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Malka D.,University Paris - Sud | Cervera P.,Saint Antoine University Hospital | Foulon S.,University Paris - Sud | Trarbach T.,University of Duisburg - Essen | And 21 more authors.
The Lancet Oncology | Year: 2014

Background: Gemcitabine plus a platinum-based agent (eg, cisplatin or oxaliplatin) is the standard of care for advanced biliary cancers. We investigated the addition of cetuximab to chemotherapy in patients with advanced biliary cancers. Methods: In this non-comparative, open-label, randomised phase 2 trial, we recruited patients with locally advanced (non-resectable) or metastatic cholangiocarcinoma, gallbladder carcinoma, or ampullary carcinoma and a WHO performance status of 0 or 1 from 18 hospitals across France and Germany. Eligible patients were randomly assigned (1:1) centrally with a minimisation procedure to first-line treatment with gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) with or without cetuximab (500 mg/m2), repeated every 2 weeks until disease progression or unacceptable toxicity. Randomisation was stratified by centre, primary site of disease, disease stage, and previous treatment with curative intent or adjuvant therapy. Investigators who assessed treatment response were not masked to group assignment. The primary endpoint was the proportion of patients who were progression-free at 4 months, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00552149. Findings: Between Oct 10, 2007, and Dec 18, 2009, 76 patients were assigned to chemotherapy plus cetuximab and 74 to chemotherapy alone. 48 (63%; 95% CI 52-74) patients assigned to chemotherapy plus cetuximab and 40 (54%; 43-65) assigned to chemotherapy alone were progression-free at 4 months. Median progression-free survival was 6·1 months (95% CI 5·1-7·6) in the chemotherapy plus cetuximab group and 5·5 months (3·7-6·6) in the chemotherapy alone group. Median overall survival was 11·0 months (9·1-13·7) in the chemotherapy plus cetuximab group and 12·4 months (8·6-16·0) in the chemotherapy alone group. The most common grade 3-4 adverse events were peripheral neuropathy (in 18 [24%] of 76 patients who received chemotherapy plus cetuximab vs ten [15%] of 68 who received chemotherapy alone), neutropenia (17 [22%] vs 11 [16%]), and increased aminotransferase concentrations (17 [22%] vs ten [15%]). 70 serious adverse events were reported in 39 (51%) of 76 patients who received chemotherapy plus cetuximab (34 events in 19 [25%] patients were treatment-related), whereas 41 serious adverse events were reported in 25 (35%) of 71 patients who received chemotherapy alone (20 events in 12 [17%] patients were treatment-related). One patient died of atypical pneumonia related to treatment in the chemotherapy alone group. Interpretation: The addition of cetuximab to gemcitabine and oxaliplatin did not seem to enhance the activity of chemotherapy in patients with advanced biliary cancer, although it was well tolerated. Gemcitabine and platinum-based combination should remain the standard treatment option. Funding: Institut National du Cancer, Merck Serono. © 2014 Elsevier Ltd.


Pallud J.,Sainte Anne Hospital | Pallud J.,University of Paris Descartes | Capelle L.,Pitie Salpetriere University Hospital | Huberfeld G.,Pitie Salpetriere University Hospital | Huberfeld G.,French Institute of Health and Medical Research
Epilepsia | Year: 2013

Gliomas are the most frequent primary brain tumors and most glioma patients have seizures. The origin and mechanisms of human glioma-related epilepsy are multifactorial and an intermix of oncologic and neuronal processes. In this brief review, we show that the infiltrated peritumoral neocortex appears to be the key structure for glioma- related epileptic activity, which depends on the interactions between the tumor per se and the surrounding brain. We shed light on the underlying mechanisms from two different "tumorocentric" and "epileptocentric" approaches, with a special emphasis on the glioma-related glutamatergic and γ-aminobutyric acid (GABA)ergic changes leading to epileptogenicity. Because gliomas use the neurotransmitter glutamate as a "tumor growth factor" to enhance glioma cell proliferation and invasion with neurotoxic, proinvasive, and proliferative effects, glutamate homeostasis is impaired, with elevated extracellular glutamate concentrations. Such excitatory effects contribute to the generation of epileptic activity in the peritumoral neocortex. GABAergic signaling is also involved both in tumor growth and in paradoxical excitatory effects mediated by alterations in neuronal and tumor cell Cl- homeostasis related to cotransporter changes. Local excitability may also be affected by an increase in extracellular K+ concentration, the alkalization of peritumoral neocortex, and alterations of gapjunction functioning. Finally, the tumor itself may mechanically affect locally neuronal behavior, connections, and networks. Better understanding of glioma-related oncologic and epileptologic processes are crucial for development of combined therapeutic strategies, but so far, the surgical management of gliomas should comprise a maximally safe surgical resection encompassing peritumoral neocortex. © 2013 International League Against Epilepsy.


Sirimarco G.,University Paris Diderot | Sirimarco G.,Bichat University Hospital | Labreuche J.,University Paris Diderot | Labreuche J.,University of Lille Nord de France | And 6 more authors.
Stroke | Year: 2014

BACKGROUND AND PURPOSE-: Treatment with statins reduces the rate of cardiovascular events in high-risk patients, but residual risk persists. At least part of that risk may be attributable to atherogenic dyslipidemia characterized by low high-density lipoprotein cholesterol (≤40 mg/dL) and high triglycerides (triglycerides ?150 mg/dL). METHODS-: We studied subjects with stroke or transient ischemic attack in the Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin With Terutroban in Patients With a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM; n=19 100) and Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL; n=4731) trials who were treated with a statin and who had high-density lipoprotein cholesterol and triglycerides measurements 3 months after randomization (n=10 498 and 2900, respectively). The primary outcome measure for this exploratory analysis was the occurrence of major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). We also performed a time-varying analysis to account for all available high-density lipoprotein cholesterol and triglyceride measurements. RESULTS-: A total of 10% of subjects in PERFORM and 9% in SPARCL had atherogenic dyslipidemia after ?3 months on start statin therapy. After a follow-up of 2.3 years (PERFORM) and 4.9 years (SPARCL), a major cardiovascular event occurred in 1123 and 485 patients in the 2 trials, respectively. The risk of major cardiovascular events was higher in subjects with versus those without atherogenic dyslipidemia in both PERFORM (hazard ratio, 1.36; 95% confidence interval, 1.14-1.63) and SPARCL (hazard ratio, 1.40; 95% confidence interval, 1.06-1.85). The association was attenuated after multivariable adjustment (hazard ratio, 1.23; 95% confidence interval, 1.03-1.48 in PERFORM and hazard ratio, 1.24; 95% confidence interval, 0.93-1.65 in SPARCL). Time-varying analysis confirmed these findings. CONCLUSIONS-: The presence of atherogenic dyslipidemia was associated with higher residual cardiovascular risk in PERFORM and SPARCL subjects with stroke or transient ischemic attack receiving statin therapy. Specific therapeutic interventions should now be trialed to address this residual risk. © 2014 American Heart Association, Inc.


Rey J.-B.,Institute Jean Godinot Clcc Of Reims | Launay-Vacher V.,Pitie Salpetriere University Hospital | Tournigand C.,University Paris Est Creteil
Targeted Oncology | Year: 2015

Regorafenib (BAY 73-4506, Stivarga® Bayer HealthCare Pharmaceutical Inc) is an oral multikinase inhibitor with a distinct and wide-ranging profile of tyrosine kinase inhibition, resulting in antiangiogenic and antiproliferative properties in tumors. Single-agent regorafenib administered as a 160-mg daily dose for the first 21 days of a 28-day cycle is approved for use in patients with pretreated metastatic colorectal cancer (mCRC) and gastrointestinal stromal tumor (GIST) progressing on imatinib and sunitinib, following publication of data from the phase III CORRECT and GRID studies respectively. Regorafenib is currently under phase III investigation in patients with hepatocellular carcinoma and is in several phase II studies in patients with gastrointestinal (GI) tumors. This review describes the clinical development of regorafenib in patients with GI cancers, and highlights the key issues important for the modern day clinical pharmacist who forms part of the multidisciplinary team ensuring safe and effective delivery of the drug to the patient. This information is considered of particular importance to the clinical pharmacist for the future development of regorafenib in this treatment setting. © 2014, The Author(s).


Nguyen-Khac E.,Amiens University Hospital | Nguyen-Khac E.,French Institute of Health and Medical Research | Thevenot T.,Besancon University Hospital Center | Piquet M.-A.,University of Caen Lower Normandy | And 12 more authors.
New England Journal of Medicine | Year: 2011

BACKGROUND: Mortality among patients with severe acute alcoholic hepatitis is high, even among those treated with glucocorticoids. We investigated whether combination therapy with glucocorticoids plus N-acetylcysteine would improve survival. METHODS: We randomly assigned 174 patients to receive prednisolone plus N-acetylcysteine (85 patients) or only prednisolone (89 patients). All patients received 4 weeks of prednisolone. The prednisolone-N-acetylcysteine group received intravenous N-acetylcysteine on day 1 (at a dose of 150, 50, and 100 mg per kilogram of body weight in 250, 500, and 1000 ml of 5% glucose solution over a period of 30 minutes, 4 hours, and 16 hours, respectively) and on days 2 through 5 (100 mg per kilogram per day in 1000 ml of 5% glucose solution). The prednisolone-only group received an infusion in 1000 ml of 5% glucose solution per day on days 1 through 5. The primary outcome was 6-month survival. Secondary outcomes included survival at 1 and 3 months, hepatitis complications, adverse events related to N-acetylcysteine use, and changes in bilirubin levels on days 7 and 14. RESULTS: Mortality was not significantly lower in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months (27% vs. 38%, P = 0.07). Mortality was significantly lower at 1 month (8% vs. 24%, P = 0.006) but not at 3 months (22% vs. 34%, P = 0.06). Death due to the hepatorenal syndrome was less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months (9% vs. 22%, P = 0.02). In a multivariate analysis, factors associated with 6-month survival were a younger age (P<0.001), a shorter prothrombin time (P<0.001), a lower level of bilirubin at baseline (P<0.001), and a decrease in bilirubin on day 14 (P<0.001). Infections were less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone- only group (P = 0.001); other side effects were similar in the two groups. CONCLUSIONS: Although combination therapy with prednisolone plus N-acetylcysteine increased 1-month survival among patients with severe acute alcoholic hepatitis, 6-month survival, the primary outcome, was not improved. Copyright © 2011 Massachusetts Medical Society.


Giampietro C.,University of L'Aquila | Fautrel B.,University Pierre and Marie Curie | Fautrel B.,Pitie Salpetriere University Hospital
International Journal of Inflammation | Year: 2012

Interleukin 1β (IL-1β) is emerging as a master mediator of adult onset Still's disease (AOSD) pathogenesis. This pleiotropic cytokine, whose expression is under the control of the inflammasome pathway, has a wide type of effects. As a key mediator of innate immunity is a potent pyrogen and facilitates neutrophilic proliferation and diapedesis into the inflamed tissues, which are key AOSD manifestations. The study of proinflammatory cytokines profiles in sera and pathological tissues of AOSD patients has shown elevated levels of IL-1β, these levels being highly correlated with disease activity and severity. These experimental evidences and the analogy with other autoinflammatory diseases that share with AOSD clinical and biological characteristics have suggested the blockade of IL-1β as a possible new therapeutic option for the AOSD, especially in conventional therapy resistant cases. Anakinra, the first anti-IL-1 agent put on the market, has demonstrated capable to induce a rapid response sustained over time, especially in systemic forms, where anti-TNFα failed to control symptoms. While a growing number of evidences supports the utilisation of anakinra in AOSD, a new generation of anti-IL1β antagonists is developing. Canakinumab and rilonacept, thanks to their higher affinity and longer half-life, could improve the management of this invalidating disease. © 2012 Cecilia Giampietro and Bruno Fautrel.


Leu-Semenescu S.,Sleep Disorders Unit | Leu-Semenescu S.,University Pierre and Marie Curie | Le Corvec T.,Sleep Disorders Unit | Groos E.,Sleep Disorders Unit | And 5 more authors.
Neurology | Year: 2015

Objective: To compare the benefits and risks of lithium therapy vs abstention/other treatments in Kleine-Levin syndrome (KLS). Methods: In a KLS cohort followed in a single center, 130 patients regularly took lithium carbonate (median dose 1,000 mg/day; n 71; 40 children), valproate (n 5), contraceptive pill (n 5), or no treatment (n 49). The disease characteristics (frequency, mean, and longest durations of episodes, time incapacitated per year) were compared before and after follow-up in the lithium vs abstention groups. Results: The time between KLS onset and therapeutic onset was 69 ± 92 months. The patients were then followed up for a mean of 21.5 ± 17.8 months. Before treatment, the 71 patients treated with lithium tended to have a higher frequency of episodes per year (3.8 ± 2.9 vs 2.9 ± 2.6) and had a longer time spent incapacitated (57 ± 51 vs 37 ± 35 days) than the untreated patients. The mean (-8 ± 20 vs 2 ± 13 days) and longest (-18 ± 35 vs -5 ± 13) episode duration, the time spent incapacitated (-37 ± 65 days vs -10 ± 38), as well as the frequency of episodes per year (-2.6 ± 2.9 vs 1.3 ± 2.78) decreased significantly more in the treated than in the untreated patients. Side effects (reported by 50% of the patients) were mild and classical with lithium (tremor, increased drinking, diarrhea, and subclinical hypothyroidism). Conclusions: In this large, prospective, open-label, controlled study, the benefit/risk ratio of lithium therapy is superior to that of abstention, supporting the concept that lithium has anti-inflammatory/neuroprotective effects. Classification of evidence: This study provides Class IV evidence that for patients with KLS, lithium decreases the frequency and duration of KLS episodes. © 2015 American Academy of Neurology.


Cariou B.,University of Nantes | Zair Y.,University of Nantes | Staels B.,University of Lille Nord de France | Bruckert E.,Pitie Salpetriere University Hospital
Diabetes Care | Year: 2011

OBJECTIVE - We evaluated the metabolic effects and tolerability of GFT505, a novel dual peroxisome proliferator-activated receptor α/δ agonist, in abdominally obese patients with either combined dyslipidemia or prediabetes. RESEARCH DESIGN AND METHODS - The S1 study was conducted in 94 patients with combined dyslipidemia while the S2 study was conducted in 47 patients with prediabetes. Participants were randomly assigned in a double-blind manner to GFT505 at 80 mg/day or placebo for 28 (S1) or 35 (S2) days. Primary efficacy end points were changes from baseline at week 4 in both fasting plasma triglycerides and HDL cholesterol in the S1 group and 2-h glucose upon oral glucose tolerance test in the S2 group. RESULTS - In comparison with placebo, GFT505 significantly reduced fasting plasma triglycerides (S1: least squares means -16.7% [95% one-sided CI -∞ to -5.3], P = 0.005; S2: -24.8% [-∞ to -10.5], P = 0.0003) and increased HDL cholesterol (S1: 7.8% [3.0 to ∞], P = 0.004; S2: 9.3% [1.7 to ∞], P = 0.009) in both studies, whereas LDL cholesterol only decreased in S2 (-11.0% [-∞ to -3.5], P = 0.002). In S2, GFT505 did not reduce 2-h glucose (-0.52 mmol/L [-∞ to 0.61], P = 0.18) but led to a significant decrease of homeostasis model assessment of insulin resistance (-31.4% [-∞ to 12.5], P = 0.001), fasting plasma glucose (-0.37 mmol/L [-∞ to -0.10], P = 0.01) and fructosamine (-3.6% [-∞ to -0.20], P = 0.02). GFT505 also reduced γ glutamyl transferase levels in both studies (S1: -19.9% [-∞ to -12.8], P < 0.0001; S2: -15.1% [-∞ to -1.1], P = 0.004). No specific adverse safety signals were reported during the studies. CONCLUSIONS - GFT505 may be considered a new drug candidate for the treatment of lipid and glucose disorders associated with the metabolic syndrome. © 2011 by the American Diabetes Association.


