Nouveautés dans l'immunothérapie du cancer [New developments in cancer immunotherapy]

Les progrès récents dans l'élucidation des bases cellulaires et moléculaires de la réponse immunitaire permettent désormais le design de thérapies novatrices pour l'immunothérapie des tumeurs. Ces approches récentes se traduisent en des taux de réponse qui surpassent souvent ce qui peut être obtenu par des chimiothérapies conventionnelles ou des thérapies ciblées. Nous présentons ici les principaux développements en cours avec un accent sur l'expérience lausannoise dans le traitement du mélanome. Premièrement, les nouveaux développements dans la vaccination peptidique sont présentés. Deuxièmement, les approches de type transfert adoptif sont illustrées avec une attention particulière pour le conditionnement du patient par lymphodéplétion. Finalement, le projet lausannois d'optimisation rationnelle du récepteur TCR des lymphocytes est décrit. Recent progress unveiling the cellular and molecular basis of the immune response allows nowadays the design of novel therapies for tumor immunotherapy. These recent approaches translate into response rates that often surpass what can be obtained by conventional chemotherapies or targeted therapies. Here we present the main current developments with an accent on the Lausanne experience in the treatment of melanoma. First, the new developments of peptide-based vaccination are presented. Second, approaches related to adoptive transfer are illustrated with a particular attention for the patient conditioning using lymphodepletion. Finally, the Lausanne project of rational lymphocyte TCR optimization is described.

Les calcifications pulmonaires métastatiques [Pulmonary metastatic calcification].

INTRODUCTION: The lung is the organ most frequently involved by metastatic calcification. This condition is probably under-diagnosed, the patients usually being asymptomatic. This article summarizes the current knowledge concerning pulmonary metastatic calcification. BACKGROUND: The pathogenesis of pulmonary metastatic calcification is not well known, but it involves phosphate-calcium balance, renal function and pH. The most frequently encountered aetiologies are hyperparathyroidism, neoplastic bony lesions, and renal failure. The definitive diagnosis is achieved by histology, radiological examinations being insensitive. The clinical manifestations are various and can include a pulmonary restrictive syndrome, diffusion abnormalities, hypoxaemia and respiratory failure. The latter can be severe and influence the prognosis adversely: 19 cases of fatal pulmonary metastatic calcification have been reported. The treatment is aetiological and symptomatic. VIEWPOINT: The prognostic factors for a poor outcome of this potentially lethal condition remain to be determined. The management of asymptomatic patients is also uncertain. CONCLUSIONS: Pulmonary metastatic calcification is a rare condition of complex pathogenesis. The clinical manifestations are varied, ranging from asymptomatic to severe, even fatal.

La perpétuation de l'oralité du muet dans quelques incipit filmiques des premières années du parlant

Partant d'une perspective sémiotique appliquée aux débuts de film pour élargir l'approche à une réflexion historique sur l'intermédialité, cet article examine le postulat selon lequel les spectacles vivants qui précédaient la projection des films dans les années 1920 ont été en quelque sorte « happés » par le discours filmique. A travers l'examen d'un ensemble de films réalisés entre 1927 et 1937 qui accordent dans leurs génériques ou leurs prologues une place prépondérante à l'adresse vocale, l'auteur met en évidence certains phénomènes de résurgence de l'oralité propre à la période « muette », les speaker des premiers talkies endossant une fonction à certains égards similaire à celle du bonimenteur des premiers temps. L'accent est mis sur la production cinématographique de Guitry, dont la passion pour la « théâtralité » l'incite à proposer des formes singulières d'auto-mise en scène et d'adresse au spectateur. La question de la réflexivité des incipit passe également par la prise en compte de la dimension technologique, qui est parfois intégrée au film même, à l'instar de l'ouverture radiophonique de L'Atlantide de Pabst. Ces considérations s'inscrivent plus généralement dans une réflexion sur les diverses imitations de la voix vive à l'ère des technologies de l'audiovisuel.

