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Studies have not yet found conclusive results on the risk of cancer in patients with multiple sclerosis (MS). This study aimed to compare the incidence of all cancers and of specific types of cancer between MS patients and the general population by age and by sex.All prevalent MS patients identified between 2008 and 2014 in the nationwide French health care database (Système National des Données de Santé) and without history of malignancy were included in a cohort study and followed up until cancer occurrence, date of death, or 31 December 2015, whichever came first. MS patients were matched based on sex and year of birth to non-MS controls from the general population without cancer before index date. Incidence rate was reported per 100,000 person-years (PY), and risk of cancer was estimated by type of cancer, age, and sex using a Cox model (hazard ratio [HR] and its 95% confidence interval [CI]).Overall, 576 cancers per 100,000 PY were observed in MS patients versus 424 per 100,000 PY in the control population. The risk of cancer was higher among MS patients than among population controls whether considered overall (HR = 1.36, 95% CI = 1.29-1.43) or for prostate (HR = 2.08, 95% CI = 1.68-2.58), colorectal and anal (HR = 1.35, 95% CI = 1.16-1.58), trachea, bronchus, and lung (HR = 2.36, 95% CI = 1.96-2.84), and to a lesser extent, breast cancer (HR = 1.12, 95% CI = 1.03-1.23).MS patients were associated with increased risk of cancer compared to population controls.

Purpose: To report the real-world effectiveness and safety of ranibizumab 0.5 mg in patients with visual impairment due to diabetic macular edema (DME). Methods: This is a French, 36-month, multicenter, observational cohort study. Between December 2013 and April 2015, ophthalmologists enrolled diabetic patients aged ≥18 years with DME-related visual impairment and for whom ranibizumab 0.5 mg was initiated. Here, we present the 12-month results from this cohort. The primary endpoint was the mean change in best-corrected visual acuity (BCVA); sample size calculations were based on RESTORE trial data (BCVA mean change = 6.8 letters, precision = 0.7 letters). Secondary endpoints included the change in central subfield thickness (CSFT), number of visits, number of injections received, and frequency of ocular and nonocular adverse events and serious adverse events. Results: Between December 2013 and April 2015, a total of 290 patients with DME were enrolled by 84 ophthalmologists; 12-month data are available for 242 patients (due to low recruitment rates, precision was recalculated for 242 evaluable patients: the precision was then of 1.0 letters). Mean age (± standard deviation) was 66.1 ± 11.0 years and 56.6% were male. The mean baseline BCVA and CSFT were 59.2 letters (95% confidence interval [CI] 57.3, 61.0) and 457 μm (95% CI: 438, 476), respectively. At month 12, the mean gain in BCVA from baseline was 7.4 letters (95% CI: 5.4, 9.4), with 36.8% of patients with BCVA >70 letters versus 13.2% at baseline. Mean change in CSFT was −125 μm (95% CI: −146, −103). The mean number of ranibizumab injections was 5.1 ± 2.3 over an average of 10.4 ± 3.0 visits. No new safety findings were identified. Conclusions: The BOREAL study confirms the effectiveness and safety of ranibizumab for the treatment of DME-related visual impairment in routine clinical practice with fewer injections than reported in clinical trials.

Introduction Bien que les medicaments indiques dans l’osteoporose aient deja fait preuve de leur efficacite dans les essais cliniques contre placebo, les donnees sur leur efficacite en situation reelle de soins sont a ce jour limitees. Patients et methodes Une etude de cohorte a ete realisee a partir des donnees de l’Assurance maladie francaise, le SNDS, incluant toute femme de 55 ans et plus initiant un traitement pour l’osteoporose (i.e., denosumab, acide zoledronique (AZ), bisphosphonates oraux (BPO), estrogenes, teriparatide et raloxifene) entre le 1er janvier 2014 et le 31 decembre 2016 selon une approche hierarchique qui suit l’ordre de commercialisation de ces medicaments en France. Les patientes incluses etaient traitees pendant au moins 6 mois par le traitement index et etaient suivies au moins 2 ans. L’incidence des fractures etait comparee au sein d’un meme groupe de traitement, en comparant le taux d’incidence des 3 mois suivant la date d’initiation (risque fracturaire de reference), avec celui des 12, 18 et 24 mois suivants. Les resultats des analyses autocontrolees « sous traitement » ont ete presentes en termes d’Incidence Rate Ratio (IRR) et de son intervalle de confiance a 95 % (IC95 %). Resultats Parmi les 200 496 patientes inclues, 33 % avaient initie du denosumab, 26 % des BPO, 21 % de l’AZ, 10 % des estrogenes, 6 % du raloxifene et 4 % du teriparatide. Les patientes avaient en moyenne entre 63 ans (SD ± 8 ans) dans le groupe estrogene et 76 ans (±9 ans) dans le groupe teriparatide. Un traitement prealable par un medicament anti-osteoporotique etait plus frequemment retrouve dans le groupe denosumab (55 %). Le risque fracturaire de reference etait variable entre les groupes de traitement ; il etait le plus eleve dans les groupes AZ (fracture de la hanche) et teriparatide (fractures vertebrales) et le plus bas dans le groupe estrogene. En comparaison avec les 3 mois suivant l’initiation, les fractures vertebrales faisant l’objet d’une hospitalisation etaient significativement reduites dans les 12, 18 et 24 mois suivants avec le denosumab (IRRs : 0,7 [0,5 ; 0,8], 0,6 [0,5 ; 0,7] et 0,6 [0,5 ; 0,7]), l’AZ (IRR : 0,4 [0,3 ; 0,4] pour les 3 periodes), le teriparatide (IRRs : 0,4 [0,3 ; 0,6], 0,4 [0,2 ; 0,5] et 0,3 [0,2 ; 0,5]) et les BPO (IRRs : 0,6 [0,4 ; 0,8] pour les 3 periodes). Comparativement aux 3 premiers mois suivant la date index, l’incidence de fracture de la hanche etait significativement plus faible avec le denosumab dans les 18 et 24 mois suivants (IRRs : 0,8 [0,6 ; 0,9]) mais significativement plus elevee pour les BPO pour l’ensemble des 3 periodes (IRRs : 1,6 [1,1 ; 2,2] dans les 12 mois suivants, et 1,7 [1,2 ; 2,3] dans les 18 et les 24 mois suivants), alors qu’aucune difference significative n’etait observee avec l’AZ et le teriparatide. Une diminution significative de l’incidence des fractures peripheriques etait observee uniquement dans le groupe denosumab pour les 3 periodes (IRRs : 0,85 [0,75 ; 0,96] dans les 12 mois suivants, 0,83 [0,73 ; 0,94] dans les 18 mois suivants et 0,82 [0,73 ; 0,92] dans les 24 mois suivants). Discussion L’incidence des fractures vertebrales a ete reduite par le traitement avec des therapies contre l’osteoporose. Une diminution significative des fractures de hanche et peripheriques a ete observee uniquement avec le denosumab. Conclusion Le traitement avec des medicaments contre l’osteoporose est efficace dans en situation reelle.

