A randomized phase II study of weekly nab-paclitaxel plus gemcitabine or simplified LV5FU2 as first-line therapy in patients with metastatic pancreatic cancer: the AFUGEM GERCOR trial

International audienceBackground : Metastatic pancreatic adenocarcinoma (PAC) prognosis remains dismal and gemcitabine monotherapy has been the standard treatment over the last decade. Currently, two first-line regimens are used in this setting: FOLFIRINOX and nab-paclitaxel plus gemcitabine. Increasing translational data on the predictive value of hENT1 for determining gemcitabine efficacy suggest that a non-gemcitabine-based regimen is favored in about 60 % of patients with PAC due to high resistance of PAC to this cytotoxic drug. This study aims to evaluate the efficacy of weekly nab-paclitaxel combined with gemcitabine or a simplified (s) LV5FU2 regimen in patients with previously untreated metastatic PAC.Methods/design : AFUGEM is a two-stage, open-label, randomized, multicenter, phase II trial. Patients with PAC who meet the inclusion criteria and provide written informed consent will be randomized in a 1:2 ratio to either nab-paclitaxel (125 mg/m 2 ) plus gemcitabine (1000 mg/m 2 ) given on days 1, 8, and 15 every 28 days or nab-paclitaxel (125 mg/m 2 ) plus sLV5FU2 (leucovorin 400 mg/m 2 followed by bolus 400 mg/m 2 5-fluorouracil and by 5-fluorouracil 2400 mg/m 2 as an 46-h intravenous infusion) given on days 1 and 15 every 28 days. A total of 114 patients will be randomized to one of the treatment arms. The primary endpoint is progression-free survival at 4 months. Secondary outcomes are rate and duration of response, disease control, overall survival, safety, and quality of life. Potential biomarkers of gemcitabine (hENT1, dCK) and 5-fluorouracil (TS) efficacy will be assessed.Discussion : The AFUGEM trial is designed to provide valuable information regarding efficacy and tolerability of nab-paclitaxel plus gemcitabine and nab-paclitaxel plus sLV5FU2 regimens. Identification of potential predictive biomarkers of gemcitabine and 5-fluorouracil is likely to drive therapeutic decisions in patients with metastatic PAC

Contribution d’une démarche quantitative à l’analyse des flux médiatiques d’information

Comment appréhender les flux médiatiques d’information qui fabriquent l’actualité ? Cette contribution propose de restituer à l’information une partie de son sens, en la replaçant dans le flux dont elle procède et qu’elle produit. L’attribution standardisée de descripteurs rédactionnels permet de multiplier les « prises » sur des corpus volumineux de sujets : le matériau, devenu descriptible dans le temps, gagne en intelligibilité par le recours à l’inférence statistique. Une saisie macroscopique et diachronique de l’information est rendue possible, qui invite à découvrir les structures, les dynamiques et les événements saillants à partir desquels se fabrique l’actualité médiatique et, au-delà, l’espace public. Cette méthode est présentée par les résultats qu’elle a fournis pour analyser dix ans d’information sportive dans les journaux télévisés hertziens français. Pour autant, l’outil n’explique pas par lui-même, et suppose de multiplier les questions, de recourir à d’autres savoirs pour rendre intelligible ce qu’il donne à lire autrement. Cette forme de travail ouvre ainsi moins des questions que de nouvelles voies pour produire des indicateurs permettant d’y répondre.How to grasp the media streams of information which make the current events ? This contribution suggests restoring to the information a part of its meaning, by replacing it in the stream of which it proceeds and which it produces. The standardized attribution of editorial descriptors allows to multiply the "grips" on voluminous corpuses of subjects : the material, become descriptible in time, wins in comprehensibility by the appeal to statistical inference. A macroscopic and diachronic seizure of the information is made possible, which invites to discover the structures, the dynamics and the striking events from which are made the media current events and, beyond, the public space. This method is presented by the results that it supplied to analyze ten years of sports information in the French Hertzian television news. For all that, the tool does not explain by itself, and supposes to multiply the questions, to resort to other knowledges to make understandable what it gives to read otherwise. This working shape so opens fewer questions than new ways to produce indicators allowing to answer it

Disseminated and circulating tumor cells in gastrointestinal oncology.