Echanges et dialogues intertextuels: l'exemple des contes de Perrault et des frères Grimm

La circulation de livres et d'individus d'une culture à une autre est un phénomène extrêmement important qui stimule la production littéraire et permet la création de nouveaux courants et la modification de certains genres. Parmi les échanges artistiques qu'elle favorise, le dialogue intertextuel, sur lequel porte cet article, est une opération par laquelle un écrivain développe une oeuvre en répondant à une autre oeuvre ou en se positionnant par rapport à elle.Les contes écrits européens sont l'objet de très nombreux échanges. Catalogues de bibliothèques et autres documents attestent la circulation de textes dont les écrivains ont connaissance lorsqu'ils rédigent leurs recueils. Prenant l'exemple des frères Grimm, cet article montre que c'est dans un dialogue avec d'autres auteurs (l'accent est mis sur Charles Perrault) qu'ils élaborent leurs Kinder- und Hausmärchen (contes de l'enfance et du foyer). Même si les philologues allemands prétendent recueillir leurs histoires dans le peuple et les transmettre le plus fidèlement possible, la comparaison de contes français et allemands révèle la manière dont ils utilisent les textes de Perrault pour créer leur recueil 'typiquement allemand'.

Neoadjuvant chemotherapy and radiotherapy followed by surgery in selected patients with stage IIIB non-small-cell lung cancer: a multicentre phase II trial.

BACKGROUND: Stage IIIB non-small-cell lung cancer (NSCLC) is usually thought to be unresectable, and is managed with chemotherapy with or without radiotherapy. However, selected patients might benefit from surgical resection after neoadjuvant chemotherapy and radiotherapy. The aim of this multicentre, phase II trial was to assess the efficacy and toxicity of a neoadjuvant chemotherapy and radiotherapy followed by surgery in patients with technically operable stage IIIB NSCLC. METHODS: Between September, 2001, and May, 2006, patients with pathologically proven and technically resectable stage IIIB NSCLC were sequentially treated with three cycles of neoadjuvant chemotherapy (cisplatin with docetaxel), immediately followed by accelerated concomitant boost radiotherapy (44 Gy in 22 fractions) and definitive surgery. The primary endpoint was event-free survival at 12 months. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030810. FINDINGS: 46 patients were enrolled, with a median age of 60 years (range 28-70). 13 (28%) patients had N3 disease, 36 (78%) had T4 disease. All patients received chemotherapy; 35 (76%) patients received radiotherapy. The main toxicities during chemotherapy were neutropenia (25 patients [54%] at grade 3 or 4) and febrile neutropenia (nine [20%]); the main toxicity after radiotherapy was oesophagitis (ten patients [29%]; nine grade 2, one grade 3). 35 patients (76%) underwent surgery, with pneumonectomy in 17 patients. A complete (R0) resection was achieved in 27 patients. Peri-operative complications occurred in 14 patients, including two deaths (30-day mortality 5.7%). Seven patients required a second surgical intervention. Pathological mediastinal downstaging was seen in 11 of the 28 patients who had lymph-node involvement at enrolment, a complete pathological response was seen in six patients. Event-free survival at 12 months was 54% (95% CI 39-67). After a median follow-up of 58 months, the median overall survival was 29 months (95% CI 16.1-NA), with survival at 1, 3, and 5 years of 67% (95% CI 52-79), 47% (32-61), and 40% (24-55). INTERPRETATION: A treatment strategy of neoadjuvant chemotherapy and radiotherapy followed by surgery is feasible in selected patients. Toxicity is considerable, but manageable. Survival compares favourably with historical results of combined treatment for less advanced stage IIIA disease. FUNDING: Swiss Group for Clinical Cancer Research (SAKK) and an unrestricted educational grant by Sanofi-Aventis (Switzerland).

Biomedical risk assessment as an aid for smoking cessation.

