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Aims: Poor efficacy has been reported for patients with BRAF mutations for metastatic colorectal cancer (mCRC). Methods: EREBUS is a French cohort study of wild‐type (wt) KRAS unresectable mCRC patients initiating a first‐line treatment with cetuximab from 2009 to 2010, followed for two years (five years for vital status). Molecular genetics platforms have provided additional RAS and BRAF mutation testing results. Progression‐free survival (PFS) and overall survival (OS) were assessed according to tumour mutation (mt) status: RASmt/BRAFany, RASwt/BRAFmt and RASwt/BRAFwt. Multivariate Cox analyses were used to evaluate association between mutation status and death or progression. Results: A total of 389 patients were included in 65 centres and with a known tumour mutation status: 64 RASmt/BRAFany (21%), 33 RASwt/BRAFmt (13%) and 213 RASwt/BRAFwt (87%). Respective baseline characteristics were: median age 65, 64 and 63 years, male gender 63%, 64% and 69%, Eastern Cooperative Oncology Group performance status ≤ 1 75%, 76% and 79%, and liver‐only metastases 39%, 33% and 40%. Median progression‐free survival was 8.0 months [5.9–9.3] for patients with RASmt/BRAFany, 6.0 months [2.3–7.2] for patients with RASwt/BRAFmt, and 10.4 months [9.5–11.0] for patients with RASwt/BRAFwt. Respectively, median overall survival was 18.4 months [10.9–23.3], 9.7 months [6.9–16.6] and 29.3 months [26.3–36.1]. In multivariate analyses, progression (HR = 2.71 [1.79–4.10]) and death (HR = 2.79 [1.81–4.30]) were more likely for RASwt/BRAFmt vs RASwt/BRAFwt patients. Conclusions: BRAF mutations were associated with markedly poorer outcomes in initially unresectable RASwt mCRC patients treated by cetuximab in first‐line treatment. [ABSTRACT FROM AUTHOR]

Aims Acute drug overdose, especially with paracetamol, may cause acute liver failure leading to registration for transplantation (ALFT). Population statistics and between-country differences for ALFT related to overdose have been poorly described. The aim of the present study was to evaluate overdose ALFT in the multi-country Study of Acute Liver Transplantation (SALT). Methods All adult overdose-related ALFT, with or without suicidal intent, in France, Greece, Ireland, Italy, the Netherlands, Portugal and the UK between 2005 and 2007 were identified from liver transplant registries and hospital records. These were compared with whole-country and per capita use of paracetamol. Results Six hundred cases of ALFT were identified in 52 of 57 eligible transplant centres, of which 114 involved overdose (72 intentional, 10 non-intentional, 32 uncertain). Overdose represented 20% of all-cause ALFT: Ireland 52%, UK 28%, France 18%, the Netherlands 8%, and Italy 1%. Overdose ALFT were mostly females (61%), mean age 33.6 ± 10.9 years. A total of 111 (97%) of the overdoses involved paracetamol. Event rates ranged from one ALFT for 20.7 tons of paracetamol in Ireland, to one for 1074 tons in Italy and one case in 60 million inhabitants over 3 years in Italy to one case in 286 000 inhabitants per year in Ireland. Per-country event rates for non-overdose ALFT exposed to paracetamol were between 2.5 and 4.0 per million treatment-years sold. Conclusions Paracetamol overdose was found to represent one-sixth of all-cause ALFT. There was a 50-fold difference in Europe in the rates of paracetamol overdose ALFT, and a 200-fold difference per million inhabitants. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose The effect of denominator options on event rates was tested on the French part of the Study of Acute Liver Transplant (SALT). Methods SALT is a case population study of acute liver failure registered for transplantation (ALFT), exposed to non-steroidal anti-inflammatory drugs (NSAIDs) or non-overdose paracetamol, from 2005 to 2007. Population exposure was computed from the Intercontinental Medical Services' (IMS) and the French national healthcare insurance system's data as the number of defined daily doses (DDDs) sold or dispensed and the number of exposed patients. Results Nine ALFT cases were exposed to 10 NSAIDs and 49 to non-overdose paracetamol. NSAID sales ranged from 0.04 billion (niflumic acid) to 0.5 billion (ibuprofen) DDDs, amounting to 2.5 billion DDDs for all NSAIDs. The mean per-person exposure ranged from 13.1 (niflumic acid) to 43.2 (ketoprofen) DDDs, reaching 60.5 DDDs for any NSAID. The number of users ranged from 2 million (niflumic acid) to 13 million (ibuprofen), which was 26.6 million for all NSAIDs. The ALFT rates per billion DDDs ranged from 0 to 26 for individual NSAIDs and amounted to 4.6 for all NSAIDs. The ALFT rates per billion DDDs were inversely correlated with the average per-patient exposure ( R2 = 0.935, p = 0.0016). The ALFT rates per million users ranged from 0.31 to 0.49, which was 0.41 for all NSAIDs, with no difference between drugs and no effect of mean per-patient exposure ( R2 = 0.01, p = 0.9). Whether measured per DDD or per user, the event rate with paracetamol was three to five times higher than with NSAIDs. Conclusion ALFT risk with NSAID seems to be user dependent rather than person-time (exposure) dependent. Choosing the wrong denominator in case population studies might give erroneous results. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose Fear of discontinuing concomitant anti-epileptic drugs (AEDs) may lead to potentially unnecessary and perhaps unsafe polypharmacy. The effect of withdrawing concomitant AEDs on epilepsy control was therefore studied in long-term users of levetiracetam. Methods The EULEV cohort followed patients initiating levetiracetam in France in 2005 or 2006 for one year. In those maintaining levetiracetam throughout the study period, the association of a reduction in the number of concomitant AEDs during the first six months with seizure-freedom during the last six months of follow-up was investigated using logistic regression. Results Of the 356 patients continuing levetiracetam for at least 1 year, 140 (39.3%) were seizure-free during the last six months of follow-up. Partial symptomatic or generalised idiopathic epilepsy were associated with greater seizure-freedom than partial cryptogenic disease. Factors associated with seizures were: longer disease duration, initial incapacity, increased number of seizures in the six months preceding levetiracetam initiation, and number of consultations for epilepsy in the six months preceding levetiracetam initiation. There was a trend for the association between the early reduction in the number of concomitant AEDs and seizure-free status later during follow-up, which however did not reach statistical significance in the final propensity score-adjusted multivariate model (OR = 1.8, 95%CI [0.8;4.0]). Conclusions Taking into account the various risk factors for seizures, the early reduction of concomitant AEDs was not associated with worse seizure rates during follow-up in real-life users of levetiracetam. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]