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1. Empirical Antibiotic Therapy for Gram-Negative Bacilli Ventilator-Associated Pneumonia: Observational Study and Pharmacodynamic Assessment

Author

Olivier Pajot, Karim Lakhal, Jérome Lambert, Antoine Gros, Cédric Bruel, Thierry Boulain, Denis Garot, Vincent Das, Jean François Timsit, Charles Cerf, Bertrand Souweine, Cendrine Chaffaut, Hervé Mentec, Jean Ralph Zahar, Jean Paul Mira, and Vincent Jullien

Subjects
VAP, pharmacokinetics, pharmacodynamics, intensive care unit, Therapeutics. Pharmacology, RM1-950
Abstract

Background: Strong evidence suggests a correlation between pharmacodynamics (PD) index and antibiotic efficacy while dose adjustment should be considered in critically ill patients due to modified pharmacokinetic (PK) parameters and/or higher minimum inhibitory concentrations (MICs). This study aimed to assess pharmacodynamic (PD) target attainment considering both antibiotics serum concentrations and measured MICs in these patients. Method: A multicentric prospective open-label trial conducted in 11 French ICUs involved patients with Gram-negative bacilli (GNB) ventilator-associated pneumonia (VAP) confirmed by quantitative cultures. Results: We included 117 patients. Causative GNBs were P. aeruginosa (40%), Enterobacter spp. (23%), E. coli (20%), and Klebsiella spp. (16%). Hence, 117 (100%) patients received β-lactams, 65 (58%) aminoglycosides, and two (1.5%) fluoroquinolones. For β-lactams, 83% of the patients achieved a Cmin/MIC > 1 and 70% had a Cmin/MIC > 4. In the case of high creatinine clearance (CrCL > 100 mL/min/1.73 m2), 70.4% of the patients achieved a Cmin/MIC ratio > 1 versus 91% otherwise (p = 0.041), and 52% achieved a Cmin/MIC ratio > 4 versus 81% (p = 0.018). For aminoglycosides, 94% of the patients had a Cmax/MIC ratio > 8. Neither β-lactams nor aminoglycosides PK/PD parameters were associated clinical outcomes, but our data suggest a correlation between β-lactams Cmin/MIC and microbiological success. Conclusion: In our ICU patients treated for GNB VAP, using recommended antibiotic dosage led in most cases to PK/PD targets attainment for aminoglycosides and β-lactams. High creatinine clearance should encourage clinicians to focus on PK/PD issues.

Published
2022
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2. Impact of cirrhosis aetiology on incidence and prognosis of hepatocellular carcinoma diagnosed during surveillance

Author

Nathalie Ganne-Carrié, Pierre Nahon, Cendrine Chaffaut, Gisèle N’Kontchou, Richard Layese, Etienne Audureau, Sylvie Chevret, Isabelle Archambeaud, Louis d’Alteroche, Frédéric Oberti, Dominique Roulot, Christophe Moreno, Alexandre Louvet, Thông Dao, Romain Moirand, Odile Goria, Eric Nguyen-Khac, Nicolas Carbonell, Jean-Charles Duclos-Vallée, Stanislas Pol, Victor de Ledinghen, Violaine Ozenne, Jean Henrion, Jean-Marie Péron, Albert Tran, Gabriel Perlemuter, Xavier Amiot, Jean-Pierre Zarski, Tarik Asselah, Dominique Guyader, Hélène Fontaine, Georges-Philippe Pageaux, Victor De Lédinghen, Denis Ouzan, Fabien Zoulim, Jean-Pierre Bronowicki, Thomas Decaens, Ghassan Riachi, Paul Calès, Laurent Alric, Marc Bourlière, Philippe Mathurin, Sebastien Dharancy, Jean-Frédéric Blanc, Armand Abergel, Olivier Chazouillères, Ariane Mallat, Jean-Didier Grangé, Pierre Attali, Claire Wartelle, Dominique Thabut, Christophe Pilette, Christine Silvain, Christos Christidis, Brigitte Bernard-Chabert, Sophie Hillaire, and Vincent Di Martino

Subjects
alcoholic liver disease, cirrhosis, primary liver cancer, competing risk analysis, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: In this study we aimed to analyse the impact of the aetiology of cirrhosis on the incidence, characteristics and prognosis of hepatocellular carcinoma (HCC) diagnosed during a surveillance program. Methods: Individual data from a randomized trial and 2 prospective cohorts of patients with compensated histologically proven cirrhosis recruited between 2000 and 2016 were pooled. The influence of cirrhosis aetiology on survival after HCC detection was assessed using multivariable regression models. Results: Among 3,533 patients (1,926 virus [VIR], 1,167 alcohol [ALC], 440 combined [MIX]), 431 were diagnosed with HCC after a median follow-up of 57.1 months. The 5-year HCC incidence was lowest in ALC (VIR 12.6%, ALC 9.1%, MIX 14.3%, p = 0.04). At the time of diagnosis, tumour burden and Child-Pugh score were comparable across aetiology groups, but early BCLC stages (0/A) were significantly less frequent in ALC (VIR 80%, ALC 37%, MIX 72%) as a result of worse ECOG performance status. However, similar access to first-line curative HCC treatment was reported across aetiology groups (p = 0.68). Median survival after HCC diagnosis was significantly reduced in ALC (VIR 39, ALC 21, MIX 34 months, p = 0.02). However, when adjusting for tumour size, ECOG and Child-Pugh score, the aetiology of the underlying cirrhosis no longer had a significant impact. Conclusion: Compared to patients with virus-related cirrhosis, patients with alcohol-related compensated cirrhosis enrolled in a surveillance program have: i) the lowest 5-year HCC incidence; ii) worse overall prognosis, mostly driven by a poor general condition, despite similar access to first-line curative treatment. Lay summary: It has been suggested that early detection of hepatocellular carcinoma (HCC) may be futile in patients with alcohol-related cirrhosis. By comparing outcomes in more than 3,000 patients with compensated cirrhosis included in surveillance programs, this study suggests that HCC surveillance enables early diagnosis in most patients with alcohol-related cirrhosis despite a higher competing risk of death in these patients. We also report similar access to first-line curative HCC treatment in these patients compared to those with viral cirrhosis, despite higher rates of comorbidities and impaired liver function. Following HCC detection, the later parameters were major drivers of death irrespective of the cause of cirrhosis. Registration: CHC2000 (NCT00190385) and CIRRAL (NCT01213927) cohorts were registered at ClinicalTrials.gov and the full protocols are available at the following links (https://clinicaltrials.gov/ct2/show/NCT00190385) and https://clinicaltrials.gov/ct2/show/NCT01213927, respectively). The full CirVir protocol is available via the ANRS Web site (http://anrs.fr).

Published
2021
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3. A phase II study of guadecitabine in higher-risk myelodysplastic syndrome and low blast count acute myeloid leukemia after azacitidine failure

Author

Marie Sébert, Aline Renneville, Cécile Bally, Pierre Peterlin, Odile Beyne-Rauzy, Laurence Legros, Marie-Pierre Gourin, Laurence Sanhes, Eric Wattel, Emmanuel Gyan, Sophie Park, Aspasia Stamatoullas, Anne Banos, Kamel Laribi, Simone Jueliger, Luke Bevan, Fatiha Chermat, Rosa Sapena, Olivier Nibourel, Cendrine Chaffaut, Sylvie Chevret, Claude Preudhomme, Lionel Adès, and Pierre Fenaux

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

High-risk myelodysplastic syndrome/acute myeloid leukemia patients have a very poor survival after azacitidine failure. Guadecitabine (SGI-110) is a novel subcutaneous hypomethylating agent which results in extended decitabine exposure. This multicenter phase II study evaluated the efficacy and safety of guadecitabine in high-risk myelodysplastic syndrome and low blast count acute myeloid leukemia patients refractory or relapsing after azacitidine. We included 56 patients with a median age of 75 years [Interquartile Range (IQR) 69-76]. Fifty-five patients received at least one cycle of guadecitabine (60 mg/m2/d subcutaneously days 1-5 per 28-day treatment cycles), with a median of 3 cycles (range, 0-27). Eight (14.3%) patients responded, including two complete responses; median response duration was 11.5 months. Having no or few identified somatic mutations was the only factor predicting response (P=0.035). None of the 11 patients with TP53 mutation responded. Median overall survival was 7.1 months, and 17.9 months in responders (3 of whom had overall survival >2 years). In multivariate analysis, IPSS-R (revised International Prognostic Scoring System) score other than very high (P=0.03) primary versus secondary azacitidine failure (P=0.01) and a high rate of demethylation in blood during the first cycle of treatment (P=0.03) were associated with longer survival. Thus, guadecitabine can be effective, sometimes yielding relatively prolonged survival, in a small proportion of high-risk myelodysplastic syndrome/low blast count acute myeloid leukemia patients who failed azacitidine. (Trial registered at clinicaltrials.gov identifier: 02197676)

Published
2019
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4. Left bundle branch block in Duchenne muscular dystrophy: Prevalence, genetic relationship and prognosis.

Author

Abdallah Fayssoil, Rabah Ben Yaou, Adam Ogna, Cendrine Chaffaut, France Leturcq, Olivier Nardi, Karim Wahbi, Denis Duboc, Frederic Lofaso, Helene Prigent, Bernard Clair, Pascal Crenn, Guillaume Nicolas, Pascal Laforet, Anthony Behin, Sylvie Chevret, David Orlikowski, and Djillali Annane

Subjects
Medicine, Science
Abstract

Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder due to mutations in the dystrophin gene on chromosome Xp21.1. We designed this study to determine the prevalence of left bundle branch block (LBBB), whether there is a relationship between LBBB and genetic pattern, and to assess predictive factors for acute cardiac events and mortality in adult DMD patients.We reviewed the charts of DMD followed at the Home Mechanical Ventilation Unit of the Raymond Poincare University Hospital.A total of 121 patients, aged from 18 to 41 years have been included in our study. Median vital capacity (VC) was 12% [7; 19.5] of predicted. Almost all patients were on home mechanical ventilation (95%). LBBB was present in 15 patients (13%); among them, 10 disclosed exonic deletions. After a median follow up of 6 years, 21 patients (17%) experienced acute heart failure (AHF), 7 patients (6%) supraventricular arrhythmia, 3 patients (2.4%) ventricular tachycardia, 4 patients (3%) significant electrical disturbances. LBBB was significantly associated with cardiac events (OR = 12.7; 95%CI [3.78-42.7]; p

Published
2018
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5. Lenalidomide combined with intensive chemotherapy in acute myeloid leukemia and higher-risk myelodysplastic syndrome with 5q deletion. Results of a phase II study by the Groupe Francophone Des Myélodysplasies

Author

Lionel Ades, Thomas Prebet, Aspasia Stamatoullas, Christian Recher, Romain Guieze, Emmanuel Raffoux, Krimo Bouabdallah, Mathilde Hunault, Eric Wattel, Laure Stalnikiewicz, Andrea Toma, Hervé Dombret, Norbert Vey, Marie Sebert, Claude Gardin, Cendrine Chaffaut, Sylvie Chevret, and Pierre Fenaux

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Patients with acute myeloblastic leukemia or higher risk myelodysplastic syndromes with 5q deletion (generally within a complex karyotype) respond poorly to intensive chemotherapy and have very poor survival. In this population, we evaluated escalating doses of lenalidomide combined with intensive chemotherapy in a phase II study. Treatment consisted of daunorubicin (45 mg/m2/day, days 1–3 in cohort 1, escalated to 60 mg/m2/day, days 1–3 in cohorts 2 and 3) combined with cytosine arabinoside (200 mg/m2/day, days 1–7) and lenalidomide (10 mg/day, days 1–21 in cohorts 1 and 2, escalated to 25 mg/day, days 1–21 in cohort 3). Eighty-two patients with 5q deletion were enrolled, including 62 with acute myeloblastic leukemia, 62/79 (78%) of whom had a complex karyotype (median 7 cytogenetic abnormalities, all but 2 of them monosomal) and three had unknown karyotypes. Thirty-eight patients (46%) achieved complete remission and the overall response rate was 58.5%. Among the 62 patients with a complex karyotype, 27 achieved complete remission (44%) and 21 had cytogenetic responses. A lower response rate was observed in patients with acute myeloblastic leukemia but other pretreatment factors, including cytogenetic complexity and treatment cohort, did not significantly influence response. Fifteen patients underwent allogeneic stem cell transplantation, including 11 patients in first remission. The 1-year cumulative incidence of relapse was 64.6% and the median overall survival was 8.2 months. By comparison with conventional intensive chemotherapy, the treatment protocol we used appeared to produce higher hematologic and cytogenetic complete remission rates in patients with very poor cytogenetics, but response duration was short in this very poor risk population, highlighting the need for better post-induction strategies. Clinical trial registry number: NCT00885508

Published
2017
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6. PROGNOSTIC VALUE OF INITIAL ASSESSMENT OF RESIDUAL HYPOVENTILATION USING NOCTURNAL CAPNOGRAPHY IN MECHANICALLY VENTILATED NEUROMUSCULAR PATIENTS: A 5 YEARS FOLLOW-UP STUDY.

Author

Adam Ogna, Julie Nardi, Helene Prigent, Maria Antonia Quera Salva, Cendrine Chaffaut, Laure Lamothe, Sylvie Chevret, Djillali Annane, David Orlikowski, and Frederic Lofaso

Subjects
prognosis, Neuromuscular Disease, Nocturnal hypoventilation, Home mechanical ventilation, restrictive respiratory failure, transcutaneous capno-oximetry, Medicine (General), R5-920
Abstract

BackgroundRestrictive respiratory failure is a major cause of morbidity and mortality in neuromuscular diseases (NMD). Home mechanical ventilation (HMV) is used to treat hypoventilation, and its efficiency is mostly assessed by daytime blood gases or nocturnal oxygen saturation monitoring (SpO2). Non-invasive transcutaneous measure of CO2 (TcCO2) allows to directly assess nocturnal hypercapnia and to detect residual hypoventilation with a higher sensitivity than SpO2.We aimed to compare the prognostic value of nocturnal SpO2 and TcCO2 in ventilated adult NMD patients. MethodsAll consecutive capno-oximetries performed between 2010 and 2011 in ventilated adult NMD patients were analysed retrospectively. Concomitant blood gas analysis and lung function data were collected. Patients on oxygen therapy were excluded. Nocturnal hypoxemia and hypercapnia (using 4 different definitions) at baseline were compared in their ability to predict mortality and respiratory events requiring ICU admission during follow-up. ResultsData from 55 patients were analysed (median age 28 IQR 25 - 36.5 years; 71% Duchenne muscular dystrophy; vital capacity 12 7 - 27 % of predicted; 51% tracheostomy).Capno-oxymetry showed hypoxemia in 14.5% and hypercapnia in 12.7 to 41.8%, according to the used definition.Over a follow-up lasting up to 5 years (median 4.0 3.6 - 4.5 years), we observed 12 deaths and 20 respiratory events requiring ICU admission. Hypercapnia was significantly associated with the study outcomes, with TcCO2 >49 mmHg during ≥10% of the time being the best definition, whilst hypoxemia was not.ConclusionsOur data show for the first time that residual hypoventilation, assessed by capnometry, is significantly associated with negative outcomes in adult ventilated NMD patients, whilst oximetry is not. Accordingly, we suggest capnometry to be included in the systematic assessment of HMV efficiency in NMD patients.