PURPOSE: To estimate annual incidence and prevalence of Treatment-Resistant Depression (TRD) in France. METHODS: We identified all adult patients (≥ 18 years) with a TRD episode between 1 January 2012 and 31 December 2014 in the EGB (Échantillon généraliste des bénéficiaires), a permanent random sample of the French nationwide claims database. After a 6-month washout period without hospitalization for depression or any antidepressants (AD), and after exclusion of psychotic or bipolar affective disorders, Parkinson's disease and dementia, a TRD episode was defined by three successive sequences of different AD over a 3-month treatment period (6 months for a sensitive analysis), with at least 3 weeks before each sequence change and a Medication Possession Ratio ≥ 80%; or by the dispensing of \textbackslashtextgreatertwo different AD together; or of an AD with a potentiator (lithium, antiepileptic drugs, antipsychotic drugs, thyroid hormones) over the same treatment period. The annual incidence rate was estimated from 2012 to 2014 and the prevalence using a Gamma parametric function based on treatment duration and a 30-year prediction. RESULTS: Between 2012 and 2014, 700 patients were identified in EGB with a TRD episode. The mean age was 47.4 years (±15.3); 52.7% were women. Annual incidence and prevalence of TRD were estimated at 5.8 and 25.8 per 10 000 patients, respectively and at 7.8 and 37.6 per 10 000 patients, respectively in the sensitivity analysis. CONCLUSION: This study provides the first population-based estimates for incidence and prevalence of TRD in France.

Purpose: To assess the efficacy, safety, and follow-up of 36-month treatment with ranibizumab in patients with diabetic macular edema (DME) in real-life setting. Methods: This is a prospective phase 4 observational study. Between December 2013 and April 2015, 84 ophthalmologists enrolled a total of 290 adult patients initiating ranibizumab for visual impairment due to DME and treated them according to their routine practice. The primary outcome (mean change in best-corrected visual acuity [BCVA] after 12 months) was previously reported. Here, we present outcomes after 36 months of follow-up for BCVA and change in central subfield thickness (CSFT) and report how participating ophthalmologists treated DME over a 3-year period (number of visits and injections and evolution of treatment strategy). Results: Of the 290 patients enrolled, 187 (64.5%) completed the 36 months of the study (entire cohort). In the entire cohort, 97 patients were treated exclusively with ranibizumab throughout the study, and 90 patients switched to other intravitreal treatments. Mean BCVA was 64.2 (20.1) letters, representing a gain of +4.1 (19.9) letters from baseline to month 36 (M36). CSFT improved over the study, and by M36 had decreased by 127 (138) µm compared to baseline. Over the 36 months of follow-up, patients in the entire cohort paid their ophthalmologists a mean of 30.9 (12.2) visits and had a mean of 7.6 (5.2) any injections. Results for quality of life questionnaires NEI-VFQ25 and HUI-3 remained stable throughout the study. Multivariate analysis on the 145 patients with evaluable BCVA data at M36 found that male gender and milder baseline DME characteristics (BCVA ≥59 and CSFT

Background Quality of coding to identify cancers and comorbidities through the French hospital diagnosis database (Programme de medicalisation des systemes d’information, PMSI) has been little investigated. Agreement between medical records and PMSI database was evaluated regarding metastatic colorectal cancer (mCRC) and comorbidities. Methods From 01/01/2013 to 06/30/2014, 74 patients aged ≥ 65 years at mCRC diagnosis were identified in Bordeaux teaching hospital. Data on mCRC and comorbidities were collected from medical records. All diagnosis codes (main, related and associated) registered into the PMSI were extracted. Agreement between sources was evaluated using the percent agreement for mCRC and the kappa (κ) statistic for comorbidities. Results Agreement for primary CRC and mCRC was higher using all types of diagnosis codes instead of the main one exclusively (respectively 95% vs. 53% for primary CRC and 91% vs. 24% for mCRC). Agreement was substantial (κ 0.65) for cardiovascular diseases, notably atrial fibrillation (κ 0.77) and hypertension (κ 0.68). It was moderate for psychiatric disorders (κ 0.49) and respiratory diseases (κ 0.48), although chronic obstructive pulmonary disease had a good agreement (κ 0.75). Within the class of endocrine, nutritional and metabolic diseases (κ 0.55), agreement was substantial for diabetes (κ 0.91), obesity (κ 0.82) and hypothyroidism (κ 0.72) and moderate for hypercholesterolemia (κ 0.51) and malnutrition (κ 0.42). Conclusion These results are reassuring with regard to detection through PMSI of mCRC if all types of diagnosis codes are considered and useful to better choose comorbidities in elderly mCRC patients that could be well identified through hospital diagnosis codes.

Purpose To investigate sunitinib in the real-life first-line treatment of metastatic renal cell carcinoma (mRCC). Methods SANTORIN is a French observational multicentre cohort. Patients initiating sunitinib in first-line mRCC therapy were included (January 2008 to April 2010) and followed for 24 months. Data were collected from medical files. The outcomes were 24-month overall survival (OS) and progression-free survival (PFS), response and safety. Results Three hundred two patients were included: median age, 64.8 years; male, 73.2%; clear cell mRCC, 83.1%; prior nephrectomy, 85.4%; >1 metastatic sites, 64.2%; brain metastases, 6.3%; ECOG-PS ≥ 2, 9.9%. Median duration of first-line therapy with sunitinib was 10.7 months. Initial sunitinib dose was 50 mg/day for 83.4% of patients; dose reduction occurred in 65.2%. Sunitinib was discontinued in 73.2% of the patients: for progression (61.1%), death (31.2%) or adverse events (6.8%). More than half (58.3%) had grade ≥3 adverse events, mainly hypertension (12.6%) and hand–foot syndrome (12.3%). The 24-month OS and PFS rates [95%CI] were 49.5% [43.7;55.0] and 16.4% [12.5;20.9], respectively. Median OS was 23.6 months [20.2;–] and median PFS 8.4 months [7.6;9.9]. Overall best response rate was 31.1%. Conclusions Results from this large observational study suggest that effectiveness of sunitinib in first-line mRCC as predicted by clinical trials is maintained in real-life clinical practice. The expected benefit in poor-prognosis patients that were not evaluated in the pivotal clinical trial remains; however, questionable and long-term safety monitoring is still warranted. Copyright © 2017 John Wiley & Sons, Ltd.