BACKGROUND: A possible strategy for increasing smoking cessation rates could be to provide smokers who have contact with healthcare systems with feedback on the biomedical or potential future effects of smoking, e.g. measurement of exhaled carbon monoxide (CO), lung function, or genetic susceptibility to lung cancer. We reviewed systematically data on smoking cessation rates from controlled trials that used biomedical risk assessment and feedback. OBJECTIVES: To determine the efficacy of biomedical risk assessment provided in addition to various levels of counselling, as a contributing aid to smoking cessation. SEARCH STRATEGY: We systematically searched he Cochrane Collaboration Tobacco Addiction Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to 2004), and EMBASE (1980 to 2004). We combined methodological terms with terms related to smoking cessation counselling and biomedical measurements. SELECTION CRITERIA: Inclusion criteria were: a randomized controlled trial design; subjects participating in smoking cessation interventions; interventions based on a biomedical test to increase motivation to quit; control groups receiving all other components of intervention; an outcome of smoking cessation rate at least six months after the start of the intervention. DATA COLLECTION AND ANALYSIS: Two assessors independently conducted data extraction on each paper, with disagreements resolved by consensus. MAIN RESULTS: From 4049 retrieved references, we selected 170 for full text assessment. We retained eight trials for data extraction and analysis. One of the eight used CO alone and CO + Genetic Susceptibility as two different intervention groups, giving rise to three possible comparisons. Three of the trials isolated the effect of exhaled CO on smoking cessation rates resulting in the following odds ratios (ORs) and 95% confidence intervals (95% CI): 0.73 (0.38 to 1.39), 0.93 (0.62 to 1.41), and 1.18 (0.84 to 1.64). Combining CO measurement with genetic susceptibility gave an OR of 0.58 (0.29 to 1.19). Exhaled CO measurement and spirometry were used together in three trials, resulting in the following ORs (95% CI): 0.6 (0.25 to 1.46), 2.45 (0.73 to 8.25), and 3.50 (0.88 to 13.92). Spirometry results alone were used in one other trial with an OR of 1.21 (0.60 to 2.42).Two trials used other motivational feedback measures, with an OR of 0.80 (0.39 to 1.65) for genetic susceptibility to lung cancer alone, and 3.15 (1.06 to 9.31) for ultrasonography of carotid and femoral arteries performed in light smokers (average 10 to 12 cigarettes a day). AUTHORS' CONCLUSIONS: Due to the scarcity of evidence of sufficient quality, we can make no definitive statements about the effectiveness of biomedical risk assessment as an aid for smoking cessation. Current evidence of lower quality does not however support the hypothesis that biomedical risk assessment increases smoking cessation in comparison with standard treatment. Only two studies were similar enough in term of recruitment, setting, and intervention to allow pooling of data and meta-analysis.

Changes in the use of broad-spectrum antibiotics after cefepime shortage: a time series analysis.

The original cefepime product was withdrawn from the Swiss market in January 2007, and replaced by a generic 10 months later. The goals of the study were to assess the impact of this cefepime shortage on the use and costs of alternative broad-spectrum antibiotics, on antibiotic policy, and on resistance of Pseudomonas aeruginosa towards carbapenems, ceftazidime and piperacillin-tazobactam. A generalized regression-based interrupted time series model assessed how much the shortage changed the monthly use and costs of cefepime and of selected alternative broad-spectrum antibiotics (ceftazidime, imipenem-cilastatin, meropenem, piperacillin-tazobactam) in 15 Swiss acute care hospitals from January 2005 to December 2008. Resistance of P. aeruginosa was compared before and after the cefepime shortage. There was a statistically significant increase in the consumption of piperacillin-tazobactam in hospitals with definitive interruption of cefepime supply, and of meropenem in hospitals with transient interruption of cefepime supply. Consumption of each alternative antibiotic tended to increase during the cefepime shortage and to decrease when the cefepime generic was released. These shifts were associated with significantly higher overall costs. There was no significant change in hospitals with uninterrupted cefepime supply. The alternative antibiotics for which an increase in consumption showed the strongest association with a progression of resistance were the carbapenems. The use of alternative antibiotics after cefepime withdrawal was associated with a significant increase in piperacillin-tazobactam and meropenem use and in overall costs, and with a decrease in susceptibility of P. aeruginosa in hospitals. This warrants caution with regard to shortages and withdrawals of antibiotics.