Published
2016
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7. Mechanisms Underpinning Increased Plasma Creatinine Levels in Patients Receiving Vemurafenib for Advanced Melanoma.

Author

Charlotte Hurabielle, Evangéline Pillebout, Thomas Stehlé, Cécile Pagès, Jennifer Roux, Pierre Schneider, Sylvie Chevret, Cendrine Chaffaut, Anne Boutten, Samia Mourah, Nicole Basset-Seguin, Emmanuelle Vidal-Petiot, Céleste Lebbé, and Martin Flamant

Subjects
Medicine, Science
Abstract

Serum creatinine has been reported to increase in patients receiving Vemurafenib, yet neither the prevalence nor the mechanism of this adverse event are known.We aimed to evaluate the frequency and the mechanisms of increases in plasma creatinine level in patients receiving Vemurafenib for advanced melanoma.We performed a retrospective monocentric study including consecutive patients treated with Vemurafenib for an advanced melanoma. We collected clinical and biological data concerning renal function before introduction of Vemurafenib and in the course of monthly follow-up visits from March 2013 to December 2014. Cystatin C-derived glomerular filtration rate was evaluated before and after Vemurafenib initiation, as increase in serum cystatin C is specific to a decrease in the glomerular filtration rate. We also performed thorough renal explorations in 3 patients, with measurement of tubular secretion of creatinine before and after Vemurafenib initiation and a renal biopsy in 2 patients.70 patients were included: 97% of them displayed an immediate, and thereafter stable, increase in creatinine (+22.8%) after Vemurafenib initiation. In 44/52 patients in whom Vemurafenib was discontinued, creatinine levels returned to baseline. Serum cystatin C increased, although proportionally less than serum creatinine, showing that creatinine increase under vemurafenib was indeed partly due to a renal function impairment. In addition, renal explorations demonstrated that Vemurafenib induced an inhibition of creatinine tubular secretion.Thus, Vemurafenib induces a dual mechanism of increase in plasma creatinine with both an inhibition of creatinine tubular secretion and slight renal function impairment. However, this side effect is mostly reversible when Vemurafenib is discontinued, and should not lead physicians to discontinue the treatment if it is effective.

Published
2016
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8. Natural History of Cardiac and Respiratory Involvement, Prognosis and Predictive Factors for Long-Term Survival in Adult Patients with Limb Girdle Muscular Dystrophies Type 2C and 2D.

Author

Abdallah Fayssoil, Adam Ogna, Cendrine Chaffaut, Sylvie Chevret, Raquel Guimarães-Costa, France Leturcq, Karim Wahbi, Helene Prigent, Frederic Lofaso, Olivier Nardi, Bernard Clair, Anthony Behin, Tanya Stojkovic, Pascal Laforet, David Orlikowski, and Djillali Annane

Subjects
Medicine, Science
Abstract

BACKGROUND:Type 2C and 2D limb girdle muscular dystrophies (LGMD) are a group of autosomal recessive limb girdle muscular dystrophies manifested by proximal myopathy, impaired respiratory muscle function and cardiomyopathy. The correlation and the prognostic impact of respiratory and heart impairment are poorly described. We aimed to describe the long-term cardiac and respiratory follow-up of these patients and to determine predictive factors of cardio-respiratory events and mortality in LGMD 2C and 2D. METHODS:We reviewed the charts of 34 LGMD patients, followed from 2005 to 2015, to obtain echocardiographic, respiratory function and sleep recording data. We considered respiratory events (acute respiratory failure, pulmonary sepsis, atelectasis or pneumothorax), cardiac events (acute heart failure, significant cardiac arrhythmia or conduction block, ischemic stroke) and mortality as outcomes of interest for the present analysis. RESULTS:A total of 21 patients had type 2C LGMD and 13 patients had type 2D. Median age was 30 years [IQR 24-38]. At baseline, median pulmonary vital capacity (VC) was 31% of predicted value [20-40]. Median maximal inspiratory pressure (MIP) was 31 cmH2O [IQR 20.25-39.75]. Median maximal expiratory pressure (MEP) was 30 cm H2O [20-36]. Median left ventricular ejection fraction (LVEF) was 55% [45-64] with 38% of patients with LVEF

Published
2016
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9. Decitabine Versus Hydroxyurea for Advanced Proliferative Chronic Myelomonocytic Leukemia: Results of a Randomized Phase III Trial Within the EMSCO Network

Author

Raphael Itzykson, Valeria Santini, Sylvain Thepot, Lionel Ades, Cendrine Chaffaut, Aristoteles Giagounidis, Margot Morabito, Nathalie Droin, Michael Lübbert, Rosa Sapena, Stanislas Nimubona, Jean Goasguen, Eric Wattel, Gina Zini, Jose Miguel Torregrosa Diaz, Ulrich Germing, Anna Maria Pelizzari, Sophie Park, Nadja Jaekel, Georgia Metzgeroth, Francesco Onida, Robert Navarro, Andrea Patriarca, Aspasia Stamatoullas, Katharina Götze, Martin Puttrich, Sandra Mossuto, Eric Solary, Silke Gloaguen, Sylvie Chevret, Fatiha Chermat, Uwe Platzbecker, and Pierre Fenaux

Subjects
Cancer Research, Oncology
Abstract

PURPOSE Hydroxyurea (HY) is a reference treatment of advanced myeloproliferative neoplasms. We conducted a randomized phase III trial comparing decitabine (DAC) and HY in advanced myeloproliferative chronic myelomonocytic leukemias (CMML). PATIENTS AND METHODS Newly diagnosed myeloproliferative CMML patients with advanced disease were randomly assigned 1:1 to intravenous DAC (20 mg/m2/d days 1-5) or HY (1-4 g/d) in 28-day cycles. The primary end point was event-free survival (EFS), events being death and acute myelomonocytic leukemia (AML) transformation or progression. RESULTS One-hundred seventy patients received DAC (n = 84) or HY (n = 86). Median age was 72 and 74 years, and median WBC count 32.5 × 109/L and 31.2 × 109/L in the DAC and HY arms, respectively. Thirty-three percent of DAC and 31% of HY patients had CMML-2. Patients received a median of five DAC and six HY cycles. With a median follow-up of 17.5 months, median EFS was 12.1 months in the DAC arm and 10.3 months in the HY arm (hazard ratio [HR], 0.83; 95% CI, 0.59 to 1.16; P = .27). There was no significant interaction between treatment effect and blast or platelet count, anemia, CMML Prognostic Scoring System, Groupe Francophone des Myelodysplasies, or CMML Prognostic Scoring System–mol risk. Fifty-three (63%) DAC patients achieved a response compared with 30 (35%) HY patients ( P = .0004). Median duration of response was similar in both arms (DAC, 16.3 months; HY, 17.4 months; P = .90). Median overall survival was 18.4 months in the DAC arm and 21.9 months in the HY arm ( P = .67). Compared with HY, DAC significantly reduced the risk of CMML progression or transformation to acute myelomonocytic leukemia (cause-specific HR, 0.62; 95% CI, 0.41 to 0.94; P = .005) at the expense of death without progression or transformation (cause-specific HR, 1.55; 95% CI, 0.82 to 2.9; P = .04). CONCLUSION Compared with HY, frontline treatment with DAC did not improve EFS in patients with advanced myeloproliferative CMML (ClinicalTrials.gov identifier: NCT02214407 ).

Published
2023

10. Integrating genetic variants into clinical models for hepatocellular carcinoma risk stratification in cirrhosis

Author

Pierre Nahon, Jessica Bamba-Funck, Richard Layese, Eric Trépo, Jessica Zucman-Rossi, Carole Cagnot, Nathalie Ganne-Carrié, Cendrine Chaffaut, Erwan Guyot, Marianne Ziol, Angela Sutton, Etienne Audureau, Tarik Asselah, Dominique Guyader, Stanislas Pol, Hélène Fontaine, Georges-Philippe Pageaux, Victor De Lédinghen, Denis Ouzan, Fabien Zoulim, Dominique Roulot, Albert Tran, Jean-Pierre Bronowicki, Thomas Decaensi, Ghassan Riachi, Paul Calès, Jean-Marie Péron, Laurent Alric, Marc Bourlière, Philippe Mathurin, Sebastien Dharancy, Jean-Frédéric Blanc, Armand Abergel, Olivier Chazouillères, Ariane Mallat, Jean-Didier Grangé, Pierre Attali, null Louis d’Alteroche, Claire Wartelle, Thông Dao, Dominique Thabut, Christophe Pilette, Christine Silvain, Christos Christidis, Eric Nguyen-Khac, Brigitte Bernard-Chabert, Sophie Hillaire, Vincent Di Martino, Isabelle Archambeaud, Louis d’Alteroche, Frédéric Oberti, Christophe Moreno, Alexandre Louvet, Romain Moirand, Odile Goria, Nicolas Carbonell, Jean-Charles Duclos-Vallée, Victor de Ledinghen, Violaine Ozenne, Jean Henrion, Gabriel Perlemuter, Xavier Amiot, Jean-Pierre Zarski, and Sylvie Chevret

Subjects
Hepatology
Abstract

This study aimed to evaluate the ability of single nucleotide polymorphisms (SNPs) to refine hepatocellular carcinoma (HCC) risk stratification.Six SNPs in PNPLA3, TM6SF2, HSD17B13, APOE, and MBOAT7 affecting lipid turnover and one variant involved in the Wnt-β-catenin pathway (WNT3A-WNT9A rs708113) were assessed in patients with alcohol-related and/or HCV-cured cirrhosis included in HCC surveillance programs (prospective CirVir and CIRRAL cohorts). Their prognostic value for HCC occurrence was assessed using Fine-Gray models combined into a 7-SNP genetic risk score (GRS). Prediction ability of two clinical scores (a routine nongenetic model determined by multivariate analysis and the external aMAP score) without then with the addition of the GRS was evaluated by C-indices. The standardized net benefit was derived from decision curves.Among 1145 patients, 86 (7.5%) developed HCC after 43.7 months. PNPLA3 and WNT3A-WNT9A variants were independently associated with HCC occurrence. The GRS stratified the population into 3 groups with progressively increased 5-yr HCC incidence [Group 1 (n=627, 5.4%), Group 2 (n=276, 10.7%), and Group 3 (n=242, 15.3%); P0.001]. The multivariate model identified age, male sex, diabetes, platelet count, GGT levels, albuminemia and the GRS as independent risk factors. The clinical model performance for 5-yr HCC prediction was similar to that of the aMAP score (C-Index 0.769). The addition of the GRS to both scores modestly improved their performance (C-Index 0.786 and 0.783, respectively). This finding was confirmed by decision curve analyses showing only fair clinical net benefit.Patients with cirrhosis can be stratified into HCC risk classes by variants affecting lipid turnover and Wnt-β-catenin pathway. The incorporation of this genetic information modestly improves the performance of clinical scores.The identification of patients at higher probability of developing liver cancer is pivotal to improve the performance of surveillance. Risk assessment can be achieved by combining several clinical and biological parameters used in routine practice. The addition of patients' genetic characteristics can modestly improve this prediction and will ultimately pave the way for precision medicine in patients eligible for HCC surveillance, allowing physicians to trigger personalized screening strategies.

Published
2023

11. Low alcohol consumption influences outcomes in individuals with alcohol-related compensated cirrhosis in a French multicenter cohort

Author

Alexandre Louvet, Valérie Bourcier, Isabelle Archambeaud, Louis d’Alteroche, Cendrine Chaffaut, Frédéric Oberti, Christophe Moreno, Dominique Roulot, Thông Dao, Romain Moirand, Jean-Charles Duclos-Vallée, Odile Goria, Eric Nguyen-Khac, Stanislas Pol, Nicolas Carbonell, Jérôme Gournay, Laure Elkrief, Isabelle Fouchard-Hubert, Sylvie Chevret, Nathalie Ganne-Carrié, null Louis d’Alteroche, Jean-Marie Péron, Victor de Lédinghen, Violaine Ozenne, Jean Henrion, Albert Tran, Gabriel Perlemuter, Xavier Amiot, Jean-Pierre Zarski, CHU Lille, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Equipe 1 : EPOPé - Épidémiologie Obstétricale, Périnatale et Pédiatrique (CRESS - U1153), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Erasme [Bruxelles], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Pontchaillou [Rennes], Hôpital Paul Brousse, Nutrition, Inflammation et axe Microbiote-Intestin-Cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-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), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Amiens-Picardie, Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247 (GRAP), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie du système immunitaire (Inserm U1223), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département d'hépatologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CIRRAL group, École pratique des hautes études (EPHE), CHU Trousseau [Tours], Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hépato-biliaire (CHB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Service d'Hépato-gastro-entérologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Référence des Maladies Rares - Maladies Inflammatoires des Voies Biliaires et Service d’Hépatologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Equipe 2 : ECSTRA - Epidémiologie Clinique, STatistique, pour la Recherche en Santé (CRESS - U1153), and Hopital Saint-Louis [AP-HP] (AP-HP)

Subjects
liver decompensation, [PHYS]Physics [physics], Alcohol-related liver disease, Cirrhosis, Hepatology, Recurrence, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Background and aims: The harmful impact of heavy alcohol recurrence has been confirmed in patients with alcohol-related cirrhosis although this is based on old studies. The drivers of long-term outcome still need to be clearly investigated.Method: All patients with biopsy-proven compensated alcohol-related cirrhosis included in the CIRRAL cohort (22 centers) were prospectively studied. Prognostic variables of survival and liver event-free survival were assessed using multivariable Cox models with stepwise selection. The prognostic impact of alcohol recurrence during follow-up (computed in glasses-years in the same way as pack-years for tobacco) was assessed using a time-dependent covariable.Results: From 2010 to 2016, 650 patients were included. The median age at baseline was 58.4 years old, 67.4% were men and the median BMI was 27.8 kg/m2, 63.8% had a history of liver decompensation, and 70.2% had discontinued alcohol. At 5 years, 30.9% of abstinent patients developed recurrence and this risk was higher in patients with a history of drug abuse and in those with shorter alcohol discontinuation times. Median survival was 97 months. Age, alcohol consumption at baseline, platelet count and Child-Pugh score >5 were associated with overall and liver event-free survival on multivariate analysis. Alcohol consumption during follow-up of more than 25 glasses-year was independently associated with lower survival and with a trend toward significant liver event-free survival, but the risk increased from 1 glass-year, though not significantly. Simon & Makuch plots confirm the benefit of no alcohol consumption (

Published
2022

12. Final Results of Ruxopeg, a Phase 1/2 Adaptive Randomized Trial of Ruxolitinib (Rux) and Pegylated Interferon Alpha (IFNa) 2a in Patients with Myelofibrosis (MF)

