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Oguri A.,Henri Mondor University Hospital | Yamamoto M.,Henri Mondor University Hospital | Mouillet G.,Henri Mondor University Hospital | Gilard M.,University of Western Brittany | And 15 more authors.
Circulation: Cardiovascular Interventions | Year: 2014

Background-Transcatheter aortic valve implantation (TAVI) performed under local anesthesia (LA) is becoming increasingly common. We aimed to compare the clinical outcomes in patients who underwent transfemoral-TAVI under general anesthesia (GA) and LA. Methods and Results-Data from 2326 patients in the French Aortic National CoreValve and Edwards 2 (FRANCE 2) registry who underwent transfemoral-TAVI were analyzed. During the study period, the percentage of LA procedures increased gradually from 14% in January 2010 to 59% in October 2011. The clinical outcomes for GA (n=1377) and LA (n=949) were compared. Numerous baseline characteristics differed between the 2 groups, and the use of transesophageal echocardiographic guidance was more common in GA than in LA (76.3% versus 16.9%; P<0.001). Device success and cumulative 30-day survival rates were similar in the 2 groups (97.6% versus 97.0%; P=0.41 and 91.6% versus 91.3%; P=0.69, respectively), whereas the incidence of postprocedural aortic regurgitation≥mild was significantly lower in GA than in LA (15.0% versus 19.1%; P=0.015). The groups were also analyzed using a propensity-matching model, including transesophageal echocardiographic usage (GA [n=401] versus LA [n=401]). This model indicated that there were no significant differences between the 2 groups in the rates of 30-day survival (GA [91.4%] versus LA [89.3%]; P=0.27] and postprocedural aortic regurgitation≥mild (GA [12.7%] versus LA [16.2%]; P=0.19). Conclusions-The less invasive transfemoral-TAVI under LA is preferred in clinical settings and seems to be acceptable; however, the higher incidence of postprocedural aortic regurgitation is emphasized. Therapeutic efforts should be made to reduce such complications during transfemoral-TAVI under LA. © 2014 American Heart Association, Inc.


Jamet E.,Hoffmann-La Roche | Akary E.,French National Institute for Agricultural Research | Poisson M.-A.,Hoffmann-La Roche | Chamba J.-F.,Hoffmann-La Roche | And 2 more authors.
Food Microbiology | Year: 2012

Prevalence of enterococci and antibiotic resistance profiles of Enterococcus faecalis was analyzed in 126 French cheeses from retail stores. Forty-four percent of pasteurized or thermised-milk cheeses, and up to 92% of raw-milk cheeses contained detectable enterococci. A total of 337 antibiotic resistant enterococci were isolated in 29% and 60% of pasteurized-milk and raw-milk cheeses, respectively. E. faecalis was the predominant antibiotic resistant species recovered (81%), followed by Enterococcus faecium (13%), and Enterococcus durans (6%). The most prevalent antibiotic resistances were tetracycline (Tet) and minocycline (Min), followed by erythromycin (Ery), kanamycin (Kan) and chloramphenicol (Cm). The most common multiple antibiotic resistance phenotype was Cm Ery Kan Min Tet. The occurrence of antibiotic genes, as searched by PCR, was 100 % for aph3'IIIa, 96 % for ermB, 90 % for tetM and 80 % for catA in isolates resistant to Kan, Ery, Tet or Cm, respectively. MLST analysis of 30 multidrug resistant E. faecalis revealed that ST19, CC21, CC25 and CC55 isolates were the most common in cheeses. In conclusion, as in many other European countries, French cheeses do contain enterococci with multiple antibiotics resistances. However, low occurrence of high-level gentamicin resistant or sulfamethoxazole/trimethoprim-resistant enterococci and absence of vancomycin- or ampicillin- resistant enterococci indicate that cheeses cannot be considered as a major reservoir for nosocomial multi-drug resistant enterococci. © 2012 Elsevier Ltd.


Quoix E.,Hopitaux Universitaires Of Strasbourg | Lena H.,University of Rennes 1 | Losonczy G.,Semmelweis University | Forget F.,Center Hospitalier Of Lardenne | And 19 more authors.
The Lancet Oncology | Year: 2016