Le contrôle des normes, spécialement par les cours constitutionnelles cantonales

Après une étude des notions de justice, juridiction et cour constitutionnelle, la présente thèse aborde le contrôle des normes par les organes de la Confédération ; un accent est mis sur le recours auTribunal fédéral contre les actes normatifs cantonaux. La justice constitutionnelle par les organes cantonaux est ensuite étudiée de façon générale, en examinant successivement les exigences posées par le droit fédéral à cet égard et les différentes formes de contrôle abstrait dans les cantons dépourvus de cour constitutionnelle. Chaque cour constitutionnelle cantonale (Nidwald, Jura, Vaud, Grisons, Genève) fait ensuite l'objet d'une analyse approfondie, portant aussi bien sur les aspects historiques et procéduraux que sur la jurisprudence. Une dernière partie est consacrée à l'examen, théorique et empirique, des arguments entrant en ligne de compte dans le choix d'un canton de se doter d'une cour constitutionnelle ou non, suivie d'une analyse comparée des cours existantes. Enfin, les rapports entre ces dernières d'une part et leTribunal fédéral d'autre part sont examinés.

Pharmacotherapeutic management of locally advanced prostate cancer: current status.

Locally advanced prostate cancer (LAPC) is a heterogeneous entity usually embracing T3-4 and/or pelvic lymph-node-positive disease in the absence of established metastases. Outcomes for LAPC with single therapies have traditionally been poor, leading to the investigation of adjuvant therapies. Prostate cancer is a hormonally sensitive tumour, which usually responds to pharmacological manipulation of the androgen receptor or its testosterone-related ligands. As such, androgen deprivation therapy (ADT) has become an important adjuvant strategy for the treatment of LAPC, particularly for patients managed primarily with radiotherapy. Such results have generally not been replicated in surgical patients. With increased use of ADT has come improved awareness of the numerous toxicities associated with long-term use of these agents, as well as the development of strategies for minimizing ADT exposure and actively managing adverse effects. Several trials are exploring agents to enhance radiation cell sensitivity as well as the application of adjuvant docetaxel, an agent with proven efficacy in the metastatic, castrate-resistant setting. The recent work showing activity of cabazitaxel, sipuleucel-T and abiraterone for castrate-resistant disease in the post-docetaxel setting will see these agents investigated in conjunction with definitive surgery and radiotherapy.

Can 3T multiparametric magnetic resonance imaging accurately detect prostate cancer extracapsular extension?

BACKGROUND: Accurate staging is essential to determine the correct management of patients diagnosed with prostate cancer. We assess the accuracy of 3T multiparametric magnetic resonance imaging (MRI) with endorectal coil (3TemMRI) in detecting prostate cancer local extension. METHODS: We retrospectively reviewed charts from January 2008 to July 2012 from all patients undergoing radical prostatectomy. Patients were only included if 3TemMRI and radical prostatectomy were performed at our institution. Based on the presence of extracapsular extension (ECE) at 3TemMRI, prostate cancer was dichotomized into locally advanced or organ-confined disease. The accuracy of 3TemMRI local staging was then evaluated using definitive pathology as a reference. RESULTS: Overall, 177 radical prostatectomies were performed within the timeframe. After applying exclusion criteria, 60 patients were included in the final analysis. The mean patient age was 67 ± 7 (standard deviation) years. Mean prostate-specific antigen value was 12.7 ± 12.7 ng/L. Based on preoperative characteristics, we considered 38 of the 60 patients (63%) patients high risk. 3TemMRI identified an organ-confined tumour in 46 patients and locally advanced disease in 14 patients. When correlated to final pathology, 3TemMRI specificity, sensitivity, negative and positive predictive values, and accuracy in detecting locally advanced prostate cancer were 90%, 35%, 57%, 79% and 62%, respectively. INTERPRETATION: This study shows that the use of preoperative 3TemMRI can be used to identify organ-confined prostate cancer when locally advanced disease is suspected.