Author

Jean-Jacques Kiladjian, Jean-Christophe Ianotto, Juliette Soret, Nabih Maslah, Cendrine Chaffaut, Françoise Boyer perrard, Fiorenza Barraco, Viviane Dubruille, Claude Capron, Amandine Tisserand, Valérie Rolland-Neyret, Zineb Ghrieb, Sylvie Chevret, Isabelle Plo, Marie-Hélène Schlageter, Veronique Meignin, Matthieu Resche-Rigon, and Bruno Cassinat

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

14. Echographic Assessment of Diaphragmatic Function in Duchenne Muscular Dystrophy from Childhood to Adulthood

Author

Pascal Crenn, Tanya Stojkovic, Dominique Mompoint, Hélène Prigent, David Orlikowski, Helge Amthor, Cendrine Chaffaut, Laure Lamothe, Susana Quijano Roy, Guillaume Bassez, Sylvie Chevret, Djillali Annane, Bernard Clair, Pascal Laforêt, Frédéric Lofaso, Robert Carlier, Paris Meng, Adam Ogna, Anthony Behin, Abdallah Fayssoil, and Bruno Eymard

Subjects
Adult, Male, 0301 basic medicine, Vital capacity, medicine.medical_specialty, Adolescent, Duchenne muscular dystrophy, Diaphragm, Diaphragmatic breathing, Muscle disorder, Pulmonary function testing, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Respiratory muscle, Humans, Medicine, Child, Retrospective Studies, Ultrasonography, business.industry, Respiration, Organ Size, Middle Aged, musculoskeletal system, medicine.disease, Respiration, Artificial, Diaphragm (structural system), Muscular Dystrophy, Duchenne, Cross-Sectional Studies, 030104 developmental biology, Neurology, Cardiology, Median body, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

BACKGROUND Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic muscle disorder. Respiratory muscle function is classically affected in this disease. Ultrasound recently emerged as a non-invasive tool to assess diaphragm function. However, there are only a few studies using diaphragm ultrasound (US) in DMD. PURPOSE We aimed to assess diaphragm ultrasound patterns in DMD, their relationship with age and their association with home mechanical ventilation (HMV). METHODS We included DMD patients followed at Raymond Poincare Hospital who benefited from diaphragm ultrasound and pulmonary function tests. RESULTS There were 110 DMD patients and 17 male sex-matched healthy subjects included. In all, 94% of patients were permanent wheelchair users. Median body mass index (BMI) was 18 kg/m2. DMD patients disclosed a reduced forced vital capacity (VC) (12% of predicted value), and 78% of patients were on HMV. In patients, right and left diaphragmatic motions on deep inspiration were reduced and end expiratory diaphragm thickness was borderline normal. In patients, right and left diaphragmatic thickening fractions (TF) were reduced 12.7% and 15.5%, respectively. Age and end expiratory thickness were significantly inversely associated (p = 0.005 for the right diaphragm, p = 0.018 for the left diaphragm). Diaphragm TF was significantly inversely associated with age (p = 0.001 for the right side, p

Published
2019

15. A phase II study of guadecitabine in higher-risk myelodysplastic syndrome and low blast count acute myeloid leukemia after azacitidine failure

Author

Sophie Park, Anne Banos, Cendrine Chaffaut, Cecile Bally, Kamel Laribi, Laurence Legros, Aline Renneville, Pierre Fenaux, Emmanuel Gyan, Eric Wattel, Marie Sebert, Marie-Pierre Gourin, Sylvie Chevret, Claude Preudhomme, Simone Jueliger, Fatiha Chermat, Pierre Peterlin, Olivier Nibourel, Odile Beyne-Rauzy, Lionel Ades, Rosa Sapena, Aspasia Stamatoullas, Luke Bevan, and Laurence Sanhes

Subjects
Male, Risk, medicine.medical_specialty, Azacitidine, Decitabine, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, medicine, Humans, Survival analysis, Aged, business.industry, Myeloid leukemia, Hematology, medicine.disease, Survival Analysis, Leukemia, Leukemia, Myeloid, Acute, Treatment Outcome, Hypomethylating agent, International Prognostic Scoring System, Myelodysplastic Syndromes, Female, business, 030215 immunology, medicine.drug
Abstract

High-risk myelodysplastic syndrome/acute myeloid leukemia patients have a very poor survival after azacitidine failure. Guadecitabine (SGI-110) is a novel subcutaneous hypomethylating agent which results in extended decitabine exposure. This multicenter phase II study evaluated the efficacy and safety of guadecitabine in high-risk myelodysplastic syndrome and low blast count acute myeloid leukemia patients refractory or relapsing after azacitidine. We included 56 patients with a median age of 75 years [Interquartile Range (IQR) 69-76]. Fifty-five patients received at least one cycle of guadecitabine (60 mg/m2/d subcutaneously days 1-5 per 28-day treatment cycles), with a median of 3 cycles (range, 0-27). Eight (14.3%) patients responded, including two complete responses; median response duration was 11.5 months. Having no or few identified somatic mutations was the only factor predicting response (P=0.035). None of the 11 patients with TP53 mutation responded. Median overall survival was 7.1 months, and 17.9 months in responders (3 of whom had overall survival >2 years). In multivariate analysis, IPSS-R (revised International Prognostic Scoring System) score other than very high (P=0.03) primary versus secondary azacitidine failure (P=0.01) and a high rate of demethylation in blood during the first cycle of treatment (P=0.03) were associated with longer survival. Thus, guadecitabine can be effective, sometimes yielding relatively prolonged survival, in a small proportion of high-risk myelodysplastic syndrome/low blast count acute myeloid leukemia patients who failed azacitidine. (Trial registered at clinicaltrials.gov identifier: 02197676).

Published
2019

16. Nutritional status, swallowing disorders, and respiratory prognosis in adult Duchenne muscular dystrophy patients

Author

Sylvie Chevret, Paris Meng, Pascal Crenn, Cendrine Chaffaut, Bernard Clair, Adam Ogna, Djillali Annane, Hélène Prigent, David Orlikowski, Pascal Laforêt, Abdallah Fayssoil, and Frédéric Lofaso

Subjects
Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Duchenne muscular dystrophy, Nutritional Status, Sepsis, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Swallowing, 030225 pediatrics, Internal medicine, medicine, Respiratory muscle, Humans, Respiratory function, Respiratory system, Mechanical ventilation, Univariate analysis, business.industry, Swallowing Disorders, medicine.disease, Prognosis, Respiratory Muscles, Deglutition, Muscular Dystrophy, Duchenne, 030228 respiratory system, Pediatrics, Perinatology and Child Health, Median body, business, Deglutition Disorders
Abstract

Malnutrition and swallowing disorders are common in Duchenne muscular dystrophy (DMD) patients. We assessed, in adult DMD with home mechanical ventilation (HMV) and cough assist device, its prevalence and the relationships with respiratory muscle strength and long-term respiratory prognosis. We reviewed the patients (n = 117, age 18-39 years [median 24]), followed in a reference center, from 2006 to 2015, to obtain clinical baseline, nutritional status, vital capacity (VC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP). The median body mass index (BMI) was low (15.6 kg/m²). Included patients had severe restrictive respiratory function with a median VC of 10.5% [7-17] of the predicted value. All patients were on HMV. Prevalence of malnutrition, swallowing disorders, and gastrostomy were respectively 62%, 34%, and 11%. BMI and serum albumin level were significantly associated with MIP, MEP, and VC. The 1-year/5-years cumulative incidences of respiratory events (pulmonary sepsis and acute respiratory distress) were, respectively, 20.7%/44.5%. Using univariate analysis, predictive factors for respiratory events were swallowing disorders (p = .001), transthyretinemia (p = .034), MIP (p = .039), and MEP (p = .03) but not BMI or albuminemia. Using multivariate analysis, only swallowing disorders remained significantly associated with respiratory events (OR = 4.2, IC 95% 1.31-12.2, p = .01). In conclusion, this study highlights the interrelationships between nutritional intake, swallowing function, airway clearance, and respiratory function in adult DMD. A multidisciplinary approach focusing on these previous factors is essential to optimize DMD patient health.

Published
2021

17. Early hepatocellular carcinoma detection using magnetic resonance imaging is cost-effective in high-risk patients with cirrhosis

Author

Pierre Nahon, Marie Najean, Richard Layese, Kevin Zarca, Laeticia Blampain Segar, Carole Cagnot, Nathalie Ganne-Carrié, Gisèle N’Kontchou, Stanislas Pol, Cendrine Chaffaut, Fabrice Carrat, Maxime Ronot, Etienne Audureau, Isabelle Durand-Zaleski, Tarik Asselah, Dominique Guyader, Hélène Fontaine, Georges-Philippe Pageaux, Victor De Lédinghen, Denis Ouzan, Fabien Zoulim, Dominique Roulot, Albert Tran, Jean-Pierre Bronowicki, Thomas Decaensi, Ghassan Riachi, Paul Calès, Jean-Marie Péron, Laurent Alric, Marc Bourlière, Philippe Mathurin, Sebastien Dharancy, Jean-Frédéric Blanc, Armand Abergel, Olivier Chazouillères, Ariane Mallat, Jean-Didier Grangé, Pierre Attali, Louis d’Alteroche, Claire Wartelle, Thông Dao, Dominique Thabut, Christophe Pilette, Christine Silvain, Christos Christidis, Eric Nguyen-Khac, Brigitte Bernard-Chabert, Sophie Hillaire, Vincent Di Martino, Delphine Bonnet, Virginie Payssan-Sicart, Chloe Pomes, François Bailly, Marjolaine Beaudoin, Dominique Giboz, Kerstin Hartig-Lavie, Marianne Maynard, Eric Billaud, David Boutoille, Morane Cavellec, Marjorie Cheraud-Carpentier, Isabelle Hubert, Jaouad Benhida, Adrien Lannes, Françoise Lunel, Frédéric Oberti, Nathalie Boyer, Nathalie Giuily, Corinne Castelnau, Giovanna Scoazec, Aziza Chibah, Sylvie Keser, Karim Bonardi, Anaïs Vallet-Pichard, Philippe Sogni, Juliette Foucher, Jean-Baptiste Hiriart, Amy Wilson, Sarah Shili, Faiza Chermak, Christelle Ansaldi, Nisserine Ben Amara, Laëtitia Chouquet, Emilie De Luca, Valérie Oules, Rodolphe Anty, Eve Gelsi, Régine Truchi, Elena Luckina, Nadia Messaoudi, Joseph Moussali, Barbara De Dieuleveult, Damien Labarriere, Pascal Poter, Si Nafa Si Ahmed, Véronique Grando-Lemaire, Valérie Bourcier, Séverine Brulé, Thomas Stalhberger, Caroline Jezequel, Audrey Brener, Anne Laligant, Aline Rabot, Isabelle Renard, Thomas F. Baumert, Michel Dofföel, Catherine Mutter, Pauline Simo-Noumbissie, Esma Razi, Hélène Barraud, Mouni Bensenane, Abdelbasset Nani, Sarah Hassani-Nani, Marie-Albertine Bernard, Michael Bismuth, Ludovic Caillo, Stéphanie Faure, Marie Pierre Ripault, Christophe Bureau, Jean Marie Peron, Marie Angèle Robic, Léa Tarallo, Marine Faure, Bruno Froissart, Marie-Noelle Hilleret, Jean-Pierre Zarski, Odile Goria, Victorien Grard, Hélène Montialoux, Muriel François, Christian Ouedraogo, Christelle Pauleau, Anne Varault, Tony Andreani, Bénédicte Angoulevant, Azeline Chevance, Lawrence Serfaty, Teresa Antonini, Audrey Coilly, Jean-Charles Duclos Vallée, Mariagrazia Tateo, Corinne Bonny, Chanteranne Brigitte, Géraldine Lamblin, Léon Muti, Abdenour Babouri, Virginie Filipe, Camille Barrault, Laurent Costes, Hervé Hagège, Soraya Merbah, Paul Carrier, Maryline Debette-Gratien, Jérémie Jacques, Guillaume Lassailly, Florent Artu, Valérie Canva, Sébastien Dharancy, Alexandre Louvet, Marianne Latournerie, Marc Bardou, Thomas Mouillot, Yannick Bacq, Didier Barbereau, Charlotte Nicolas, Caroline Chevalier, Isabelle Archambeaud, Sarah Habes, Danièle Botta-Fridlund, Eric Saillard, Marie-Josée Lafrance, Patrice Cacoub, Patrizia Carrieri, Elisabeth Delarocque-Astagneau, Victor De Ledinghen, Céline Dorival, Jean Dubuisson, Chantal Housset, Dominique Larrey, Patrick Marcellin, Jean-Michel Pawlotsky, Ventzislava Petrov-Sanchez, Sophie Vaux, Linda Wittkop, Yazdan Yazdanpanah, Jessica Zucman-Rossi, Christophe Moreno, Romain Moirand, Nicolas Carbonell, Jean-Charles Duclos-Vallée, Victor de Ledinghen, Violaine Ozenne, Jean Henrion, Gabriel Perlemuter, Xavier Amiot, Sylvie Chevret, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13), Génomique fonctionnelle des tumeurs solides = Functional Genomics of Solid Tumors [CRC] (FunGeST), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Henri Mondor, Unité de recherche clinique en économie de la santé [Paris] (URC Eco), Délégation de la Recherche Clinique et de l’Innovation [Paris] (DRCI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de santé publique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), ANRS|Maladies infectieuses émergentes (ANRS|MIE), Université Sorbonne Paris Nord, Hôpital Cochin [AP-HP], Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Equipe 2 : ECSTRA - Epidémiologie Clinique, STatistique, pour la Recherche en Santé (CRESS - U1153), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de santé publique [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Hôpital Beaujon [AP-HP]

Subjects
AMRI, abbreviated magnetic resonance imaging, NAFLD, non-alcoholic fatty liver disease, medicine.medical_specialty, Cirrhosis, Cost effectiveness, [SDV]Life Sciences [q-bio], Population, TACE, transarterial chemoembolization, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Gastroenterology, QALY, quality-adjusted life year, Internal medicine, Internal Medicine, LY, life years, Immunology and Allergy, Medicine, Early Hepatocellular Carcinoma, liver cancer risk, education, cost-effectiveness, RFA, radiofrequency ablation, education.field_of_study, AFP, alpha-fetoprotein, US, ultrasound, Hepatology, medicine.diagnostic_test, business.industry, cirrhosis, LYG, life years gained, Incidence (epidemiology), BCLC, Barcelona Clinic Liver Cancer, ICER, incremental cost-effectiveness ratio, Magnetic resonance imaging, medicine.disease, HR, hazard ratio, digestive system diseases, Hepatocellular carcinoma, SHR, subdistribution hazard ratio, surveillance, HCC, hepatocellular carcinoma, business, MRI, magnetic resonance imaging, Incremental cost-effectiveness ratio, Research Article, MRI
Abstract

