16. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer

Author

Christiane Langer, Yousif A. Abubakr, Ernst U. Steinhauer, Christophe Borg, M. Eugenia Vega-Villegas, Manfred P. Lutz, A. Zubel, Hendrik Kröning, Heinz-Josef Lenz, Justin Kopit, O. Kisker, Cathy Eng, Alberto Sobrero, Howard A. Burris, Gabriele Luppi, Gary Middleton, Jana Prausova, Joan Maurel, Werner Scheithauer, Louis Fehrenbacher, 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]), Saas, Philippe, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
Male, Cancer Research, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, Cetuximab, Gastroenterology, MESH: Antibodies, Monoclonal, 0302 clinical medicine, MESH: Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Medicine, Neoplasm Metastasis, Aged, 80 and over, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Hazard ratio, MESH: Organoplatinum Compounds, Antibodies, Monoclonal, Middle Aged, 3. Good health, ErbB Receptors, Oxaliplatin, MESH: Antineoplastic Combined Chemotherapy Protocols, Oncology, 030220 oncology & carcinogenesis, MESH: Camptothecin, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Colorectal Neoplasms, medicine.drug, Adult, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Receptor, Epidermal Growth Factor, Neutropenia, Antibodies, Monoclonal, Humanized, Irinotecan, Disease-Free Survival, 03 medical and health sciences, Internal medicine, Panitumumab, Humans, neoplasms, 030304 developmental biology, Aged, Chemotherapy, MESH: Humans, business.industry, MESH: Quality of Life, MESH: Adult, medicine.disease, MESH: Neoplasm Metastasis, digestive system diseases, MESH: Male, Surgery, Pyrimidines, MESH: Pyrimidines, MESH: Disease-Free Survival, Quality of Life, Camptothecin, business, MESH: Female, MESH: Colorectal Neoplasms
Abstract

Purpose To determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin. Patients and Methods This multicenter, open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor–expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m2 day 1 followed by 250 mg/m2 weekly) plus irinotecan (350 mg/m2 every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL). Results Median OS was comparable between treatments: 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (hazard ratio [HR], 0.975; 95% CI, 0.854 to 1.114; P = .71). This lack of difference may have been due to post-trial therapy: 46.9% of patients assigned to irinotecan eventually received cetuximab (87.2% of those who did, received it with irinotecan). Cetuximab added to irinotecan significantly improved PFS (median, 4.0 v 2.6 months; HR, 0.692; 95% CI, 0.617 to 0.776; P ≤ .0001) and RR (16.4% v 4.2%; P < .0001), and resulted in significantly better scores in the QOL analysis of global health status (P = .047). Cetuximab did not exacerbate toxicity, except for acneform rash, diarrhea, hypomagnesemia, and associated electrolyte imbalances. Neutropenia was the most common severe toxicity across treatment arms. Conclusion Cetuximab and irinotecan improved PFS and RR, and resulted in better QOL versus irinotecan alone. OS was similar between study groups, possibly influenced by the large number of patients in the irinotecan arm who received cetuximab and irinotecan poststudy.

Published
2008

17. Concomitant administration of weekly oxaliplatin, fluorouracil continuous infusion, and radiotherapy after 2 months of gemcitabine and oxaliplatin induction in patients with locally advanced pancreatic cancer: a Groupe Coordinateur Multidisciplinaire en Oncologie phase II study

Author

Olivier Dupuis, Emmanuel Touboul, Christophe Louvet, Gérard Lledo, Laurence Moureau-Zabotto, Jacques Balosso, Laurent Mineur, Véronique Vendrely, Jean-Marc Phelip, Pauline Afchain, Thierry André, Florence Huguet, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Sainte Catherine [Avignon], Centre Hospitalier Universitaire Saint André, Université Bordeaux Segalen - Bordeaux 2, Clinique Saint-Jean, Centre de Radiothérapie, Collaboration, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Serduc, Raphael