Jean-Léon Gérôme: un peintre d'histoire présumé "cinéaste"

La riche exposition consacrée par le Musée d'Orsay au peintre académique Jean-Léon Gérôme développait un discours explicite sur la relation entre ce peintre et le cinéma en des termes susceptibles d'ouvrir un débat fécond sur les manières d'envisager les liens entre le film et les arts plastiques qui l'ont précédé. L'accrochage, le catalogue, certaines interventions du colloque "Regarder Gérôme", ainsi que le "cycle péplum" présenté au Musée ont engagé, sur cette question de la référence au cinéma, de stimulantes réflexions d'ordre méthodologique et historiographique. En effet, l'accent n'a pas porté sur une contextualisation directe qui mette en perspective l'oeuvre de Gérôme par rapport aux avancées des techniques d'enregistrement de son époque, de projection et d'animation mécanique des images et qui ont conduit, dès les années 1880, à l'émergence du médium cinématographique. L'argument de l'exposition visait plutôt à dégager de l'oeuvre de Gérôme les signes d'une véritable "préfiguration" du cinéma, organisée en fonction de deux grands axes: d'une part l'influence manifeste de la peinture d'histoire sur l'iconographie des films de fiction à grand spectacle; d'autre part, des procédés visuels plus généraux, susceptibles d'être reliés à des effets spécifiquement cinématographiques. En reprenant la question du point de vue des recherches en histoire du cinéma, cet article souhaite soulever à cette occasion quelques problèmes d'ordre méthodologique.

Tailored thoracomyoplasty as a valid treatment option for chronic postlobectomy empyema.

BACKGROUND: Chronic post-lobectomy empyema is rare but may require space obliteration for infection control. We report our experience by using a tailored thoracomyoplasty for this specific indication with respect to infection control and functional outcome. METHODS: We retrospectively analyzed 17 patients (11 men, 6 women) with chronic postlobectomy empyema who were treated by thoracomyoplasty in our institution between 2000 and 2011. All patients underwent an initial treatment attempt by use of chest tube drainage and antibiotics except those with suspicion of pleural aspergillosis (n = 6). In 5 patients, bronchus stump insufficiency was identified at preoperative bronchoscopy. A tailored thoracoplasty was combined with a serratus anterior-rhomboid myoplasty, which also served to close a bronchopleural fistula, if present. The first rib was resected in 11 of 17 patients. RESULTS: The 90-day mortality was 11.7%. Thoracomyoplasty was successful in all surviving patients with respect to infection control, space obliteration, and definitive closure of bronchopleural fistula, irrespective of the type of infection, the presence of a bronchopleural fistula, or whether a first rib resection was performed. Postlobectomy pulmonary function testing before and after thoracoplasty revealed a mean predicted FEV(1) of 63.0% ± 8.5% and 51.5% ± 4.2% (p = 0.01) and a mean predicted DLCO of 59.8% ± 11.6% and 54.5% ± 12.5%, respectively. Postoperative shoulder girdle dysfunction and scoliosis were prevented in patients willing to undergo intense physiotherapy. CONCLUSIONS: Tailored thoracomyoplasty represents a valid option for patients with chronic postlobectomy empyema without requiring a preceding open window thoracostomy. Space obliteration and infection control were equally obtained with and without first rib resection.

Efficacy of in-hospital multidimensional interventions of secondary prevention after acute coronary syndrome: a systematic review and meta-analysis

BACKGROUND: Secondary prevention programs for patients experiencing an acute coronary syndrome have been shown to be effective in the outpatient setting. The efficacy of in-hospital prevention interventions administered soon after acute cardiac events is unclear. We performed a systematic review and meta-analysis to determine whether in-hospital, patient-level interventions targeting multiple cardiovascular risk factors reduce all-cause mortality after an acute coronary syndrome. METHODS AND RESULTS: Using a prespecified search strategy, we included controlled clinical trials and before-after studies of secondary prevention interventions with at least a patient-level component (ie, education, counseling, or patient-specific order sets) initiated in hospital with outcomes of mortality, readmission, or reinfarction rates in acute coronary syndrome patients. We classified the interventions as patient-level interventions with or without associated healthcare provider-level interventions and/or system-level interventions. Twenty-six studies met our inclusion criteria. The summary estimate of 14 studies revealed a relative risk of all-cause mortality of 0.79 (95% CI, 0.69 to 0.92; n=37,585) at 1 year. However, the apparent benefit depended on study design and level of intervention. The before-after studies suggested reduced mortality (relative risk [RR], 0.77; 95% CI, 0.66 to 0.90; n=3680 deaths), whereas the RR was 0.96 (95% CI, 0.64 to 1.44; n=99 deaths) among the controlled clinical trials. Only interventions including a provider- or system-level intervention suggested reduced mortality compared with patient-level-only interventions. CONCLUSIONS: The evidence for in-hospital, patient-level interventions for secondary prevention is promising but not definitive because only before-after studies suggest a significant reduction in mortality. Future research should formally test which components of interventions provide the greatest benefit.

La part du national. Comparer des politiques infranationales dans un environnement multi-niveaux

Si des enjeux, des configurations d'acteurs, ou la définition de certains problems peuvent être propres au niveau local, ceux-ci sont fréquemment influencés par des paramètres définis à d'autres niveaux de gouvernement. En particulier, il est nécessaire que les dispositifs de recherche centrés sur la comparaison de politiques infranationales abordent directement la question de l'intégration et de l'impact du cadre national. Comment faire la part du national dans les comparaisons de politiques infranationales ? À partir d'un ensemble de travaux de sociologie de l'action publique, cet article montre que dominent deux manières d'articuler national et infranational. Certains travaux privilégient le niveau national, et prennent en compte ce qui se joue à d'autres niveaux pour observer des déclinaisons ou des réappropriations de politiques mises en place au niveau national. D'autres travaux, en particulier la littérature centrée sur la gouvernance territoriale ou urbaine, accordent un primat au local tout en prenant acte de la multiplication des niveaux de gouvernement. Enfin, l'accent est placé sur les tentatives visant à concilier ces perspectives. À l'appui de nos propres travaux, nous montrons comment des approches centrées sur les acteurs permettent d'ouvrir des pistes stimulantes pour articuler plusieurs niveaux d'analyse.

Transmyocardial laser revascularisation in acutely ischaemic myocardium.

OBJECTIVE: Although recent experience suggests that transmyocardial laser revascularisation (TMLR) relieves angina, its mechanism of action remains undefined. We examined its functional effects and analysed its morphological features in an animal model of acute ischaemia. METHODS: A total of 15 pigs were randomised to ligation of left marginal arteries (infarction group, n = 5), to TMLR of the left lateral wall using a holmium:yttrium-aluminium garnet (Ho:YAG) laser (laser group, n = 5), and to both (laser-infarction group, n = 5). All the animals were sacrificed 1 month after the procedure. Haemodynamics and echocardiography with segmental wall motion score were carried out at both time intervals (scale 0-3: 0, normal; 1, hypokinesia; 2, akinesia; 3, dyskinesia). Histology of the involved area was analysed. RESULTS: Laser group showed no change of the segmental wall motion score of the involved area 30 min after the laser channels were made (score: 0 +/- 0). Infarction and laser infarction groups both showed a persistent and definitive increase of the segmental wall motion score (at 30 min: 1.6 +/- 0.3 and 2 +/- 0, respectively; at 1 month: 1.8 +/- 0.2 and 1.8 +/- 0.4, respectively). These increases were all statistically significant in comparison with baseline values (P < 0.5), however comparison between infarction and laser-infarction groups showed no significant difference. On macroscopic examination of the endocardial surface, no channel was opened. On histology, there were signs of neovascularisation around the channels in the laser group, whereas in the laser-infarction group the channels were embedded in the infarction scar. CONCLUSIONS: In this acute pig model, TMLR did not provide improvement of contractility of the ischaemic myocardium. To the degree that the present study pertains to the clinical setting, the results suggest that mechanisms other than blood flow through the channels should be considered, such as a laser-induced triggering of neovascularisation or neural destruction.