Background & Aims Reinforced hepatocellular carcinoma (HCC) surveillance using magnetic resonance imaging (MRI) could increase early tumour detection but faces cost-effectiveness issues. In this study, we aimed to evaluate the cost-effectiveness of MRI for the detection of very early HCC (Barcelona Clinic Liver Cancer [BCLC] 0) in patients with an annual HCC risk >3%. Methods French patients with compensated cirrhosis included in 4 multicentre prospective cohorts were considered. A scoring system was constructed to identify patients with an annual risk >3%. Using a Markov model, the economic evaluation estimated the costs and life years (LYs) gained with MRI vs. ultrasound (US) monitoring over a 20-year period. The incremental cost-effectiveness ratio (ICER) was calculated by dividing the incremental costs by the incremental LYs. Results Among 2,513 patients with non-viral causes of cirrhosis (n = 840) and/or cured HCV (n = 1,489)/controlled HBV infection (n = 184), 206 cases of HCC were detected after a 37-month follow-up. When applied to training (n = 1,658) and validation (n = 855) sets, the construction of a scoring system identified 33.4% and 37.5% of patients with an annual HCC risk >3% (3-year C-Indexes 75 and 76, respectively). In patients with a 3% annual risk, the incremental LY gained with MRI was 0.4 for an additional cost of €6,134, resulting in an ICER of €15,447 per LY. Compared to US monitoring, MRI detected 5x more BCLC 0 HCC. The deterministic sensitivity analysis confirmed the impact of HCC incidence. At a willingness to pay of €50,000/LY, MRI screening had a 100% probability of being cost-effective. Conclusions In the era of HCV eradication/HBV control, patients with annual HCC risk >3% represent one-third of French patients with cirrhosis. MRI is cost-effective in this population and could favour early HCC detection. Lay summary The early identification of hepatocellular carcinoma in patients with cirrhosis is important to improve patient outcomes. Magnetic resonance imaging could increase early tumour detection but is more expensive and less accessible than ultrasound (the standard modality for surveillance). Herein, using a simple score, we identified a subgroup of patients with cirrhosis (accounting for >one-third), who were at increased risk of hepatocellular carcinoma and for whom the increased expense of magnetic resonance imaging would be justified by the potential improvement in outcomes., Graphical abstract, Highlights • HCC risk stratification in patients with cirrhosis aims at improving performance of cancer surveillance. • Using a simple scoring system, one-third of patients with cirrhosis with an annual HCC risk >3% can be easily identified. • Semi-annual surveillance using MRI in this population could enable the cost-effective detection of 5x more BCLC 0 HCCs.

Published
2022

18. Association of systemic secondary brain insults and outcome in patients with convulsive status epilepticus: A post hoc study of a randomized controlled trial

Author

Bruno Mégarbane, Christophe Guitton, Jonathan Chelly, Matthieu Resche-Rigon, Hervé Mentec, Cendrine Chaffaut, Candice Fontaine, Jean-Yves Lefrant, Aicha Hamdi, Ferhat Meziani, Virginie Lemiale, Stéphane Legriel, Maleka Schenck, Alain Cariou, Thomas Geeraerts, Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Centre Hospitalier de Melun, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre Hospitalier Le Mans (CH Le Mans), Hôpital de Hautepierre [Strasbourg], Hôpital Lariboisière-Fernand-Widal [APHP], Centre Hospitalier Victor Dupouy, AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPC)

Subjects
Male, Fever, Population, Glasgow Outcome Scale, law.invention, Hypercapnia, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Status Epilepticus, Randomized controlled trial, law, Hypothermia, Induced, Intensive care, Clinical endpoint, Medicine, Humans, 030212 general & internal medicine, education, Hypoxia, Aged, Randomized Controlled Trials as Topic, education.field_of_study, business.industry, Brain, Odds ratio, Middle Aged, medicine.disease, Respiration, Artificial, 3. Good health, Blood pressure, Anesthesia, Female, Neurology (clinical), Hypotension, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

ObjectiveTo evaluate the association between systemic factors (mean arterial blood pressure, arterial partial pressures of carbon dioxide and oxygen, body temperature, natremia, and glycemia) on day 1 and neurologic outcomes 90 days after convulsive status epilepticus.MethodsThis was a post hoc analysis of the Evaluation of Therapeutic Hypothermia in Convulsive Status Epilepticus in Adults in Intensive Care (HYBERNATUS) multicenter open-label controlled trial, which randomized 270 critically ill patients with convulsive status epilepticus requiring mechanical ventilation to therapeutic hypothermia (32°C–34°C for 24 hours) plus standard care or standard care alone between March 2011 and January 2015. The primary endpoint was a Glasgow Outcome Scale score of 5, defining a favorable outcome, 90 days after convulsive status epilepticus.ResultsThe 172 men and 93 women had a median age of 57 years (45–68 years). Among them, 130 (49%) had a history of epilepsy, and 59 (29%) had a primary brain insult. Convulsive status epilepticus was refractory in 86 (32%) patients, and total seizure duration was 67 minutes (35–120 minutes). The 90-day outcome was unfavorable in 126 (48%) patients. In multivariate analysis, none of the systemic secondary brain insults were associated with outcome; achieving an unfavorable outcome was associated with age >65 years (odds ratio [OR] 2.17, 95% confidence interval [CI] 1.20–3.85; p = 0.01), refractory convulsive status epilepticus (OR 2.00, 95% CI 1.04–3.85; p = 0.04), primary brain insult (OR 2.00, 95% CI 1.02–4.00; p = 0.047), and no bystander-witnessed seizure onset (OR 2.49, 95% CI 1.05–5.59; p = 0.04).ConclusionsIn our population, systemic secondary brain insults were not associated with outcome in critically ill patients with convulsive status epilepticus.ClinicalTrials.gov identifierNCT01359332.

Published
2020

19. Allogeneic Hematopoietic Stem Cell Transplantation (allo HSCT) in Patients with IPSS Low or Intermediate-1 Myelodysplastic Syndrome (MDS): A Prospective Multicenter Phase II Study Based on Donor Availability By the GFM & SFGM-TC 'MDS-ALLO-Risk'

Author

Lionel Ades, Michael Loschi, Marie Robin, Marie Sebert, Amandine Charbonnier, Pierre Fenaux, Corentin Orvain, Pierre Peterlin, Cendrine Chaffaut, Fatiha Chermat, Sylvie Chevret, Thomas Cluzeau, Gaelle Fossard, Stephanie Nguyen-Quoc, Rosa Sapena, Nathalie Fegueux, Anne Huynh, Odile Beyne Rauzy, Sophie Park, Sylvain Thepot, Marie-Thérèse Rubio, Patrice Chevallier, and Maud d'Aveni

Subjects
Oncology, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Allo hsct, Phases of clinical research, Cell Biology, Hematology, Hematopoietic stem cell transplantation, Biochemistry, Internal medicine, Medicine, In patient, business
Abstract

Background: Allo HSCT is a potentially curative treatment in MDS which, in higher risk (IPSS high and int 2) MDS demonstrated an overall survival (OS) advantage over conventional treatment (especially HMAs) in retrospective (Koreth et al., JCO 2013) and prospective (Robin et al. leukemia 2015) studies. Retrospective studies, on the other hand, suggested no OS advantage for allo HSCT in lower risk MDS (IPSS low and int 1), except possibly in the "poorest" lower risk MDS subsets, as classified by the WPSS (Alessandrino et al. AMJH 2013) However, about 25% of lower risk MDS patients are reclassified as higher risk by the R-IPSS and a proportion of other lower risk MDS can also harbor some higher risk features that compromise their outcome. MDS-ALLO-RISK trial (clinicaltrial.gov NCT02757989), was designed to assess outcome of lower risk MDS patients with some high-risk features after HLA-matched donor HSCT. Method: The primary objective of this study was to demonstrate an OS improvement in lower risk MDS patients with some high risk features with a donor compared with those without a donor (with a 3 year OS of 70% versus 40%, respectively) . Inclusion criteria were: IPSS low or int1 MDS with at least one of the following characteristics: 1) R-IPSS intermediate or higher 2) RBC transfusion dependent anemia and failure to two or more treatments (including EPO, Lenalidomide or HMA ); 3) platelets < 20 G/L requiring transfusions 4) ANC < 0.5 G/L with severe infection 5) no contra indication to allo HSCT 6) age Results: 79 patients were included, 64 in group A and 15 in group B. Median age was 62.4 (IQR: 58-65) years in group A and 66 (IQR: 60.5-68) years in group B. Patients in group A were more frequently males (73 vs 40%, p=0.029), WHO was CMML in 8 (10%), MDS-SLD in 5 (8%), MDS-MLD in 9 (11%), MDS-EB1 in 41 (52%), MDS-RS in 12 (15%), unclassified in 4 (6%) without significant differences between the two groups. IPSS /IPSS-R was similar in both groups: IPSS low in 10% (11% in group A and 7% in group B) and Int-1 in 90%. IPSS-R: very low risk (6% vs 0%); low risk (25% vs 27%); intermediate (50% vs 47%); high (19% vs 27%); no very high risk. Among the 64 patients with a donor, 58 (92%) received HSCT, 2 died before HSCT; 2 had progressive disease and 2 are planned for HSCT. Transplanted patients received reduced intensity conditioning regimen with busulfan 6.4mg/kg, fludarabine 150mg/m2 and ATG (rabbit antithymocyte globulin therapy, grafalon®) 30mg/kg and cyclosporine-mycophenolate mofetil as GVHD prophylaxis. In group A, 21/64 had died, including 13 died from a non-relapse cause. In group B, 4/15 patients had died, 3 from MDS progression and one from CNS bleeding. Three-year OS was 60% (95%CI: 46.9-76.8) in group A and 64.2% (41.3-99.6) in group B (p=NS). At the time of analysis, 20 and 5 patients had progressed/relapsed in group A and B respectively. with a cumulative incidence of relapse/progression (from inclusion) of 27.4% (IC95%: 15;39.8) in group A and 41.7% (IC95%:9.2;74.2) in group B (p=0.71). Among the 58 transplanted patients, 11 (19%) died without disease progression, including one death from a solid tumor. 3 years non-relapse mortality in transplanted patients was 23.4% (IC95%:9.7;37). 3 years Incidence of grade 2 to 4 acute GVHD was 40.8% and 3 years chronic GVHD was 24.9%. Conclusion: In this, to our knowledge, first prospective study in IPSS lower risk patients with some unfavorable clinical or biological features, HLA identical donor (sibling or 10/10 unrelated) HSCT yielded a 3-year OS of 60%. Non relapse mortality was however 23%, and OS somewhat lower than expected (70% at 3 years) and similar to that observed in patients without a donor. Long-term follow-up is needed to better define subgroups of IPSS lower risk MDS that may benefit from allo HSCT. Disclosures Sebert: Abbvie: Consultancy; BMS: Consultancy. Cluzeau: Pfizer: Other: travel, accommodations, expenses; Astellas: Speakers Bureau; Amgen: Speakers Bureau; Agios: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Takeda: Other: travel, accommodations, expenses; Jazz Pharma: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau. Loschi: AbbVie: Ended employment in the past 24 months, Honoraria; CELGENE/BMS: Honoraria; Gilead: Ended employment in the past 24 months, Honoraria; Novartis: Ended employment in the past 24 months, Honoraria; Servier: Ended employment in the past 24 months, Honoraria; MSD: Honoraria. Huynh: Jazz Pharmaceuticals: Honoraria. Ades: ABBVIE: Honoraria; NOVARTIS: Honoraria; CELGENE/BMS: Honoraria; CELGENE: Research Funding; JAZZ: Honoraria, Research Funding; TAKEDA: Honoraria. Fenaux: JAZZ: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Robin: NEOVII MEDAC NOVARTIS: Research Funding.

Published
2021

20. Ivosidenib Monotherapy Is Effective in Patients with IDH1 Mutated Myelodysplastic Syndrome (MDS): The Idiome Phase 2 Study By the GFM Group

Author

Cecile Bally, Pierre Fenaux, Raphael Itzykson, Aspasia Stamatoulas Bastard, Sébastien Maury, Sophie Dimicoli-Salazar, Lionel Ades, Gaelle Fossard, Fatiha Chermat, Pierre Peterlin, Marie-Pierre Gourin, Thomas Cluzeau, Cendrine Chaffaut, Marie Sebert, Sylvie Chevret, Sylvain Thepot, Oana Brehar, Lamya Ait Si Selmi, Odile Beyne Rauzy, Emmanuelle Clappier, and Sophie Park

Subjects
medicine.medical_specialty, IDH1, business.industry, Group (mathematics), Immunology, Phases of clinical research, Cell Biology, Hematology, Biochemistry, Gastroenterology, Internal medicine, Medicine, In patient, business
Abstract

Background: Ivosidenib (IVO) is an oral, targeted, small-molecule inhibitor of mutant IDH1 approved in the US for adult patients with unfit or relapse/refractory AML with IDH1 mutation. Little is known on its efficacy in patients with IDH1 mutated MDS. Here we report interim results of a Phase 2 study evaluating safety and efficacy of IVO in three different cohorts of MDS patients: Higher risk MDS having failed azacytidine (AZA) (cohort A, n=29), untreated higher risk MDS without life threatening cytopenias (ie ANC < 500/mm3 or any recent severe infections and/or platelets below 30,000/mm3 and any bleeding symptom,) as a first line treatment (cohort B, with the addition of AZA in non-Responders after 3 cycles, n=29) and lower risk MDS having failed EPO (cohort C, n=10). (ClinicalTrials.gov NCT03503409). Methods: Subjects enrolled in cohort A, B or C received continuous 28-day cycles of IVO - 500 mg orally QD. In cohort B, AZA (75 mg/m2/d x 7 days, SC) was added to IVO after 3 cycles, only in the absence of IWG 2006 response (absence of CR, PR or HI). The primary endpoint was overall hematological response rate (ORR) at 3 and 6 months (including CR, PR, stable disease with HI according to IWG 2006). All responders allowed to continue treatment until loss of response. Secondary endpoints included safety, duration of response, EFS, overall survival and translational project evaluating the role of biomarkers on response. We report the preliminary results on the first 26 pts enrolled. Results: At data cut off (6/15/2021), 32 patients had been enrolled, including 26 who were evaluable for the primary endpoint. 13, 11 and 2 were enrolled in cohort A, B and C respectively. Median age was 76 years and 50% were female. WHO was MDS-MLD, MDS-EB1, MDS-EB2, CMML and low blast count AML in 2, 2, 12, 1 and 9 patients respectively. IPSS-R was low, intermediate, high and very high in 2, 6, 5 and 13 resp. IDH1 mutation was p.R132C in 15 patients, p.R132H in 7, p.R132G/S in 3 and not specified in 1. The ORR was 69% (18 patients) including 12 CR (46%), 1 PR and 5 HI. Most patients achieved response after 3 cycles (17/18). Response was achieved in 7 (54%), 10 (91%) and 1 (50%) in cohort A, B and C respectively. Moreover, CR was achieved in 3, 8 and 1 in cohort A, B and C respectively. In cohort B, AZA was added to IVO in one patient after 3 cycles, without additional response. With a median follow up of 9.1 months, the median duration of response of the 18 responders was 7.4 months, 9 of them lost their response, and two had died without loss of response (from bleeding and after HSCT, respectively). IPSS-R was the only prognostic factor of response after 6 cycles. At data cut off, 12 patients had progressed (9 in cohort A, 2 in cohort B and 1 in cohort C) and 11 (42%, 10 in cohort A and 1 in cohort C) patients had died, mostly of relapse/progression (n=5/11), infection in 1, suicide in 1, hemorrhage in 1 and other unrelated causes in 3. Median overall survival was 14 months in the whole cohort, 7.7 and not reached in cohort A and B resp. The most common treatment-related serious adverse event (SAE) was differentiation syndrome (4/5), one died and three resolved without sequelae. One patient had febrile neutropenia related to IVO, resolved without sequelae. Conclusion: IVO was well tolerated in MDS patients with significant responses in all the cohorts. With a response rate of 91%, IVO was particularly effective in treatment naïve higher risk MDS patients with IDH1 mutations (cohort B). These encouraging preliminary results have to be confirm in more patients. The IDIOME study is still ongoing, and molecular monitoring results of IDH1 mutations will be presented. Disclosures Sebert: BMS: Consultancy; Abbvie: Consultancy. Cluzeau: Abbvie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Speakers Bureau; Agios: Honoraria; Amgen: Speakers Bureau; Takeda: Other: travel, accommodations, expenses; Astellas: Speakers Bureau; Jazz Pharma: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Other: travel, accommodations, expenses. Stamatoulas Bastard: Pfizer: Other: Travel Support; Celgene: Membership on an entity's Board of Directors or advisory committees. Fenaux: Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Ades: Abbvie: Honoraria; Takeda: Honoraria; Novartis: Honoraria; JAZZ: Honoraria; Celgene: Honoraria, Research Funding.