International audienceCirculating (CTCs) and disseminated tumor cells (DTCs) are two different steps in the metastatic process. Several recent techniques have allowed detection of these cells in patients, and have generated many results using different isolation techniques in small cohorts. Herein, we review the detection results and their clinical consequence in esophageal, gastric, pancreatic, colorectal, and liver carcinomas, and discuss their possible applications as new biomarkers

Does Chemotherapy-Induced Liver Injury Impair Postoperative Outcomes After Laparoscopic Liver Resection for Colorectal Metastases?

peer reviewed[en] BACKGROUND: Chemotherapy-associated liver injuries (CALI) have been associated with poor postoperative outcome after open liver resection. To date, no data concerning any correlation of CALI and laparoscopic liver resection (LLR) are available. In the present study, we evaluated the impact of CALI on short-term outcomes in patients undergoing LLR. MATERIALS AND METHODS: All patients who underwent in our department LLR for colorectal liver metastases (CRLM) from 2000 to 2016 were retrospectively reviewed. Patients were divided in 4 groups according to their pathological histology. In group 1 patients had normal liver parenchyma. Group 2 included patients with steatosis and steatohepatitis. Patients with sinusoidal obstruction syndrome (SOS) and nodular regenerative hyperplasia (NRH) were allocated to group 3, whereas the remaining with fibrosis and cirrhosis, were assigned to group 4. RESULTS: A total of 490 LLR for CRLM were included in the study. Perioperative details and morbidity did not differ significantly between the four groups. Subgroup analysis showed that NRH was associated with higher amount of blood loss (p = 0.043), overall (p = 0.021) and liver-specific morbidity (p = 0.039). CONCLUSION: NRH is a severe form of CALI that may worsen the short-term outcomes of patients undergoing LLR for CRLM. However, the remaining forms of CALI do not have a significant impact on perioperative outcomes after LLR

Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>Single-agent gemcitabine (GEM) is a standard treatment for advanced and metastatic pancreatic cancer. This study examines the question whether GEM-based combination chemotherapy can further improve treatment efficacy.</p> <p>Methods</p> <p>A meta-analysis was performed to evaluate randomized trials comparing GEM versus GEM+X (X = cytotoxic agent). Fifteen trials including 4465 patients were eligible for an analysis of overall survival, the primary end-point of this investigation.</p> <p>Results</p> <p>The meta-analysis revealed a significant survival benefit for GEM+X with a pooled hazard ratio (HR) of 0.91 (95% CI: 0.85 – 0.97, p = 0.004). The overall test for heterogeneity resulted in p = 0.82 (I²= 0%). The analysis of platinum-based combinations indicated a HR of 0.85 (95% CI: 0.76 – 0.96, p = 0.010), while for fluoropyrimidine-based combinations the HR was 0.90 (95% CI: 0.81 – 0.99, p = 0.030). No risk reduction was observed in the group of trials combining GEM with irinotecan, exatecan or pemetrexed (HR = 0.99). A meta-analysis of the trials with adequate information on baseline performance status (PS) was performed in five trials with 1682 patients. This analysis indicated that patients with a good PS had a marked survival benefit when receiving combination chemotherapy (HR = 0.76; 95% CI: 0.67 – 0.87; p < 0.0001). By contrast, application of combination chemotherapy to patients with an initially poor PS appeared to be ineffective (HR = 1.08; 95% CI: 0.90 – 1.29, p = 0.40).</p> <p>Conclusion</p> <p>The meta-analysis of randomized trials indicated a significant survival benefit when GEM was either combined with platinum analogs or fluoropyrimidines. Based on a preliminary subgroup analysis (representing 38% of all patients included in this meta-analysis), pancreatic cancer patients with a good PS appear to benefit from GEM-based cytotoxic combinations, whereas patients with a poor PS seem to have no survival benefit from combination chemotherapy.</p