Subjects
Male, Cancer Research, MESH: Combined Modality Therapy, Organoplatinum Compounds, Gastroenterology, Deoxycytidine, 0302 clinical medicine, MESH: Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Medicine, Infusions, Intravenous, MESH: Treatment Outcome, Aged, 80 and over, MESH: Aged, 0303 health sciences, education.field_of_study, MESH: Middle Aged, MESH: Organoplatinum Compounds, Middle Aged, Combined Modality Therapy, 3. Good health, Oxaliplatin, Survival Rate, MESH: Antineoplastic Combined Chemotherapy Protocols, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Female, Fluorouracil, MESH: Pancreatic Neoplasms, medicine.drug, Adult, medicine.medical_specialty, MESH: Survival Rate, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, GemOx, Adenocarcinoma, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Humans, education, MESH: Infusions, Intravenous, Survival rate, 030304 developmental biology, Aged, MESH: Humans, Performance status, business.industry, MESH: Adenocarcinoma, MESH: Deoxycytidine, Induction chemotherapy, MESH: Adult, Gemcitabine, MESH: Male, Surgery, Pancreatic Neoplasms, Concomitant, Feasibility Studies, business, MESH: Feasibility Studies, MESH: Female, MESH: Fluorouracil
Abstract

Background According to previously reported Groupe Coordinateur Multidisciplinaire en Oncologie (GERCOR) studies in locally advanced pancreatic cancer (LAPC), concomitant chemoradiotherapy (CCRT) may be recommended for patients who do not experience disease progression after systemic induction chemotherapy (CT). To further improve patient outcome with classical fluorouracil (FU)-based CCRT, this study was designed to prospectively investigate a CCRT with FU infusion and weekly oxaliplatin after 2 months of gemcitabine and oxaliplatin (GEMOX) induction chemotherapy. Patients and Methods Nonpretreated patients with LAPC having WHO performance status (PS) of 0 to 2 received four induction cycles of GEMOX (gemcitabine 1 g/m2 on day 1 and oxaliplatin 100 mg/m2 on day 2; day 1 of a 15-day cycle). One month after cycle 4, patients who did not experience disease progression with PS 0 to 2 received 45 Gy over 5 weeks + 10 Gy (as a concomitant boost during the last 2 weeks) of radiotherapy (RT), with daily 250 mg/m2 FU as a continuous infusion and 60 mg/m2of oxaliplatin weekly. Results Of 59 patients, 50 patients (84.7%) received CCRT, whereas nine patients did not because of disease progression (seven patients), CT toxicity (one patient), or personal decision (one patient). Forty-four patients (74.5%) completed the fully planned CCRT. Median progression-free survival and overall survival durations were 7.6 and 12.2 months, respectively, for the whole population and 9.4 and 12.6 months, respectively, for patients who completed CCRT. CCRT grade 3 to 4 toxicities (National Cancer Institute Common Toxicity Criteria) were neutropenia (10.4%), thrombocytopenia (8.4%), nausea and vomiting (16.7%), and diarrhea (12.5%). Conclusion Concomitant administration of weekly oxaliplatin, continuous-infusion FU, and RT in patients with LAPC is feasible, with an acceptable acute and late safety profile. The encouraging results observed despite a nonoptimal patient selection (owing to the short induction time) indicates that further randomized evaluation to better define the specific role of oxaliplatin in CCRT is deserved.

Published
2008

18. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy

Author

Franck J. Barrat, Jean Bourhis, Patrick Saulnier, Carla Ortiz, Laurence Zitvogel, Grégoire Mignot, Sebastian Amigorena, Bernard Ryffel, Guido Kroemer, Catherine Noguès, Alfredo Criollo, Suzette Delaloge, Huan Yang, Francis Lévi, Michel Obeid, Agnès Chompret, Paul Saftig, Françoise Clavel-Chapelon, Jean-Paul Mira, M. Chiara Maiuri, Fabrice Andre, Lionel Apetoh, Evelyn Ullrich, Antoine Tesniere, François Ghiringhelli, Virginie Joulin, T. Tursz, Rosette Lidereau, Apetoh, L, Ghiringhelli, F, Tesniere, A, Obeid, M, Ortiz, C, Criollo, A, Mignot, G, Maiuri, MARIA CHIARA, Ullrich, E, Saulnier, P, Yang, H, Amigorena, S, Ryffel, B, Barrat, Fj, Saftig, P, Levi, F, Lidereau, R, Nogues, C, MIRA J., P, Chompret, A, Joulin, V, CLAVEL CHAPELON, F, Bourhis, J, Andr, F, Delaloge, S, Kroemer, G, Zitvogel, L., Institut Gustave Roussy (IGR), Immunologie et Embryologie Moléculaires (IEM), and Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Cell Line, Tumor, MESH: Osteosarcoma, medicine.medical_treatment, MESH: Mice, Inbred BALB C, Immunoadjuvant, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Medicine, MESH: Animals, MESH: Neoplasms, MESH: Mice, MESH: Colonic Neoplasms, Toll-like receptor, MESH: Humans, business.industry, MESH: Organoplatinum Compounds, MESH: Pyridines, Abscopal effect, Cancer, General Medicine, MESH: Toll-Like Receptor 4, medicine.disease, MESH: Bone Neoplasms, 3. Good health, Radiation therapy, 030220 oncology & carcinogenesis, Immunology, Immunogenic cell death, MESH: Antineoplastic Agents, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Disease Models, Animal, business, 030215 immunology
Abstract

Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.

Published
2007

19. Economic impact of simplified de Gramont regimen in first-line therapy in metastatic colorectal cancer

Author

Christine Legat-Fagnoni, Samuel Limat, Claire-Hélène Bracco-Nolin, Bernard Huchet, Xavier Pivot, Ulrich Stein, Marie-Christine Woronoff-Lemsi, Loic Chaigneau, Département de pharmacie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Recherches épidémiologiques et cliniques en cancérologie digestive, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Caisse régionale d'assurance maladie (CPAM), CPAM, 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]), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Caisse régionale d'assurance maladie ( CPAM ), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Saas, Philippe, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC)

Subjects
Male, Organoplatinum Compounds, MESH : Retrospective Studies, MESH : Antineoplastic Combined Chemotherapy Protocols, Colorectal cancer, medicine.medical_treatment, Economics, Econometrics and Finance (miscellaneous), Leucovorin, MESH : Aged, MESH : Camptothecin, MESH : Leucovorin, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH : Health Services, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, MESH : Female, Neoplasm Metastasis, health care economics and organizations, MESH: Aged, MESH: Middle Aged, MESH: Health Services, 030503 health policy & services, Health Policy, MESH: Organoplatinum Compounds, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Health Care Costs, Health Services, Middle Aged, 3. Good health, MESH: Antineoplastic Combined Chemotherapy Protocols, 030220 oncology & carcinogenesis, MESH : Neoplasm Metastasis, MESH : Fluorouracil, MESH: Camptothecin, Female, Fluorouracil, MESH : Colorectal Neoplasms, Colorectal Neoplasms, 0305 other medical science, MESH : Health Care Costs, medicine.drug, medicine.medical_specialty, MESH : Male, MESH : Drug Administration Schedule, MESH: Health Care Costs, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Drug Administration Schedule, MESH : Organoplatinum Compounds, Drug Administration Schedule, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, FOLFIRI Regimen, Humans, MESH : Middle Aged, Intensive care medicine, Adverse effect, Aged, Retrospective Studies, Chemotherapy, MESH: Humans, business.industry, MESH : Humans, Retrospective cohort study, MESH: Retrospective Studies, medicine.disease, MESH: Neoplasm Metastasis, MESH: Male, Oxaliplatin, Irinotecan, Regimen, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Camptothecin, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Leucovorin, MESH: Female, MESH: Fluorouracil, MESH: Colorectal Neoplasms
Abstract

International audience; The cost of chemotherapy has dramatically increased in advanced colorectal cancer patients, and the schedule of fluorouracil administration appears to be a determining factor. This retrospective study compared direct medical costs related to two different de Gramont schedules (standard vs. simplified) given in first-line chemotherapy with oxaliplatin or irinotecan. This cost-minimization analysis was performed from the French Health System perspective. Consecutive unselected patients treated in first-line therapy by LV5FU2 de Gramont with oxaliplatin (Folfox regimen) or with irinotecan (Folfiri regimen) were enrolled. Hospital and outpatient resources related to chemotherapy and adverse events were collected from 1999 to 2004 in 87 patients. Overall cost was reduced in the simplified regimen. The major factor which explained cost saving was the lower need for admissions for chemotherapy. Amount of cost saving depended on the method for assessing hospital stay. In patients treated by the Folfox regimen the per diem and DRG methods found cost savings of Euro 1,997 and Euro 5,982 according to studied schedules; in patients treated by Folfiri regimen cost savings of Euro 4,773 and Euro 7,274 were observed, respectively. In addition, travel costs were also reduced by simplified regimens. The robustness of our results was showed by one-way sensitivity analyses. These findings demonstrate that the simplified de Gramont schedule reduces costs of current first-line chemotherapy in advanced colorectal cancer. Interestingly, our study showed several differences in costs between two costing approaches of hospital stay: average per diem and DRG costs. These results suggested that standard regimen may be considered a profitable strategy from the hospital perspective. The opposition between health system perspective and hospital perspective is worth examining and may affect daily practices. In conclusion, our study shows that the simplified de Gramont schedule in combination with oxaliplatin or irinotecan is an attractive option from the French Health System perspective. This safe and less costly regimen must compared to alternative options such as oral fluoropyrimidines.

Published
2006

20. Investigation of sulfur containing amino acids at the lipoxygenase active site using a platinum complex

Author

Isabelle Michaud-Soret, Jean-Claude Chottard, Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Organoplatinum Compounds, Protein Conformation, Lipoxygenase, Biochemistry, chemistry.chemical_compound, Methionine, MESH: Protein Conformation, Lipoxygenase Inhibitors, MESH: Soybeans, chemistry.chemical_classification, 0303 health sciences, biology, MESH: Kinetics, 030302 biochemistry & molecular biology, MESH: Organoplatinum Compounds, Tryptophan, Amino acid, Seeds, Ditiocarb, MESH: Ditiocarb, MESH: Spectrometry, Fluorescence, Stereochemistry, Biophysics, Fluorescence spectrometry, MESH: Lipoxygenase Inhibitors, 03 medical and health sciences, Cysteine, Binding site, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, MESH: Tryptophan, MESH: Lipoxygenase, 030304 developmental biology, Binding Sites, Electron Spin Resonance Spectroscopy, Substrate (chemistry), Active site, Cell Biology, MESH: Cysteine, Kinetics, Spectrometry, Fluorescence, Enzyme, chemistry, MESH: Binding Sites, MESH: Seeds, MESH: Methionine, biology.protein, MESH: Electron Spin Resonance Spectroscopy, Soybeans
Abstract

International audience; Inactivation of native soybean lipoxygenase-1 was observed upon preincubation with (NEt4)[PtCl3(P(Bun)3)]. Removal of the platinum complex(es) from the inactivated enzyme by treatment with sodium diethyldithiocarbamate (Naddtc) which reverses methionine but not cysteine binding, restores most of the activity. Linoleic acid, an enzyme substrate, protects it from inactivation. The quenching of the fluorescence of the putative active site tryptophans which accompanies inactivation disappears after Naddtc reactivation. The (NEt4)[PtCl3(P(Bun)3)]-inactivated enzyme iron(II) cannot be oxidized at variance with that of the native or Naddtc reactivated enzyme, as checked by EPR spectroscopy. These results show that at least one methionine is close to the iron binding site in soybean lipoxygenase-1.

Published
1992

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