Introduction Le dextropropoxyphene (DXP) etait l’antalgique opioide faible le plus prescrit jusqu’a son retrait en 2011. L’objectif de cette etude est de decrire les delivrances d’antalgiques chez les utilisateurs chroniques de DXP au moment du retrait et pendant 18 mois suivant le retrait du DXP. Methodes Ce projet est derive de l’etude DANTE [1] . Les utilisateurs chroniques de DXP ont ete definis comme des patients ayant recu au moins 40 boites de DXP dans l’annee precedant l’arret du DXP. Les donnees sur la delivrance d’antalgiques chez ces patients ont ete analysees a l’arret du DXP (T0) puis tous les 6 mois pendant 18 mois. Resultats Soixante-trois mille six-cent soixante et onze (63671) sujets ont eu un remboursement de DXP dans l’annee precedant son arret dont 7,1 % (n = 4495) identifies comme utilisateurs chroniques (âge moyen : 71,5 ans, femmes : 68,7 %). Six mois apres le retrait du DXP, 8,5 % sont decedes et 11,7 % ont cesse de recevoir un antalgique ; 79,7 % ont ete traites avec au moins un autre antalgique : au moins un antalgique-peripherique (majoritairement paracetamol) pour plus de la moitie ; au moins un opioide-faible (majoritairement tramadol) pour pres de la moitie. Si l’on suit la trajectoire de chaque patient, parmi les patients prenant du DXP seul a T0 (74,6 %), 1/4 est passe a un antalgique-peripherique, 1/4 a une combinaison antalgique-peripherique/opioide-faible, 1/4 a un opioide-faible ; l’autre quart a principalement interrompu son traitement (14,1 %) ou est decede. Au cours des 12 mois suivants, parmi les sujets ne prenant que des antalgiques-peripheriques, la majorite a maintenu ce traitement, tandis que la moitie des sujets ayant une combinaison opioide-faible/antalgique-peripherique ou ne prenant qu’un antalgique-faible sont restes sous ce type de traitement. Discussion Apres l’arret du DXP, 11,7 % des patients ont cesse de prendre un antalgique, les autres ayant poursuivi majoritairement avec du paracetamol et/ou du tramadol. Il est necessaire d’etre vigilant a toute modification d’antalgiques, en reevaluant regulierement la douleur et, dans le cas des traitements opioides, en surveillant le risque de trouble de l’usage notamment avec le tramadol, compte tenu de l’augmentation croissante de ces signes de mesusage [2] .

Metastatic colorectal cancer (mCRC) is frequent among elderly patients. However, in the era of new targeted therapies, little is known about real-life mCRC treatment in this population. This study aimed to describe elderly mCRC patients and the current real-life treatment practices. mCRC patients aged ≥65 years were identified using the registry of multidisciplinary team meetings, mandatory for all cancer patients, held between January 1, 2013 and June 30, 2014 at the Bordeaux University Hospital. Data were collected from medical records using a standardized questionnaire. Treatment type was defined as follows: at least one anticancer medication administered vs. best supportive care (BSC). A total of 78 patients were included; median age was 74 years and the M/F sex ratio 1.6. Eleven patients (14.1%) were referred to a geriatric oncology consultation. One patient died before treatment initiation, 28 (35.9%) had BSC, and 49 (62.8%) were treated with anticancer medications: 20 (25.6%) had chemotherapy combined with a targeted therapy, and 28 (35.9%) chemotherapy alone (one missing data for treatment). Compared to patients treated with anticancer medications, BSC patients were older (P < 0.0001) and had more often metachronous metastases (P = 0.01), more comorbidities (P = 0.05), and a greater number of concomitant medications (P = 0.004). This study is one of the rare investigations providing insight to treatment practices in all elderly mCRC patients, not just those who receive anticancer medications. Our results suggest that efforts must be pursued to better integrate geriatric oncology in daily clinical practice.

International audience; BACKGROUND: Metastatic colorectal cancer (mCRC) is increasingly treated using targeted therapies. Their real-life evaluation is insufficient, especially in elderly and frail patients. The aim was to describe use, safety, and effectiveness of targeted therapies in first-line mCRC treatment according to age. PATIENTS AND METHODS: Two field cohorts of patients initiating bevacizumab or cetuximab for first-line mCRC were pooled. Patients characteristics, use, and safety were compared between younger and elderly patients (/=75 years). Two-year overall survival (OS) and progression-free survival (PFS) were estimated in both age groups using the Kaplan-Meier method adjusted on factors associated with death or progression identified with Cox multivariate modeling. RESULTS: Eight hundred patients (n = 411, 51.4% bevacizumab) were included: 498 (62.3%) male, median age 64 years, 118 (14.8%) Eastern Cooperative Oncology Group performance status (ECOG-PS) >/=2. Elderly patients (n = 126, 15.8%) were more often treated with 5-fluorouracil alone than younger. Severe adverse events were equivalent across age groups. ECOG-PS >/=1, abnormal hemoglobin, and abnormal alkaline phosphatases were associated with a higher risk of death; OS adjusted on these factors was similar between elderly and younger patients. ECOG-PS >/=1, lung metastases, abnormal hemoglobin, and abnormal creatinine clearance were associated with a higher risk of progression or death; PFS adjusted on these factors was similar across groups. CONCLUSION: Despite treatment adaptations, elderly patients could benefit from targeted therapies as younger without safety warning.

Contexte Entre 15 % et 30 % des patients depressifs presenteraient une depression resistante au traitement (DR). La definition la plus communement admise est l’echec d’au moins deux essais successifs de traitement antidepresseur bien conduits en termes de dose et duree. A ce jour, la situation epidemiologique de la DR est mal connue, notamment en France. Objectif Estimer l’incidence et la prevalence annuelles de la DR en France et decrire les caracteristiques des patients concernes, a partir des donnees du Systeme national des donnees de sante (SNDS). Methodes Tous les sujets adultes (≥ 18 ans) presentant un episode de DR entre le 1er janvier 2012 et le 31 decembre 2014 ont ete identifies dans l’EGB (Echantillon generaliste de beneficiaires), l’echantillon permanent au 1/97 du SNDS. Apres exclusion des patients presentant des troubles psychotiques ou bipolaires, une maladie de Parkinson ou une demence, un episode de DR a ete defini par la succession de trois sequences d’antidepresseurs (AD) differents, ou par la combinaison d’un AD avec un medicament qui potentialise l’effet de l’AD (lithium, antiepileptiques, antipsychotiques ou hormones thyroidiennes), delivres sur une periode de trois mois avec au minimum trois semaines de traitement entre chaque sequence et avec un Medication Possession Ratio ≥ 80 %. Les patients DR devaient ne pas avoir eu d’AD ou d’hospitalisation pour depression dans les six mois precedant la premiere delivrance d’AD (i.e. date d’initiation). Le taux d’incidence a ete estime annuellement de 2012 a 2014, puis moyenne. La prevalence annuelle a ete modelisee a partir d’une fonction parametrique Gamma, en projetant sur 30 ans les probabilites d’arret de traitement de DR estimees en 2012. Resultats Entre 2012 et 2014, 700 patients ont ete identifies avec au moins un episode de DR dont 6 patients avec un deuxieme episode. L’âge moyen etait de 47,4 ans (± 15,3) avec 52,7 % de femmes. La duree mediane d’un episode revolu de DR etait de 5,4 mois. L’incidence annuelle a ete estimee a 5,8 par 10 000 personnes et la prevalence annuelle a 25,8 par 10 000 personnes. Discussion Cette etude fournit des donnees actualisees de la prevalence et de l’incidence de la DR en France, inconnues jusqu’alors. Ces estimations correspondent aux valeurs basses decrites dans la litterature, mais l’algorithme d’identification de la DR utilise dans cette etude englobe l’ensemble des strategies de traitement de la DR.