Background: MUC1 is a tumour-associated antigen expressed by many solid tumours, including non-small-cell lung cancer. TG4010 is a modified vaccinia Ankara expressing MUC1 and interleukin 2. In a previous study, TG4010 combined with chemotherapy showed activity in non-small-cell lung cancer and the baseline value of CD16, CD56, CD69 triple-positive activated lymphocytes (TrPAL) was shown to be potentially predictive of TG4010 efficacy. In this phase 2b part of the phase 2b/3 TIME trial, we further assess TG4010 in combination with first-line chemotherapy and use of the TrPAL biomarker in this setting. Methods: In this phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial, we recruited previously untreated patients aged 18 years or older with stage IV non-small-cell lung cancer without a known activating EGFR mutation and with MUC1 expression in at least 50% of tumoural cells. Patients were randomly allocated (1:1) by an external service provider to subcutaneous injections of 108 plaque-forming units of TG4010 or placebo from the beginning of chemotherapy every week for 6 weeks and then every 3 weeks up to progression, discontinuation for any reason, or toxic effects, stratified according to baseline value of TrPAL (≤ or > the upper limit of normal [ULN]) and, in addition, a dynamic minimisation procedure was used, taking into account chemotherapy regimen, histology, addition or not of bevacizumab, performance status, and centre. Patients, site staff, monitors, the study funder, data managers, and the statistician were masked to treatment identity. The primary endpoint was progression-free survival, assessed every 6 weeks, to validate the predictive value of the TrPAL biomarker. If patients with TrPAL values of less than or equal to the ULN had a Bayesian probability of more than 95% that the true hazard ratio (HR) for progression-free survival was less than 1, and if those with TrPAL values of greater than the ULN had a probability of more than 80% that the true HR for progression-free survival was more than 1, the TrPAL biomarker would be validated. We did primary analyses in the intention-to-treat population and safety analyses in those who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Monitors, site staff, and patients are still masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT01383148. Findings: Between April 10, 2012, and Sept 12, 2014, we randomly allocated 222 patients (TG4010 and chemotherapy 111 [50%]; placebo and chemotherapy 111 [50%]). In the whole population, median progression-free survival was 5·9 months (95% CI 5·4-6·7) in the TG4010 group and 5·1 months (4·2-5·9) in the placebo group (HR 0·74 [95% CI 0·55-0·98]; one-sided p=0·019). In patients with TrPAL values of less than or equal to the ULN, the HR for progression-free survival was 0·75 (0·54-1·03); the posterior probability of the HR being less than 1 was 98·4%, and thus the primary endpoint was met. In patients with TrPAL values of greater than the ULN, the HR for progression-free survival was 0·77 (0·42-1·40); the posterior probability of the HR being greater than 1 was 31·3%, and the primary endpoint was not met. We noted grade 1-2 injection-site reactions in 36 (33%) of 110 patients in the TG4010 group versus four (4%) of 107 patients in the placebo group. We noted no grade 3 or 4 nor serious adverse events deemed to be related to TG4010 only. Four (4%) patients presented grade 3 or 4 adverse events related to TG4010 and other study treatments (chemotherapy or bevacizumab) versus 11 (10%) in the placebo group. No serious adverse event was related to the combination of TG4010 with other study treatments. The most frequent severe adverse events were neutropenia (grade 3 29 [26%], grade 4 13 [12%] in the TG4010 group vs grade 3 22 [21%], grade 4 11 [10%] in the placebo group), anaemia (grade 3 12 [11%] vs grade 3 16 [15%]), and fatigue (grade 3 12 [11%], grade 5 one [1%] vs grade 3 13 [12%]; no grade 4 events). Interpretation: TG4010 plus chemotherapy seems to improve progression-free survival relative to placebo plus chemotherapy. These data support the clinical value of the TrPAL biomarker in this clinical setting; because the primary endpoint was met, the trial is to continue into the phase 3 part. Funding: Transgene, Avancées Diagnostiques pour de Nouvelles Approches Thérapeutiques (ADNA), and OSEO. © 2016 Elsevier Ltd.


PubMed | Center Francois Baclesse, University of Barcelona, Semmelweis University, Institute Gustave Roussy and 13 more.
Type: Clinical Trial, Phase II | Journal: The Lancet. Oncology | Year: 2016

MUC1 is a tumour-associated antigen expressed by many solid tumours, including non-small-cell lung cancer. TG4010 is a modified vaccinia Ankara expressing MUC1 and interleukin 2. In a previous study, TG4010 combined with chemotherapy showed activity in non-small-cell lung cancer and the baseline value of CD16, CD56, CD69 triple-positive activated lymphocytes (TrPAL) was shown to be potentially predictive of TG4010 efficacy. In this phase 2b part of the phase 2b/3 TIME trial, we further assess TG4010 in combination with first-line chemotherapy and use of the TrPAL biomarker in this setting.In this phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial, we recruited previously untreated patients aged 18 years or older with stage IV non-small-cell lung cancer without a known activating EGFR mutation and with MUC1 expression in at least 50% of tumoural cells. Patients were randomly allocated (1:1) by an external service provider to subcutaneous injections of 10(8) plaque-forming units of TG4010 or placebo from the beginning of chemotherapy every week for 6 weeks and then every 3 weeks up to progression, discontinuation for any reason, or toxic effects, stratified according to baseline value of TrPAL ( or > the upper limit of normal [ULN]) and, in addition, a dynamic minimisation procedure was used, taking into account chemotherapy regimen, histology, addition or not of bevacizumab, performance status, and centre. Patients, site staff, monitors, the study funder, data managers, and the statistician were masked to treatment identity. The primary endpoint was progression-free survival, assessed every 6 weeks, to validate the predictive value of the TrPAL biomarker. If patients with TrPAL values of less than or equal to the ULN had a Bayesian probability of more than 95% that the true hazard ratio (HR) for progression-free survival was less than 1, and if those with TrPAL values of greater than the ULN had a probability of more than 80% that the true HR for progression-free survival was more than 1, the TrPAL biomarker would be validated. We did primary analyses in the intention-to-treat population and safety analyses in those who had received at least one dose of study drug and had at least one valid post-baseline safety assessment. Monitors, site staff, and patients are still masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT01383148.Between April 10, 2012, and Sept 12, 2014, we randomly allocated 222 patients (TG4010 and chemotherapy 111 [50%]; placebo and chemotherapy 111 [50%]). In the whole population, median progression-free survival was 59 months (95% CI 54-67) in the TG4010 group and 51 months (42-59) in the placebo group (HR 074 [95% CI 055-098]; one-sided p=0019). In patients with TrPAL values of less than or equal to the ULN, the HR for progression-free survival was 075 (054-103); the posterior probability of the HR being less than 1 was 984%, and thus the primary endpoint was met. In patients with TrPAL values of greater than the ULN, the HR for progression-free survival was 077 (042-140); the posterior probability of the HR being greater than 1 was 313%, and the primary endpoint was not met. We noted grade 1-2 injection-site reactions in 36 (33%) of 110 patients in the TG4010 group versus four (4%) of 107 patients in the placebo group. We noted no grade 3 or 4 nor serious adverse events deemed to be related to TG4010 only. Four (4%) patients presented grade 3 or 4 adverse events related to TG4010 and other study treatments (chemotherapy or bevacizumab) versus 11 (10%) in the placebo group. No serious adverse event was related to the combination of TG4010 with other study treatments. The most frequent severe adverse events were neutropenia (grade 3 29 [26%], grade 4 13 [12%] in the TG4010 group vs grade 3 22 [21%], grade 4 11 [10%] in the placebo group), anaemia (grade 3 12 [11%] vs grade 3 16 [15%]), and fatigue (grade 3 12 [11%], grade 5 one [1%] vs grade 3 13 [12%]; no grade 4 events).TG4010 plus chemotherapy seems to improve progression-free survival relative to placebo plus chemotherapy. These data support the clinical value of the TrPAL biomarker in this clinical setting; because the primary endpoint was met, the trial is to continue into the phase 3 part.Transgene, Avances Diagnostiques pour de Nouvelles Approches Thrapeutiques (ADNA), and OSEO.


Zsiros J.,University of Amsterdam | Brugieres L.,Institute Gustave Roussy | Brock P.,Great Ormond Street Hospital | Roebuck D.,Great Ormond Street Hospital | And 15 more authors.
The Lancet Oncology | Year: 2013

Background: The objective of this study was to establish the efficacy and safety of a new treatment regimen consisting of dose-dense cisplatin-based chemotherapy and radical surgery in children with high-risk hepatoblastoma. Methods: SIOPEL-4 was a prospective single-arm feasibility study. Patients aged 18 years or younger with newly diagnosed hepatoblastoma with either metastatic disease, tumour in all liver segments, abdominal extrahepatic disease, major vascular invasion, low α fetoprotein, or tumour rupture were eligible. Treatment consisted of preoperative chemotherapy (cycles A1-A3: cisplatin 80 mg/m2 per day intravenous in 24 h on day 1; cisplatin 70 mg/m2 per day intravenous in 24 h on days 8, 15, 29, 36, 43, 57, and 64; and doxorubicin 30 mg/m2 per day intravenous in 24 h on days 8, 9, 36, 37, 57, and 58) followed by surgical removal of all remaining tumour lesions if feasible (including liver transplantation and metastasectomy, if needed). Patients whose tumour remained unresectable received additional preoperative chemotherapy (cycle B: doxorubicin 25 mg/m2 per day in 24 h on days 1-3 and 22-24, and carboplatin area under the curve [AUC] 10·6 mg/mL per min per day intravenous in 1 h on days 1 and 22) before surgery was attempted. After surgery, postoperative chemotherapy was given (cycle C: doxorubicin 20 mg/m2 per day in 24 h on days 1, 2, 22, 23, 43, and 44, and carboplatin AUC 6·6 mg/mL per min per day in 1 h on days 1, 22, and 43) to patients who did not receive cycle B. The primary endpoint was the proportion of patients with complete remission at the end of treatment. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00077389. Findings: We report the final analysis of the trial. 62 eligible patients (39 with lung metastases) were included and analysed. 60 (98%, 95% CI 91-100) of 61 evaluable patients (one child underwent primary hepatectomy) had a partial response to preoperative chemotherapy. Complete resection of all tumour lesions was achieved in 46 patients (74%). At the end of therapy, 49 (79%, 95% CI 67-88) of 62 patients were in complete remission. With a median follow-up of 52 months, 3-year event-free survival was 76% (95% CI 65-87) and 3-year overall survival was 83% (73-93). 60 (97%) patients had grade 3-4 haematological toxicity (anaemia, neutropenia, or thrombocytopenia) and 44 (71%) had at least one episode of febrile neutropenia. Other main grade 3 or 4 toxicities were documented infections (17 patients, 27%), anorexia (22, 35%), and mucositis (seven, 11%). One child died of fungal infection in neutropenia. Moderate-to-severe ototoxicity was documented in 31 (50%) patients. 18 serious adverse events (including two deaths) reflecting the observed side-effects were reported in the trial (the most common was ototoxicity in five patients). Interpretation: The SIOPEL-4 treatment regimen is feasible and efficacious for complete remission at the end of treatment for patients with high-risk hepatoblastoma. Funding: Cancer Research UK and Cancer Research Switzerland/Oncosuisse. © 2013 Elsevier Ltd.


Italiano A.,Institute Bergonie | Italiano A.,Sloan Kettering Cancer Center | Cioffi A.,Sloan Kettering Cancer Center | Cioffi A.,Institute Gustave Roussy | And 13 more authors.
Cancer | Year: 2012

BACKGROUND: Data regarding the role of anthracyclines and taxanes as first-line treatments of metastatic angiosarcoma are limited. METHODS: Records of 117 metastatic angiosarcoma patients who were treated with either doxorubicin or weekly paclitaxel were reviewed. RESULTS: Seventy-five patients (64%) were treated with weekly paclitaxel and 42 (36%) with single-agent doxorubicin. Patients in the weekly paclitaxel group were older and more frequently had angiosarcomas arising from the skin. In the doxorubicin group, 34 patients were evaluable for response: 2 (6%) had complete response, 8 (23.5%) had partial response, 10 (29.5%) had stable disease, and 14 (41%) had progressive disease. In the weekly paclitaxel group, 68 patients were evaluable for response: 9 (13%) had complete response, 27 (40%) had partial response, 20 (29.5%) had stable disease, and 12 (17.5%) had progressive disease. Objective responses to weekly paclitaxel were more frequent in cutaneous angiosarcomas, whereas tumor location did not impact response to doxorubicin. Median progression-free survival (PFS) was 4.9 months (95% confidence interval [95% CI], 3.9-6.0 months). Median overall survival (OS) was 8.5 months (95% CI, 6.4-10.7 months). On multivariate analysis, ECOG performance status (PS) was the sole independent factor associated with PFS and OS. CONCLUSIONS: First-line single-agent doxorubicin and weekly paclitaxel seem to have similar efficacy in metastatic angiosarcomas. Cutaneous angiosarcomas respond favorably to weekly paclitaxel. Best supportive care should be considered in patients with poor PS. © 2011 American Cancer Society.


Background: The Tigecycline Evaluation and Surveillance Trial is an antimicrobial susceptibility surveillance program that collects gram-positive and gram-negative organisms globally. Objective: This analysis reports on antimicrobial susceptibility among 23,918 gram-negative isolates collected from intensive care units globally between 2004 and 2009. Methods: MICs and susceptibility were determined according to the guidelines of the Clinical and Laboratory Standards Institute (US Food and Drug Administration breakpoints were applied against tigecycline). Results: Gram-negative isolates were collected from 6 geographical regions: North America, 8099 isolates; Europe, 9244; Asia-Pacific Rim, 1573; Latin America, 3996; the Middle East, 635; and Africa, 371. North America reported the lowest rates of extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae and Escherichia coli both overall (12.8% and 4.7%, respectively) and in each year of collection. High rates of ESBL production were reported among K pneumoniae from Latin America (45.5%) and Africa (54.9%) and for E coli from the Middle East (32.4%). Imipenem and tigecycline maintained >90% susceptibility against K pneumoniae, E coli, Klebsiella oxytoca, Enterobacter cloacae, and Serratia marcescens for all regions. Susceptibility to meropenem was >90% against all K oxytoca and S marcescens. Large regional variations in susceptibility among Acinetobacter baumannii were reported, with the largest variations reported for amikacin (75.2% in North America, 21.8% in the Middle East) and meropenem (60.4% in North America, 15.9% in Africa). MIC 90 values for tigecycline against A baumannii were low (1-2 mg/L) for all regions. Against P aeruginosa, susceptibility to amikacin (97.5% in North America, 67.5% in Latin America) and meropenem (79.1% in North America, 51.4% in Africa) had the largest variations. Conclusions: Antimicrobial resistance among gram-negative intensive care unit isolates was highly variable between geographic regions. The carbapenems were active in vitro against Enterobacteriaceae, . A baumannii and . P aeruginosa, and tigecycline continued to be active in vitro against members of the Enterobacteriaceae and . A baumannii collected from intensive care units in North America, Europe, the Asia-Pacific Rim, Latin America, the Middle East, and Africa. © 2012 Elsevier HS Journals, Inc.


Talon D.,Center Hospitalier University Besancon | Talon D.,University of Franche Comte | Marion C.,Center Hospitalier University Besancon | Thouverez M.,Center Hospitalier University Besancon | And 3 more authors.
Journal of Hospital Infection | Year: 2011

The rate of mupirocin resistance in meticillin-resistant Staphylococcus aureus (MRSA) in Besançon University Hospital is low with a decreasing trend, from 10% in 2004 to 3% in 2009. This trend in resistance paralleled mupirocin consumption. Genotyping results showed that this decrease was not linked to a change in MRSA clones. It appears that the way in which the mupirocin is used, rather than the volume, plays a role in the emergence of resistance and that its cautious use is likely to maintain the mupirocin resistance at a low level, thus preserving its efficacy. © 2011 The Healthcare Infection Society.


Slekovec C.,Center Hospitalier University Besancon | Gbaguidi-Haore H.,Center Hospitalier University Besancon | Coignard B.,Institute of Veille Sanitaire | Bertrand X.,Center Hospitalier University Besancon | Talon D.,Center Hospitalier University Besancon
Journal of Hospital Infection | Year: 2011

Using a multi-level logistic regression model, we determined whether there was any relationship between alcohol-based hand-rub consumption and prevalence of device-associated infections (DAIs) in French healthcare facilities (HCFs). Two national databases were used: the 2006 French prevalence survey of nosocomial infections, and the 2006 French infection control indicator database which includes alcohol-based hand-rub consumption as an indicator (ICSHA: indicateur de consommation de solution hydro-alcoolique). Only patients with at least one medical device (urinary catheter, vascular catheter or tracheal tube) who were present in an HCF for at least two days were included in the analysis. A multi-level statistical analysis was performed to assess the joint effect of patient-level and hospital-level variables. In all, 814 HCFs, each with a minimum of 15 study patients, were included, giving a total of 53 459 patients. The overall prevalence of DAI was 6.7% (95% confidence interval: 6.4-6.9). The median value of ICSHA was 37.2%. There was no association between DAI prevalence and ICSHA, but all patient-level variables were associated with DAI prevalence. Patient-level variables explain 25% of the hospital-level variation in DAI prevalence, although 60% of this variation remains unexplained when both patient and hospital variables are included in the model. To further assess any association between DAI prevalence and hand hygiene, additional studies on hand hygiene practices specifically associated with invasive medical device manipulation are required. © 2011 The Healthcare Infection Society.


Aires J.,University of Paris Descartes | Thouverez M.,Center Hospitalier University Besancon | Allano S.,University of Paris Descartes | Butel M.J.,University of Paris Descartes
Systematic and Applied Microbiology | Year: 2011

Bifidobacterial population dynamics were investigated by the longitudinal analysis of the dominant population isolated from the feces of young infants. After molecular identification and fingerprinting comparison, clone identity of the consecutive strains belonging to the same species for one individual was performed by pulsed-field gel electrophoresis. The results, obtained from 15 individuals sampled four times over a five-week period suggested a turnover of the dominant bifidobacteria in the population not only at the species but also at its species representative levels. This study provides new insights of the in vivo dynamics of commensal bifidobacteria. It highlights the need to take into consideration the fluctuation of bifidobacterial populations that may occur in one individual in order to investigate reliably the impact of dietary components, such as probiotics or prebiotics, on the intestinal ecosystem. © 2011 Elsevier GmbH.

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