Published
2021

21. Decitabine Versus Hydroxyurea for Advanced Proliferative CMML: Results of the Emsco Randomized Phase 3 Dacota Trial

Author

Jean E. Goasguen, Anna Maria Pelizzari, Francesco Onida, Pierre Fenaux, Raphael Itzykson, Cendrine Chaffaut, Stanislas Nimubona, Aspasia Stamatoulas Bastard, Eric Wattel, Fatiha Chermat, Sandra Mossuto, Margot Morabito, Ades Lionel, Aristoteles Giagounidis, Nathalie Droin, Valeria Santini, Sophie Park, Sylvain Thepot, Sylvie Chevret, Georgia Metzgeroth, Ulrich Germing, Rosa Sapena, Jose Miguel Torregrosa Diaz, Andrea Patriarca, Nadja Jaekel, Uwe Platzbecker, Silke Gloaguen, Robert Navarro, Eric Solary, Martin Puttrich, Michael Luebbert, and Gina Zini

Subjects
education.field_of_study, medicine.medical_specialty, business.industry, Immunology, Population, Significant difference, Decitabine, Context (language use), Cell Biology, Hematology, Competing risks, Biochemistry, Hematological toxicity, Internal medicine, Medicine, Survival advantage, Response Duration, education, business, medicine.drug
Abstract

Context. The perhaps only CMML-specific Randomized Clinical Trial (RCT) established hydroxyurea (HY) as the main treatment (Tx) for advanced proliferative CMML (Wattel Blood 1996). In Europe, the only hypomethylating agent (HMA) approved in CMML is AZA in non proliferative CMML-2. Phase 2 trials reported the activity of decitabine (DAC) in advanced proliferative CMML (Braun Blood 2011, Santini Leukemia 2018). We performed a RCT of DAC (±HY during the first 3 cycles) vs HY alone in those pts. Methods. The DACOTA trial (EudraCT 2014-000200-10) accrued pts with previously untreated (or < 6 weeks of HY), proliferative (WBC ≥ 13x109/L) CMML with advanced disease defined per Wattel et al as presence of extramedullary disease or ≥2 criteria among: BM blasts ≥5%, abnormal karyotype (except -Y), ANC ≥ 16x109/L, Hb < 10 g/dL, platelets < 100 x109/L or splenomegaly > 5 cm below costal margin. Pts were randomized 1:1 to DAC (20 mg/m2/d IV 5d/28d) or HY (1g/d, adjusted on WBC, 28d cycles) and treated until death, AML transformation or progression. The primary endpoint was EFS, events being death, transformation to AML, progression of myeloproliferation after 3+ cycles or progression of blasts and cytopenias after 6+ cycles. Response was assessed with IWG 2006 criteria modified to account for improvement of myeloproliferation, after central morphology review. Intent-to-treat analyses were done considering missing responses as failures. Results. From Oct 2014 to Sep 2019, 217 pts from 47 centers were screened and 170 randomized (84 DAC and 86 HY), including 12 pts (6 DAC and 6 HY) who never started Tx. Median age was 73 years (IQR 68-78). WHO was CMML-NA/1/2 in 2, 114 and 54 pts, respectively (resp). Median WBC 34.9 x109/L (IQR 22.9-55.7). Cytogenetic risk (Such Haematologica 2011) was fav 69%, int 12%, adv 18% NA 1%. Mutations in TET2, SRSF2, ASXL1 and signaling genes (CBL, JAK2, FLT3, KIT, NRAS, KRAS and CSF3R) were present in 64%, 51%, 62% and 57% resp. 72 pts had received HY for a median 27 days prior to randomization. Aside from older age in the HY arm (median 74 vs 71.5y in the DAC arm), there was no imbalance between Tx arms. DAC and HY pts received a median of 5 (IQR 3-12) and 6 (IQR 3-14) cycles, resp. As of 15th June 2020, 5 and 10 DAC and HY pts were still on Tx. Reasons for Tx cessation in the DAC arm were death (n=19), AML transformation (n=16), progression (n=9) , hematological toxicity (n=13) or other (n=21). Reasons for Tx cessation in the HY arm were death (n=14), AML transformation (n=13), progression (n=18), hematological toxicity (n=6) or other (n=20). 126 and 85 pts received 3 and 6 cycles, resp. In the ITT population, ORR at 3 cycles was 56% (7CR, 25 mCR±HI, 15 SD+HI) and 30% (0 CR, 8 mCR±HI, 18 SD+HI) in the DAC and HY arms, resp (p=0.0011) and ORR at 6 cycles was 32% (6 CR, 9 mCR±HI, 12 SD+HI) and 17% (2 CR, 4 mCR±HI, 9 SD+HI) in the DAC and HY arms, resp (p=0.033). Median response duration was 15.9 vs 18.2 months (mos) in the DAC and HY arm, resp (p=0.81). Infection and hemorrhage occurred at least once in 49% and 31% of pts, resp. 55% of DAC pts and 38% of HY pts required hospitalization at least once (p=0.05). Non-heme ≥ grade 2 AEs occurred in 79% and 63% of DAC and HY arms, resp (p=0.03). Grade ≥3 cardiac AEs occurred in 13 DAC and 4 HY pts, resp. With a median follow-up of 13.9 mos, median EFS was 12.6 vs 10.3 mos in the DAC and HY arms, resp (reference DAC arm, HR= 1.14 CI95 0.8-1.64, p= 0.46). Median AML-free survival (AMLFS) was 13.6 and 15.8 mos in the DAC and HY arms resp (p=0.86). Median OS was 18.4 and 23.1 mos in the DAC and HY arms, resp (p=0.72). Considering death and AML transformation as competing risks there was no significant difference in cumulative incidence of AML (p=0.1) or death without transformation (p=0.06) between arms. 30 pts from the HY arm received an HMA (DAC n= 13, AZA n= 16, both=1) after study exit. Censoring at HMA onset in the HY arm, median OS was 18.4 vs 30.4 in the DAC and HY arm, resp (p=0.15). 13 pts were transplanted (DAC n= 10, HY n= 3). There was no interaction between Tx arm and CMML-0/1 vs -2, platelets ≥ vs 0.05). Conclusion. RCTs are feasible in advanced proliferative CMML, which remains an unmet medical need. In these pts, DAC did not provide an overall or event-free survival advantage over HY. HY remains a valid option in advanced proliferative CMML. However, one third of HY pts subsequently received an HMA and more DAC pts achieved a response and were bridged to HSCT. Figure Disclosures Itzykson: Abbvie: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Sanofi: Honoraria; BMS (Celgene): Honoraria; Janssen: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stemline: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncoethix (now Merck): Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Santini:BMS, J&J, Novartis: Honoraria; Acceleron, BMS, Menarini, Novartis: Consultancy; Takeda, Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Lionel:Abbvie: Consultancy; Takeda: Consultancy; Celgene/BMS: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Luebbert:Janssen: Research Funding. Park:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Other: Travel expenses. Stamatoulas Bastard:Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria; Takeda: Consultancy. Solary:Janssen: Research Funding. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Fenaux:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. OffLabel Disclosure: Decitabine for CMML with WBC > 13 x109/L.

Published
2020

22. Prognosis of alcoholic or viral B/C cirrhosis according to ABO blood group: results of abocirralvir, from CIRRAL and ANRS CO12 CirVir cohorts

Author

Isabelle Ollivier-Hourmand, Pierre Nahon, Cendrine Chaffaut, Thong Dao, Nga Nguyen, Marcellin Patrick, Dominique Roulot, Victor de Lédinghen, Stanislas Pol, Dominique Guyader, Isabelle Mabile-Archambeaud, Fabien Zoulim, Frédéric Oberti, Albert Tran, Jean-Pierre Bronowicki, Louis Dalteroche, Denis Ouzan, Jean Marie Peron, Jean-Pierre Zarski, Marc Bourliere, Dominique Larrey, Alexandre Louvet, Paul Cales, Armand Abergel, Philippe Mathurin, Ariane Mallat, Jean-Frédéric Blanc, Eric Nguyen Khac, Ghassan Riachi, Laurent Alric, Lawrence Serfaty, Tereza Antonini, Christophe Moreno, Pierre Attali, Dominique Thabut, Christophe Pilette, Jean Didier Grange, Christine Silvain, Nicolas Carbonell, Brigitte Bernard Chabert, Odile Goria, Claire Wartelle-Bladou, Romain Moirand, Christos Christidis, Gabriel Perlemuter, Violaine Ozenne, Jean Henrion, Sophie Hillaire, Vincent Di Martino, Xavier Amiot, Angela Sutton, Nathalie Barget, Yohann Repesse, Sylvie Chevret, and Nathalie Ganne-Carrié

Subjects
Hepatology
Published
2020

24. Estimate of hepatocellular carcinoma incidence in patients with alcoholic cirrhosis

Author

Jean-Marie Péron, Jean-Pierre Zarski, Perarnau Jm, Albert Tran, Dominique Roulot, Isabelle Archambeaud, Xavier Amiot, Nicolas Carbonell, Odile Goria, Cendrine Chaffaut, Frédéric Oberti, Eric Nguyen-Khac, Violaine Ozenne, Alexandre Louvet, Stanislas Pol, Gabriel Perlemuter, Sylvie Chevret, Thong Dao, Christophe Moreno, Nathalie Ganne-Carrié, Jean Henrion, Valérie Bourcier, Teresa Antonini, Michel Beaugrand, Victor de Lédinghen, Romain Moirand, Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13), Université Sorbonne Paris Cité (USPC), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Equipe 2 : ECSTRA - Epidémiologie Clinique, STatistique, pour la Recherche en Santé (CRESS - U1153), Université Paris Diderot - Paris 7 (UPD7)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), 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)-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), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Unité d'Hématologie [Bruxelles, Belgium] (CUB Hôpital Erasme), Université libre de Bruxelles (ULB)-CUB Hôpital Erasme [Bruxelles, Belgium], Unité d'Hématologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'Hématologie Biologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), CHU Amiens-Picardie, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Paul Brousse, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Département d'hépatologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Lariboisière-Fernand-Widal [APHP], Unité d'Hématologie [CH de Jolimont-Lobbes, Belgium], Centre Hospitalier de Jolimont-Lobbes [Haine Saint-Paul, Belgium], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), AP-HP - Hôpital Antoine Béclère [Clamart], CHU Tenon [AP-HP], CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, The promoter of the study was the Assistance Publique des Hôpitaux de Paris (APHP), and the cohort was funded by the Institut National du Cancer (INCa) and the French Association for Research in Cancer and the National Agency for Research on HIV and Hepatitis., Jonchère, Laurent, Université Fédérale Toulouse Midi-Pyrénées, Ligue Nationnale Contre le Cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris], Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université Libre de Bruxelles [Bruxelles] (ULB)-CUB Hôpital Erasme [Bruxelles, Belgium], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [APHP], CHU Cochin [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Cochin [AP-HP], Hôpital Lariboisière, Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Antoine Béclère, CHU Tenon [APHP], Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Male, Alcoholic liver disease, Cirrhosis, Biopsy, Gastroenterology, Liver disease, 0302 clinical medicine, Liver Cirrhosis, Alcoholic, Risk Factors, Gastro-entérologie, Prospective Studies, HCC, Prospective cohort study, education.field_of_study, Mortality rate, Incidence (epidemiology), Incidence, Liver Neoplasms, Age Factors, Middle Aged, Progression-Free Survival, 3. Good health, Liver, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Female, Prothrombin, alpha-Fetoproteins, medicine.medical_specialty, Carcinoma, Hepatocellular, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Milan criteria, 03 medical and health sciences, Competing risk analysis, Sex Factors, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, education, Aged, Hepatology, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Bilirubin, medicine.disease, digestive system diseases, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Multivariate Analysis, Compensated cirrhosis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Follow-Up Studies
Abstract

Background & Aims: More than 90% of cases of hepatocellular carcinoma (HCC) occur in patients with cirrhosis, of which alcohol is a major cause. The CIRRAL cohort aimed to assess the burden of complications in patients with alcoholic cirrhosis, particularly the occurrence of HCC. Methods: Patients with biopsy-proven compensated alcoholic cirrhosis were included then prospectively followed. The main endpoint was the incidence of HCC. Secondary outcomes were incidence of hepatic focal lesions, overall survival (OS), liver-related mortality and event-free survival (EFS). Results: From October 2010 to April 2016, 652 patients were included in 22 French and Belgian centers. During follow-up (median 29 months), HCC was diagnosed in 43 patients. With the limitation derived from the uncertainty of consecutive patients’ inclusion and from a sizable proportion of dropouts (153/652), the incidence of HCC was 2.9 per 100 patient-years, and one- and two-year cumulative incidences of 1.8% and 5.2%, respectively. Although HCC fulfilled the Milan criteria in 33 cases (77%), only 24 patients (56%) underwent curative treatment. An explorative prognostic analysis showed that age, male gender, baseline alpha-fetoprotein, bilirubin and prothrombin were significantly associated with the risk of HCC occurrence. Among 73 deaths, 61 had a recorded cause and 27 were directly attributable to liver disease. At two years, OS, EFS and cumulative incidences of liver-related deaths were 93% (95% CI 90.5–95.4), 80.3% (95% CI 76.9–83.9), and 3.2% (95% CI 1.6–4.8) respectively. Conclusion: This large prospective cohort incompletely representative of the whole population with alcoholic cirrhosis showed: a) an annual incidence of HCC of up to 2.9 per 100 patient-years, suggesting that surveillance might be cost effective in these patients; b) a high proportion of HCC detected within the Milan criteria, but only one-half of detected HCC cases were referred for curative treatments; c) a two-year mortality rate of up to 7%. Lay summary: Cirrhosis is a risk factor for primary liver cancer, leading to recommendations for periodic screening. However, for alcohol-related liver disease the rational of periodic screening for hepatocellular carcinoma (HCC) is controversial, as registry and databased studies have suggested a low incidence of HCC in these patients and highly competitive mortality rates. In this study, a large cohort of patients with biopsy-proven alcoholic cirrhosis prospectively screened for HCC demonstrated a high annual incidence of HCC (2.9%) and a high percentage of small cancers theoretically eligible for curative treatment. This suggests that patients with liver disease related to alcohol should not be ruled out of screening., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2017