Introduction L’objectif etait d’estimer l’incidence et la prevalence de la depression resistante (DR) en France avec les donnees du systeme national des donnees de sante (SNDS) et un algorithme complexe. Methodes L’algorithme a ete construit dans l’EGB : adultes du Regime general, avec une premiere delivrance d’antidepresseur (AD), suivie d’au moins deux delivrances d’AD sur six mois, sans delivrance d’AD dans les six mois precedents, ni antecedent de maladie de Parkinson, de demence, de troubles psychotiques ou bipolaires. Un episode incident de DR a ete defini par la succession de trois sequences d’antidepresseurs differents sur une periode de trois mois, au moins trois semaines de traitement pour chaque sequence et des delivrances couvrant au moins 80 % du temps, ou des la prescription d’un antidepresseur avec un potentialisateur. Le taux d’incidence annuelle d’un episode de DR a ete estime entre 2012 et 2014, et la prevalence avec une fonction gamma sur 30 ans basee sur le taux d’incidence annuelle et de la probabilite d’arret de l’episode de DR sur trois ans. Ces taux ont ete extrapoles aux donnees de l’Insee avec standardisation sur l’âge et le sexe pour estimer l’incidence annuelle et la prevalence de la population francaise. Resultats Entre 2012 et 2014, 706 patients ont ete identifies dans l’EGB avec un episode incident de DR (58,1 % de femmes, âge moyen 48 ans ( ± 16 ans) et duree mediane de l’episode 7,1 mois). Le taux d’incidence annuelle estime etait de 5,79 pour 10 000 (IC 95 % = [5,06 ; 6,52]) personnes et la prevalence a 25,79 pour 10 000 [24,23 ; 27,35], soit une estimation nationale de 29 015 sujets par an avec un episode incident de DR [25 315 ; 32 735] et 129 275 sujets prevalents [121 465 ; 137 106]. Discussion/Conclusion Une analyse de sensibilite avec allongement a six mois pour la succession des trois sequences d’AD donne un taux d’incidence annuelle et de prevalence de la DR en France plus eleve de respectivement 34 et 46 %.

In response to a regulatory request for real-life data on patterns of use and survival outcomes, 793 patients initiating bortezomib for multiple myeloma in France (May 2004-April 2006) were included in this observational study. Data were collected from medical files and patients were followed for 2 years, with vital status collected after 3 years. In total 779 patients were analyzed: 83.1% had immunoglobulin G (IgG) or IgA M-component, mean age was 65.7 years and 46.5% were female. Bortezomib was initiated as third-or-later line in 82.0%. For 75.9%, the starting dose was 1.3 mg/m(2); 42.6% had bortezomib alone, 54.0% with dexamethasone. The mean number of bortezomib cycles was 5.0. Three-year overall survival from bortezomib initiation was 31.4% (95% confidence interval, CI [28.1; 34.7]) and median overall survival was 19.6 months. Two-year progression-free survival was 12.0% (95% CI [9.8; 14.4]), and median progression-free survival was 7.2 months. Overall best response was 44.0%. Survival outcomes during real-life use of bortezomib were within the range of those reported in clinical trials.

Objective Estimate the effect of lifestyle adjustment activities in patients with metabolic syndrome treated by prescribed balneotherapy. Methods Observational pilot cohort study with 12-month follow-up after multidimensional lifestyle training (physical, dietary, educational) during 3-week standard stay in the spa town of Eugenie-les-Bains. Results Of 145 eligible patients, 97 were included; 63 were followed and analysable. At inclusion all had ≥ 3 National cholesterol education program-Adult treatment panel III (NCEP-ATPIII) criteria defining metabolic syndrome, 76.2% were female, mean age was 61.2 years. At the end of follow-up (median:10.4 months, Inter-Quartile Range: [6.7;11.4]), 48 of these 63 patients (76.2%) no longer had metabolic syndrome (95%CI [65.7;86.7]). These 48 patients without metabolic syndrome at the end of follow-up represented 49.5% of the 97 included (95%CI [39.5;59.4]). Conclusions Future studies of lifestyle interventions taking advantage of the spa environment can be expected to find least one third of patients free of metabolic syndrome at the end of 12-month follow-up in the intervention group.

To investigate sunitinib in the real-life first-line treatment of metastatic renal cell carcinoma (mRCC).SANTORIN is a French observational multicentre cohort. Patients initiating sunitinib in first-line mRCC therapy were included (January 2008 to April 2010) and followed for 24 months. Data were collected from medical files. The outcomes were 24-month overall survival (OS) and progression-free survival (PFS), response and safety.Three hundred two patients were included: median age, 64.8 years; male, 73.2%; clear cell mRCC, 83.1%; prior nephrectomy, 85.4%;1 metastatic sites, 64.2%; brain metastases, 6.3%; ECOG-PS ≥ 2, 9.9%. Median duration of first-line therapy with sunitinib was 10.7 months. Initial sunitinib dose was 50 mg/day for 83.4% of patients; dose reduction occurred in 65.2%. Sunitinib was discontinued in 73.2% of the patients: for progression (61.1%), death (31.2%) or adverse events (6.8%). More than half (58.3%) had grade ≥3 adverse events, mainly hypertension (12.6%) and hand-foot syndrome (12.3%). The 24-month OS and PFS rates [95%CI] were 49.5% [43.7;55.0] and 16.4% [12.5;20.9], respectively. Median OS was 23.6 months [20.2;-] and median PFS 8.4 months [7.6;9.9]. Overall best response rate was 31.1%.Results from this large observational study suggest that effectiveness of sunitinib in first-line mRCC as predicted by clinical trials is maintained in real-life clinical practice. The expected benefit in poor-prognosis patients that were not evaluated in the pivotal clinical trial remains; however, questionable and long-term safety monitoring is still warranted. Copyright © 2017 John WileySons, Ltd.