L-Ilf3 and L-NF90 Traffic to the Nucleolus Granular Component: Alternatively-Spliced Exon 3 Encodes a Nucleolar Localization Motif

Ilf3 and NF90, two proteins containing double-stranded RNA-binding domains, are generated by alternative splicing and involved in several functions. Their heterogeneity results from posttranscriptional and posttranslational modifications. Alternative splicing of exon 3, coding for a 13 aa N-terminal motif, generates for each protein a long and short isoforms. Subcellular fractionation and localization of recombinant proteins showed that this motif acts as a nucleolar localization signal. Deletion and substitution mutants identified four arginines, essential for nucleolar targeting, and three histidines to stabilize the proteins within the nucleolus. The short isoforms are never found in the nucleoli, whereas the long isoforms are present in the nucleoplasm and the nucleoli. For Ilf3, only the posttranslationally-unmodified long isoform is nucleolar, suggesting that this nucleolar targeting is abrogated by posttranslational modifications. Confocal microscopy and FRAP experiments have shown that the long Ilf3 isoform localizes to the granular component of the nucleolus, and that L-Ilf3 and L-NF90 exchange rapidly between nucleoli. The presence of this 13 aminoacid motif, combined with posttranslational modifications, is responsible for the differences in Ilf3 and NF90 isoforms subcellular localizations. The protein polymorphism of Ilf3/NF90 and the various subcellular localizations of their isoforms may partially explain the various functions previously reported for these proteins

Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study

peer reviewedBackground: Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence. Methods: We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794. Findings: Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% [95% CI –∞ to 21·1]; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% [95% CI 5·8–27·6]) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 [95% CI −0·07 to 0·55]), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 [95% CI 0·17–0·82]). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio [HR] 0·87 [95% CI 0·33–2·26]); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 [95% CI 0·16–0·47] and 0·21 [0·13–0·32]). Interpretation: We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis. Funding: The present study has been granted by the French Ministry of Health—Programme Hospitalier de Recherche Clinique 2010

Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.

Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance

L’accident du Tricolor et ses effets sur la côte d’Opale : bilan de deux modes synchrones de gestion de la lutte à terre d’une pollution d’origine maritime de moyenne ampleur

International audienc

Comparaison de l expression de HER-2 dans les biopsies diagnostiques et les pièces opératoires d adénocarcinomes gastriques et du bas œsophage (influence de la chimiothérapie néoadjuvante)

Le récepteur HER-2 est surexprimé dans 15% à 20% des adénocarcinomes (ADK) gastriques et du bas œsophage ; il constitue une cible thérapeutique pour le trastuzumab, validée en situation métastatique.L objectif principal était : comparer l expression de la protéine et du gène HER-2 entre les biopsies diagnostiques et les pièces opératoires d ADK gastriques, et déterminer si la chimiothérapie néoadjuvante (CNA) modifie cette expression.Méthodes : récupération des blocs issus des biopsies diagnostiques des patients opérés à visée curative à l Institut Mutualiste Montsouris et à l hôpital Saint-Antoine entre 2004 et 2011 ; constitution de deux cohortes selon la réalisation ou non d une CNA. Analyse de HER-2 sur les biopsies et les pièces opératoires par deux examens anatomopathologiques indépendants réalisés en aveugle.Les prélèvements de 201 patients ont été analysés. Le taux de surexpression de HER-2 était de 16,4% sur les biopsies et de 19,4% sur les pièces opératoires. Les tumeurs HER-2 positives étaient principalement des tumeurs du cardia ou du bas œsophage, de type histologique intestinal et bien différenciées. Le statut HER-2 était différent sur la biopsie et sur la pièce opératoire pour 10% des patients. Après CNA, il y avait une tendance à une moins bonne sensibilité pour identifier HER-2 sur la pièce opératoire que sur la biopsie.Le statut HER-2 est variable entre les analyses réalisées sur les biopsies et sur les pièces opératoires. Ceci montre l intérêt de la recherche répétée de la surexpression de HER-2 afin d optimiser la détermination de la population pouvant bénéficier du trastuzumab.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF