Résumé
Il existe trois étapes successives en vue de l’utilisation de produits de santé dans notre pratique quotidienne. Une première validant le bénéfice et la sécurité du médicament (Autorisation de ...mise sur le marché AMM) à dimension européenne et régulée par l’EMA (European Medicine Agency) qui permet un accès au médicament sur notre territoire dans le cadre d’une procédure centralisée valable pour l’ensemble des pays de la Communauté européenne (CE) et mutualisée au niveau des pays membres de la CE. Une deuxième évaluation technologique, propre à chaque pays, qui correspond à la prise en charge du médicament par la solidarité nationale. Cette dernière, en France, implique différents niveaux, la Commission de transparence qui valide un intérêt clinique via le SMR (Service médical rendu) et un intérêt clinique supplémentaire par rapport à l’existant via l’amélioration du service médical rendu, la Commission d’évaluation économique en santé publique (CEESP) qui détermine le QALY « Quality-Adjusted Life Expectancy » et l’ICER « Incremental Cost Effectiveness Ratio). Et enfin une troisième étape permettant de fixer le prix par l’intermédiaire du CEPS (Comité économique des produits de santé). Compte tenu de l’importance des sommes impliquées dans le financement des produits de santé, le législateur a mis en place une procédure supplémentaire appelée « liste en sus » qui touche directement les hôpitaux en permettant le financement de médicaments innovants et onéreux, en plus des tarifs d’hospitalisation. En l’absence de ce circuit de financement, face à des médicaments dont le prix reste élevé, les hôpitaux sont confrontés à une forme de « reste à charge » qu’ils doivent décider d’assumer ou non, cette charge n’étant pas réellement reconnue comme telle par les tutelles et parfois mal expliquée aux prescripteurs et aux patients qui, in fine, peuvent ne pas bénéficier d’un produit de santé, car trop cher pour l’établissement. Tenant compte de notre système de régulation, nous proposons diverses adaptations possibles vis-à-vis des décisions de non-inscription ou de radiation de la « liste en sus », comme: réévaluer la place des médicaments dans la stratégie thérapeutique, en vie réelle et avec du recul par rapport à l’AMM, intégrer une réflexion médicoéconomique dans nos pratiques; utiliser le modèle de l’oncologie et en particulier la réunion de concertation pluridisciplinaire dans nos décisions de traitement de énième ligne aidées par les recommandations de la commission de transparence (plus de transparence sur la fixation du prix, le paiement au parcours de soins); et enfin favoriser les renégociations de prix avec les industriels. La pérennité du dispositif « liste en sus » est questionnée. Bien qu’il ait été modernisé avec une entrée par indication et non plus exclusivement par médicament, la « liste en sus » vient d’être considérablement décrédibilisée par le remplacement du conseil de l’hospitalisation par un décret quelque peu rigide, ne laissant que peu de place à l’interprétation. Il apparaît ainsi urgent de repenser la régulation « liste en sus » dans une vision, toujours fondée sur des critères d’efficacité, mais plus humaniste, et surtout plus en accord avec la vie réelle du terrain.
Abstract Cystic lesions of the pancreas are increasingly recognized. While some lesions show benign behaviour (serous cystic neoplasm), others have an unequivocal malignant potential (mucinous cystic ...neoplasm, branch- and main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm). European expert pancreatologists provide updated recommendations: diagnostic computerized tomography and/or magnetic resonance imaging are indicated in all patients with cystic lesion of the pancreas. Endoscopic ultrasound with cyst fluid analysis may be used but there is no evidence to suggest this as a routine diagnostic method. The role of pancreatoscopy remains to be established. Resection should be considered in all symptomatic lesions, in mucinous cystic neoplasm, main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm as well as in branch duct intraductal papillary mucinous neoplasm with mural nodules, dilated main pancreatic duct >6 mm and possibly if rapidly increasing in size. An oncological partial resection should be performed in main duct intraductal papillary mucinous neoplasm and in lesions with a suspicion of malignancy, otherwise organ preserving procedures may be considered. Frozen section of the transection margin in intraductal papillary mucinous neoplasm is suggested. Follow up after resection is recommended for intraductal papillary mucinous neoplasm, solid pseudo-papillary neoplasm and invasive cancer.
Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the ...complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives. An extensive panel of international experts in neurophysiological and psychosocial aspects of fibromyalgia discussed the collected evidence and progressively refined and conceptualized its interpretation. This work constitutes an essential step towards the development of a model capable of integrating the main factors implicated in fibromyalgia into a single, unified construct which appears indispensable to foster the understanding, assessment, and intervention for fibromyalgia.
•Fibromyalgia is a common, complex and highly disabling condition.•Central sensitization is the currently prevailing paradigm of its pathophysiology.•This concept largely disregards the flagrant psychosocial carvings of fibromyalgia.•These two fields are, nonetheless, involved in a prolific multidirectional crosstalk.•This underscores the need for an integrative framework to advance the field.
In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. ...Here, we report the planned final analysis based on the prespecified number of occurring events.
PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901.
3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3–8·8), 704 events relevant to disease-free survival were observed (345 20·4% in the 12-month group and 359 21·2% in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93–1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group.
The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months.
The French National Cancer Institute.
Background: A randomized, multicenter phase II study evaluating oxaliplatin alone (OXA) and oxaliplatin–5-fluorouracil combination (OXFU) in advanced hormone-refractory prostate cancer (HRPC) ...patients. Patients and methods: Metastatic, pathologically proven prostate carcinoma patients, progressing despite anti-androgen therapy, received intravenous OXA (130 mg/m2 over 2 h), alone or with 5-FU (1000 mg/m2/day, continuous intravenous infusion, days 1–4), every 3 weeks. OXA patients could receive OXFU after treatment failure. Results: Fifty-four patients (26 OXA, 28 OXFU) from nine centers received 269 treatment cycles (106 OXA, 163 OXFU; median 3.5 OXA or 5 OXFU cycles per patient; range 1–10 or 1–14, respectively). Patient characteristics were similar in both arms. Three partial responses (PR) occurred in 21 evaluable OXA patients 14%; 95% confidence interval (CI) 1% to 30%, and in five of 26 evaluable OXFU patients (19%; 95% CI 7% to 39%). Clinical benefit response (pain, performance status and weight changes) was assessed in 20 OXA and 22 OXFU symptomatic patients, with more responders in the OXFU arm (39% compared with 12%). Median time to progression in the OXA and OXFU arms was 2.6 and 3.4 months, and median overall survival was 9.4 and 11.4 months, respectively. Hematotoxicity was common, but mostly mild to moderate. Neutropenia was more common in OXFU than OXA patients. After oxaliplatin failure, 12 patients received 46 cycles of OXFU and one of 11 evaluable patients had a PR. Conclusion: The objective response rate, palliation benefit, survival and manageable toxicity obtained in this heavily pretreated HRPC population with OXFU merit further study.
This paper deals with two-dimensional composites made of several isotropic linearly conducting phases in prescribed volume fractions. The primary focus is on the three-phase case; the generalization ...to a larger number of phases is straightforward.
A class of high- but finite-rank laminates is introduced. The laminates saturate the known inequality bounds—due to the work of Hashin and Shtrikman, Lurie and Cherkaev, Tartar, and Murat and Tartar—on the effective conductivity tensor of any composite. These bounds depend only on the constituent material properties and volume fractions and not on the placement of these materials in the composite. The bounds are known not to be optimal for all admissible choices of the conductivities and volume fractions. However, they are now known to be realizable in a much larger range of these parameters than was previously known.
The range of effective properties of our multiphase laminates strictly includes those corresponding to the composites found earlier by Milton and Kohn, Lurie and Cherkaev, and Gibiansky and Sigmund. The new optimal laminates are found in a systematic fashion by satisfying sufficient conditions on the fields in each layer. This leads to a simple algorithm for generating optimal laminates.
In addition a new supplementary bound for multiphase structures is also proven which must be satisfied by composites with smooth interfaces.
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