Objectif Evaluer les modalites d’utilisation et l’efficacite en vie reelle du traitement par injection intravitreenne (IVT) de ranibizumab chez des patients presentant une baisse de l’acuite visuelle (BAV) due a un œdeme maculaire secondaire a une occlusion veineuse retinienne (OM-OVR) qu’elle soit de branche (B) ou centrale (C), a la demande de la Haute Autorite de sante. Methode Etude de cohorte observationnelle nationale de patients initiant un traitement par IVT de ranibizumab pour une BAV due a un OM-OVR, inclus et suivis pendant 24 mois par des retinologues. Le critere principal d’evaluation est la variation de la Meilleure acuite visuelle corrigee (MAVC) a six mois par rapport a l’inclusion. Les criteres secondaires sont la variation de la MAVC, celle de l’epaisseur de la zone centrale de la retine (ECR), la description des modalites du suivi ophtalmologique et les evenements indesirables au cours des 24 mois de suivi. Resultats Entre decembre 2013 et avril 2015, pour les cohortes B/C, 226/196 patients ont ete inclus dans l’etude et 162/139 (71,7/70,9 %) presentaient des donnees de suivi analysables a 24 mois. Les caracteristiques des patients etaient un âge moyen (e-t) de 70,9 ans (11,1)/70,4 (14,3) ans avec 48,7/51,5 % d’hommes, une MAVC moyenne a l’inclusion de 55,2 ans (18,7)/40,4 (25,6) lettres ETDRS et une ECR moyenne de 550 (175)/643 (217) μm. A 6 (± 1,5) mois de suivi, la variation moyenne de la MAVC [IC 95 %] par rapport a l’inclusion etait de +14,1 [11,7 a 16,5]/ + 9,5 [5,5 a 13,5] lettres. Cette evolution se stabilisait au cours du temps avec +13,0 [10,2 a 15,9]/ + 9,2 [4,5 a 13,9] lettres a 12 (± 1,5) mois et +11,4 [7,7 a 15,2]/ + 8,3 [3,7 a 12,8] lettres a 24 (± 1,5) mois, avec 53,1/38,9 % des patients presentant une MAVC superieure a 70 lettres. La variation moyenne de l’ECR etait de −223 [−254 a −192]/−267 [−314 a −220] μm a 6 (±1,5) mois, −225 [−260 a −191]/−284 [−334 a −233] μm a 12 (±1,5) mois et −211 [−251 a −170]/−305 [−356 a −255] μm a 24 (±1,5) mois. A 24 mois, le nombre moyen d’IVT etait de 7,2 (4,3)/7,1 (4,4) par œil etudie et 85,8/85,6 % des yeux etudies ont eu au moins une interruption des IVT de ranibizumab (72,6/62,5 % pour amelioration de la pathologie et 15,2/26,7 % pour manque d’efficacite). A 24 mois, 69,8/62,6 % des yeux etudies ont recu seulement un traitement par ranibizumab et 30,2/37,4 % un autre traitement intravitreen (premier switch : 15,4/12,2 % par dexamethasone, 13,6/20,9 % par aflibercept, 1,2/0 % par triamcinolone et 0/4,3 % par bevacizumab). Aucun nouveau signal de pharmacovigilance n’a ete detecte. Conclusion Les resultats obtenus en vie reelle a 24 mois chez des patients initiant un traitement par IVT de ranibizumab dans l’OM-OVR montrent une relative stabilite par rapport a ceux observes a six mois. Ces resultats sont un peu plus faibles que ceux des essais cliniques a 24 mois avec une intensite plus faible d’injections en vie reelle (7,2/7,1 dans BOREAL contre 11,4/13,1 dans BRIGHTER/CRYSTAL).

Effectiveness of bevacizumab for metastatic colorectal cancer in elderly patients has been investigated in observational studies, mainly associated with oxaliplatin-based regimens. Here, using the ETNA cohort in which the majority of patients received bevacizumab+FOLFIRI, the effectiveness of this combination in elderly patients is explored.Patients initiating first-line therapy with bevacizumab between January 2006 and December 2007 were identified in 28 French centres and followed for 24months. Vital status was collected over 36months. In the present analysis those who received FOLFIRI were retained (85% of those included), and patients were stratified by age (70/≥70years). The Kaplan-Meier method estimated progression-free survival (PFS) and overall survival (OS), and Cox models were used to assess the independent effect of age on survival outcomes.Among the 351 patients who received bevacizumab+FOLFIRI, 33.9% were aged ≥70years, 66.1%70years. Respectively 15.1% and 9.5% of patients had ECOG-PS ≥2; 49.6% and 40.1% used 'stop-and-go' treatment scheduling; and 56.3% and 44.4% experienced grade 3/4 adverse events. Overall response rate was 58.8% and 62.5%. Median [95% confidence interval, CI] OS was respectively 24.1 [20.4; 26.2] and 28.5 [25.0; 31.0] months; age≥70years and ECOG-PS≥2 were significantly associated with death. Median PFS [95% CI] was respectively 10.9 [9.4; 12.6] and 9.8 [9.2; 11.2] months; hepatic metastases was associated with progression, and age ≥70years was associated with progression after 14months of follow-up but not before.The present study adds to the literature on the safe and beneficial effect of bevacizumab in the elderly receiving FOLFIRI regimen.

Therapeutical options for older multiple myeloma patients have been improved with the advent of new drugs, yet there is a lack of observational data for such patients. To address this issue, an age-stratified analysis of the VESUVE cohort of bortezomib users was performed. Among the 779 patients included in the analysis, 358 (46%) were aged ≤ 65 years, 282 (36%) were between 65-75 years and 139 (18%) were more than 75 years old. There were few significant differences in treatment parameters across age groups; notably, older patients received a lower dose of bortezomib and more frequently experienced general or administration site conditions, metabolism or nutrition disorders and cardiac disorders. Overall best response rate and progression-free survival were similar across age groups. Taken together, these results indicate that older patients do benefit from bortezomib and that tailored treatment in real-life clinical practice does not compromise effectiveness.

Objectifs Compte tenu du vieillissement de la population, l’oncogeriatrie est devenue une priorite de sante publique. Les patients âges etant le plus souvent exclus des essais therapeutiques, il n’existe pas de recommandations specifiques validees pour le traitement du cancer chez les patients âges en France. De plus, il n’y a pas de donnees observationnelles disponibles sur l’utilisation du cetuximab pour cette population. Dans le cadre de la cohorte EREBUS, la population âgee de plus de 70 ans a ete comparee a la population d’âge inferieur ou egal a 70 ans, en termes de conditions d’utilisation du cetuximab, de securite d’emploi et d’efficacite avec la survie sans progression et le taux de reponse tumorale en situation reelle de soins. Methode EREBUS est une etude de cohorte francaise multicentrique (n = 92), qui a inclus 389 patients inoperables initiant, en situation reelle de soins, du cetuximab en premiere ligne de traitement pour un cancer colorectal metastatique entre 2009 et 2010. Ces patients ont ete identifies a partir des registres de delivrance des pharmacies hospitalieres et suivis 24 mois. Resultats Un total de 116 patients (29,8 %) etaient âges de plus de 70 ans (« âges ») et 273 patients (70,2 %) avaient un âge ≤70 ans (« non âges »). Les patients « âges » etaient relativement comparables aux patients « non âges » selon le sexe et le score ECOG (62,1 % hommes versus 69,6 % [p = 0,15] ; ECOG 0–1 : 72,4 % versus 80,2 % [p = 0,12]). La duree mediane du traitement par cetuximab etait significativement plus courte chez les « âges » (3,7 versus 5,3 mois, p = 0,03). La frequence d’association a une chimiotherapie a base d’irinotecan (54,3 % versus 56,8 %, p = 0,64) ou a base d’oxaliplatine (36,2 % versus 38,5 %, p = 0,67) et l’incidence des evenements indesirables tout grade confondu n’etaient pas statistiquement differentes (hematologiques [91,4 % versus 90,8 %, p = 0,87], digestifs [79,3 % versus 85,7 %, p = 0,12], dermatologiques [77,6 % versus 85,0 %, p = 0,08], et neurosensitifs [37,9 % versus 47,6 %, p = 0,08]). La survie sans progression et la reponse tumorale au traitement n’etaient pas differentes entre les « âges » et « non âges » : mediane de survie sans progression : 9,5 mois (IC 95 % [7,1–10,5]) versus 9,2 mois [8,1–9,8] et taux de reponse : 46,5 % [37,4–55,6] versus 56,7 % [50,8–62,6]. Conclusion Dans la cohorte EREBUS, l’efficacite et la securite d’emploi du cetuximab associe a une chimiotherapie chez les patients « âges » n’etait pas differente de celles observees chez les patients « non âges ». Des resultats similaires ont ete rapportes pour une autre therapie ciblee dans le traitement du cancer colorectal metastatique ; le bevacizumab dans la cohorte ETNA en France et dans la cohorte BRITE aux Etats-Unis.