Chapman M.J.,French Institute of Health and Medical Research | Orsoni A.,French Institute of Health and Medical Research | Robillard P.,French Institute of Health and Medical Research | Hounslow N.,Kowa Research Europe | And 2 more authors.
Current Medical Research and Opinion | Year: 2014

Aims: Statin treatment may impair glucose homeostasis and increase the risk of new-onset diabetes mellitus, although this may depend on the statin, dose and patient population. We evaluated the effects of pitavastatin 4mg/day on glucose homeostasis in patients with metabolic syndrome in the CAPITAIN trial. Findings were validated in a subset of patients enrolled in PREVAIL-US. Methods: Participants with a well defined metabolic syndrome phenotype were recruited to CAPITAIN to reduce the influence of confounding factors. Validation and comparison datasets were selected comprising phenotypically similar subsets of individuals enrolled in PREVAIL-US and treated with pitavastatin or pravastatin, respectively. Mean change from baseline in parameters of glucose homeostasis (fasting plasma glucose [FPG], glycated hemoglobin [HbA1c], insulin, quantitative insulin-sensitivity check index [QUICKI] and homeostasis model of assessment-insulin resistance [HOMA-IR]) and plasma lipid profile were assessed at 6 months (CAPITAIN) and 3 months (PREVAIL-US) after initiating treatment. Results: In CAPITAIN (n=12), no significant differences from baseline in HbA1c, insulin, HOMA-IR and QUICKI were observed at day 180 in patients treated with pitavastatin. A small (4%) increase in FPG from baseline to day 180 (P<0.05), was observed. In the validation dataset (n=9), no significant differences from baseline in glycemic parameters were observed at day 84 (all comparisons P>0.05). Similar results were observed for pravastatin in the comparison dataset (n=14). Conclusions: Other than a small change in FPG in the CAPITAIN study, neutral effects of pitavastatin on glucose homeostasis were observed in two cohorts of patients with metabolic syndrome, independent of its efficacy in reducing levels of atherogenic lipoproteins. The small number of patients and relatively short follow-up period represent limitations of the study. Nevertheless, these data suggest that statin-induced diabetogenesis may not represent a class effect. © 2014 All rights reserved.


Bouleti C.,Bichat University Hospital | Iung B.,Bichat University Hospital | Laouenan C.,University Paris Diderot | Himbert D.,Bichat University Hospital | And 8 more authors.
Circulation | Year: 2012

Background-Long-term follow-up after percutaneous mitral commissurotomy enables predictive factors of late results to be identified. Methods and Results-Late results of percutaneous mitral commissurotomy were assessed in 1024 consecutive patients. Good immediate results, defined as valve area 1.5 cm without mitral regurgitation >2/4, were obtained in 912 patients (89%). These 912 patients were randomly split into 2 cohorts comprising 609 and 303 patients that were used to develop and validate, respectively, a scoring system predicting late functional results. The 20-year rate of good functional results (survival without cardiovascular death, mitral surgery, or repeat percutaneous mitral commissurotomy and in New York Heart Association class I or II) was 30.2±2.0%. A multivariable Cox model identified 7 predictive factors of poor late functional results: higher final mean gradient (P<0.0001), interaction between age and final mitral valve area (P<0.0001) showing that the impact of valve area decreases with age, interaction between sex and valve calcification (P<0.0001) showing that the impact of valve anatomy is stronger in men, and interaction between rhythm and New York Heart Association class showing an impact of New York Heart Association class only in patients in atrial fibrillation (P<0.0001). A 13-point score enabled 3 risk groups to be defined, corresponding to predicted good functional results of 55.1%, 29.1%, and 10.5% at 20 years in the validation cohort. Conclusions-Twenty years after percutaneous mitral commissurotomy in a population of patients with varied characteristics, 30% still had good functional results. Prediction of late functional results is multifactorial and strongly determined by age and the quality of immediate results. A simple validated scoring system is useful for estimating individual patient outcome. © 2012 American Heart Association, Inc.

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