25. Lenalidomide combined with intensive chemotherapy in acute myeloid leukemia and higher-risk myelodysplastic syndrome with 5q deletion. Results of a phase II study by the Groupe Francophone Des Myélodysplasies

Author

Marie Sebert, Hervé Dombret, Norbert Vey, Sylvie Chevret, Mathilde Hunault, Lionel Ades, Pierre Fenaux, Aspasia Stamatoullas, Emmanuel Raffoux, Andrea Toma, Romain Guieze, Laure Stalnikiewicz, Christian Recher, Eric Wattel, Cendrine Chaffaut, Claude Gardin, Thomas Prebet, Krimo Bouabdallah, Service d'hématologie clinique [Avicenne], 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), Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Mohamed Boudiaf de M'sila, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lymphocyte et cancer, IFR105-Institut National de la Santé et de la Recherche Médicale (INSERM), Hematology (IPC-Marseille), Hôpital Avicenne [AP-HP], Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne, CRLCC Henri Becquerel, Service d'hématologie, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias - Clermont Auvergne (CHELTER), Université Clermont Auvergne (UCA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital avicenne, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-CHU Saint Louis [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut national du cancer [Boulogne] (INCA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL)

Subjects
Acute Myeloid Leukemia, Adult, Male, medicine.medical_specialty, Acute myeloblastic leukemia, Population, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Cumulative incidence, education, Lenalidomide, ComputingMilieux_MISCELLANEOUS, Aged, education.field_of_study, business.industry, Myelodysplastic syndromes, Myeloid leukemia, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Articles, Middle Aged, medicine.disease, Prognosis, 3. Good health, Thalidomide, Transplantation, Leukemia, Leukemia, Myeloid, Acute, Treatment Outcome, 030220 oncology & carcinogenesis, Myelodysplastic Syndromes, Immunology, Chromosomes, Human, Pair 5, Female, Chromosome Deletion, business, 030215 immunology, medicine.drug
Abstract

Patients with acute myeloblastic leukemia or higher risk myelodysplastic syndromes with 5q deletion (generally within a complex karyotype) respond poorly to intensive chemotherapy and have very poor survival. In this population, we evaluated escalating doses of lenalidomide combined with intensive chemotherapy in a phase II study. Treatment consisted of daunorubicin (45 mg/m2/day, days 1-3 in cohort 1, escalated to 60 mg/m2/day, days 1-3 in cohorts 2 and 3) combined with cytosine arabinoside (200 mg/m2/day, days 1-7) and lenalidomide (10 mg/day, days 1-21 in cohorts 1 and 2, escalated to 25 mg/day, days 1-21 in cohort 3). Eighty-two patients with 5q deletion were enrolled, including 62 with acute myeloblastic leukemia, 62/79 (78%) of whom had a complex karyotype (median 7 cytogenetic abnormalities, all but 2 of them monosomal) and three had unknown karyotypes. Thirty-eight patients (46%) achieved complete remission and the overall response rate was 58.5%. Among the 62 patients with a complex karyotype, 27 achieved complete remission (44%) and 21 had cytogenetic responses. A lower response rate was observed in patients with acute myeloblastic leukemia but other pretreatment factors, including cytogenetic complexity and treatment cohort, did not significantly influence response. Fifteen patients underwent allogeneic stem cell transplantation, including 11 patients in first remission. The 1-year cumulative incidence of relapse was 64.6% and the median overall survival was 8.2 months. By comparison with conventional intensive chemotherapy, the treatment protocol we used appeared to produce higher hematologic and cytogenetic complete remission rates in patients with very poor cytogenetics, but response duration was short in this very poor risk population, highlighting the need for better post-induction strategies. Clinical trial registry number: NCT00885508.

Published
2017

26. Prognostic value of nocturnal hypoventilation in neuromuscular patients

Author

Frédéric Lofaso, Nicholas Heming, Cendrine Chaffaut, David Orlikowski, Maria-Antonia Quera Salva, Adam Ogna, Sylvie Chevret, Djillali Annane, and Hélène Prigent

Subjects
Adult, Male, medicine.medical_specialty, Vital capacity, Neuromuscular disease, medicine.medical_treatment, Nocturnal, Hypercapnia, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Genetics (clinical), Mechanical ventilation, business.industry, Hazard ratio, Hypoventilation, Neuromuscular Diseases, Middle Aged, medicine.disease, Prognosis, Respiration, Artificial, Surgery, 030228 respiratory system, Neurology, Pediatrics, Perinatology and Child Health, Cohort, Cardiology, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

In neuromuscular disease (NMD) patients, current guidelines recommend the initiation of home mechanical ventilation (HMV) in case of daytime hypercapnia or nocturnal desaturation as an indirect sign of hypoventilation. Transcutaneous capno-oximetry (TcCO 2 ) enables the direct assessment of nocturnal hypercapnia; however the best cut-off value remains to be defined. We aimed to compare the prognostic value of several published definitions of nocturnal hypercapnia in a cohort of NMD patients. All consecutive TcCO 2 recordings performed between 2010 and 2014 in unventilated adult NMD patients in a tertiary reference centre were retrospectively collected. Initiation of HMV and mortality were collected as outcomes of interest. 124 patients with normal daytime blood gazes were analysed (median age 39 [IQR 31–55] years; vital capacity 61% [43–82] of predicted). The prevalence of nocturnal hypercapnia ranged from 3% to 44%, depending on the definition. Over a median follow-up duration of 2.5 years [IQR 1.6–4.1], HMV was initiated for 51 patients, whilst 4 patients died. Nocturnal peak TcCO 2 ≥49 mmHg was the best predictor of HMV initiation in the follow-up, being associated with a hazard ratio of 2.6 [95% CI 1.4–4.6] in a multivariate analysis adjusting for lung function parameters. Nocturnal TcCO 2 identifies NMD patients at risk for subsequent need for HMV in the following few years, who were not identified by daytime blood gases or nocturnal oximetry. As a consequence, peak nocturnal TcCO 2 ≥49 mmHg should be considered as one of the criteria to start HMV in patients with NMDs, along with symptoms of hypoventilation, daytime hypercapnia, abnormal nocturnal oximetry results, and a diminished level of forced vital capacity.

Published
2016

27. Left bundle branch block in Duchenne muscular dystrophy: Prevalence, genetic relationship and prognosis

Author

F. Leturcq, Bernard Clair, H. Prigent, D. Orlikowski, Adam Ogna, Frédéric Lofaso, Djillali Annane, R. Ben Yaou, Cendrine Chaffaut, Sylvie Chevret, Abdallah Fayssoil, and Olivier Nardi

Subjects
musculoskeletal diseases, Mechanical ventilation, congenital, hereditary, and neonatal diseases and abnormalities, Supraventricular arrhythmia, medicine.medical_specialty, biology, business.industry, Left bundle branch block, medicine.medical_treatment, Duchenne muscular dystrophy, medicine.disease, University hospital, Predictive factor, Heart failure, Internal medicine, medicine, biology.protein, Cardiology, Cardiology and Cardiovascular Medicine, Dystrophin, business
Abstract

Background Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder due to mutations in the dystrophin gene on chromosome Xp21.1. We designed this study to determine the prevalence of LBBB, whether there is a relationship between LBBB and genetic pattern and to assess predictive factors of acute cardiac events in adult DMD patients. Methods We reviewed the charts of DMD followed at the Home Mechanical Ventilation Unit of the Raymond Poincare University Hospital. Results A total of 121 patients, aged from 18 years to 41 years were included in our study. Median VC was 12% [7;19.5] of predicted. Almost all patients were on home mechanical ventilation (95%). LBBB was present in 15 patients (13%); among them, 10 disclosed exonic deletions. After a median follow-up of 6 years, 21 patients (17%) experienced acute heart failure (AHF), 7 patients (6%) supraventricular arrhythmia, 3 patients (2.4%) ventricular arrhythmia, 4 patients (3%) significant electrical disturbances. LBBB was significantly associated with cardiac events (OR = 12.7; 95%CI [3.78–42.7]; P Conclusion LBBB is a major predictive factor of cardiac events in DMD. Presence of residual dystrophin protein seems to be associated with less cardiac events.

Published
2018

28. Natural History of Cardiac and Respiratory Involvement, Prognosis and Predictive Factors for Long-Term Survival in Adult Patients with Limb Girdle Muscular Dystrophies Type 2C and 2D

Author

Bernard Clair, Sylvie Chevret, Djillali Annane, Raquel Guimarães-Costa, Abdallah Fayssoil, Tanya Stojkovic, Cendrine Chaffaut, Olivier Nardi, David Orlikowski, Adam Ogna, Pascal Laforêt, Karim Wahbi, Anthony Behin, Hélène Prigent, Frédéric Lofaso, HAL UPMC, Gestionnaire, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de réanimation médicale[Poincaré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Centre d’Investigation Clinique 1429 [Garches] (CIC 1429), Hôpital Raymond Poincaré [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Cardiologie [CHU Cochin], Service de physiologie et d'explorations fonctionnelles [CHU Raymond-Poincaré], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut national du cancer [Boulogne] (INCA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hôpital Cochin [AP-HP]

Subjects
Male, Heredity, Pulmonology, Genetic Linkage, Physiology, Vital Capacity, Cardiomyopathy, lcsh:Medicine, Duchenne Muscular Dystrophy, Cardiovascular Physiology, Muscular Dystrophies, 0302 clinical medicine, Medicine and Health Sciences, Medicine, Respiratory function, Respiratory system, lcsh:Science, Multidisciplinary, Ejection fraction, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Heart, Prognosis, Respiratory Muscles, 3. Good health, Neurology, X-Linked Traits, Sex Linkage, Cardiology, Female, Cardiomyopathies, Respiratory Insufficiency, Research Article, Adult, medicine.medical_specialty, Death Rates, Diastole, 03 medical and health sciences, Population Metrics, Respiratory Failure, Diagnostic Medicine, Internal medicine, Respiratory muscle, Sarcoglycanopathies, Genetics, Humans, Demography, Clinical Genetics, Population Biology, business.industry, lcsh:R, Biology and Life Sciences, Arrhythmias, Cardiac, medicine.disease, Surgery, 030228 respiratory system, Respiratory failure, Muscular Dystrophies, Limb-Girdle, Heart failure, People and Places, lcsh:Q, business, Physiological Processes, Sleep, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Ejection Fraction
Abstract

BACKGROUND:Type 2C and 2D limb girdle muscular dystrophies (LGMD) are a group of autosomal recessive limb girdle muscular dystrophies manifested by proximal myopathy, impaired respiratory muscle function and cardiomyopathy. The correlation and the prognostic impact of respiratory and heart impairment are poorly described. We aimed to describe the long-term cardiac and respiratory follow-up of these patients and to determine predictive factors of cardio-respiratory events and mortality in LGMD 2C and 2D. METHODS:We reviewed the charts of 34 LGMD patients, followed from 2005 to 2015, to obtain echocardiographic, respiratory function and sleep recording data. We considered respiratory events (acute respiratory failure, pulmonary sepsis, atelectasis or pneumothorax), cardiac events (acute heart failure, significant cardiac arrhythmia or conduction block, ischemic stroke) and mortality as outcomes of interest for the present analysis. RESULTS:A total of 21 patients had type 2C LGMD and 13 patients had type 2D. Median age was 30 years [IQR 24-38]. At baseline, median pulmonary vital capacity (VC) was 31% of predicted value [20-40]. Median maximal inspiratory pressure (MIP) was 31 cmH2O [IQR 20.25-39.75]. Median maximal expiratory pressure (MEP) was 30 cm H2O [20-36]. Median left ventricular ejection fraction (LVEF) was 55% [45-64] with 38% of patients with LVEF

Published
2016

29. Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: A randomized trial comparing 3- and 6-month periodicities

Author

Valérie Bourcier, Sylvie Chevret, Jean-Pierre Bronowicki, Jean-Pierre Vinel, Isabelle Ollivier, Valérie Vilgrain, Cendrine Chaffaut, Sophie Hillaire, Philippe Mathurin, Paul Calès, Jean-Claude Trinchet, Ariane Mallat, Michel Beaugrand, Dominique Roulot, Françoise Degos, Gisèle N'Kontchou, Hélène Fontaine, Jean Henrion, Service d'hépato-gastroentérologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Hôpital Jean Verdier [AP-HP], Université Paris Nord (Paris 13), Service d'hépatologie, Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Hôpital de Jolimont, Hopital de Jolimont, Service d'hépatologie médicale [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Service de Gastro-entérologie [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Foch [Suresnes], Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Gastro-entérologie - Hépatologie [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service d'Hépato-gastroentérologie, Hôpital Huriez-Université de Lille, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'imagerie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Biostatistique et épidemiologie clinique, UFR Santé, Médecine et Biologie Humaine (UFR SMBH), Université Sorbonne Paris Nord, Service d’Hépatologie [Hôpital Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Cochin [AP-HP], Université Paris Descartes - Paris 5 (UPD5), Université Paris 13 (UP13), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Beaujon, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP]

Subjects
Liver Cirrhosis, Male, medicine.medical_specialty, Carcinoma, Hepatocellular, Cirrhosis, [SDV]Life Sciences [q-bio], medicine.disease_cause, Gastroenterology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Belgium, Randomized controlled trial, law, Internal medicine, Carcinoma, Humans, Medicine, Cumulative incidence, Early Detection of Cancer, Ultrasonography, Hepatitis B virus, Hepatology, business.industry, Incidence, Incidence (epidemiology), Liver Neoplasms, Middle Aged, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Female, 030211 gastroenterology & hepatology, France, alpha-Fetoproteins, Radiology, business, Follow-Up Studies
Abstract

International audience; Detection of small hepatocellular carcinoma (HCC) eligible for curative treatment is increased by surveillance, but its optimal periodicity is still debated. Thus, this randomized trial compared two ultrasonographic (US) periodicities: 3 months versus 6 months. A multicenter randomized trial was conducted in France and Belgium (43 sites). Patients with histologically proven compensated cirrhosis were randomized into two groups: US every 6 months (Gr6M) or 3 months (Gr3M). For each focal lesion detected, diagnostic procedures were performed according to European Association for the Study of the Liver guidelines. Cumulative incidence of events was estimated, then compared using Gray's test. The prevalence of HCC ≤30 mm in diameter was the main endpoint. A sample size of 1,200 patients was required. A total of 1,278 patients were randomized (Gr3M, n = 640; Gr6M, n = 638; alcohol 39.2%, hepatitis C virus 44.1%, hepatitis B virus 12.5%). At least one focal lesion was detected in 358 patients (28%) but HCC was confirmed in only 123 (9.6%) (uninodular 58.5%, ≤30 mm in diameter 74%). Focal-lesion incidence was not different between Gr3M and Gr6M groups (2-year estimates, 20.4% versus 13.2%, P = 0.067) but incidence of lesions ≤10 mm was increased (41% in Gr3M versus 28% in Gr6M, P = 0.002). No difference in either HCC incidence (P = 0.13) or in prevalence of tumors ≤30 mm in diameter (79% versus 70%, P = 0.30) was observed between the randomized groups. Conclusion: US surveillance, performed every 3 months, detects more small focal lesions than US every 6 months, but does not improve detection of small HCC, probably because of limitations in recall procedures. (HEPATOLOGY 2011;)

Published
2011

30. Natural history of cardiac function in Duchenne and Becker muscular dystrophies on home mechanical ventilation

Author

Sylvie Chevret, Djillali Annane, Xavier Ambrosi, Abdallah Fayssoil, Frédéric Lofaso, Bernard Clair, Laure Lamothe, Cendrine Chaffaut, David Orlikowski, Adam Ogna, Olivier Nardi, and Hélène Prigent

Subjects
Duchenne muscular dystrophy, Adult, Cardiac function curve, medicine.medical_specialty, Adolescent, Heart Diseases, pneumothorax, medicine.medical_treatment, Diastole, Observational Study, heart failure, mechanical ventilation, 030204 cardiovascular system & hematology, Doppler echocardiography, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, echocardiography, Humans, Cumulative incidence, Tidal volume, Retrospective Studies, Mechanical ventilation, Ejection fraction, medicine.diagnostic_test, business.industry, respiratory failure, Heart, General Medicine, Respiration, Artificial, Echocardiography, Doppler, 3. Good health, Muscular Dystrophy, Duchenne, 030228 respiratory system, Becker muscular dystrophy, Spirometry, Breathing, Cardiology, Respiratory Insufficiency, business, Research Article
Abstract

Heart impairment is classical in dystrophinopathies and its management relies on medical drugs. Mechanical ventilation is used to treat respiratory failure, but can affect cardiac function. We aimed to investigate the natural history of cardiac function in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies on home mechanical ventilation (HMV). We reviewed the chart of DMD and BMD patients, followed in our institution, to obtain ventilation setting at HMV initiation and echocardiographic data at baseline and end follow up, as well as onset cardiac events and thoracic mechanical complication. We analyzed cumulative incidence of cardiac events as well as echocardiographic parameters evolution and its association with ventilation settings. We included 111 patients (101 DMD and 10 BMD). Median age was 21 years [18–26], median pulmonary vital capacity (VC) 15% of predicted [10–24]. All patients were on HMV and 46% ventilated using tracheostomy. After a median follow up of 6.3 years, we found a slight decrease of the left ventricular ejection fraction (LVEF) (45% at end follow up vs 50% at baseline P = .019) and a stabilization of the LV end diastolic diameter indexed (LVEDD indexed 29.4 mm/m2 vs 30.7 mm/m2 at end follow up, P = .17). Tidal volume (VT) level was inversely associated with the annual rate of the LVEF decline (r = −0.29, P = .025). Left atrium (LA) diameter decreased with mechanical ventilation (24 mm vs 20 mm, P = .039) and we found a reduction of systolic pulmonary pressure (35 mm Hg vs 25 mm Hg, P = .011). The cumulative incidence of cardiac events was 12.6%. Pneumothorax occurred in 4% of patients. Hypoxic arrest secondary to the presence of tracheal plugin occurred in 4% of patients with invasive ventilation. HMV is not harmful, decreases pulmonary pressure and may protect heart in dystrophinopathies, in addition with cardioprotective drugs. In patients with DMD and BMD on HMV, cumulative incidence of cardiac events remains moderate and incidence of pneumothorax is rare.

Published
2018

31. G08 : Incidence of hepatocellular carcinoma (HCC) and complications in alcoholic compensated cirrhosis. Preliminary results of a multicenter prospective French and belgian cohort (INCA Cirral)

Author

Xavier Amiot, Cendrine Chaffaut, Jean Charles Duclos-Vallée, I. Archambaud, Dominique Roulot, Albert Tran, Eric Nguyen-Khac, Odile Goria, Violaine Ozenne, Romain Moirand, Jean-Pierre Zarski, Nicolas Carbonell, V. de Ledinghen, Stanislas Pol, Sylvie Chevret, Alexandre Louvet, Christophe Moreno, V. Bourcier, Thong Dao, Jean-Marc Perarnau, Jean Henrion, Nathalie Ganne, Frédéric Oberti, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier St. Joseph, Department of Gastroenterology, Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
0303 health sciences, medicine.medical_specialty, Cirrhosis, [ SDV ] Life Sciences [q-bio], Hepatology, 030309 nutrition & dietetics, business.industry, Incidence (epidemiology), [SDV]Life Sciences [q-bio], 030209 endocrinology & metabolism, medicine.disease, Gastroenterology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Hepatocellular carcinoma, Cohort, medicine, business, ComputingMilieux_MISCELLANEOUS
Abstract

International audience; no abstract

Published
2015

32. Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort)

Author

Yannick Bacq, Victor de Ledinghen, Gérard Thiéfin, Claire Wartelle, Marc Bourlière, Sylvie Chevret, Lawrence Serfaty, Christophe Pilette, Jean-Pierre Zarski, S. Allam, Denis Ouzan, Dominique Guyader, Yves Benhamou, Jean-Didier Grangé, Cendrine Chaffaut, Jean-Marie Péron, Dominique Larrey, Ariane Mallat, Dominique Roulot, Fabien Zoulim, Dominique Capron, Odile Goria, Catherine Buffet, Vincent Di Martino, Jean-Pierre Bronowicki, Armand Abergel, Christine Silvain, Sophie Hillaire, Mohand Ait Ahmed, Pierre Nahon, Stanislas Pol, Christos Christidis, Valérie Bourcier, Jean-Claude Trinchet, Thong Dao, Jean-Frédéric Blanc, Laurent Alric, Albert Tran, Paul Calès, Philippe Mathurin, Patrick Marcellin, Service d'Hépato-gastroentérologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hépatologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Cellules souches normales et cancéreuses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Institut Arnaud Tzanck, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Service de Gastro-entérologie [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Département digestif, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Département d'hépato-gastroentérologie, CHU Grenoble-Université Grenoble Alpes (UGA), CHU Rouen, Normandie Université (NU), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Service d'hépato-gastro-entérologie, Assistance Publique - Hôpitaux de Marseille (APHM), Hôpital Huriez-Université de Lille, Inserm, UMR-1053, Université de Bordeaux, Bordeaux, F-33076, France, Centre hospitalier universitaire de Bordeaux, Department of Hepatology, Hôpital Saint-André, Bordeaux, F-33076, France, CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Service d'hépatologie [Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de gastro-entérologie [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hopital d'Aix en Provence, Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Mobilités : Attention, Orientation et Chronobiologie (COMETE), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Le Mans (CH Le Mans), Hôpital de la Milétrie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'Hépatogastroentérologie, CHU Amiens-Picardie, Institut Mutualiste de Montsouris (IMM), Hôpital Foch [Suresnes], Hôpital JeanMinjoz, Service d'hépato-gastroentérologie, Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biostatistique et épidemiologie clinique, Agence Nationale de Recherches sur le Sida et les Hepatites Virales, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Grenoble Alpes (UGA)-CHU Grenoble, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Jean Verdier, Centre de recherche sur l'Inflammation ( CRI ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -CHU Saint-Eloi, Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hospices Civils de Lyon ( HCL ), Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, CHU Nice, Centre méditérannéen de médecine moléculaire ( C3M ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble, Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques ( HIFIH ), Université d'Angers ( UA ), Hepato-gastro-enterology, Toulouse University hospital, Pharmacochimie et Pharmacologie Pour le Développement ( PHARMA-DEV ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique ( CNRS ), Assistance Publique - Hôpitaux de Marseille ( APHM ), Centre Hospitalier Universitaire Estaing, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Service de gastro-entérologie, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Service d'Hépato-Gastro-Enterologie et Nutrition [Caen], Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, Mobilités : Attention, Orientation et Chronobiologie ( COMETE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Service d'Hépato-Gastroentérologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre hospitalier universitaire de Poitiers ( CHU Poitiers ), Assistance publique - Hôpitaux de Paris (AP-HP), Centre de recherche biomédicale Bichat-Beaujon ( CRB3 ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Jean Verdier [AP-HP], Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Service d’Hépatologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], 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), Département d'hépatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département d'Hépato-Gastroentérologie et de Transplantation Hépatique [CHU Saint-Eloi], Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hépatologie et de Gastroentérologie [Lyon], Université Nice Sophia Antipolis (1965 - 2019) (UNS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Service d'hépatologie et de gastroentérologie [Hôpital Saint-Joseph - Marseille], Aix Marseille Université (AMU)-Hôpital Saint-Joseph [Marseille], Hôpital Claude Huriez [Lille], CHU Lille, Hôpital Saint-André, Service d'Hépatologie Gastro-entérologie [CHU Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Institut mutualiste Monsouris (IMM), CHU Saint-Eloi-Université de Montpellier (UM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Service d'hépatologie [CHU Saint-Antoine], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], and Service d'Hépato-gastro-entérologie [CHU Saint-Antoine]

Subjects
Liver Cirrhosis, Male, Cirrhosis, [SDV]Life Sciences [q-bio], Hepatocellular / physiopathology, Liver Neoplasms / mortality, medicine.disease_cause, Gastroenterology, Cohort Studies, Liver disease, Cause of Death, Liver Cirrhosis / complications, Longitudinal Studies, Prospective Studies, Prospective cohort study, Liver Failure / mortality, Hepatocellular / virology, Liver Neoplasms, Hepatitis C / complications, Middle Aged, Hepatitis B, Hepatitis C, 3. Good health, Hepatocellular carcinoma, Disease Progression, Female, France, Liver cancer, Hepatitis C / pathology, Hepatitis B / pathology, Adult, medicine.medical_specialty, Carcinoma, Hepatocellular, Liver Neoplasms / pathology, Milan criteria, Risk Assessment, Liver Cirrhosis / virology, Predictive Value of Tests, Internal medicine, Liver Failure / pathology, medicine, Humans, Decompensation, Hepatitis B / complications, Proportional Hazards Models, Hepatitis B virus, Liver Failure / virology, Analysis of Variance, Hepatology, [ SDV ] Life Sciences [q-bio], business.industry, Carcinoma, medicine.disease, Survival Analysis, digestive system diseases, Liver Neoplasms / virology, Liver Cirrhosis / mortality, Multivariate Analysis, Hepatocellular / mortality, business, Liver Failure
Abstract

International audience; Various critical events, liver related or not, occur in patients with compensated cirrhosis, but their respective burden remains to be prospectively assessed. The aim of this prospective cohort study involving 35 French centers was to capture the whole spectrum of complications occurring in compensated viral cirrhosis (VC) using competing risks analyses. Inclusion criteria were: histologically proven cirrhosis resulting from hepatitis C virus (HCV) or hepatitis B virus (HBV); Child-Pugh A; and no previous hepatic complications. The cohort was considered as a multistate disease model, cumulative incidences (CumIs) of events were estimated in a competing risks framework. A total of 1,654 patients were enrolled from 2006 to 2012 (HCV, 1,308; HBV, 315; HCV-HBV, 31). During a median follow-up of 34 months, at least one liver nodule was detected in 271 patients, confirmed as hepatocellular carcinoma (HCC) in 128 (4-year cumI: 10.5%) and cholangiocarcinoma in 3. HCC incidence was higher in HCV (4-year cumI: 11.4% vs. 7.4%; P = 0.05). HCC fulfilled Milan criteria in 79.3%, leading to curative treatment in 70.4%. Liver decompensation occurred more frequently in HCV patients (4-year cumI: 10.8% vs. 3.6%; P = 0.0004). Virological eradication/control was achieved in 34.1% of HCV and 88.6% of HBV patients and was associated with a marked decrease in HCC, decompensation, and bacterial infection incidences. Survival was shorter in HCV patients (4-year cumI: 91.6% vs. 97.2%; P = 0.0002). Death (n = 102; missing data: 6) was attributed to liver disease in 48 (47%; liver cancer: n = 18; miscellaneous, n = 30) and extrahepatic causes in 48 (47%; bacterial infection: n = 13; extrahepatic cancers: n = 10; cardiovascular events: n = 5; miscellaneous, n = 20). CONCLUSION: After 3 years of follow-up, extrahepatic events still explained half of deaths in patients with compensated VC. A strong decrease in complications was linked to virological eradication/control. (Hepatology 2015;62:737-750)

Published
2015

33. Outcome of and Prognostic Factors for Herpes Simplex Encephalitis in Adult Patients: Results of a Multicenter Study

Author

Sylvie Chevret, Philippe Canton, Cendrine Chaffaut, Frédérique Delatour, Thomas de Broucker, Franck Raschilas, Flore Rozenberg, Michel Wolff, and Pierre Lebon

Subjects
Adult, Male, Microbiology (medical), medicine.medical_specialty, Multivariate analysis, Adolescent, Acyclovir, medicine.disease_cause, Antiviral Agents, Herpesviridae, Central nervous system disease, Internal medicine, Humans, Multicenter Studies as Topic, Medicine, Risk factor, Simplified Acute Physiology Score, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Brain, Retrospective cohort study, Middle Aged, Prognosis, medicine.disease, Surgery, Radiography, Treatment Outcome, Infectious Diseases, Multivariate Analysis, Female, Encephalitis, Herpes Simplex, Viral disease, business, Encephalitis
Abstract

Management of herpes simplex encephalitis (HSE) has been considerably improved by the availability of acyclovir therapy and rapid polymerase chain reaction (PCR)-based diagnostic assays. Prognostic factors for this rare affliction are, however, misestimated. We conducted a large retrospective multicenter study that included 93 adult patients in whom HSE was diagnosed by PCR from 1991 through 1998 and who were treated with intravenous acyclovir. Among the 85 patients assessed at 6 months, 30 (35%) had a poor outcome, which led to death in 13 patients (15%) and severe disability in 17 (20%). The outcome was favorable for 55 patients (65%). A multivariate analysis identified 2 factors that were found to be independently associated with poor outcome: a Simplified Acute Physiology Score II >/=27 at admission and a delay of >2 days between admission to the hospital and initiation of acyclovir therapy. Early administration of antiviral therapy is the only parameter that can be modified to improve the prognosis of patients with HSE.