A yeast mutant was isolated that was resistant to Bax-induced cell death. It supports a mutation leading to decreased amounts of the protein Uth1p. A strain in which the UTH1 gene is disrupted also exhibits resistance to Bax expression. The absence of Uth1p does not change the mitochondrial localization of Bax, its insertion in the mitochondrial outer membrane or its cytochrome c-releasing activity. On the other hand, the absence of Uth1p does prevent the appearance of other hallmarks related to Bax expression in yeast, such as oxidation of mitochondrial lipid, production of reactive oxygen species and maintenance of plasma membrane properties after ethanol stress. The absence of Uth1p was also found to induce resistance to rapamycin, a specific inducer of autophagy. This resistance only appears when cells are grown under respiratory conditions, but not under fermentative conditions, suggesting that Uth1p acts in an autophagic pathway involving mitochondria, in accordance with its main localization in the outer mitochondrial membrane. Taken together, these data show that Bax is able to activate a death pathway related to autophagy in yeast, which also exhibits typical hallmarks of apoptosis, revealing a possible dual function of Bax in both types of death. This hypothesis is discussed in the light of observations suggesting a co-regulation of apoptosis and autophagy in mammalian cells.

The oxidant function of pro-apoptotic protein Bax was investigated through heterologous expression in yeast. Direct measurements of fatty acid content show that Bax-expression induces oxidation of mitochondrial lipids. This effect is prevented by the coexpression of Bcl-xL. The oxidation actually could be followed on isolated mitochondria as respiration-induced peroxidation of polyunsaturated cis-parinaric acid and on whole cells as the increase in the amount of thiobarbituric acid-reactive products. Treatments that increase the unsaturation ratio of lipids, making them more sensitive to oxidation, increase kinetics of Bax-induced death. Conversely, inhibitors of lipid oxidation and treatments that decrease the unsaturation ratio of fatty acids decrease kinetics of Bax-induced death. Taken together, these results show that Bax-induced mitochondrial lipid oxidation is relevant to Bax-induced cell death. Conversely, lipid oxidation is poorly related to the massive Bax-induced superoxide and hydrogen peroxide accumulation, which occurs at the same time, as chemical or enzymatic scavenging of ROS does not prevent lipid oxidation nor has any effects on kinetics of Bax-induced cell death. Whatever the origin of mitochondrial lipid oxidation, these data show that it represents a major step in the cascade of events leading to Bax-induced cell death. These results are discussed in the light of the role of lipid oxidation both in mammalian apoptosis and in other forms of cell death in other organisms.

Objectif Evaluer les modalites d’utilisation et l’efficacite en vie reelle du traitement par injection intravitreenne (IVT) de ranibizumab chez des patients presentant une baisse de l’acuite visuelle (BAV) due a un œdeme maculaire secondaire a une occlusion veineuse retinienne (OM-OVR) qu’elle soit de branche (B) ou centrale (C), a la demande de la Haute Autorite de sante (HAS). Methode Etude de cohorte observationnelle nationale de patients initiant un traitement par IVT de ranibizumab pour une BAV due a un OM-OVR (320 patients attendus par pathologie, pour avoir une precision de ± 2 lettres), inclus et suivis pendant 24 mois par des ophtalmologistes specialistes de la retine (retinologues). Le critere principal d’evaluation est la variation de la meilleure acuite visuelle corrigee (MAVC) a six mois par rapport a l’inclusion. Les criteres secondaires sont la variation de la MAVC, celle de l’epaisseur de la zone centrale de la retine (ECR), la description des modalites du suivi ophtalmologique ainsi que les evenements indesirables au cours du suivi. Resultats Entre decembre 2013 et avril 2015, pour les cohortes B/C, 223/196 patients ont ete inclus dans l’etude et 207/180 (92,8/91,8 %) presentaient des donnees de suivi analysables a six mois. Les caracteristiques des patients etaient un âge moyen (ET) de 70,3 (11,1)/70,5 (14,4) ans avec 47,8/50,6 % d’hommes, des premiers symptomes apparus en moyenne depuis 4,4 (12,6)/3,0 (6,0) mois, 9,2/8,3 % des patients deja traites pour leur OM-OVR (4,8/0,0 % par laser maculaire, 6,3/7,8 % par corticotherapie intravitreenne, 1,0/1,1 % par un autre anti-VEGF), et 3,9/2,8 % avec une atteinte bilaterale. A l’inclusion, la MAVC moyenne etait de 54,7 (18,9)/40,5 (25,7) lettres d’ETDRS avec 13,5/8,3 % des patients qui presentaient une MAVC superieure a 70 lettres. L’ECR moyenne etait de 558 (178)/649 (216) μm. Au cours des trois premiers mois, 80,7/76,1 % des patients avaient recu les trois IVT recommandees (traitement d’induction). A 3 (± 1,0) mois de suivi, la variation moyenne de la MAVC [IC 95 %] par rapport a l’inclusion etait de 14,7 [12,4 a 17,1]/16,0 [12,1 a 19,8] lettres et l’evolution de l’ECR etait de −240 [−269 a −211]/−323 [−371 a −275] μm. A six mois de suivi, le nombre moyen d’IVT etait de 3,8 (1,2)/3,6 (1,2) par œil etudie et 59,4/56,1 % des patients avaient eu au moins une interruption des IVT de ranibizumab (52,7/38,3 % pour amelioration de la pathologie et 7,2/15,6 % pour manque d’efficacite). A 6 (± 1,5) mois de suivi, la variation moyenne de la MAVC par rapport a l’inclusion etait de 13,9 [11,5 a 16,3]/9,5 [5,5 a 13,5] lettres avec 43,5/30,6 % des patients presentant une MAVC superieure 70 lettres. En parallele, l’evolution de l’ECR etait de −223 [−254 a −192]/−264 [−311 a −217] μm. Conclusion Cette etude en vie reelle chez des patients initiant un traitement par IVT de ranibizumab dans l’OM-OVR montre une amelioration de l’acuite visuelle a trois mois proche de celle des essais cliniques pre-AMM (BRAVO/CRUISE), et un peu plus faible a six mois mais avec une intensite plus faible d’injections en vie reelle (3,8/3,6 dans BOREAL contre 6 dans BRAVO/CRUISE).

Objectif Evaluer les modalites d’utilisation et l’efficacite en vie reelle du traitement par injection intravitreenne (IVT) de ranibizumab chez des patients presentant une baisse de l’acuite visuelle secondaire a un œdeme maculaire diabetique (OM-D), a la demande de la Haute Autorite de sante (HAS). Methode Etude de cohorte observationnelle nationale de patients initiant un traitement par IVT de ranibizumab pour une baisse de l’acuite visuelle due a un OM-D inclus et suivis pendant 36 mois par des ophtalmologistes specialistes de la retine (retinologues). Le critere principal d’evaluation est la variation de la meilleure acuite visuelle corrigee (MAVC) a 12 mois par rapport a l’inclusion (304 patients attendus pour avoir une precision de ± 1 lettre). Les criteres secondaires sont la variation de la MAVC, celle de l’epaisseur de la zone centrale de la retine (ECR), la description des modalites du suivi ophtalmologique ainsi que les evenements indesirables au cours du suivi. Resultats Entre decembre 2013 et avril 2015, 290 patients ont ete inclus dans l’etude et 242 (83,4 %) presentaient des donnees de suivi analysables a 12 mois. Les caracteristiques des patients etaient un âge moyen (ET) de 66,1 (11,0) ans avec 56,6 % d’hommes, 43,8 % avec un OM-D de plus de 6 mois, 13,2 % deja traites pour leur OM-D (8,3 % par laser maculaire, 4,5 % par corticotherapie intravitreenne, 2,5 % par un anti-VEGF autre que le ranibizumab) et 66,5 % avec une atteinte bilaterale. A l’inclusion, la MAVC moyenne etait de 59,2 (15,0) lettres d’ETDRS avec 13,2 % des patients qui presentaient une MAVC superieure a 70 lettres. L’ECR moyenne etait de 457 (144) μm. Au cours des trois premiers mois, 83,9 % des patients avaient recu les trois premieres injections recommandees (traitement d’induction). A 12 mois de suivi, le nombre moyen d’IVT etait de 5,1 (2,3) par œil etudie et 83,1 % des patients avaient eu au moins une interruption des IVT de ranibizumab (45,4 % pour amelioration de la pathologie et 27,7 % pour manque d’efficacite). A 12 (± 1,5) mois de suivi, la variation moyenne de la MAVC [IC 95 %] par rapport a l’inclusion etait de 7,4 [5,4 a 9,4] lettres avec 36,8 % des patients presentant une MAVC superieure 70 lettres. En parallele, l’evolution de l’ECR etait de −125 [−146 a 103] μm. Conclusion Cette etude en vie reelle chez des patients initiant un traitement par IVT de ranibizumab dans l’OM-D montre une amelioration de l’acuite visuelle proche de celle de l’essai clinique pre-AMM RESTORE avec en moyenne un peu moins d’IVT realisees (5,1 dans BOREAL contre 7 injections en moyenne dans RESTORE sur 12 mois).

Objectifs Historiquement, les etudes pharmaco-epidemiologiques en rapport avec l’oncologie concernaient le risque de cancer associe a l’exposition a certains medicaments. Depuis une dizaine d’annees, la commercialisation des therapies ciblees (TC) offre des opportunites de recherche centrees sur les medicaments anticancereux. Nous proposons de decrire l’experience de la plate-forme de recherche en pharmaco-epidemiologie de Bordeaux dans l’evaluation de l’utilisation et de l’efficacite des medicaments anticancereux en situation reelle de soins. Methode Depuis 2004 la plate-forme, enregistree a l’ENCePP, a permis de realiser des etudes de terrain et sur bases de donnees. Quatre cohortes multicentriques de nouveaux utilisateurs de TC pour le traitement de differents cancers ont ete conduites. Les patients ont ete identifies par le biais des donnees de dispensations nominatives hospitalieres ou des prescripteurs. Des donnees detaillees ont ete recueillies a partir des dossiers medicaux consultes dans chaque centre. Les patients ont ete suivis pendant au moins deux ans afin d’evaluer la survie sans progression (SSP) telle que rapportee par les medecins, et la survie globale (SG). Des analyses stratifiees ont ete effectuees dans le but de comparer l’utilisation et l’efficacite des TC entre les patients âges et plus jeunes. Des etudes d’utilisation ont egalement ete conduites a partir des donnees de remboursement de l’Echantillon Generaliste des Beneficiaires (EGB) de l’Assurance Maladie francaise, en particulier sur les medicaments anticancereux oraux dans le cancer du sein. Resultats Pres de 2000 patients ont ete inclus dans les cohortes (28 a 92 centres) : 793 patients debutant un traitement par bortezomib pour myelome multiple, 411 par bevacizumab et 389 par cetuximab pour cancer colorectal et 302 par sunitinib pour cancer du rein. Dans chaque cohorte, la SSP et la SG etaient proches de celles rapportees dans les essais cliniques pivots. Bien que differents en termes de comorbidites et de modalites d’utilisation, les patients âges traites par bortezomib, bevacizumab ou cetuximab presentaient des resultats de survie comparables a ceux obtenus chez les patients plus jeunes. Parmi 600 femmes debutant une hormonotherapie pour cancer du sein identifiees a partir des donnees de l’EGB, plus de 40 % ne continuaient pas a prendre le traitement a 5 ans. Conclusion Les donnees disponibles grâce a la plate-forme donnent une vision d’ensemble interessante et rassurante de l’efficacite des TC en situation reelle de soins. Les resultats suggerent une prescription preferentielle des TC aux patients en meilleur etat de sante ; des cohortes complementaires de patients ayant un cancer nouvellement diagnostique doivent etre mises en place pour mieux comprendre les determinants de la prescription et comparer l’efficacite en situation reelle de soins entre TC. Il serait egalement important d’etudier l’adherence aux medicaments anticancereux oraux et la securite d’emploi des TC a long terme.

A retrospective, observational, cohort study in primary care. To determine the total direct medical and non-medical cost of chronic low back pain (LBP) in France and its associated factors. Chronic LBP affects 5-10% of the population its burden in France is unknown. Ninety-eight randomly selected general practitioners included 796 adult patients with chronic LBP between October 2001 and December 2002. Direct costs due to physician visits, investigations, medications, hospitalizations, and other medical and non-medical resource use were collected for the 6 months prior to study visit. Costs both reimbursed and not by the French health insurance system were considered. Quality of life (QoL) and disease severity were measured using Short Form (SF)-8 and Roland-Morris disability questionnaire (RMDQ), respectively. Costs were updated to represent 2007 prices. Men represented 50.6% of the 796 patients, mean age was 53 +/- 11.3 years, and the duration of LBP was more than 1 year in 80.9% of patients. The total mean cost per patient over six months was 715.6 euro (95% CI: 644.2-797.8). Of these costs, 22.9% related to care provided by physiotherapists and allied specialists, 19.5% to medications, 17.4% to hospitalizations, 9.6% to investigations, and 12.5% to physician fees. In multivariate analysis, the factors associated with the cost of chronic LBP were disease severity (RMDQ score) and age of the patients. LBP is a disease that is both common and costly.

Introduction En 2012, le cancer colorectal (CCR) etait le 3e cancer le plus frequent en France. Alors que l’âge moyen au diagnostic excede 70 ans, il n’existe pas de referentiel de prise en charge medicamenteuse pour la population âgee, surtout au stade metastatique depuis l’arrivee des therapies ciblees. La realisation d’un « etat des lieux » est donc necessaire. Decrire les modalites de prise en charge medicamenteuse des sujets âges de 65 ans et plus, a l’issue d’un diagnostic de CCR metastatique (CCRm) : traitement recommande incluant une therapie ciblee versus chimiotherapie seule ou abstention therapeutique. Methode Une etude pilote a ete conduite au Centre hospitalier universitaire (CHU) de Bordeaux. Les patients suivis dans ce CHU et âges d’au moins 65 ans au diagnostic d’un CCRm ont ete identifies a partir des donnees des reunions de concertation pluridisciplinaire (RCP) entre le 01/01/2013 et le 30/06/2014. Pour chaque patient, les donnees demographiques, socio-environnementales, clinico-biologiques, relatives a la prise en charge medicamenteuse du CCRm ainsi que les effets indesirables survenant au cours du traitement ont ete recueillis a partir des dossiers medicaux a l’aide d’un questionnaire standardise. Une analyse descriptive a ete realisee de maniere globale puis stratifiee selon les modalites de traitement. Resultats Parmi les 78 patients inclus, l’âge median etait de 74 ans et 61,5 % etaient des hommes. Le nombre median de comorbidites et de medicaments concomitants etait de 4 et la majorite des patients (70,5 %) etait en bon etat general (capacite de vie OMS de 0 ou 1). La tumeur primitive etait situee en majorite au niveau du colon (57,7 %). Plus de la moitie des patients (59,0 %) presentait des metastases synchrones et pres des trois quarts (74,4 %), un seul site metastatique. Quarante-neuf patients (62,8 %) avaient recu un traitement anticancereux et 28 (35,9 %) etaient en abstention therapeutique (1 patient decede). Les patients traites etaient significativement plus jeunes (p Conclusion Cette etude pilote est une des rares etudes de terrain permettant de decrire les patients âges atteints de CCRm traites et non traites et d’effectuer une stratification sur les modalites de traitement anticancereux. Elle donne des pistes quant aux facteurs associes a la mise sous traitement anticancereux, d’une part, et a l’administration de medicaments innovants, d’autre part, dans cette population fragile et suggere que le profil des patients traites, en particulier par therapie ciblee, se rapproche de celui des patients plus jeunes.

A yeast mutant was isolated that was resistant to Bax-induced cell death. It supports a mutation leading to decreased amounts of the protein Uth1p. A strain in which the UTH1 gene is disrupted also exhibits resistance to Bax expression. The absence of Uth1p does not change the mitochondrial localization of Bax, its insertion in the mitochondrial outer membrane or its cytochrome c-releasing activity. On the other hand, the absence of Uth1p does prevent the appearance of other hallmarks related to Bax expression in yeast, such as oxidation of mitochondrial lipid, production of reactive oxygen species and maintenance of plasma membrane properties after ethanol stress. The absence of Uth1p was also found to induce resistance to rapamycin, a specific inducer of autophagy. This resistance only appears when cells are grown under respiratory conditions, but not under fermentative conditions, suggesting that Uth1p acts in an autophagic pathway involving mitochondria, in accordance with its main localization in the outer mitochondrial membrane. Taken together, these data show that Bax is able to activate a death pathway related to autophagy in yeast, which also exhibits typical hallmarks of apoptosis, revealing a possible dual function of Bax in both types of death. This hypothesis is discussed in the light of observations suggesting a co-regulation of apoptosis and autophagy in mammalian cells.

The oxidant function of pro-apoptotic protein Bax was investigated through heterologous expression in yeast. Direct measurements of fatty acid content show that Bax-expression induces oxidation of mitochondrial lipids. This effect is prevented by the coexpression of Bcl-xL. The oxidation actually could be followed on isolated mitochondria as respiration-induced peroxidation of polyunsaturated cis-parinaric acid and on whole cells as the increase in the amount of thiobarbituric acid-reactive products. Treatments that increase the unsaturation ratio of lipids, making them more sensitive to oxidation, increase kinetics of Bax-induced death. Conversely, inhibitors of lipid oxidation and treatments that decrease the unsaturation ratio of fatty acids decrease kinetics of Bax-induced death. Taken together, these results show that Bax-induced mitochondrial lipid oxidation is relevant to Bax-induced cell death. Conversely, lipid oxidation is poorly related to the massive Bax-induced superoxide and hydrogen peroxide accumulation, which occurs at the same time, as chemical or enzymatic scavenging of ROS does not prevent lipid oxidation nor has any effects on kinetics of Bax-induced cell death. Whatever the origin of mitochondrial lipid oxidation, these data show that it represents a major step in the cascade of events leading to Bax-induced cell death. These results are discussed in the light of the role of lipid oxidation both in mammalian apoptosis and in other forms of cell death in other organisms.

400 Background: Until 2006, treatment options for metastatic renal cell carcinoma (mRCC) were limited to cytokine therapy and surgery. Sunitinib, an oral antiangiogenic agent, received European marketing authorisation in Jan 2007 for first-line treatment in advanced and/or mRCC. The SANTORIN study was designed to describe patterns of use and estimate survival outcomes in mRCC patients treated with sunitinib in a real-life setting. Methods: SANTORIN was an observational cohort conducted in 36 French centres including patients initiating first-line treatment with sunitinib from Jan 2008-Apr 2010, followed 2 years after treatment onset. Treatment characteristics, response (evaluated by investigator based on RECIST criteria) and survival outcomes were collected from medical files. Overall and progression-free survival (OS and PFS) results were estimated using Kaplan-Meier method. Results: Characteristics of the 302 included patients were: mean age 64.3 years; male 73.2%; clear-cell histological component 83.1%; ECOG ≥2 9.9%, prior nephrectomy 85.4%. Baseline sunitinib dose was 50 mg/day for 83.4% of patients. The median duration of first-line treatment was 10.7 months (median number of cycles: 6). Dose reduction occurred in 65.2% of patients. Reasons for discontinuation of first-line treatment were progressive disease (61.1%), death (31.2%), adverse events (6.8%), and other reasons (1.0%). OS was 70.8% at 1 year (95%CI [65.3;75.5]) and 49.5% at 2 years [43.7;55.0]. Median OS was 23.6 months [19.9;27.4] (not reached in patients with clear-cell component). PFS was 38.2% at 1 year [32.7;43.7] and 16.4% at 2 years [12.5;20.9]. Median PFS was 8.4 months [7.6;9.9] (9.5 months [8.1;11.0] in patients with clear-cell component). Overall best response was 31.1% (2.3% complete, 28.8% partial), 40.1% had stable and 18.5% progressive disease. Conclusions: Despite certain differences regarding severity of cancer, these results demonstrated that effectiveness of sunitinib in mRCC is close to efficacy reported in the pivotal clinical trial (median OS: 26.4 months [95% CI 23.0 ; 32.9], median PFS: 11.0 months [11.0 ; 13.0]), especially in patients with clear-cell component.

e18522 Background: Targeted therapies are a very important therapeutic progress in the treatment of multiple myeloma (MM). Bortezomib (BTZ), the first proteasome inhibitor, was registered in France...