Published
2002

34. Results of a Phase II Study of Guadecitabine (SGI-110) in Higher Risk MDS, CMML or Low Blast Count AML Patients Refractory to or Relapsing after Azacitidine (AZA) Treatment

Author

Sophie Park, Fatiha Chermat, Cecile Bally, Odile Beyne-Rauzy, Eric Wattel, Emmanuel Gyan, Laurence Sanhes, Benedicte Samey, Pierre Peterlin, Cendrine Chaffaut, Laurence Legros, Marie Sebert, Marie Pierre Gourin, Kamel Laribi, Aspasia Stamatoullas, Luke Bevan, Anne Banos, Pierre Fenaux, Sylvie Chevret, Simone Jueliger, Lionel Ades, and Rosa Sapena

Subjects
medicine.medical_specialty, medicine.medical_treatment, Immunology, Population, Azacitidine, Decitabine, Phases of clinical research, Epley maneuver, Biochemistry, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Refractory, Internal medicine, medicine, Myocardial infarction, education, education.field_of_study, biology, business.industry, C-reactive protein, Cell Biology, Hematology, medicine.disease, 030220 oncology & carcinogenesis, biology.protein, business, 030215 immunology, medicine.drug
Abstract

Background: Hypomethylating agents (HMAs) have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and median survival after HMA failure is only about 6 months (Prébet et al, JCO 2011). Guadecitabine (GDAC, SGI-110) is a novel HMA dinucleotide of Decitabine and deoxyguanosine, administered SC, which results in extended DAC exposure. In a phase I-II study in AML (Issa, Lancet Oncol, 2015) a dose of 60mg/m2/day for 5 consecutive days was recommended. We designed a national multicenter phase II study evaluating the efficacy of GDAC in higher-risk MDS patients, refractory or relapsing after AZA (NCT02197676). Methods: Main inclusion criteria were (1) IPSS int-2 or high MDS, or CMML with WBC < 13 G/l and marrow blasts > 10%, or AML with 20-30% marrow blasts (2) Refractory to 6 cycles of AZA or relapsing after response, but without overt progression (i.e., greater than doubling of marrow blasts compared to pre AZA values) (3) Age ≥ 18 years (4) Normal liver and renal functions. Patients received GDAC 60mg/m2/d x5 d every 28 d until progression, death or no response after 6 cycles (extended to 9 cycles after the 20 first pts). Global DNA methylation was assessed at baseline and on d 8, 15, 22 and 28 of cycle 1 in blood, and on d 28 of cycles 1 , 3 and 6 in BM and blood ,using bisulfite-converted DNA followed by pyrosequencing technology measuring 3 representative CpG sites of the LINE-1 promoter region. An intent-to-treat analysis was performed on June 2016, with a median FU of 9.6 months Results: Between Aug 2014 and Jan 2016, 56 pts from 13 centers were enrolled, M/F: 37/19, median age 75 years [IQR, 69-76]. 15 patients had primary resistance after 6 cycles of AZA, and 41 patients had relapsed after a response and a median of 13 AZA cycles [IQR 9.75-23]). 15 pts had IWG 2006 progression between onset of AZA and inclusion. At inclusion, WHO classification was RCMD in 2 pts, CMML in 1 pt, RAEB-1 in 11 pts, RAEB-2 in 31 pts and AML in 11 pts; . IPSS was int-1, int-2 and high in 4 (6%), 27 (50%) and 23 (42%) pts, resp. (2NA), and R-IPSS was low, int., high and very high in 1 (2%), 3 (6%), 13 (26%), and 34 (60.7%) pts resp (5NA). 43 (77%) pts were RBC transfusion-dependent (TD) and ECOG was >1 in 5 (9%) pts. The average baseline LINE-1 methylation level in the 45 pts evaluated was 73% in blood and 72% in BM. One pt died before any treatment, and 55 patients received at least one cycle of GDAC, with a median of 3 cycles [IQR, 2-5.5]. 9 pts responded (8 after 3 cycles) with 1 (3%) CR, 2 (5%) CRp, 5 (14%) marrow CR and 1 HI; ie an ORR of 16% (95%CI, 8-28%). Responses were seen in 4/15 (26.6%) primary refractory, and in 5/41 (12.2%) relapsing patients (p=NS). On average, the maximum LINE-1 demethylation occurred during the first cycle on day 8 in blood (median -11.3%), and on day 28 in BM (median -3.1%). Median duration of response was 9 months including so far 2 responses ≥ 1 year (12 and 18 months). 49 SAE occurred in 44 pts, and were mostly hematological, with myelosupression in 35/56 (63%) of pts 49 patients ended the study, because of progression (n=20), death (n=14), investigator or patient decision (n= 8), toxicities (n= 6) and pt withdrawal (n=1). Median OS from inclusion was 6.7 months (IC95% [5.6-11.8]). 33 pts had died, because of MDS progression in 14 (42%), infection in 13 (39.3%), bleeding in 1 (3%), and other causes in 5 (15%) pts (2 UK, 2 general deterioration, 1 heart attack). No significant prognostic factor of response to GDAC, including age, sex, ECOG, TD, baseline Hb, platelet, ANC, marrow blast %, cytogenetics, IPSS, IPSS-R, type of AZA failure (primary or secondary), LINE1 baseline methylation or demethylation rate was found. OS was significantly shorter in pts with high IPSS (HR=2.1, 95%CI, 1.04-4.20, p=0.04), and with very poor IPSS-R cytogenetics (HR=4.3, 95%CI, 2.0-9.1, p=0.0015), the latter remaining prognostic in multivariate analysis. Using the recent prognostic model for MDS pts having failed HMA (Nazha et al, hematologica 2016), that includes ECOG>1, very poor cytogenetics, age, marrow blasts >20%, TD, platelets Conclusion: Response rates with GDAC, in this population of higher risk MDS, CMML or low blast count AML with failure to AZA (and often with IWG 2006 progression) were modest. Tolerance was similar to that of conventional HMA treatment. Disclosures Beyne-Rauzy: Celgene, Novartis: Honoraria. Park:Novartis: Research Funding. Jueliger:astex: Employment. Bevan:astex: Employment. Ades:Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding.

Published
2016

35. Azacitidine (AZA) Combined with Idarubicin in Higher Risk MDS - Results of a Phase I/II Study By the Groupe Francophone Des Myelodysplasies (GFM)

Author

Balkis Meddeb, Fatiha Chermat, Jacques Delaunay, Ramzi Jeddi, Cendrine Chaffaut, Pierre Fenaux, Lionel Ades, Sylvie Chevret, Aspasia Stamatoullas, Benoit de Renzis, Thorsten Braun, Benedicte Samey, Marie Sebert, and Mathilde Hunault Berger

Subjects
medicine.medical_specialty, Univariate analysis, Performance status, business.industry, Immunology, Azacitidine, Cell Biology, Hematology, medicine.disease, Biochemistry, Chemotherapy regimen, Gastroenterology, Surgery, Median follow-up, hemic and lymphatic diseases, Internal medicine, Cohort, medicine, Idarubicin, business, Febrile neutropenia, medicine.drug
Abstract

Background: Hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and must be further improved. In addition, AZA yields only about 30% of marrow responses (including CR+PR+marrow CR). Intensive chemotherapy combining Idarubicin (IDA) and AraC yields 30 to 50 % CR in higher risk MDS (Beran and all, cancer 2001) and IDA, as single agent, induces about 30% CR in elderly AML patients (Carella, haematologica 1990). We designed a phase I/II study evaluating the safety and efficacy of the combination of AZA and IDA (1 day during each AZA cycle) in higher risk MDS patients (NCT01305135). Methods: Main Inclusion criteria were: (1) IPSS int-2 or high MDS, or CMML with WBC < 13 G/l and marrow blasts > 10%, or AML with 20-30% marrow blasts (2) Age ≥ 18 years (3) Performance Status (PS) Results: Between Dec 2010 and Jan 2014, 41 patients (from 13 centers) were enrolled, including 13 women and 28 men with a median age of 74 years [IQR 70; 76]. At inclusion, WHO classification was RCMD in 1 pt, CMML in 2 pts, RAEB-1 in 10 pts, RAEB-2 in 13 pts, AML in 12 pts and unclassified MDS in 3 pts. Median marrow blast % was 9.5 [IQR: 6-19.9] and karyotype according to IPSS was favorable in 12 (29%), intermediate in 9 (22%) and unfavorable in 18 pts (44%) (2 cytogenetic failures). IPSS was int-2 and high in 56% and 44%, respectively. PS was 0 in 39%, 1 in 55% and 2 in 6% pts. 10 patients received 5 mg/m2 of idarubicin (cohort 1) and 31 received 10 mg/m2 (cohort 2). 375 cycles of AZA were administered (219 of them with AZA+IDA, as IDA was used only for the first 9 cycles), with a median number of 6 cycles/patient (median 6 in the IDA 5 mg/m2 cohort and 4 in the 10 mg/m2 cohort (p=0.9). Of the 41 patients enrolled, 20(48.8%, 95%CI: 32.9-64.9) achieved response (6 CR, 7 PR, 4 mCR and 3 stable disease with HI) with no difference between the two cohorts (50% vs 48%) and a marrow response rate (CR + PR + mCR) of 41,5%. Thirteen of the 22 patients with abnormal karyotype were evaluable for cytogenetic response: 5 achieved cytogenetic response (4 complete, 1 partial), 1 in cohort 1 and 4 in cohort 2. With a median follow up of 14 months, 9 of the 20 responders had relapsed. Median response duration was 11 months [3.2-42.7], with no difference between the two cohorts. Median OS was 14.3 months [IC95%: 12.5; NA] and 2y OS was 24.8%, with no significant difference between the 2 cohorts (p=0.43). By univariate analysis no baseline parameter including gender, karyotype, marrow blast %, IPSS and IDA dosage (5 or 10 mg/m2), had any significant impact on response or survival. 45 SAEs were reported in 26 patients, including febrile neutropenia (n=25), bleeding (n=7) and 2 non-clinically significant reductions in left ventricular ejection fraction (1 transient, and 1 persisting without symptoms). The number of infections per cycle [9/85 (10%) in the IDA 5 mg/m2 arm and 38/281 (14%) in the IDA 10 mg/m2 arm] and the number of bleeding events (9% vs 17%) did not significantly differ between the two cohorts. Conclusion: In our experience, Idarubicin (on day 8 of each cycle) can be combined to Azacitidine without any additional toxicity. The marrow response rate obtained with the combination (41.5%) may be higher than with AZA alone. We are currently comparing in higher risk MDS patients this AZA-IDA combination versus AZA alone (and other combinations of AZA with other drugs) in a prospective randomized GFM trial. Disclosures Sebert: Celgene: Research Funding. Fenaux:Celgene: Research Funding.

Published
2015

36. Mechanisms of elevated serum creatinine in patients receiving vemurafenib for advanced melanoma

Author

Emmanuelle Vidal-Petiot, Evangeline Pillebout, J. Roux, Céleste Lebbé, Nicole Basset-Seguin, Sylvie Chevret, Charlotte Hurabielle, P. Schneider, Cendrine Chaffaut, Thomas Stehlé, Samia Mourah, Cécile Pagès, and Martin Flamant

Subjects
Cancer Research, Pathology, medicine.medical_specialty, business.industry, behavioral disciplines and activities, Gastroenterology, Elevated serum creatinine, Oncology, Internal medicine, medicine, In patient, Vemurafenib, business, Adverse effect, medicine.drug, Advanced melanoma
Abstract

e20022 Background: We and others have observed elevated serum creatinine levels (sCr) in patients receiving vemurafenib (V), yet the prevalence and mechanism of this adverse event is unknown Method...

Published
2015

37. 123 AZACITIDINE (AZA) COMBINED WITH IDARUBICIN (IDA) IN HIGHER RISK MDS (HRMDS) – RESULTS OF A PHASE I/II STUDY BY THE GFM

Author

Ramzi Jeddi, S. Chevert, Marie Sebert, Thorsten Braun, Lionel Adès, Jacques Delaunay, Aspasia Stamatoullas, B. de Renzis, Benedicte Samey, Cendrine Chaffaut, Balkis Meddeb, M. Hunault Berger, Pierre Fenaux, and Fatiha Chermat

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Phase i ii, business.industry, Internal medicine, Azacitidine, medicine, Idarubicin, Hematology, business, medicine.drug
Published
2015

38. 112 INCIDENCE AND PREDICTIVE FACTORS OF HEPATOCELLULAR CARCINOMA AND COMPLICATIONS IN HBV- OR HCV-RELATED COMPENSATED CIRRHOSIS. A MULTICENTER PROSPECTIVE COHORT IN 1653 PATIENTS (ANRS CO12 CirVir)

Author

Fabien Zoulim, V. de Ledinghen, Stanislas Pol, Sylvie Chevret, Denis Ouzan, Cendrine Chaffaut, Jean-Claude Trinchet, Dominique Roulot, V. Bourcier, Dominique Guyader, M. Ait Ahmed, Jean-Pierre Zarski, Dominique Larrey, Patrick Marcellin, and P. Nahon

Subjects
medicine.medical_specialty, Pediatrics, Cirrhosis, Hepatology, business.industry, Incidence (epidemiology), medicine.disease, St louis, Liver disease, Hepatocellular carcinoma, Internal medicine, Medicine, business, Prospective cohort study
Abstract

J.C. Trinchet, V. Bourcier, C. Chaffaut, M. Ait Ahmed, P. Marcellin, D. Guyader, S. Pol, D. Larrey, F. Zoulim, D. Roulot, V. De Ledinghen, D. Ouzan, J.P. Zarski, P. Nahon, S. Chevret, ANRS CO12 CirVir Study Group. Hepatology Unit, Jean Verdier Hospital AP-HP, University Paris 13, Bondy, DBIM St Louis, AP-HP – University Paris 7, Paris, Hepatology Unit, Beaujon Hospital AP-HP, Clichy, Liver Disease Unit, CHU Rennes Ponchaillou, Rennes, Hepatology Unit, Cochin Hospital AP-HP, Paris, Hepatology Unit, CHU Montpellier St Eloi, Montpellier, Hepatology Unit, CHU Lyon – La Croix Rousse, Lyon, Hepatology Unit, Avicenne Hospital AP-HP, Bobigny, Hepatology Unit, CHU Bordeaux – Haut Leveque, Bordeaux, Hepatology Unit, Arnault Tzanck Institute, St Laurent du Var, Hepatology Unit, CHU Grenoble – Michallon, Grenoble, France E-mail: pierre.nahon@jvr.aphp.fr

Published
2013

40. Portal pressure is not predictive of death in patients with Child-Pugh a HCV-cirrhosis

Author

Sylvie Chevret, Michel Beaugrand, N. Garnne-Carrié, Pierre Nahon, Christos Christidis, K. Nahon, C. Najepoum, Jean-Claude Trinchet, Françoise Degos, and Cendrine Chaffaut

Subjects
medicine.medical_specialty, Cirrhosis, Hepatology, business.industry, Portal venous pressure, Internal medicine, medicine, In patient, medicine.disease, business, Intensive care medicine
Published
2001

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